Facile, economical and direct synthesis of 9-anilinoacridines

Article abstract of DOI:10.1080/14786410601129887

Acridines are well-known group of compounds with a wide variety of biological properties. We describe herein an expeditious approach to prepare anilinoacridine derivatives from mefenamic acid. It is the first report of a one-pot approach to anilinoacridines in good to excellent yields.

Full text of DOI:10.1080/14786410601129887

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Natural Product Research: Formerly
Natural Product Letters
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Facile, economical and direct synthesis
of 9-anilinoacridines
Khalid M. Khan a , Nosheen A. Rao a , Zia-Ullah a , Muhammad Ali
a , Shahnaz Perveen b , Muhammad Iqbal Choudhary a , Atta-Ur-
Rahman a & Wolfgang Voelter c
a International Center for Chemical and Biological Sciences ,
H.E.J. Research Institute of Chemistry, University of Karachi ,
Karachi, Pakistan
b PCSIR Laboratories Complex , Shahrah-e-Dr. Salimuz Zaman
Siddiqui, Karachi, Pakistan
c Interfakultäres Institut für Biochemie der Universität Tübingen ,
Hoppe-Seyler, Straße 4, Tübingen, Germany
Published online: 29 Oct 2009.
To cite this article: Khalid M. Khan , Nosheen A. Rao , Zia-Ullah , Muhammad Ali , Shahnaz
Perveen , Muhammad Iqbal Choudhary , Atta-Ur-Rahman & Wolfgang Voelter (2009) Facile,
economical and direct synthesis of 9-anilinoacridines, Natural Product Research: Formerly Natural
Product Letters, 23:1, 5-9, DOI: 10.1080/14786410601129887
To link to this article: http://dx.doi.org/10.1080/14786410601129887
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Natural Product Research
Vol. 23, No. 1, 10 January 2009, 5–9
Facile, economical and direct synthesis of 9-anilinoacridines
a
a
a
a
b
*
Khalid M. Khan , Nosheen A. Rao , Zia-Ullah , Muhammad Ali , Shahnaz Perveen ,
Muhammad Iqbal Choudharya, Atta-Ur-Rahmana and Wolfgang Voelterc
aInternational Center for Chemical and Biological Sciences, H.E.J. Research Institute of Chemistry,
University of Karachi, Karachi, Pakistan; PCSIR Laboratories Complex, Shahrah-e-Dr. Salimuz
b
c
Zaman Siddiqui, Karachi, Pakistan; Interfakultares Institut fur Biochemie der Universitat
¨
Tubingen, Hoppe-Seyler, Straße 4, Tubingen, Germany
¨
¨
¨
¨
(Received 5 December 2005; final version received 22 August 2007)
Acridines are well-known group of compounds with a wide variety of biological
properties. We describe herein an expeditious approach to prepare anilinoacridine
derivatives from mefenamic acid. It is the first report of a one-pot approach to
anilinoacridines in good to excellent yields.
Keywords: mefanamic acid; phosphorous oxytrichloride; 9-anilino-acridines;
one-pot synthesis
1. Introduction
Acridines are known to have activities against numerous solid tumours i.e. sarcoma,
myeloma, carcinoma, and melanoma (Bonse, Santelli-Rouvier, Barbe, & Krauth-Siegel,
1999; Kirk, Luedtke, & Tor, 2000; Lee et al., 1996; Lorente et al., 1995; Magiatis et al.,
1999; Magiatis et al., 1999; McConnaughie & Jenkins, 1995). They have a wide spectrum of
other important activities, such as antiplasmodial (Chavalitshewinkoon et al., 1993),
antibactarial (Tabarrini et al., 1999), immunostimulating (Dzierzbicka, Kolodziejczyk,
Wysocka-Skrzela, Mysliwski, & Sosnowska, 2001), antiallergic, anti-inflamatory (Lin,
´
Chang, Tseng, & Wang, 2002), photosensitizing (in the photodynamic therapy of malignant
cancers) (Mehta, Sambaiah, Maiya, Sirish, & Chatterjee, 1993), and antifeedant (Tringali,
Spatafora, Calı, & Simmonds, 2001). For decades, a number of acridine derivatives have
been discovered with potent biological activities, however, due to toxicity and other adverse
side effects, most of them were not developed as therapeutic agents. Nevertheless, more
recently various chemical modifications of these known active compounds have been
carried out to enhance and modify their activity profiles and decrease toxicity (Skonieczny,
1980). The use of acridines as trypanocidal and antibacterial agents was first proposed by
Ehrlich, Benda, and Browning in 1912/13, and the first clinical use of these agents started in
1917 (Wainwright, 2001). Due to the extensive clinical use of acridine chromophores, such
as proflavine, euflavine, diflavine, sinflavin, flavicid, ethacridine, and aminacrine
(Wainwright, 2001), we describe here a preparation of several new anilinoacridine
derivatives from mefenamic acid. Previously, 9-anilinoacridines were synthesised via
*Corresponding author. Email: hassaan2@super.net.pk
ISSN 1478–6419 print/ISSN 1029–2349 online
ß 2009 Taylor & Francis
DOI: 10.1080/14786410601129887
http://www.informaworld.com

6
K.M. Khan et al.
Ullmann reaction in 40–60% yield (Groundwater & Munawar, 1997; Sa
´
nchez, del Campo,
Avendano, & Llama, 1990). Our one-pot reaction is carried out without isolating the
intermediate 9-chloroacridine, as it is readily hydrolysed in neutral and acidic solutions
(Wainwright, 2001) resulting in high yields.
R1
R2
R3
COOH
i) POCl3/110°C
HN
R5
R4
ii) Ethanol/
Substituted
Aniline
N
H
CH3
CH3
N
CH3
1
CH3
2
2. Results and discussion
The synthetic pathway described here is based on the preparation of different derivatives
of 9-anilinoacridine by the treatment of mefenamic acid (2,3-dimethyl-N-Phenyl-
anthranilic acid) with appropriate anilines in the presence of POCl3. This has resulted in
the formation of 9-chloroacridines (Scheme 1). 9-Chloroacridine reacts smoothly with
anilines resulting in the formation of 9-anilinoacridines in different yields, depending upon
the substituents present on the aromatic ring. Anilines with electron-withdrawing groups
at ortho, or para positions, such as those with nitro groups for the synthesis of compounds
4 and 14 decrease the nucleophilicity of the amino group and cause reduction of the yields.
On the other hand, anilines with electron-donating groups in ortho or para positions, such
as methyl, methoxy, or chloro substituents, facilitate the electron density at the amino
group thus enhance the nucleophilicity and results in excellent yields. In case of meta
substituents, inductively electron donating groups increase the reactivity of anilines that
result in an increase in percent yields e.g., compounds 8 and 11 (Table 1).
In conclusion, an efficient, economical, high yielding and simple one-pot method for
the conversions of mefenamic acid into 9-anilinoacridines using phosphoryl chloride and
respective anilines has been developed.
R
R
5
4
R
NH
R –R :
Acr
3
1
5
R
R
2
1
3. Experimental
3.1. General
Melting points were determined on a Buchi 434 melting point apparatus and are
¨
uncorrected. NMR was performed on a Bruker AM 300 MHz. CHN analysis was
performed on a Carlo Erba Strumentazion-Mod-1106 Italy. The ultraviolet spectra (UV)
were recorded on Perkin-Elmer Lambda-5 UV/VIS spectrometer, the infrared spectra (IR)
on JASCO IR-A-302 spectrometer and the electron impact mass spectra (EIMS) on

Natural Product Research
7
Cl
N
COOH
(i)
N
H
1
CH3
CH3
CH3
CH3
2
R3
(ii)
R2
R1
R4
R5
NH
N
CH3
CH3
3
Scheme 1. (i) POCl3/110ꢀC; (ii) Ethanol/substituted aniline.
Table 1. Yields of the one-pot syntheses of 9-anilinoacridines.
Compound
R1
R2
R3
R4
R5
Yield (%)
3
4
5
6
7
H
CH3
OCH3
H
Cl
H
CH3
H
CH3
CH3
H
H
H
H
H
H
CH3
H
Cl
H
CH3
CH3
H
H
H
H
CH3
Cl
H
CH3
Cl
H
H
H
NO2
CH3O
H
CH3
H
H
CH3
H
H
H
H
H
NO2
H
H
H
H
H
H
H
H
H
H
Cl
82
68
78
75
93
92
88
97
88
90
91
63
93
8
9
10
11
12
13
14
15
H
CH3
NO2
H
H
Cl
H
Finnigan MAT-311A Germany. TLC was performed on precoated silica gel glass plates
(Kieselgel 60, 254, E. Merck, Germany). Chromatograms were visualised by UV at 254
and 365 nm, respectively.
3.2. General procedure for the preparation of compounds 3–15
A mixture of mefenamic acid (0.1 g, 0.4 mmol) and phosphoryl chloride (0.5 mL, 3.2 mmol)
was stirred at 110ꢀC for completion of the reaction (TLC analysis), and then POCl3 was
evaporated under high-reduced pressure yielding air-sensitive residues. The residues were
dissolved in anhydrous ethanol, and after adding an appropriate amount of differently-
substituted anilines (0.8 mmol), the reaction was complete within 30 min (TLC analysis).
The solvent was evaporated under reduced pressure, the residue suspended in water and
extracted with dichloromethane (3 ꢁ 50 mL). The organic phase was washed with brine,
dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure.

8
K.M. Khan et al.
The obtained product, if solid, was recrystallised from ethanol and in case of liquid was
distilled under reduced pressure.
3,4-Dimethyl-9-anilinoacridine (3) Yield 0.15 g (82%); Rf ¼ 0.65 (hexane/ethyl acetate,
1
8: 2); m.p. 152–154ꢀC; H NMR (300 MHz, CDCl3): ꢀ 8.00 (d, 2H, J ¼ 6.2 Hz, H-5,8), 7.6
(ddd, 1H, J ¼ 7.9, J ¼ 6.9, J ¼ 1.4 Hz, H-6),y 7.5 (br.s, 1H, N-H), 7.35 (ddd, 1H, J ¼ 7.9,
¨
J ¼ 7.1, J ¼ 1.5 Hz, H-7), 7.24 (m, 5H, Ar-H), 6.81 (d, 2H, J ¼ 7.1 Hz, H-1,2), 2.81
(s, 3H, CH3), 1.57 (s, 3H, CH3); IR (KBr) ꢁmax 3010, 2990, 1715, 1605, 1514, 1250, 1170,
1010 cmꢂ1; MS: m/z (%) ¼ 298 (Mþ), 222 (100), 204 (5), 281 (27), 84 (8), 82 (13); Anal.
Calcd for C21H18N2: C, 84.53; H, 6.08; N, 9.39; Found: C, 84.08; H, 6.16; N, 9.45.
Acknowledgements
One of us, Mr Zia-Ullah, is thankful to the Higher Education Commission (HEC) Pakistan for
granting a ‘‘Merit Scholarship for Ph.D. Studies in Science and Technology 200 Scholarships.’’ We
are also thankful to Pakistan Telecommunication Company Limited (PTCL) for financial assistance.
References
Bonse, S., Santelli-Rouvier, C., Barbe, J., & Krauth-Siegel, R.L. (1999). Inhibition of Trypanosoma
cruzi trypanothione reductase by acridines: Kinetic studies and structure-activity relationships.
Journal of Medicinal Chemistry, 42, 5448–5454.
Chavalitshewinkoon, P., Wilairat, P., Gamage, S., Denny, W., Figgitt, D., & Ralph, R. (1993).
Structure-activity relationships and modes of action of 9-anilinoacridines against chloroquine-
resistant Plasmodium falciparum in vitro. Antimicrobial Agents And Chemotherapy, 37,
403–406.
Dzierzbicka, K., Kolodziejczyk, A.M., Wysocka-Skrzela, B., Mysliwski, A., & Sosnowska, D.
´
(2001). Synthesis and antitumor activity of conjugates of muramyldipeptide, normuramyldi-
peptide, and desmuramylpeptides with acridine/acridone derivatives. Journal of Medicinal
Chemistry, 44, 3606–3615.
Gamage, S.A., Spicer, J.A., Atwell, G.J., Finlay, G.J., Baguley, B.C., & Denny, W.A. (1999).
Structure-activity relationships for substituted bis(acridine-4-carboxamides): A new class of
anticancer agents. Journal of Medicinal Chemistry, 42, 2383–2393.
Groundwater, P.W., & Munawar, M.A. (1997). In A.R. Katritzky (Ed.), Advances in Heterocyclic
Chemistry (Vol. 70, p. 89). San Diego: Academic Press.
Kirk, S.R., Luedtke, N.W., & Tor, Y. (2000). Neomycin-acridine conjugate: A potent inhibitor of
rev-RRE binding. Journal of the American Chemical Society, 122, 980–981.
Lee, H.H., Wilson, W.R., Ferry, D.M., van Zijl, P., Pullen, S.M., & Denny, W.A. (1996). Hypoxia-
selective antitumor agents. 13. Effects of acridine substitution on the hypoxia-selective
cytotoxicity and metabolic reduction of the bis-bioreductive agent nitracrine N-oxide. Journal
of Medicinal Chemistry, 39, 2508–2517.
Lin, T.P., Chang, C.P., Tseng, R.T., & Wang, J.P. (2002). Synthesis, anti-allrgic and anti-
inflamatory activities of N-substituted benzyl-6 (or 7)-chloro-2,3,4,9-tetrahydrofuro[2,3-b]
quinolin-3,4-diones. Chinese Pharamaceutical Journal, 54, 115–126.
´
Lorente, A., Fernandez-Saiz, M., Espinosa, J.F., Jaime, C., Lehn, J.M., & Vigneron, J.P. (1995).
Cyclo-bis-intercalands with acridine subunits linked by rigid spacers. Tetrahedron Letters, 36,
5261–5265.
Magiatis, P., Mitaku, S., Skaltsounis, A.L., Tillequin, F., Koch, M., Pierre, A., & Atassi, G. (1999).
Synthesis and cytotoxic activity of 1-alkoxy- and 1-amino-2-hydroxy-1,2-dihydroacronycine
derivatives. Chemical & Pharmaceutical Bulletin, 47, 611–614.

Natural Product Research
9
McConnaughie, A.W., & Jenkins, T.C. (1995). Novel acridine-triazenes as prototype combilexins:
Synthesis, DNA binding, and biological activity. Journal of Medicinal Chemistry, 38,
3488–3501.
Mehta, G., Sambaiah, T., Maiya, B.G., Sirish, M., & Chatterjee, D. (1993). Synthesis and nuclease
activity of some ‘porphyrin-acridone’ hybrid molecules. Journal of the Chemical Society-
Perkin Transactions 1, 22, 2667–2670.
´
Sanchez, E., del Campo, C., Avendano, C., & Llama, E. (1990). New 7-anilinobenzo [b][1,8]
phenanthrolines. Heterocycles, 31, 2003–2010.
Skonieczny, S. (1980). Reactions at C-9 of acridine derivatives. Part XXV. Heterocycles, 14,
985–1032.
Tabarrini, O., Cecchetti, V., Fravolini, A., Nocentini, G., Barzi, A., Sabatini, S., Miao, H., & Sissi,
C. (1999). Design and synthesis of modified quinolones as antitumoral acridones. Journal of
Medicinal Chemistry, 42, 2136–2144.
Tringali, C., Spatafora, C., Calı, V., & Simmonds, M.S.J. (2001). Antifeedant constituents from
Fagara macrophylla. Fitoterapia, 72, 538–543.
Wainwright, M. (2001). Journal of Antimicrobial Chemotherapy, 47, 1.