Synthesis of new atropisomers derived from methoxychloroacridine. Preparation of enantiomerically pure (aR)-(-)-2,2′-dihydroxy-9,9′-biacridine

Article abstract of DOI:10.3987/com-01-9408

New biacridinyl atropisomers were obtained from symmetric ligand 2,2′-dihydroxy-9,9′-biacridine (4), prepared from 9-chloro-2-methoxyacridine. Alternative O-acylation and alkylation led to different polycycles and to a biacridinyl crown ether. The molecular structures of 2,2′-di(p-chlorobenzoyloxy)-9,9′-biacridinyl (5) and (9,9′-bisacridinyl)-2,2′-dihydroxy-bis-(camphanate) ester (13) were solved by X-Ray crystallography, showing a 'scissor-like' host conformation and guest inclusion of chloroform and acetonitrile. The determination of X-Ray structure of one diastereomer (13) allows to assign the absolute configuration of enantiomerically recovered (aR)-(-)-2,2′-dihydroxy-9,9′-biacridinyl.

Full text of DOI:10.3987/com-01-9408

HETEROCYCLES, Vol. 57, No. 3, 2002, pp. 449 - 463, Received, 29th November, 2001
SYNTHESIS
OF
NEW
ATROPISOMERS
DERIVED
FROM
METHOXYCHLOROACRIDINE. PREPARATION OF ENANTIO-
MERICALLY PURE (aR)-(-)-2,2’-DIHYDROXY-9,9’-BIACRIDINE
*
Anh Tuan Lormier, Gérard Boyer, Robert Faure, and Jean Pierre Galy
UMR 6009, Laboratoire de Valorisation de la Chimie Fine, case 552, Université
Aix-Marseille III, Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex
20, France. E-mail: gerard.boyer@mvcf.u-3mrs.fr
Abstract - New biacridinyl atropisomers were obtained from symmetric ligand
2,2'-dihydroxy-9,9'-biacridine (4), prepared from 9-chloro-2-methoxyacridine.
Alternative O-acylation and alkylation led to different polycycles and to a
biacridinyl crown ether. The molecular structures of 2,2’-di(p-chlorobenzoyloxy)-
9,9’-biacridinyl (5) and (9,9’-bisacridinyl)-2,2’-dihydroxy-bis-(camphanate) ester
(13) were solved by X-Ray crystallography, showing a 'scissor-like' host
conformation and guest inclusion of chloroform and acetonitrile. The
determination of X-Ray structure of one diastereomer (13) allows to assign the
absolute configuration of enantiomerically recovered (aR)-(-)-2,2'-dihydroxy-9,9’-
biacridinyl.
INTRODUCTION
Among the numerous C2-symmetry derivatives prepared in the literature,1 binaphthyl and especially the
chiral bidentate ligand 2,2’-dihydroxy-1,1'-binaphthyl has been widely used in asymmetric synthesis2 and
is known as a good host in optical resolution of chiral guest species. In connection with our experience in
the synthesis of acridinic derivatives, well known for their therapeutic effects,3 we got involved in the
preparation of symmetrical heterocyclic host compounds related to bianthryl but using 9,9-biacridinyl.4
Dimethoxy atropisomers were also prepared; the corresponding 2,2’-dimethoxy-9,9’-biacridine has
proved useful in molecular recognition with chloroform inclusion in its crystalline structure.5 We report
now the synthesis and characterization of new atropisomers obtained using 2,2’-dihydroxy-9,9’-
biacridine (4) as starting material.
RESULTS AND DISCUSSION

In the first pathway of the synthesis, attention was placed on the preparation of O-acyl derivatives. First,
4’-methoxyphenylanthranilic acid (1) was prepared by Ullmann’s reaction between o-bromobenzoic acid
and p-methoxyaniline.6 Cyclization of this anthranilic acid in the presence of POCl3 led to 2-methoxy-9-
chloroacridine (2).7 Homocoupling of 2 with zinc powder in anhydrous methanol under nitrogen afforded
2,2’-dimethoxy-9,9’-biacridine (3) with 49 % yield.8 The 2,2’-dihydroxy-9,9’-biacridine (4) was obtained
by demethylation of 3 with 48 % hydrobromic acid (Scheme 1).
OCH3
COOH
OCH3
COOH
+
Cu, C2H5OH
110°C, 4 h, 96 %
Br
H2N
N
H
1
Cl
OCH3
POCl3
1
130°C, 2 h, 71%
N
N
2
N
OH
Zn, CH3OH
OCH3
OCH3
HBr
reflux, 48 h, 62%
1
4
2
8
8a
9a
2 OH
reflux, 4 h, 49%
7
6
9
3
N
N
10a 4a
10
3
5
4
Scheme 1: Synthesis of diol (4)
Next, reaction of 4 with p-methoxybenzoyl chloride in anhydrous dichloromethane led to the 2,2’-bis[(p-
methoxybenzoyl)oxy]-9,9’-biacridine (5) (36 %); p-chlorobenzoyl chloride and p-fluorobenzoyl chloride
provided the corresponding 2,2’-bis(acyloxy)-9,9’-biacridines (6) and (7) in 52 and 48 % yields
respectively (Scheme 2).
N
O
OCH3
Cl
F
O
O
Ar
Ar
NaOH
4
Ar =
ArCOCl, 20 min, rt
36 - 52%
5
6
7
O
N
Scheme 2: Synthesis of atropisomers (5-7)
We also focused on the preparation of O-alkyl atropisomers. For example allyl groups were introduced on
diol (4) by reaction with allyl bromide, leading to 2,2’-bis(allyloxy)-9,9’-biacridine (8) in 65 % yield.
Moreover tetraacridinic polycycles can also be obtained using bromomethylacridine, previously prepared
in the laboratory.9 Polyacridine (9) was obtained with 40 % yield with potassium carbonate in acetone
(Scheme 3).

N
N
K2CO3, allyl bromide
O
O
4
acetone, reflux, 8 h, 65%
8
N
N
N
O
K2CO3, bromomethylacr.
acetone, reflux, 28 h, 40%
O
4
N
9
Scheme 3: Synthesis of atropisomers (8-9)
We were also interested in the preparation of macrocycles derived from an acridine moiety. Host
macrocycles like crown ethers are much studied host compounds.10 Among them, one class is the crown
ethers containing heterocyclic subunits such as the proton ionizable pyridin-4-one derivatives of
Bradshaw.11 These polyether-diester ligands serve to study the influence of the crown ether on the
tautomerism of the heterocycle12 and on their complexing properties. Moreover, Cram has described
numerous crown ethers obtained from 2,2'-dihydroxy-1,1'-binaphthyl and usable for structural recognition
of chemical substrates by molecular complexation,13 for example with cations.14 Lehn has reported the
preparation of macrocyclic cyclo-bis-intercaland receptors containing two acridine units,15 and we
previously obtained crown ethers from 2,7- and 2,3-dihydroxyacridan-9-ones.16
N
Cs2CO3, Br(CH2)3Br
O
O
Br
Br
4
acetone, reflux, 21 h, 52%
10
N
N
O
O
Cs2CO3, Br(CH2)12Br
4
4
acetone, reflux, 21 h, 14%
N
N
11
12
O
O
O
O
NaOH, toluene
glycol tosylate, TEBAC,
85°C, 48 h, 13%
N
Scheme 4 O-alkyl derivatives (10-12)

Coupling 1,3-dibromopropane with 4 in acetone with cesium carbonate led us to obtain the symmetrical
bis-bromopropyl compound (10) with 52 % yield; only the monomeric macrocycle (11) was obtained
using 1,12-dibromododecane (14 % yield). Phase transfer catalysis17 was used to prepare the bisacridinyl
crown (12) by reaction of diol 4 in alkaline toluene during two days with triethyleneglycol ditosylate.
Only one monomeric crown ether was recovered with 14 % yield, (Scheme 4).
All compounds were characterized by NMR spectroscopy. For monomers (11) and (12), no further
1
information could be gained from the simplified H and 13C NMR spectra; HR MS spectrometry
confirmed the propose structure of a single monomeric biacridine.
The resolution of racemic 2,2’-dihydroxy-9,9’-biacridine (4) was performed by the crystallization of a
mixture of diastereomers (13) obtained by derivatization of precursor (4) with (1S)-(-)-camphanic acid
chloride. Because of the poor solubility of 4 we used a modified procedure of esterification in a mixture
of pyridine18 and 4-dimethylaminopyridine19 to prepare the bis(camphanate)esters (13). After 3 days
under reflux a mixture of diesters (13) was recovered (55 % yield). First recrystallization from ethyl
acetate gave two fractions: an insoluble fraction enriched with one diastereomer (13a) (de 75 %) and a
filtrate with the ester (13b) (de 60 %). Then, all attempts to improve the diastereomeric purification of
13a and 13b failed and we decided to use acetonitrile as recrystallization solvent. In this case only
20
compound (13a) was recovered diastereomerically pure ([α]D = -100°, c = 0.08 CHCl3); it provided
crystals suitable for X-Ray crystallography. From the crystallographic structure, we determined the
absolute configuration of the biacridinyl moiety of ester (13a) as (aR), (see the ORTEP drawing of
diester (13a) represented in Figure 2). Then (aR)-(-)-13a was saponified in EtOH20 to yield
enantiomerically pure (R)-(-)-diol (4) ([α]D20 = -120°, c = 0.025 MeOH). (Scheme 5).
N
N
DMAP, pyridine
reflux, 72 h, 55%
OR
OR
OR
OR
(+)-4 + RCl
+
13a
13b
N
N
O
O
N
N
N
R =
O
NaOH, C2H5OH
reflux, 22 h, 80%
1) ethyl acetate
2) acetonitrile
OR
OR
OH
OH
13a, 13b
N
(R)-(-)-4
(R)-(-)-13a
Scheme 5: Enantioselective separation of the axially chiral biacridine ((R)-(-)-4)
by crystallization in acetonitrile.

The X-Ray structures of 9,9’-bianthryl- and 10,10’-biacridinyl-9,9’-diones have been reported.4,21 The
averaged torsion angles between the anthracene or acridinone rings were 74.2(3)° and 85.3(3)°
respectively but no guest inclusion was observed. We turned to dimethoxy and dihydroxy derivatives and
obtained a crystal structure of racemic dimethoxy-9,9’-biacridinyl that showed a CHCl3 1:1 inclusion.
Because racemic diol (4) is poorly soluble we did not obtain crystals suitable for an X-Ray study, but
after derivatization we obtained the structure of 6 with one molecule of CHCl3 included. The torsion
between the two acridine moieties is 97.2(8)° and 85.8(1)° for compounds (6) and (13a) respectively.
The two p-chlorophenyl rings have a dihedral angle of 117.8(7)° and 79.3(8)° relative to the acridine
moiety of 6, and the camphoric groups have 104.8(9)° and 99.5(8)° for compound (13a). Selected
geometrical parameters of 6 and 13a are gathered in Table 1 according to the numbering scheme
displayed in Figure 1 and Figure 2.
Table 1. Data collection and processing parameters for derivatives (6) and (13a)
Compound
Empirical formula
Molecular mass
Crystal system
Space group
a [Å]
6
13a
C110H107N16O13
1861.12
Triclinic
P1
C41H23N2O4Cl5
784.91
Orthorhombic
P bcn
14.8574(9)
17.732(2)
27.494(3)
90.00 (1)
90.00 (1)
90.00 (1)
7243.1(2)
8
13.1169(7)
14.334(1)
14.452(1)
85.692 (3)
74.197 (3)
79.549 (3)
2570.2(3)
1
b [Å]
c [Å]
α [deg]
β[deg]
γ [deg]
V [Å3]
Z
Crystal size [mm]
d calcd [g.cm-3]
µ (MoKα), cm-1
θ range [°]
0.2x0.2x0.1
1.44
0.4x0.3x0.05
1.202
2.21
0.080
4-21
7-26
Reflexions collected
R
4415
9482
0.088 (2616 refl.>3 σ(F))
0.097 (6463 refl.>4 σ(F))
Rw
0.092
0.148

C4
C8
N6
C9
C5
C3
C7
C2
C14
O29
C30
C10
C32
C12
C1
C33
C34
C35
C27
C28
C13
C15
C16
C11
C46
C26
O31
C25
C37
C36
Cl38
C23
C17
C18
C24
Cl48
C44
C47
C45
C42
C21
N22
C52
O39
C19
C40
C43
Cl50
O41
C20
Cl51
Cl49
Figure 1 Perspective view of 6 showing the numbering system and chloroform inclusion
Table 2 Selected bond lengths (Å) for derivatives (6) and (13a)
Compounds
C(2)-O(29)
O(29)-C(30)
C(30)-C(32)
C(13)-C(15)
C(18)-O(39)
O(39)-C(40)
C(40)-C(42)
6
13a
1.40(8)
1.38(8)
1.487(7)
1.495(7)
1.42(7)
1.492(7)
1.50(2)
O(43)-C(18)
O(43)-C(44)
C(44)-C(46)
C(13)-C(15)
1.416(9)
1.328(1)
1.516(1)
1.490(1)
O(29)-C(2) 1.395(9)
O(29)-C(30)
C(30)-C(32)
1.359(1)
1.512(1)
Table 3 Selected bond and torsion angles (Å, °) for derivatives (6) and (13a)
Compounds
6
13a
C(2)-O(29)-C(30)
C(32)-C(30)-O(29)
C(18)-O(39)-C(40)
114.9(5)
110.9(3)
116.3(4)
C(18)-O(43)-C(44)
O(43)-C(44)-C(46)
C(30)-O(29)-C(2)
116.5(6)
113.2(7)
116.1(6)
85.8(1)
C(16)-C(15)-C(13)-C(14) 97.2(8)
C(1)-C(2)-O(29)-O(30) 117.8(7)
C(19)-C(18)-O(39)-C(40) 79.3(8)
C(14)-C(13)-C(15)-C(16)
C(17)-C(18)-O(43)-C(44) 104.8(9)
C(30)-O(29)-C(2)-C(3) 99.5(8)
The absolute configuration of saponified diol (4) was determined using the X-Ray data of structure (13a).

The latter was obtained after recrystallization in ethyl acetate and acetonitrile of 13, leading to only one
diastereomer (13a). The structure of 13a consists of two independent units packed with nine molecules
of acetonitrile. Only one diastereomer without solvent molecules is shown in Figure 2.
C24
N22
C25
C20
C21
C23
C19
C18
C26
O45
C16
C28
C15
C13
C1
C27
O37
C55
C11
C44
C56
C17
C36
C35
C34
C10
O43
C12
C7
C32
C47
C48
C46
C30
C38
C14
C9
C50
O51
C8
C2
O29
C33
O31
N6
C52
O53
C49
C5
C4
C54
C3
C41
C42
C40
Figure 2 ORTEP drawing of diester ((aR)-(-)-13a). Only one unit is represented
without acetonitrile inclusion.
CONCLUSION
We synthesized new biacridinic derivatives by using the racemic 9,9’-biacridinyl-2,2’-diol; the (aR)-(-)-
9,9’-biacridinyl-2,2’-diol obtained was enantiomerically pure. Further studies on the use of such
compounds as chiral ligands in asymmetric synthesis are in progress.
EXPERIMENTAL
Solvents or reagents were grade quality and were used without further purification, except methanol.
Melting points were measured on an Electrothermal IA 9300 apparatus and were uncorrected. Analytical
thin layer chromatography (TLC) was performed on aluminum sheets pre-coated with silica gel (Merck
Kieselgel, 60 F254, layer thickness 0.25 mm). Column chromatography was performed on silica gel
1
13
(Merck Kieselgel, 230-240 mesh). H NMR and C NMR spectra were recorded on BRUKER AM 200
and AMX 400 spectrometers. Spectra were referenced to the residual solvent peak. Optical rotations
were obtained on a Perkin-Elmer 141 polarimeter at 589 nm (sodium D line) using 1.0 dm cells. Specific
rotations, [α]D are reported in degrees per decimeter at 25 o C, and the concentration (c) is given in grams
per 100 mL.
4'-Methoxy-N-phenylanthranilic acid (1)
A mixture of p-anisidine (12.4 g, 0.1 mol), o-bromobenzoic acid (24.3 g, 0.1 mol), copper (1 g, 16 mmol)
and ethanol (200 mL) was heated at 110°C for 4 h. After evaporation of the solvent, the residue was

dissolved in hot water (350 mL) and filtered. After cooling, the pH was adjusted to 3 with 6N HCl. The
precipitate obtained was washed with water and dried to yield 23.5 g (96 %) of 1; mp 187°C (from
ethanol), (lit.,4 186°C). TLC/Rf: 0.4 (CH2Cl2/EtOH, 6/4). 1H NMR (DMSO-d6): δ = 3.76 (s, 3H), 6.69 (t,
1H, J = 7.1 Hz), 6.93 (d, 1H, J = 8.0 Hz), 6.96 (d, 2H, J = 9.0 Hz), 7.19 (d, 2H, J = 9.0 Hz), 7.31 (ddd,
13
1H, J = 1.4, 7.1 and 8.5 Hz), 7.88 (d, 1H, J = 7.8 Hz), 9.45 (s, 2H). C NMR (DMSO-d6): δ = 55.33,
111.43, 112.86, 114.84 (2C), 116.34, 125.12 (2C), 131.86, 133.04, 134.23, 148.88, 156.15, 170.15.
2-Methoxy-9-chloroacridine (2)
A mixture of 4-methoxyphenylanthranilic acid (1) (8.33 g, 34 mmol) and phosphorous oxychloride (33
mL, 0.36 mmol) was heated at 90°C for 15 min, and then for 2 h at 130°C. After evaporation of the
solvent, the residue was dissolved in chloroform (100 mL) and washed successively with aqueous
2N ammonia and water. The organic layer was dried over MgSO4 and evaporated. The residue was
recrystallized from ethanol to yield 5.94 g (71 %) of 2 as yellow needles; mp 152°C (from ethanol),
(lit.,22 152-153°C). TLC/Rf: 0.6 (Et2O/hexane, 8/2). 1H NMR (CDCl3): δ = 3.99 (s, 3H), 7.43 (dd, 1H, J =
2.1, 10.1 Hz), 7.45 (d, 1H, J = 2.5 Hz), 7.58 (td, 1H, J = 2.1, 7.2 Hz), 7.73 (td, 1H, J = 2.2, 7.1 Hz), 8.08
13
(d, 1H, J = 10.1 Hz), 8.17 (d, 1H, J = 8.1 Hz), 8.36 (d, 1H, J = 6.2 Hz). C (CDCl3): δ = 55.99, 99.75,
124.10, 124.42, 125.23,125.86, 126.98, 129.30, 129.73, 131.43, 138.16, 146.05, 147.14, 158.14.
2,2’-Dimethoxy-9,9’-biacridine (3)
A mixture of 2-methoxy-9-chloroacridine (2) (2 g, 8 mmol) and zinc powder (0.6 g, 9 mmol) was
refluxed in anhydrous methanol (60 mL) under nitrogen for 4 h. After filtration of the hot solution, the
residue obtained was dissolved in hot chloroform (120 mL), and the zinc was eliminated by filtration. The
organic phase was dried over MgSO4 and concentrated to give a crude compound which was
recrystallized from chloroform to yield a yellow powder (3) (1.68 g, 49 %); mp 264°C (from chloroform).
TLC/Rf: 0.60 (AcOEt/CH2Cl2, 1/1). 1H NMR (DMSO-d6): δ = 3.33 (s, 6H), 6.18 (d, 2H, J = 2.5 Hz), 6.92
(br d, 2H, J = 8.5 Hz), 7.35 (br dd, 2H, J = 7.8 and 8.5 Hz), 7.59 (dd, 2H, J = 2.5 and 9.4 Hz), 7.79 (br dd,
2H, J = 7.8 and 8.5 Hz), 8.29 (d, 2H, J = 9.4 Hz), 8.31 (br d, 2H, J = 8.5 Hz). 13C NMR (DMSO-d6): δ =
56.02, 101.13, 125.14, 125.28, 125.28 (2C), 127.18, 129.40, 129.80, 131.76, 137.52, 145.19, 146.61,
157.35. Anal. Calcd. for C42H28N2O6: C, 76.82; H, 4.30; N, 4.27. Found: C, 76.60; H, 4.55; N, 4.42. Anal.
Calcd for C28H20N2O2: C, 80.75; H, 4.84; N, 6.73. Found: C, 80.59; H, 4.61; N, 6.97.
2,2’-Dihydroxy-9,9’-biacridine (4)
A mixture of 2,2’-dimethoxy-9,9’-biacridine (3) (1.3 g, 3.12 mmol) and 48 % hydrobromic acid (80 mL)
was heated under reflux for 48 h. After cooling, the solution was poured into ice and the pH was adjusted

to 7 by addition of 5N ammonia. The precipitate obtained was filtered and dried to yield after
recrystallization from methanol (40 mL) a yellow powder (4) (0.75 g, 62 %); mp >300°C (from
methanol). TLC/Rf: 0.40 (AcOEt/CH2Cl2, 1/1). 1H NMR (DMSO-d6): δ = 6.17 (d, 2H, J = 2.5 Hz), 6.95
(br d, 2H, J = 8.3 Hz), 7.33 (ddd, 2H, J = 1.2, 6.7 and 8.2 Hz), 7.48 (dd, 2H, J = 2.5 and 9.4 Hz), 7.76
(ddd, 2H, J = 1.3, 6.7 and 8.5 Hz), 8.24 (d, 2H, J = 9.4 Hz), 8.29 (br d, 2H, J = 8.7 Hz), 9.95 (s, 2H). 13C
NMR (DMSO-d6): δ = 103.93, 125.26, 125.33, 125.88, 126.56, 127.07, 129.10, 129.88, 131.76, 137.04,
145.07,146.38, 155.75. Anal. Calcd for C26H16N2O2: C, 80.40; H, 4.15; N, 7.21. Found: C, 80.59; H,
4.37; N, 6.92.
General procedure for synthesis of esters (5-7).
2,2’-Bis[(p-methoxybenzoyl)oxy]-9,9’-biacridine (5)
To a solution of diol (4) (100 mg, 0.25 mmol) dissolved in a 2 % NaOH solution (6 mL) was added p-
anisoyl chloride (132 mg, 0.77 mmol). The mixture was shaken vigorously for 20 min at rt. The solid
product obtained was filtered and washed thoroughly with water. The residue was dissolved in
dichloromethane (80 mL), dried over MgSO4, filtered, and concentrated to yield 75 mg of crude ester.
Flash column chromatography (silica gel, CH2Cl2/AcOEt 12/1) yielded pure ester (5) (60 mg, 36%); mp
263°C (from dichloromethane). TLC/Rf: 0.30 (CH2Cl2/AcOEt, 12/1). 1H NMR (CDCl3): δ = 3.81 (s, 6H),
6.81 (d, 2H, J = 2.4 Hz), 6.85 (d, 4H, J = 8.9 Hz), 7.06 (br d, 2H, J = 8.5 Hz), 7.31 (ddd, 2H, J = 1.0, 6.7
and 8.4 Hz), 7.72 (dd, 2H, J = 2.4 and 9.2 Hz), 7.80 (ddd, 2H, J = 1.1, 6.6 and 8.4 Hz), 7.98 (d, 4H, J =
13
8.9 Hz), 8.38 (br d, 2H, J = 8.5 Hz), 8.43 (d, 2H, J = 9.3 Hz). C NMR (CDCl3): δ = 55.56, 113.87,
115.88, 121.15, 125.85, 125.97, 126.06, 127.42, 127.53, 130.15, 130.59, 131.56, 132.45, 140.26, 147.02,
148.57, 149.29, 164.11, 164.64. Anal. Calcd for C42H28N2O6: C, 76.82; H, 4.30; N, 4.27. Found: C, 76.60;
H, 4.55; N, 4.42.
2,2’-Bis[(p-chlorobenzoyl)oxy]-9,9’-biacridine (6)
As described for 5 but with diol (4) (100 mg, 0.25 mmol) and p-chlorobenzoyl chloride (135 mg, 0.77
mmol). After work up, recrystallization from ethanol (30 mL) yielded compound (6) (85 mg, 52%); mp
1
287°C (from ethanol). TLC/Rf: 0.80 (CH2Cl2/AcOEt, 9/1). H NMR (CDCl3): δ = 6.86 (d, 2H, J = 2.1
Hz), 7.12 (d, 2H, J = 8.6 Hz), 7.38 (d, 4H, J = 8.5 Hz), 7.47 (t, 2H, J = 7.6 Hz), 7.89 (dd, 2H, J = 2.1 and
9.4 Hz), 7.95 (d, 4H, J = 8.5 Hz), 7.97 (t, 2H, J = 7.6 Hz), 8.75 (d, 2H, J = 8.8 Hz), 8.82 (d, 2H, J = 9.5
13
Hz). C NMR (CDCl3): δ = 115.85, 125.79 (2C), 125.80, 126.85, 127.35, 127.39, 128.90, 129.11 (2C),
129.66, 129.66, 131.68 (2C), 133.26, 140.85, 143.54, 145.19, 149.90, 163.80. Anal. Calcd for
C40H22N2O4Cl2: C, 72.19; H, 3.33; N, 4.27. Found: C, 72.52; H, 3.10; N, 4.04.

2,2’-Bis[(p-fluorobenzoyl)oxy]-9,9’-biacridine (7)
As described for 5 but with diol (4) (100 mg, 0.25 mmol) and p-fluorobenzoyl chloride (122 mg, 0.77
mmol). After work up the obtained powder was triturated in hot ethanol (30 mL), filtered, and dried; this
provided ester (6) (75 mg, 48%); mp 273°C (from dichloromethane). TLC/Rf: 0.70 (CH2Cl2/AcOEt, 9/1).
1H NMR (CDCl3): δ = 6.82 (d, 2H, J = 2.4 Hz), 7.06 (t, 4H, J = 8.4 Hz), 7.08 (d, 2H, J = 8.5 Hz), 7.34 (t,
2H, J = 7.4 Hz), 7.73 (dd, 2H, J = 2.5 and 9.4 Hz), 7.76 (t, 2H, J = 7.4 Hz), 8.05 (dd, 4H, J = 5.3 and 8.8
Hz), 8.43 (d, 2H, J = 8.7 Hz), 8.49 (d, 2H, J = 9.4 Hz). 13C NMR (CDCl3): δ = 115.84 (d, JCF = 22 Hz),
115.84, 125.04 (d, JCF = 2 Hz), 125.77, 125.93 (2C), 127.41, 127.62, 129.82, 130.95, 131.40, 132.89 (d,
JCF = 10 Hz), 140.54, 146.58, 148.23, 149.03, 162.40, 165.16 (d, JCF = 245 Hz). Anal. Calcd for
C40H22N2O4F2: C, 75.94; H, 3.51; N, 4,43. Found: C, 76.26; H, 3.84; N, 4,20.
2,2’-Bis(vinyloxy)-9,9’-biacridine (8)
A mixture of diol (4) (250 mg, 0.65 mmol), allyl bromide (158 mg, 1.31 mmol), anhydrous cesium
carbonate (181 mg, 1.31 mmol), and dry acetone (50 mL) was refluxed for 8 h under stirring. After
cooling, the mixture was filtered and the precipitate washed with chloroform (60 mL). The organic
phases were recovered, dried over MgSO4, and filtrated to yield a green powder which was recrystallized
from chloroform to yield compound (8) (201 mg, 65 %); mp 177 °C (from chloroform). TLC/Rf: 0.72
(CH2Cl2/AcOEt 1/1). 1H NMR (CDCl3): δ = 4.02 (br d, 4H, J = 5.5 Hz), 4.88 (dq, 2H, J = 1.1 and 17.2
Hz), 4.92 (dq, 2H, J = 1.1 and 17.2 Hz), 5.68 (ddd, 2H, J = 5.4, 9.8 and 17.0 Hz), 6.18 (d, 2H, J = 2.6 Hz),
7.03 (br d, 2H, J = 8.6 Hz), 7.24 (br t, 2H, J = 8.0 Hz), 7.48 (dd, 2H, J = 2.6 and 9.5 Hz), 7.71 (ddd, 2H, J
= 1.2, 6.7 and 8.6 Hz), 8.28 (d, 2H, J = 9.5 Hz), 8.34 (d br, 2H, J = 8.8 Hz). 13C NMR (CDCl3): δ = 68.93,
102.84, 118.31, 125.86 (2C), 126.54, 126.81 (2C), 129.39, 129.96, 131.62, 132.15, 138.63, 146.05,
147.27, 156.56. Anal. Calcd for C32H24N2O2F2: C, 82.03; H, 5.16; N, 5.98. Found: C, 81.81; H, 5.33; N,
4.27.
2,2’-Bis(4-acridylmethoxy)-9,9’-biacridine (9)
To a solution of 2,2’-dihydroxy-9,9’-biacridine (4) (100 mg, 0.25 mmol), anhydrous acetone (50 mL) and
cesium carbonate (840 mg, 2.58 mmol) was added dropwise with stirring, under nitrogen, a solution of 4-
bromomethylacridine (140 mg, 0.516 mmol) in anhydrous acetone (20 mL). The mixture was heated to
reflux for 28 h and filtered hot, and the precipitate was washed with acetone (50 mL). The organic phase
was recovered and concentrated. The residue was extracted with water/dichloromethane (1/1). The
organic phase was separated, dried over MgSO4, filtered, and evaporated. The obtained oil was triturated
with hexane to yield a yellow powder which was recrystallized from dichloromethane to yield compound
1
(9) (81 mg, 40 %); mp 164 °C (from dichloromethane). TLC/Rf: 0.65 (CH2Cl2/AcOEt, 9/1). H NMR

(CDCl3): δ = 5.51 (d, 2H, J = 14.1 Hz), 5.58 (d, 2H, J = 14.1 Hz), 6.09 (d, 2H, J = 2.7 Hz), 6.69 (br d, 2H,
J = 8.2 Hz), 7.04 (ddd, 2H, J = 1.1, 6.6 and 8.3 Hz), 7.20 (dd, 2H, J = 7.0 and 8.3 Hz), 7.49 (dd, 2H, J =
2.7 and 9.5 Hz), 7.53 (ddd, 2H, J = 1.3, 6.5 and 8.5 Hz), 7.57 (dd, 2H, J = 1.1 and 8.1 Hz), 7.60 (ddd, 2H,
J = 1.1, 6.5 and 8.1 Hz), 7.68 (br d, 2H, J = 7.6 Hz), 7.75 (ddd, 2H, J = 1.4, 6.5 and 7.9 Hz), 7.83 (br d,
2H, J = 8.1 Hz), 7.90 (d, 2H, J = 9.5 Hz), 7.99 (br d, 2H, J = 8.7 Hz), 8.04 (br d, 2H, J = 8.4 Hz), 8,62 (s,
2H). 13C NMR (CDCl3): δ = 66.36, 103.94, 124.83, 125.44, 125.48, 125.48, 125.79, 125.95, 126.10,
126.17, 126.45, 127.39, 127.61, 128.11, 128.72, 129.71, 129.91, 130.08, 131.15, 133.87, 136.07, 138.18,
145.25, 145.90, 146.58, 148.15, 156.27. Anal. Calcd for C54H34N4O2: C, 84.14; H, 4.45; N, 7.27. Found:
C, 84.36; H, 4.63; N, 7.02.
2,2’-Bis(3-bromopropyloxy)-9,9’-biacridine (10)
To a solution of diol (4) (100 mg, 0.25 mmol) in anhydrous acetone (30 mL) was added cesium carbonate
(406 mg, 1.25 mmol) and 1,3-dibromopropane (520 mg, 2.5 mmol). The mixture was refluxed in the dark
for 21 h. After cooling, the cesium salts were removed by filtration and washed with acetone. The
organic filtrate was evaporated and the residue was purified by column chromatography (silica gel,
chloroform/acetone 15/1) to yield 10 (81 mg, 52 %); mp 146 °C (from chloroform). TLC/Rf: 0.70
(CH2Cl2/AcOEt 9/1). 1H NMR (CDCl3): δ = 2.05 (quint, 4H, J = 6.1 Hz), 3.38 (t, 4H, J = 6.8 Hz), 3.56
(td, 2H, J = 6.1 and 9.6 Hz), 3.61 (td, 2H, J = 6.1 and 9.5 Hz), 6.21 (d, 2H, J = 2.6 Hz), 7.01 (d, 2H, J =
8.7 Hz), 7.25 (ddd, 2H, J = 1.2, 6.6 and 8.7 Hz), 7.46 (dd, 2H, J = 2.7 and 9.5 Hz), 7.72 (ddd, 2H, J = 1.3,
6.6 and 8.0 Hz), 8.28 (d, 2H, J = 9.5 Hz), 8.34 (d, 2H, J = 8.4 Hz). 13C NMR (CDCl3): δ = 29.51, 31.87,
65.38, 102.32, 125.74, 125.87, 126.54, 126.90 (2C), 129.46, 130.05, 131.85, 138.57, 146.19, 147.36,
156.80. Anal. Calcd for C32H26N2O2Br2: C, 60.97; H, 4.16; N, 4.44. Found: C, 61.19; H, 4.31; N, 4.68.
9,9’-Bisacridinyl-22-crown-2 (11)
To a solution of diol (4) (100 mg, 0.25 mmol) in anhydrous acetone (30 mL) were added cesium
carbonate (406 mg, 1.25 mmol) and 1,12-dibromododecane (84 mg, 0.26 mmol). The mixture was
refluxed in the dark for 21 h. After cooling, the cesium salts were removed by filtration and the
precipitate washed with acetone. The organic phase was dried over MgSO4 and evaporated to obtain an
oil, which was purified by flash column chromatography (silica gel, CH2Cl2/AcOEt 4/1) to yield ether
(11) (20 mg, 14 %); mp 183 °C (from dichloromethane). TLC/Rf: 0.75 (CH2Cl2/AcOEt 4/1). 1H (CDCl3):
δ = 1.22 (m, 20H), 3.39 (td, 2H, J = 3.9 and 9.7 Hz), 3.60 (td, 2H, J = 5.1 and 9.6 Hz), 6.25 (d, 2H, J =
2.0 Hz), 6.96 (d, 2H, J = 8.6 Hz), 7.22 (t, 2H, J = 7.5 Hz), 7.50 (dd, 2H, J = 2.2 and 9.5 Hz), 7.69 (t, 2H, J
= 7.4 Hz), 8.29 (d, 2H, J = 9.4 Hz), 8.32 (d, 2H, J = 8.7 Hz). 13C NMR (CDCl3): δ = 24.83, 27.06, 27.17,
27.57, 27.85, 67.36, 101.96, 125.85, 126.01, 126.27, 126.62, 126.81, 129.44, 129.65, 131.31, 138.74,

145.78, 146.91, 157.46. Anal. Calcd for C38H38N2O2: C, 82.28; H, 6.90; N, 5.05. Found: C, 82.01; H,
7.19; N, 4.87. HR MS (FAB: measured on M+H+ peak); found: 554.
Bisacridinyl-18-crown-4 (12)
To a solution of diol (4) (158 mg, 0.40 mmol) dissolved in an alkaline solution (H2O/NaOH, 9 mL, 30
mg, 0.8 mmol) were added under stirring toluene (30 mL) triethyleneglycol-di-p-tosylate (124 mg, 0.27
mmol) and tetrabutyl ammonium bromide (87 mg, 0.27 mmol). The mixture was stirred at 85 °C for 2
days. After cooling, toluene (50 mL) was added and the residue was washed with brine (3 x 50 mL). The
aqueous phase was extracted with chloroform (3 x 50 mL), the organic phase was dried over MgSO4,
filtered and concentrated. Flash column chromatography of the residue (silica gel, chloroform/ethyl
acetate 1/1) yielded crown ether (12) (18 mg, 14 %); mp 213 °C (from chloroform). TLC/Rf: 0.35 (light
petroleum/AcOEt 7/3). 1H (DMSO-d6): δ = 3.42 (m, 8H), 3.89 (m, 4H), 6.36 (d, 2H, J = 2.4 Hz), 6.91 (d,
2H, J = 8.3 Hz), 7.32 (t, 2H, J = 7.5 Hz), 7.61 (dd, 2H, J = 2.5 and 9.5 Hz), 7.77 (t, 2H, J = 7.9 Hz), 8.28
(d, 2H, J = 9.4 Hz), 8.29 (d, 2H, J = 8.7 Hz). 13C NMR (200 MHz, CDCl3): δ = 67.56, 67.94, 70.08 (2C),
102.87, 125.85, 125.93, 126.23, 126.28, 127.43, 129.13, 129.67, 131.64, 137.10, 145.21, 147.33, 156.15.
Anal. Calcd for C32H26N2O4: C, 76.48; H, 5.21; N, 5.57. Found: C, 76.65; H, 5.50; N, 5.36. HR MS (FAB:
measured on M+H+ peak); found: 502.
(9,9’-Bisacridinyl)-2,2’-dihydroxybis(camphanate) esters (13a-b)
To a mixture of diol ((±)-4) (0.6 g, 1.5 mmol) and (1S)-(-)-camphanic acid chloride (3.3 g, 15.2 mmol) in
dry pyridine (40 mL) was added 4-dimethylaminopyridine (60 mg, 0.49 mmol). The solution was
refluxed for 72 h under nitrogen. The reaction mixture was extracted with ethyl acetate (3 x 60 mL). The
organic phase was washed with water, dried over MgSO4, and evaporated in vacuo to give
bis(camphanate)ester diastereomers ((±)-13) (0.630 g, 55 %). This powder (13) was recrystallized from
ethyl acetate (10 mL) to yield after filtration an insoluble fraction and a filtrate. Then, this insoluble
compound was recrystallized from acetonitrile (5 mL) to yield after filtration one insoluble part of pure
diastereomer (13a) and a mixture of non isolable esters (13) dissolved in the filtrate. (20 mg, 18 %).
[α]D20 = -100° (c = 0.08 CHCl3); mp 289°C (from acetonitrile). TLC/Rf: 0.37 (CHCl3/acetonitrile 6/1). 1H
NMR (CDCl3): δ = 0.93 (s, 6H), 1.00 (s, 6H), 1.06 (s, 6H), 1.66 (m, 2H), 1.90 (m, 2H), 2.02 (m, 2H), 2.39
(m, 2H), 6.75 (d, 2H, J = 2.6 Hz), 7.02 (br d, 2H, J = 8.4 Hz), 7.31 (dt, 2H, J = 1.0 and 7.6 Hz), 7.60 (dd,
2H, J = 2.5 and 9.4 Hz), 7.81 (dt, 2H, J = 1.4 and 7.6 Hz), 8.39 (br d, 2H, J = 8.5 Hz), 8.44 (d, 2H, J = 9.3
Hz). 13C NMR (DMSO-d6): δ = 9.71, 16.89 (2C), 28.87, 28.87, 30.80, 54.88, 90.61, 115.84, 125.62,
125.95, 125.99, 126.38, 127.76, 130.23, 130.90, 132.09, 140.19, 147.00, 148.12, 148.93, 165.96, 177.60.
Anal. Calcd for C46H40N2O8: C, 73.78; H, 5.38; N, 3.74. Found: C, 74.01; H, 5.14; N, 3.98.

(aR)-(-)-2,2’-Dihydroxy-9,9’-biacridine (4)
A mixture of recrystallized ester (13a), (-)-(9,9’-biacridinyl)-2,2’-diol bis-(camphanate) (10 mg, 0.013
mmol) and NaOH (3.2 mg, 0.08 mmol) in EtOH (4 mL) was refluxed for 22 h. The solvent was
evaporated and the residue was dissolved in water (4 mL) and neutralized by 9 % HCl. The precipitate
20
obtained was filtered to yield 43 mg (80%) of (aR)-(-)-2,2’-dihydroxy-9,9’-biacridine (4). [α]D = -120°
(c = 0.025 MeOH); mp >300 °C (from methanol).
X-Ray Crystallographic Study23
The X-Ray diffractions were measured at room temperature on an Enraf Nonius Kappa CCD
diffractometer with monochromated MoKα (λ = 0.71073 Å) radiation. A set of 90 frames was measured
for 6 and 13a through a 180°C ϕ scan in the following conditions: 2° ϕ steps, 120 seconds per frame
repeated two times. Lorentz polarization corrections were applied to the raw data, which were not
corrected for absorption. The structures were solved by direct methods calculations using SIR.24 All non
hydrogen atoms were refined anisotropically through cycles of full-matrix least squares using Maxus25 for
6 or SHELXL26 for 13a.
ACKNOWLEDGMENTS
We thank Dr. M. Giorgi for his kind assistance with the X-ray analyses of compounds (6) and (13a).
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