One-pot derivatization of medicinally important 9-aminoacridines by reductive amination and SNAr reaction

Article abstract of DOI:10.1016/j.tetlet.2009.12.020

A new highly efficient one-pot derivatization of medicinally important 9-aminoacridines (9-AA) at the amine position is described. Simple reductive amination and S_NAr reaction using easily accessible starting materials give a fast entry to novel 9-AA derivatives for biological screening.

Full text of DOI:10.1016/j.tetlet.2009.12.020

Tetrahedron Letters 51 (2010) 836–839
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot derivatization of medicinally important 9-aminoacridines
by reductive amination and SNAr reaction
*
Gary Gellerman , Vladimir Gaisin, Tamara Brider
Department of Biological Chemistry, Ariel University Center of Samaria, PO Box 3, Ariel 40700, Israel
a r t i c l e i n f o
a b s t r a c t
Article history:
A new highly efficient one-pot derivatization of medicinally important 9-aminoacridines (9-AA) at the
amine position is described. Simple reductive amination and SNAr reaction using easily accessible starting
materials give a fast entry to novel 9-AA derivatives for biological screening.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 15 October 2009
Revised 25 November 2009
Accepted 4 December 2009
Available online 11 December 2009
Keywords:
9-Aminoacridine
Reductive alkylation
Nucleophilic substitution
One-pot synthesis
The 9-aminoacridine (9-AA) core is a structure of interest to
medicinal chemists and appears in many biologically active com-
pounds, mostly with anticancer and antimalarial applications.
9-AA derivatives such as quinacrine1 are able to intercalate with
DNA, and consequently, can inhibit DNA transcription in para-
sites.2 9-Anilinoacridines have good antimalarial activities and
are potent parasite DNA topoisomerase II inhibitors.3 N-alkylated
9-AA analogs have been shown to be potent inhibitors of prion dis-
ease in cultured neuroblastoma cells, which also show inhibition
by lysosomotropic agents and cysteine protease inhibitors.4
In the field of antitumor DNA-intercalating agents, 9-AA deriva-
tives play an important role due to their antiproliferative proper-
ties.5 Several cancer chemotherapeutics such as Amascrine and
Ledakrin based on the 9-aminoacridine scaffold have been devel-
oped.6a In addition, a series of potential topoisomerase II-mediated
anticancer 9-anilinoacridines, which are designed to avoid bio-
oxidation and which possess long durations of drug action, have
been reported.7 Among these substances, 3-(9-acridinylamino)-5-
hydroxymethylaniline (AHMA) (Fig. 1) and its alkylcarbamate deriv-
atives have been developed for potential clinical application.8
9-Aminoacridines have also been investigated as potential
photoaffinity labels9 and as fluorescent probes used to detect can-
cer cells.10
pounds does not involve genotoxic stress and is mediated by the
suppression of NF- B activity. Active NF- B signaling provides
selective advantages to tumor cells by inhibiting apoptosis and
promoting proliferation by stimulating expression of antiapoptotic
factors.
These findings, together with those mentioned above, indicate
that 9-AA derivatives have potential for anticancer applications
and this has inspired us to look for a short and efficient method
for the derivatization of 9-AA suitable for the rapid generation of
new compounds for evaluation.
Herein we report a new, highly-efficient, one-pot derivatization
of 9-AA at the amine position by simple reductive amination or
SNAr reaction, using commercially available synthons. Reductive
amination of aldehydes and ketones is an important and direct
method for the transformation of these functionalities into
amines.12 In this carbon–nitrogen bond-forming process, the inter-
mediate imine is not pre-formed.13 Thus, the chosen reducing
agent should be stable enough for the in situ formation of the
imine and avoid undesirable carbonyl reduction to alcohol by-
products. Mild NaCNBH3 in a weak acidic media is a widely re-
ported reducing reagent for reductive amination and was therefore
employed as the reagent of choice. To demonstrate the synthetic
potential of NaCNBH3 in the reductive amination of 9-AA under
standard conditions (1% AcOH in MeOH, rt, 3 h) we employed
two classes of aldehydes: aromatic and aliphatic (Scheme 1), yield-
ing N(9)-benzylacridines 1a–h and 2-(acridin-9-ylamino)acetic
acid 1i, respectively, in moderate to good yields (Table 1).14 The
N(9)-aminobenzyl analogs synthesized bear representative elec-
tron-donating (ED) and electron-withdrawing (EW) groups as well
as aryl and indolyl systems at various positions around the benzyl
j
j
Recently, 9-aminoacridine analogs, including the antimalarial
drug quinacrine, were found to present strong induction of p53
function in renal cell carcinomas (RCCs) and other types of cancer
cells.11 Interestingly, induction of p53 function by these com-
* Corresponding author. Tel.: +972 3 937 1442; fax: +972 3 906 6634.
E-mail address: garyg@ariel.ac.il (G. Gellerman).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.020

G. Gellerman et al. / Tetrahedron Letters 51 (2010) 836–839
837
NH2
R4
2'
4'
R5
X
OH
5'
HN
9
NH
N
HN
N
8
1
6
3
N
1
2
AHMA
R1
R2
R3
X = CO2H,
R1,R2,R3 = Br, OH, OMe, CO2H, NO2, aryl, indolyl
R4, R5 = CO2H, CO2Me, NO2, CF3, CN.
Figure 1. General structures of 9-aminoacridines.
R1
Table 1
Reaction data for reductive amination of 9-AA
R2
R3
Entry
1
Aldehyde
Product
Yield (%)
NH
CO2H
Aryl aldehyde
3a-h
3a
3b
1a
92
89
O
O
a
N
NH2
O
1a-h
2
3
1b
1c
HO2C
CO2H
NH
OH
N
9-AA
HO2C
O
3c
87
3i
NO2
a
N
1i
4
5
3d
3e
1d
1e
66a
68a
Scheme 1. Synthesis of 9-aminoacridine derivatives 1 by reductive amination.
Reagents and conditions: (a) NaCNBH3, 1% AcOH in MeOH, 3 h, rt.
O
MeO
O
ring. Such syntheses are more difficult to accomplish using the
classical ‘reverse’ synthetic approach in which 9-chloroacridine
reacts with benzylamines,15 due to the poor commercial availabil-
ity of substituted benzylamines. The aliphatic analog 1i was pre-
pared in the same manner using the corresponding glyoxylic acid
hydrate (3i).
In the context of exploring the rapid derivatization of the 9-AA
scaffold we found that the amine (NH2) at position nine is nucleo-
philic enough to take part in nucleophilic aromatic substitution
(SNAr) to give medicinally important 9-anilinoacridines.16
We successfully reacted representative electrophilic haloaryls
4a–e (Scheme 2), bearing one or two strongly electron-withdraw-
ing groups, with 9-AA in the presence of one equivalent (half molar
ratio) of Cs2CO3 in DMF at 90 °C to afford the substituted 9-anilino-
acridines 2a–e in good yields (Table 2).17 The uniqueness of this
method is in its ability to form the anilino tether in 9-AAs with
two EW groups which is very difficult to accomplish using the
standard ‘reverse’ approach, namely nucleophilic substitution of
the deactivated anilines on 9-chloroacridines.
MeO
OMe
Br
O
6
7
3f
1f
72a
MeO
OMe
O
OH
3g
1g
83
O
MeO
O
8
9
3h
3i
1h
1i
58a
91
N
H
CO2H
a
After chromatography.
The anilinic amine in such a ‘reverse’ reaction is strongly deac-
tivated by EW groups leading mostly to unreacted materials or
black tars. The additional advantage of the SNAr reaction with
9-AAs is the extensive commercial availability of appropriately
substituted haloaryls. Interestingly, 4-chloro-3-nitrobenzoic acid
(4c) which bears an acidic CO2H group smoothly undergoes the
SNAr reaction to give product 2c even in the presence of
basic Cs2CO3. Moreover, the CO2H group in 2c (as well as in the

838
G. Gellerman et al. / Tetrahedron Letters 51 (2010) 836–839
R5
R4
O2N
F
NO2
NH
R5
R4
O2N
F
NO2
F
NH2
NH
X (Halogen)
4a-e
4f
a
N
a
N
N
9-AA
2f
2a R4 =NO2, R5 = H
2b R4 =NO2, R5 = NO2
2c R4 =NO2, R5 = CO2H
2d R4 =CF3, R5 = CO2Me
2e R4 =NO2, R5 = CN
O2N
(9)-AA
NO2
(9)-AA
5
Scheme 2. Synthesis of 9-aminoacridine derivatives 2 by SNAr reaction. Reagents and conditions: (a) Cs2CO3, DMF, 90 °C, 12 h.
donating (ED) free amine bases, as in 2b and 2d, are shifted high-
Table 2
er-field to d 7.01 and d 6.85, respectively (see Supplementary data
for 2b,d). Other one-pot derivatizations of 9-AA are under investi-
gation.
Reaction data for SNAr reaction of 9-AA
Entry
1
Haloarene
Product
Yield (%)
73a
NO2
In conclusion, we have developed a new method for the effi-
cient one-pot derivatization of the medicinally important 9-amino-
acridine (9-AA) scaffold. A simple reductive amination of 9-AA
with aldehydes yielded a series of novel substituted N(9)-benzyla-
minoacridines and N(9)-alkylaminoacridines. An SNAr reaction be-
tween 9-AA and halobenzenes that had strong EW groups gave
novel N(9)-anilinoacridines. All the products were obtained from
commercially available synthons in good yields. These synthetic
routes provide easy and rapid access to novel 9-AA derivatives
which can be further explored for their biological properties.
Br
4a
4b
2a18
NO2
Cl
2
3
2b
2c
78a
86
O2N
NO2
Cl
4c
HO2C
Acknowledgment
CF3
The authors thank Dr. Alexandra Massarwa for the HRMS mea-
surements of all new compounds.
F
4
5
4d
4e
2d
2e
76a
71a
MeO2C
Supplementary data
NO2
Cl
Supplementary data (selected 1H and 13C NMR, HRMS spectra)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2009.12.020.
NC
NO2
F
References and notes
6
4f
2f
52a
O2N
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previously mentioned carboxy and hydroxy analogs 1a–c, g, and i)
could serve as a linking group to various carriers for possible deliv-
ery. Another attempt was made to obtain bis-9-AA 5 (Scheme 2) by
reacting 2.5 equiv of 9-AA with 1 equiv of 1,5-difluoro-2,4-dinitro-
benzene. Unfortunately, only the mono adduct 2f was obtained in a
moderate yield, most probably due to severe steric hindrance.
All the products synthesized in this work which possess acidic
CO2H or phenolic substitution (1a,b,c,g,i, and 2c) precipitated from
acetone as pure (more than 94% by HPLC) yellow solids, while
unreacted starting materials and solvents were completely soluble
in acetone. Such a phenomenon can be attributed to the formation
of poorly soluble (in organic solvents) zwitterions. This hypothesis
is supported by an observed low-field shift in the 1H NMR spec-
trum for the anilinic H-2’ in 2c, ortho to the EW positively charged
9-aminoacridinium moiety (d 7.76, J = 6.5 Hz, see data for 2c in the
Supplementary data). Typically, protons ortho to strongly electron-
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5423.

G. Gellerman et al. / Tetrahedron Letters 51 (2010) 836–839
839
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14. General procedure for the synthesis of 1a–i via reductive amination: 9-AA
(0.194 g, 1 mmol) and the corresponding aldehyde (1 mmol) were added to
5 mL of MeOH/AcOH (99:1) and the mixture stirred at room temperature until
the starting material dissolved (15 min). Then, NaCNBH3 (0.09 g, 1.5 mmol)
was added in small portions with stirring. After additional stirring for 3 h at
room temperature, the solvent was evaporated and the residue was taken into
acetone. The resulting precipitate was filtered under vacuum, washed with
acetone, and dried to give the product as a yellow solid. Compounds that did
not precipitate were purified by flash column chromatography on silica gel 60
(5% MeOH in EtOAc) to yield pure (yellow) products. Data for 1a (0.3 g, 92%
17. General procedure for the synthesis of 2a–e via SNAr reaction: 9-AA (0.194 g,
1 mmol), haloaryl compound (1 mmol), and Cs2CO3 (0.161 g, 0.5 mmol) were
heated in 5 mL of dry DMF at 90 °C for 12 h. While heating, the color of the
reaction mixture changed to dark red. After completion of the reaction (TLC
monitoring in CH2Cl2) the mixture was cooled and poured into water. In the
case of 2c, the pH was adjusted to 6 by careful addition of 0.1 N HCl. The
resulting precipitate was collected by filtration, washed several times with
water, and dried to give a crude orange solid. The products (except 2c which
precipitated in pure form) were purified by flash column chromatography on
silica gel 60 (CH2Cl2). Data for 2a (orange solid, 0.23 g, 73% yield): mmax (KBr):
1670, 1650, 1190 cmÀ1; HRMS (CI, m/z) calcd for C19H14N3O2 (MH+) 316.101,
found 316.061; 1H NMR (300 MHz, CDCl3): d 9.32 (br s, 1, NH), 8.24 (d, 2H,
J = 6.8 Hz), 8.01–7.88 (m, 3H), 7.71–7.53 (m, 4H), 7.33 (t, 1H, J = 7.0 Hz), 6.62 (d,
1H, J = 7.0 Hz). 13C NMR (75 MHz, CDCl3): 165.2, 154.3, 147.7, 144.1, 133.4,
130.0, 129.7, 128.7, 127.2, 125.6, 124.7, 122.3, 120.5.
yield): m
max (KBr): 3500–3180 (br, s), 1700 (C@O), 1640, 1290 cmÀ1; HRMS (CI,
m/z) calcd for C21H17N2O2 (MH+) 329.121, found 329.102; 1H NMR (300 MHz,
DMSO-d6): d 8.50 (d, 2H, J = 7.0 Hz), 7.92 (d, 2H, J = 7.0 Hz), 7.77 (d, 1H,
J = 6.8 Hz), 7.68–7.65 (m, 2H), 7.41–7.36 (m, 2H), 7.30–7.24 (m, 3H), 4.54 (s,
2H, –NH–CH2–); 13C NMR (75 MHz, CDCl3): 171.9 (CO2H), 168.7, 152.7, 146.5,
141.5, 139.0, 131.5, 130.6, 130.1, 128.6, 128.2, 126.3, 125.5, 123.6, 122.1, 64.1.
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