Direct and facile synthesis of 9-aminoacridine and acridin-9-yl-ureas

Article abstract of DOI:10.1016/j.tetlet.2016.06.103

The ability of urea anions to react as nucleophiles with acridine has been investigated. An effective SNH synthesis of 9-aminoacridine was developed using the urea/NaH/DMSO system. However, when mono substituted ureas containing bulky substituents or 1,1-dialkyl substituted ureas were used, products of the SNH reaction of alkyl carbamoyl amination were obtained. Single crystal structure and the tautomerism of selected compound were studied.

Full text of DOI:10.1016/j.tetlet.2016.06.103

Accepted Manuscript
Direct and Facile Synthesis of 9-Aminoacridine and Acridin-9-yl-ureas
Ivan V. Borovlev, Oleg P. Demidov, Gulminat A. Amangasieva, Elena K.
Avakyan
PII:
S0040-4039(16)30782-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.06.103
TETL 47830
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
12 May 2016
9 June 2016
22 June 2016
Please cite this article as: Borovlev, I.V., Demidov, O.P., Amangasieva, G.A., Avakyan, E.K., Direct and Facile
Synthesis of 9-Aminoacridine and Acridin-9-yl-ureas, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/
j.tetlet.2016.06.103
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Graphical Abstract
Direct and Facile Synthesis of 9-
Aminoacridine and Acridin-9-yl-ureas
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Ivan Borovlev,* Oleg Demidov, Gulminat Amangasieva, Elena Avakyan

1
Tetrahedron Letters
journal homepage: www.els evier.com
Direct and Facile Synthesis of 9-Aminoacridine and Acridin-9-yl-ureas
a
Ivan V. Borovlev,* Oleg P. Demidov, Gulminat A. Amangasieva and Elena K. Avakyan
a
a
a
a
Department of Chemistry, North Caucasus Federal University, Pushkin st. 1, Stavropol, 355009, Russia
ARTICLE INFO
ABSTRACT
Article history:
Received
The ability of urea anions to react as nucleophiles with acridine has been investigated. An
effective SNH synthesis of 9-aminoacridine was developed using the urea/NaH/DMSO system.
However, when mono substituted ureas containing bulky substituents or 1,1-dialkyl substituted
ureas were used, products of the SNH reaction of alkyl carbamoyl amination were obtained.
Single crystal structure and the tautomerism of selected compound were studied.
Received in revised form
Accepted
Available online
Keywords:
Acridine
2016 Elsevier Ltd. All rights reserved.
Nucleophilic aromatic substitution of hydrogen
Amination
Carbamoyl amination
Tautomerism
The extensive use of acridines in medical sciences has been
stimulated by their pharmaceutical properties. Initially, they were
reactions of this heterocycle using urea anions as nucleophilic
reagents.
At first, we studied the reaction of acridine 1 with urea. As in
1
a
1b
shown to have antibacterial, trypanocidal, or antimalarial
1c
1
activities amongst other properties. Later, the high antitumor
d,e
7
the previous work, the process was carried out in anhydrous
1f
potency of acridines has also been reported. The anticancer
activity of acridine derivatives is a result of their capacity to
DMSO without isolation from oxygen. The reaction proceeded
readily in DMSO at room temperature via reaction of the urea
anion with the heterocycle to form, after addition of water, 9-
2
interact with nucleic acids. In many cases acridines,
8
demonstrating anticancer properties, have a substituted amino
group at position 9 and the nature of the substituent has proven to
aminoacridine 3 in 78% yield (Scheme 1).
3
be important for biological activity. The anticancer activity of 9-
DMSO, rt
H2NC(O)NH- Na+
H2NC(O)NH2 + NaH
-
H2
aminoacridine derivatives was confirmed in vitro, as well as in
4
vivo for selected molecules.
O
HN
NH2
NH2
9-Amino acridines have been synthesized using multi-step
reactions, the final stage of which was the nucleophilic
substitution of chlorine or another nucleofuge in position 9 of the
H2NC(O)NH Na+
DMSO, O2, rt
-
2
H O
N
N
N
5
Ar reaction). In whole, the nucleophilic
acridine molecule (S
aromatic substitution of hydrogen (S
N
1
2
3
H
H
) is well known for the
acridine series but examples of reactions with N-nucleophiles are
N
Scheme 1. S -Amination of acridine 1 by the urea anion.
N
still rare. According to a communication by Bauer and co-
The reaction progresses according to Scheme 1, with the
unstable intermediate acridin-9-yl-urea 2 undergoing conversion
into amine 3 in accordance with the previously reported
6a
workers, acridine readily undergoes the Chichibabin reaction to
form 9-aminoacridine in 72% yield upon reaction with sodium
amide in dimethylaniline (DMA) at 150 °C. However, in an
7
pathway, including deprotonation of the NH
2
group and
6b
attempt to reproduce this experiment, the authors obtained a
different result which resulted in the isolation of three
compounds - the starting acridine (14%), 9-aminoacridine (31%),
and 9,9’-diacridanyl. Recent work has shown that solvent-free
Chichibabin reaction conditions in melted acridine led to the
same result.
Recently, we developed a novel approach for the introduction
of an amino group or urea moiety to the 1,3,7-triazapyrene
7
molecule. In the course of this study and taking into account the
subsequent elimination of the 9-aminoacridine anion as a leaving
group. Addition of water to the reaction mixture leads to
protonation of this anion to form product 3. To confirm that
oxygen was the oxidant for this reaction we performed the
reaction in DMSO under an argon atmosphere. In this case only
traces of product 3 were detected by TLC. Moreover a mixture of
oligomerization products was obtained while the starting acridine
reacted completely under these conditions. Thus, it is obvious
that acridine itself is not an effective acceptor of a hydride ion
and the decisive factor for the subsequent aromatization of the
6c
biological significance of amino acridines, we became interested
to test the possibility for S
H
H
amination and carbamoyl amination
σ -adduct is access to oxygen.
The use of phenyl urea in the reaction with acridine 1 led to
same primary amine 3 in 74% yield. Further results were
N

2
Tetrahedron
obtained using mono substituted ureas, such as propyl-urea, tert-
butyl-urea and (1,1-dimethyl-pentyl)-urea. The anions of these
reagents readily reacted with acridine under the same conditions
to form the products of nucleophilic substitution of hydrogen in
the acridine moiety by the alkyl carbamoyl amino groups - 1-
acridin-9-yl-3-propyl-urea 4, 1-acridin-9-yl-3-tert-butyl-urea 5
and 1-acridin-9-yl-3-(1,1-dimethyl-pentyl)-urea 6, respectively
In contrast to intermediate 2 (Scheme 1) compounds 4-6
proved to be more stable. The probable cause of their
comparative stability is spatial interference in the deprotonation
of the NHR groups which is necessary for further conversion. It
could be assumed that 1,1-disubstituted ureas also give rise to the
products of dialkyl carbamoyl amination. Indeed, when the
anions of 1,1-dimethylurea or amides of pyrrolidine-1-carboxylic
acid, piperidine-1-carboxylic acid and morpholine-4-carboxylic
acid were reacted with acridine under the same conditions, 3-
(
Table 1, Scheme 2).
(
(
acridin-9-yl)-1,1-dimethyl-urea 7, pyrrolidine-1-carboxylic acid
acridin-9-yl)-amide 8, piperidine-1-carboxylic acid (acridin-9-
yl)-amide 9 and morpholine-4-carboxylic acid (acridin-9-yl)-
amide 10 were obtained, respectively, in 82-89% yields (Table 1,
Scheme 2).
Scheme 2. Reaction of acridine 1 with mono alkyl ureas and 1,1-disubstituted
1
13
Compounds 4-6 have a doubled set of H and C signals in
the NMR spectra in DMSO-d . Undoubtedly these compounds
represent novel examples of the known prototropic tautomeric
ureas at room temperature.
6
a
Table 1. Synthesis of 9-aminoacridine and acridin-9-yl-ureas
9
equilibrium of the "aminoacridine - acridanimine" type and exist
in DMSO solutions as an equilibrium system of tautomers a and
b in an approximately 1:1 ratio (Fig. 1). Increasing the
Entry Urea
Product
Yield (%)
78
1
temperature of the mixture of tautomers 5a,b in DMSO-d
6
to 70
1
C did not lead to coalescence of the proton signals in the H
°
NMR spectrum; only their broadening was observed to some
extent. Further temperature increases led to decomposition. On
the other hand, the addition of a small amount of trifluoroacetic
2
3
74
78
6
acid to the solution in DMSO-d led to a simplification of the
spectrum, since both tautomers after protonation give the same
cation in which a positive charge is delocalized between the two
nitrogen atoms.
4
5
6
7
8
67
67
89
84
84
82
O
1
Figure 1. H NMR spectrum of the tautomeric equilibrium for 1-acridin-9-yl-
HN
N
N
H
3
6
-tert-butyl-urea 5 in DMSO-d .
1
To perform the assignment of all H NMR signals of
tautomers 5a and 5b we attempted to synthesize their fixed N-
methylated forms. Reaction of the ambident anion of compound
6
5
, generated in situ by reaction of NaH with methyl iodide in
anhydrous acetonitrile, proceeded unselectively at room
temperature to form a mixture of both model compounds: 1-tert-
butyl-3-(10-methyl-10H-acridin-9-ylidene)-urea (11, 26%) and 1-
10
acridin-9-yl-3-tert-butyl-1-methyl-urea (12, 51%) (Scheme 3).
Scheme 3. Synthesis of the fixed N-methylated analogs of tautomers 5a and
5
b.
9
O
Proton and carbon assignments in the NMR spectra of
compounds 11 and 12 were made on the basis of COSY,
NOESY, HSQC and HMBC experiments. In turn we were able to
1
assign all H signals in the NMR spectra of tautomers 5a and 5b.
The structure of compound 5 was also confirmed by single
crystal X-ray determination. It is noteworthy that the crystal
obtained from low-polarity chloroform had in the unit cell both
tautomeric forms 5a and 5b which were connected by an
HN
N
N
O
10
a
In all experiments, the use of urea (6 equiv.) and NaH (6 equiv.) was
found to be optimal.

3
1
1
intermolecular hydrogen bond (Fig. 2). However, the crystal
grown by slow evaporation from more polar ethyl acetate existed
References and notes
12
only as 1-acridin-9-yl-3-tert-butyl-urea (tautomer 5a). The
single crystal X-ray data show that the dihydroacridine fragment
of compound 5b was not planar and the angle between the planes
of the two benzene rings was 7.63°.
1. (a) Wainwright, M. J. Antimicrob. Chemother. 2001, 47, 1. (b)
Gamage, S. A.; Figgitt, D. P.; Wojcik, S. J.; Ralph, R. K.; Ransijn,
A.; Mauel, J.; Yardley, V.; Snowdon, D.; Croft, S. L.; Denny, W.
A. J. Med. Chem. 1997, 40, 2634. (c) Chauhan, P. M.; Srivastava,
S. K. Curr. Med. Chem. 2001, 8, 1535. (d) Kumar, R.; Kaur, M.;
Kumari, M.. Acta Poloniae Pharmaceutica-Drug Research, 2012,
6
9, 3. (e) Hamy, F.; Brondani, V.; Flörsheimer, A.; Stark, W.;
Blommers, M. J. J.; Klimkait, T. Biochemistry 1998, 37, 5086. (f)
Belmont, P.; Bosson, J.; Godet, T.; Tiano, M. Anti-Cancer Agents
Med. Chem. 2007, 7, 139.
2
.
(a) Campbell, N. H.; Parkinson, G. N.; Reszka, A. P.; Neidle, S. J.
Am. Chem. Soc. 2008, 130, 6722. (b) Bridewell, D. J.; Finlay, G.
J.; Baguley, B. C. Anti-Cancer Drug Des. 2001, 16, 317. (c) Rene,
B.; Fosse, P.; Khelifa, T.; Jacquemin-Sablon, A.; Bailly, C. Mol.
Pharmacol. 1996, 49, 343. (d) Denny, W. A. Anti-Cancer Drug
Des. 1989, 4, 241.
3
4
.
.
(a) Moore, M. J.; Schultes, C. M.; Cuesta, J.; Cuenca, F.;
Gunaratnam, M.; Tanious, F. A.; Wilson, W. D.; Neidle, S. J.
Med. Chem. 2006, 49, 582. (b) Kumar, P.; Kumar, R.; Prasad, D.
N. Arab. J. Chem. 2013, 6, 79.
(a) Burger, A. M.; Dai, F.; Schultes, C. M.; Reszka, A. P.; Moore,
M. J.; Double, J. A.; Neidle, S. Cancer Res. 2005, 65, 1489. (b)
Oppegard, L. M.; Ougolkov, A. V.; Luchini, D. N.; Schoon, R. A.;
Goodell, J. R.; Kaur, H.; Billadeau, D. D.; Ferguson, D. M.; Hiasa,
H. Eur. J. Pharmacol. 2009, 602, 223.
5
.
see reviews: (a) Chiron, J.; Galy, J.-P. Synthesis 2004, No. 3, 313.
(
Figure 2. ORTEP diagram of compounds 5a,b.
b) Skonieczny, S. Heterocycles 1980, 14,. 985. (c) Albert, A. In
The Acridines, 2nd Ed.; St. Martin’s Press: New York, 1966. (d)
Acheson, R. M. In Acridines, 2nd Ed.; John Wiley & Sons: New
York, 1973.
In contrast to products 4-6 the tautomeric equilibrium for
compounds 7-10 in DMSO was almost completely shifted
towards one tautomer. To identify in which form they existed in
DMSO, COSY, NOESY, HSQC and HMBC NMR experiments
were performed. As it turned out, their preferred tautomeric
forms were imino forms 7b-10b. This was in accordance with the
6. (a) Bauer, K. Ber. 1950, 83, 10. (b) Pozharskii, A. F.;
Konstantinchenko, A. A. Chem. Heterocycl. Compd. 1972, 8,
1
518. (c) Kitahara, T.; Ishihara, Y.; Takano, J. Nippon Kagaku
Kaishi 1997, 12, 876; Chem. Abstr. 1997, 128: 22802.
Borovlev, I. V.; Demidov, O. P.; Amangasieva, G. A.; Avakyan,
E. K.; Kurnosova, N. A. Arkivoc, 2016, 58.
7
.
9
a
9
observation that any hindrance for free rotation around the C -N
bond in 9-alkylaminoacridines makes the imino form more
preferable.
8. General procedure: To a solution of the corresponding urea (3
mmol) in anhydrous dimethyl sulfoxide (5 mL), sodium hydride (3
mmol, based on active ingredient) was added at room temperature.
When hydrogen bubbling ceased, acridine (0.5 mmol) was added.
The mixture was stirred vigorously at room temperature for 24 h.
Then water (30 mL) was added and the precipitate was filtered off,
washed with water and dried. Compounds 3, 7 and 10 were
purified by recrystallization from the appropriate solvents (see
ESI). Product 6 was additionally washed with hot water on the
filter (~70 °C; 40 mL) during isolation to remove excess starting
materials and the dry product was recrystallized from a mixture of
dichloromethane and petroleum-ether. Compound 5 was purified
by silica gel flash chromatography, eluting with a 5:1 mixture of
benzene-EtOAc (colorless fraction) and then with EtOAc (yellow
fraction). The first fraction containing the starting materials was
discarded; product 5 was obtained from the second fraction after
solvent evaporation.
1
A distinctive feature of the H NMR spectrum of compound 7
was the magnetic nonequivalence of the N-methyl groups which
gave two proton singlets at 2.82 and 3.01 ppm, i.e. they are
1
3
separated by 76 Hz. In the C NMR spectrum there were also
two carbon signals. A similar phenomenon was observed in the
NMR spectra of compounds 8-10, where individual signals were
formed from the α-methylene groups at the nitrogen atom as well
as the β-methylene groups. This may be explained in at least two
ways: (i) the known restricted rotation about the C-N bond for
amides or (ii) the influence of the magnetic field of the benzene
ring in the region of these substituents.
Compounds 4-10 were unstable upon heating in the crystalline
state as well as in solution and upon slow heating gradually
change color and eventually melt at the melting point of 9-
aminoacridine 3.
Data for 9-aminoacridine (3): yellow solid (76 mg, 78% upon use
o
urea and 72 mg, 74%, using phenyl urea); mp 232-233
C
6
b
o
(EtOAc). Lit mp 233-234 C. H NMR (400 MHz, DMSO-d
1
6
): δ
.39 (2H, br. d, J = 8.4 Hz, H-1,8); 7.81 (2H, br. d, J = 8.5 Hz, H-
8
4
In conclusion, the advantages of the described method for the
synthesis of 9-aminoacridine and acridin-9-yl-ureas include
reagent availability, experimental simplicity and its applicability
to the synthesis of a broad range of 9-amino substituted acridines.
The crystal structure and tautomerism of selected compounds
were investigated.
,5); 7.77 (2H, br. s, NH ); 7.64 (2H, ddd, J = 8.5 Hz, J = 8.0 Hz,
2
J = 1.0 Hz, H-3,6); 7.31 (2H, ddd, J = 8.4 Hz, J = 8.0 Hz, J = 1.0
13
Hz, H-2,7). C NMR (100 MHz, DMSO-d
6
): δ 150.1; 148.8;
1
29.8; 128.7; 123.3; 121.5; 112.9. IR (thin film) 3342, 3181, 1649,
+
-
1
1613, 1562 cm . ESI-HRMS: calcd for
95.0917, found 195.0919.
C
13
H
11
N
2
[М+H]
1
9
.
(a) Stezowski, J. J.; Kollat, P.; Bogucka-Ledochowska, M. P;
Glusker, J. J. Am. Chem. Soc. 1985, 107, 2067. (b) Rak, J.;
Blazejowski, J.; Zauhar, R. J. J. Org. Chem. 1992, 57, 3720. (c)
Boyd, M.; Denny, W. A. J. Med. Chem. 1990, 33, 2656.
Acknowledgments
This project received financial support from the Ministry of
Education and Scienceof the Russian Federation in the
framework of the State Assignment to the Higher Education
Institutions № 4.141.2014/K.
10. Procedure for the synthesis of 1-tert-butyl-3-(10-methyl-10H-
acridin-9-ylidene)-urea (11) and 1-(acridin-9-yl)-3-tert-butyl-1-
methyl-urea (12). To a solution of 1-acridin-9-yl-3-tert-butyl-urea
(
5; 147 mg, 0.5 mmol) in anhydrous acetonitrile (5 mL), sodium
hydride (20 mg, 0.5 mmol, based on active ingredient) was added
at room temperature. After stirring for 0.5 h methyl iodide (71 mg,
0
.5 mmol) was added and the mixture was stirred for 1.5 hours at
room temperature. Then water (20 mL) was added and the
precipitate was filtered off, washed with water and dried.

4
Tetrahedron
Separation of the isomers was performed using dry silica gel flash
11. CCDC 1472661 (5a, 5b) contains the crystallographic data for the
crystal from chloroform for this manuscript.
chromatography, eluting with benzene-EtOAc 5:1 (colorless
fraction) and then with ethyl acetate (yellow fraction). From the
first fraction compound 12 was obtained and from the second
product 11 was isolated.
12. CCDC 1465304 (5a) contains the supplementary crystallographic
data for the crystal from ethyl acetate for this paper. These data
can be obtained free of charge from the Cambridge
Data for 1-tert-butyl-3-(10-methyl-10H-acridin-9-ylidene)-urea
Crystallographic Data
www.ccdc.cam.ac.uk/data_request/cif.
Centre
via
o
(
11): maize yellow solid (40 mg, 26%); mp 182-183 C (CH
2
Cl
): δ
.19 (2H, d, J = 8.4 Hz, H-1,8); 7.64 (2H, br. t, J = 7.6 Hz, H-3,6);
.59 (2H, d, J = 8.4 Hz, H-4,5); 7.16 (2H, br. t, J = 7.2 Hz, H-2,7);
2
1
with petr.-ether; with dec.). H NMR (400 MHz, DMSO-d
6
8
7
7
1
3
Supplementary Material
.00 (1H, s, N
1
H); 3.75 (3H, s, NСH
): δ 164.0 (CO); 151.4 (C-9); 141.4
C-4a,10a); 132.2 (C-3,6); 126.9 (C-1,8); 120.5 (C-2,7); 120.0 (C-
3 3 3
); 1.32 (9H, s, C(CH ) ). C
NMR (100 MHz, DMSO-d
6
(
Supplementary data associated with this article can be found,
in the online version, at…
8
a,9a); 115.2 (C-4,5); 49.8 (C(CH
3 3 3
) ); 34.1 (NСH ); 28.7
-
(
C(CH
.
3
)
ESI-HRMS: calcd for C19
3
). IR (thin film): 3340, 3271, 3065, 2960, 1637, 1569 cm
+
1
22 3
H N O [М+H] 308.1757, found
3
08.1775.

5
•
•
•
C-N bond formation by direct oxidative
nucleophilic substitution of hydrogen
A new approach to synthesize 9-
aminoacridine
A new synthesis of 1-(acridin-9-yl)-3-
alkyl(dialkyl)-ureas has been developed