Microwave synthesis of 9-substituted acridine derivatives

Article abstract of DOI:10.1081/SCC-120002511

Synthesis of 9-substituted acridine derivatives from diphenyl amine and appropriate carboxylic acid catalyzed by zinc chloride was carried out in the microwave reactor. Application of the microwave irradiation shortened the reaction time from 20-40 h to 5

Full text of DOI:10.1081/SCC-120002511

This article was downloaded by: [University of Sussex Library]
On: 08 September 2013, At: 04:51
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
MICROWAVE SYNTHESIS OF 9-SUBSTITUTED ACRIDINE
DERIVATIVES
Eva Veverková a , Marika Nosková a & Štefan Toma a
a Faculty of Natural Sciences, Comenius University, SK-842 15, Bratislava, Slovakia
Published online: 16 Aug 2006.
To cite this article: Eva Veverková , Marika Nosková & Štefan Toma (2002) MICROWAVE SYNTHESIS OF 9-SUBSTITUTED
ACRIDINE DERIVATIVES, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 32:5, 729-733, DOI: 10.1081/SCC-120002511
To link to this article: http://dx.doi.org/10.1081/SCC-120002511
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of
the Content. Any opinions and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied
upon and should be independently verified with primary sources of information. Taylor and Francis shall
not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other
liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

SYNTHETIC COMMUNICATIONS, 32(5), 729–733 (2002)
MICROWAVE SYNTHESIS OF
9-SUBSTITUTED ACRIDINE
DERIVATIVES
Eva Veverkova, Marika Noskova, andS tefan Toma*
Faculty of Natural Sciences, Comenius University,
SK-842 15 Bratislava, Slovakia
ABSTRACT
Synthesis of 9-substituted acridine derivatives from diphenyl
amine and appropriate carboxylic acid catalyzed by zinc chlo-
ride was carried out in the microwave reactor. Application
of the microwave irradiation shortened the reaction time
from 20–40 hto 5 min affording good (60–80%) yields of the
products.
Acridine derivatives are frequently used in the industry, especially at
production of dyes,1,2 but also in pharmaceutical industry because acridine
moiety is present in several antidepresives,3 antimalarial and antitumor
agents.4,5 The general means of producing 9-alkyl- and 9-arylacridines is
through the Bernthsen reaction,6 which is heating of diphenylamine, alipha-
tic or aromatic carboxylic acid and ZnCl2 at 200–220ꢀC over a long reaction
time. The yields achieved by this method are rather low, up to 30%. Graef7
has modified this method using esterchlorides of dicarboxylic acids as the
reagents. An interesting paper8 was published very recently. The authors
*Corresponding author. E-mail: toma@fns.uniba.sk
729
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
730
VEVERKOVA, NOSKOVA, AND TOMA
modified the Bernthsen’s method by addition of 20% H2SO4 to the reaction
mixture after heating it at 230ꢀC for 20–40 h. This methodology raised the
yields of acridinylalkanoic acids in some cases up to 80%. The beneficial
effect of microwave irradiation on several organic reactions is well docu-
mented9–14 and we decided therefore to explore if it could be applied also for
synthesis of 9-substituted acridines.
The reaction route of the 9-substituted acridine derivatives is depicted
in the scheme.
Scheme. R ¼ COOH, n ¼ 2, 3, 4, 8 or R ¼ Aryl, n ¼ 1
From the results given in Table 1 follows that reasonable yields
(59–80%) of the products were achieved after only 3.5–6 min of microwave
irradiation using the same reactant ratio as described in the literature8
for dicarboxylic acids and in the literature15 for arylacetic acids. The
yields we achieved for dicarboxylic acids (Table 1, Entries 1, 2, 4–6) were
10–20% lower than described. This fact can be explained by the very short
reaction time, but this time cannot be prolonged, as an extremely exother-
mic reaction leading to a polymer material was observed after prolonging
the MWI. On the other hand, we did not observe exothermic polymerization
when this reaction was carried out conventionally at 230ꢀC (Entry 3).
It can be concluded that the exothermic reaction is not due to thermo-
lysis, implying that specific (non-thermal) microwave effect was involved.
It is known that microwave absorption depend on the polarity of the
system.16 The (3-acridin-9-yl)alkanoic acids contain the polar groups, they
can absorb microwaves and, in addition, another reaction leading to
polymer materials take place. Probably due to the very short reaction
time we did not observe the formation of a,o-bis(acridin-9-yl)alkenes, as
presented in the literature,8 even when the molar ratio diphenylamine :
dicarboxylic acid : ZnCl2 was changed from 1 : 3 : 5 to 2.5 : 1 : 5.
In conclusion, application of the microwave irradiation consi-
derably enhanced the synthesis of 9-substituted acridine derivatives
beginning withdipehnylamine and appropriate carboxylic acids under
ZnCl2 catalysis.

ORDER
REPRINTS
9-SUBSTITUTED ACRIDINE DERIVATIVES
731
Table 1. Microwave-Assisted Preparation of 9-Substituted Acridine Derivatives
P ¼ 120 W, Tfin ¼ 200ꢀC
Time
(min : s)
Yield
(%)
M.P.
(ꢀC)
M.P.ref.
(ꢀC)
Entry
Compound
R
n
1
2
3*
4
5
6
7
8
9
IIIa
IIIb
IIIb
IIIc
IIId
IIIe
IIIf
COOH
COOH
COOH
COOH
COOH
COOH
phenyl
1
2
2
3
4
8
1
1
1
8 : 20
6 : 00
6 : 00
4 : 53
4 : 17
3 : 50
5 : 00
5 : 00
5 : 00
57
80
64
71
72
60
75
60
50
decomp.
308–9
308–9
218–22
266–70
207–9
174–5
146–7
184–6
–
30517
30517
22018
265–697
207–87
17315
–
IIIg
IIIh
p-tolyl
1-naphthyl
–
*The mixture was kept in an oil bath preheated to 230ꢀC.
EXPERIMENTAL
The experiments were carried out in the SYNTHEWAVE 402,
PROLABO microwave reactor. All initial materials were commercial
reagents. The products were characterized by their physical properties and
1H NMR spectral characteristics. Melting points were determined on
1
Kofler apparatus and are not corrected. H NMR spectra were measured
at 300 MHz on Varian Gemini spectrometer in hexadeuteriodimethyl
sulphoxide with hexamethyldisiloxane as an internal standard.
Preparation of u-(Acridin-9-yl)alkanoic Acids (IIIa–e)
The mixture of diphenylamine I (0.01 mol), dikarboxylic acid IIa–e
(0.03 mol) and anhydrous ZnCl2 (2.0 g, 0.05 mol) was irradiated in the
microwave reactor (120 W input power) for the time given in Table 1 until
the temperature of the reaction mixture reached 200ꢀC. The 20% aqueous
solution of H2SO4 (50 ml) was then added to the reaction mixture, which
was afterwards heated until all of the solid mass was dissolved. The aqueous
solution of ammonia (25%) was then added to the cooled reaction mixture
until neutralisation. The solid material was filtered off and dissolved
continually into methanol. The residue left after vacuum evaporation of
the methanol was pure product IIIa–e. The results are given in Table 1.

ORDER
REPRINTS
732
VEVERKOVA, NOSKOVA, AND TOMA
Preparation of 9-Arylalkylacridines (IIIf–h)
The mixture of diphenylamine I (0.01 mol), arylacetic acid IIf–h
(0.02 mol) and anhydrous ZnCl2 (0.03 mol) was irradiated in the microwave
reactor (120 W) until the temperature of the reaction mixture reached 200ꢀC
(5 min). Then the reaction mixture was dissolved in hot ethanol (100 ml) and
then filtered. After evaporization of the solvent the crude product IIIf–h was
recrystalized from benzene. The results are given in Table 1.
1H NMR Spectra of 9-Substituted Acridines IIIa–h
((d) ¼ ppm, (J ) ¼ Hz)
IIIa: 3.31 (s, 2H, CH2-COOH), 7.94–7.99 (m, 2H, Ar-H), 8.29–8.35
(t, 2H, Ar-H), 8.55 (d, 2H, J ¼ 9.0, Ar-H), 8.80 (d, 2H, J ¼ 9.0, Ar-H).
IIIb: 2.66 (t, 2H, J ¼ 3.04, CH2), 3.92 (t, 2H, J ¼ 3.07, CH2-COOH),
7.63–7.68 (m, 2H, Ar-H), 7.82–7.87 (m, 2H, Ar-H), 8.15 (d, 2H, J ¼ 9.0,
Ar-H), 8.41 (d, 2H, J ¼ 9.0, Ar-H).
IIIc: 1.92–2.39 (m, 4H, 2 ꢁ CH2), 3.68 (t, 2H, J ¼ 8.1, CH2), 7.59–7.64
(m, 2H, Ar-H), 7.79–7.82 (m, 2H, Ar-H), 8.12 (d, 2H, J ¼ 8.7, Ar-H), 8.51
(d, 2H, J ¼ 8.7, Ar-H).
IIId: 1.67–1.80 (m, 4H, 2 ꢁ CH2), 2.29 (t, 2H, J ¼ 7.2, CH2), 3.66
(t, 2H, J ¼ 7.2, CH2), 7.61–7.67 (m, 2H, Ar-H), 7.79–7.84 (m, 2H, Ar-H),
8.12 (d, 2H, J ¼ 8.7, Ar-H), 8.33 (d, 2H, J ¼ 8.7, Ar-H).
IIIe: 1.25–1.75 (m, 12H, 3 ꢁ CH2), 2.11 (t, 2H, J ¼ 7.5, CH2), 3.64
(t, 2H, J ¼ 7.5, CH2), 7.61–7.66 (m, 2H, Ar-H), 7.81–8.87 (m, 2H, Ar-H),
8.13 (d, 2H, J ¼ 9.0, Ar-H), 8.39 (d, 2H, J ¼ 9.0, Ar-H).
IIIf: 5.11 (s, 2H, CH2), 7.13–7.21 (m, 5H, Ar-H), 7.63–7.68 (m, 2H,
Ar-H), 7.83–7.87 (m, 2H, Ar-H), 8.18 (d, 2H, J ¼ 8.7, Ar-H), 8.45 (d, 2H,
J ¼ 8.7, Ar-H).
IIIg: 2.27 (s, 3H, CH3), 5.05 (s, 2H, CH2), 6.96 (d, 2H, J ¼ 8.1, Ar-H),
7.05 (d, 2H, J ¼ 8.1, Ar-H), 7.61–7.66 (m, 2H, Ar-H), 7.91–7.97 (m, 2H,
Ar-H), 8.32 (d, 2H, J ¼ 9.0, Ar-H), 8.65 (d, 2H, J ¼ 8.7, Ar-H).
IIIh: 5.52 (s, 1H, CH2), 6.20 (d, 1H, Ar-H), 7.11 (m, 1H, Ar-H),
7.50–7.56 (m, 2H, Ar-H), 7.65–7.71 (m, 2H, Ar-H), 7.74–7.87 (m, 4H, Ar-H),
8.01 (d, 1H, J ¼ 8.1, Ar-H), 8.18 (d, 2H, J ¼ 8.7, Ar-H), 8.23 (d, 2H, J ¼ 8.7,
Ar-H), 8.65 (d, 2H, J ¼ 8.7, Ar-H).

ORDER
REPRINTS
9-SUBSTITUTED ACRIDINE DERIVATIVES
ACKNOWLEDGMENTS
733
This work was supported by Slovak grant agency VEGA grant
No. 1/7348/20 and was carried out under the auspices of COST D10, project
No. 0014/98.
REFERENCES
1. Tilak, B.D.; Ayyangar, N.R. Chem. Heterocycl. Compd. 1973, 9, 579.
2. Albert, A. The Acridines, Edward Arnold Publ., Ltd.: London, 1966.
3. Magison, O.J.; Grigorowski, A.M. Chem. Ber. 1936, 69, 396.
4. Zirkle, C.L. U.S. 3,131 190; Chem. Abstr. 1964, 61, 4326a.
5. Bischoff, R.; Regnier, F. J. Chromatogr. 1987, 397, 13–24.
6. Bernthsen, A. Justus Liebigs Ann. Chem. 1884, 1, 224.
7. Graef, E.; Fredericksen, J.M.; Burger, A. J. Org. Chem. 1946, 11,
257–267.
8. Eldho, N.V.; Saminathan, M.; Ramaiah, D. Synth. Commun. 1999,
22, 4007.
ˇ
9. Toma, S. Chem. Listy 1993, 87, 627.
10. Baghurst, D.R.; Mingos, D.M.P. Chem. Soc. Rev. 1991, 20, 1.
11. Caddick, S. Tetrahedron 1995, 51, 10403.
12. Strauss, C.R.; Trainor, R.W. Austr. J. Chem. 1995, 48, 1665.
13. Loupy, A.; Petit, A.A.; Hamelin, J.; Texier-Boulett, F.; Jacqualt, P.;
´
Mathe, D. Synthesis 1998, 1213.
14. Gedye, R.; Wei, J.B. Can. J. Chem. 1998, 76, 525.
15. Buu-Hoi; Lecocq, J. Rec. Trav. Chim. 1945, 64, 25; Chem. Abstr. 1946,
40, 4068.
16. Bram, G.; Loupy, A.; Majdoub, M.; Gutierrez, E.; Ruiz-Hitzky, E.
Tetrahedron 1990, 46, 5167.
17. Campbell, A.; Franklin, C.S.; Morgan, E.N.; Tivey, D.J. J. Chem. Soc.
1958, 1145.
18. Huntress, E.H.; Shaw, E.N. J. Org. Chem. 1948, 13, 674.
Received in the UK December 20, 2000

Request Permission or Order Reprints Instantly!
Interested in copying and sharing this article? In most cases, U.S. Copyright
Law requires that you get permission from the article’s rightsholder before
using copyrighted content.
All information and materials found in this article, including but not limited
to text, trademarks, patents, logos, graphics and images (the "Materials"), are
the copyrighted works and other forms of intellectual property of Marcel
Dekker, Inc., or its licensors. All rights not expressly granted are reserved.
Get permission to lawfully reproduce and distribute the Materials or order
reprints quickly and painlessly. Simply click on the "Request
Permission/Reprints Here" link below and follow the instructions. Visit the
U.S. Copyright Office for information on Fair Use limitations of U.S.
copyright law. Please refer to The Association of American Publishers’
(AAP) website for guidelines on Fair Use in the Classroom.
The Materials are for your personal use only and cannot be reformatted,
reposted, resold or distributed by electronic means or otherwise without
permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the
limited right to display the Materials only on your personal computer or
personal wireless device, and to copy and download single copies of such
Materials provided that any copyright, trademark or other notice appearing
on such Materials is also retained by, displayed, copied or downloaded as
part of the Materials and is not removed or obscured, and provided you do
not edit, modify, alter or enhance the Materials. Please refer to our Website
User Agreement for more details.
Order now!
Reprints of this article can also be ordered at
http://www.dekker.com/servlet/product/DOI/101081SCC120002511