Efficient Protocol for Synthesis of Pyrazolo[3,4-a]acridines

Article abstract of DOI:10.1080/00397911.2015.1070433

A new class of pyrazolo[3,4-a]acridines have been prepared. The synthon acridones were obtained in very good yield by a one-pot reaction of 2-amino-5-chloro or nitro substituted benzophenones with 1,3-cyclic diketones in the presence of freshly prepared E

Full text of DOI:10.1080/00397911.2015.1070433

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Efficient Protocol for Synthesis of Pyrazolo[3,4-
a]acridines
Rajendran Satheeshkumar, Werner Kaminsky, Hazel A. Sparkes & Karnam
Jayarampillai Rajendra Prasad
To cite this article: Rajendran Satheeshkumar, Werner Kaminsky, Hazel A. Sparkes
& Karnam Jayarampillai Rajendra Prasad (2015) Efficient Protocol for Synthesis
of Pyrazolo[3,4-a]acridines, Synthetic Communications, 45:19, 2203-2215, DOI:
10.1080/00397911.2015.1070433
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Date: 11 September 2015, At: 09:25

Synthetic Communications1, 45: 2203–2215, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2015.1070433
EFFICIENT PROTOCOL FOR SYNTHESIS OF PYRAZOLO
[3,4-a]ACRIDINES
Rajendran Satheeshkumar,1 Werner Kaminsky,2
Hazel A. Sparkes,3 and Karnam Jayarampillai
Rajendra Prasad1
1Department of Chemistry, Bharathiar University, Coimbatore, India
2Department of Chemistry, University of Washington, Seattle,
Washington, USA
3Department of Chemistry, University of Bristol, Bristol, United Kingdom
GRAPHICAL ABSTRACT
Abstract A new class of pyrazolo[3,4-a]acridines have been prepared. The synthon
acridones were obtained in very good yield by a one-pot reaction of 2-amino-5-chloro or
nitro substituted benzophenones with 1,3-cyclic diketones in the presence of freshly
prepared Eaton’s reagent without solvent, using Friedländer synthesis. The intermediates
were reacted with ethylformate followed by hydrazine hydrate to afford pyrazolo[3,4-a]
acridines. All of the compounds were purified by recrystallization only, and no
chromatographic workup was required. The structures of the synthesized compounds
were deduced by spectroscopic techniques, including single-crystal x-ray diffraction.
Keywords Eaton’s reagent; ethylformate; Friedländer synthesis; hydrazine hydrate;
pyrazolo[3,4-a]acridines
Received June 12, 2015.
Address correspondence to Karnam Jayarampillai Rajendra Prasad, Department of Chemistry,
Bharathiar University, Coimbatore 641046, India. E-mail: prasad_125@yahoo.com
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
2203

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R. SATHEESHKUMAR ET AL.
INTRODUCTION
Heterocyclic compounds, featuring an acridine scaffold, exhibit a wide var-
iety of biological properties and functions and are of interest in organic chemistry.
Acridine derivatives (ADs), known since the 19th century, were first used as
pigments and dyes[1] and have been used for commercial purposes for more than
a century. Several naturally occurring as well as synthetic ADs are known for
antitumor,[2] antioxidant,[3] anticancer,[4] antimicrobial, and antiparasitic activi-
ties. The acridine nucleus, condensed with additional heterocyclic rings, is also
endowed with high cytotoxicity. Specifically, incorporation of five-membered
heterocyclic rings into the acridine chromophore strongly favors passive cellular
drug uptake, rendering the efflux by multidrug resistance (MDR) transporters
inefficient.[5] The pyrazole nucleus is of interest for the development of new drugs,
because of its synthetic accessibility and diverse chemical and biological proper-
ties such as fungicidal, antimicrobial, antiparasitic, anti-inflammatory, antican-
cer, and antiviral activities.[6] Some pyrazoloacridine derivatives are known to
fragment DNA through intercalation, causing apoptosis.[7] Within the
pyrazoloacridine family, pyrazolo[3,4,5,-kl]acridine (PZA, I) (Fig. 1) compounds
containing electron-deactivating nitro groups are a very exciting new class of antitu-
mor agents. PZA is currently undergoing phase II clinical trials after exhibiting a
broad spectrum of antitumor activities in preclinical in vivo assays.[7,8] PZA displays
solid tumor selectivity, activity against hypoxic cells and cytotoxicity in noncycling
cells.[9] In addition, 4,5-dihydropyrazolo[3,4-a]acridines were recently found to func-
tion as acetyl cholinesterase inhibitors.[10]
A well-known method for obtaining quinolines and related poly heterocycles
involves the Friedländer quinoline synthesis. Known for more than a century,
Friedländer synthesis[11] was applied to prepare quinoline derivatives by conden-
sation of 2-aminoarylketones with carbonyl compounds possessing a reactive
methylene group, followed by cyclodehydration.[12] Although considered the most
useful method for the preparation of such a class of compounds, the synthetic
protocols for polycyclic quinolines reported so far lead to poor yields, extended
reaction times, and dependence on harmful and often expensive catalyst systems,
making the development of a simple, ecofriendly, low-cost protocol desirable. We
recently reported[13] cyclic imide synthesis using Eaton’s reagent[14] (phosphorus
pentoxide–methanesulfonic acid) through cyclization with hydrazinylquinolines
Figure 1. Pyrazolo[3,4,5,-kl]acridine scaffold for using clinical trial compounds.

PYRAZOLO[3,4-a]ACRIDINES
2205
Scheme 1. Synthesis of 7-nitro-9-phenyl-3,4-dihydroacridin-1(2H)-ones (3a).
and cyclic anhydrides and successfully employed the Friedlander method on
polycyclic quinolines using Eaton’s reagent.
Here we report a practical and easy workup method for the synthesis of poly-
substituted quinolines using Eaton’s reagent as alternative to polyphosphoric acid
(PPA) under solvent-free conditions.
The reaction of 2-amino-5-nitrobenzophenone (1a) and 1,3-cyclohexanedione
(2a) in the presence of freshly prepared Eaton’s reagent (phosphorus pentoxide–
methanesulfonic acid) as a catalyst without solvent at 90 °C afforded 3a in 89% yield
(Scheme 1). The IR spectrum for 3a shows an absorption band at 1694 cmꢀ1 due to
the presence of the C=O group and a sharp band at 1552 cmꢀ1 confirmed the pres-
1
ence of the C=N group. The H NMR (CDCl3, 400 MHz) spectrum for 3a shows a
multiplet at d 2.187–2.251 due to the C3-CH2 protons, a multiplet at d 2.665–2.698
due to the C2-CH2 protons, and a multiplet at d 3.334–3.366 due to the C4-CH2
protons. The remaining aromatic protons appeared in the region of d 7.109–8.435.
The 13C NMR (CDCl3, 100 MHz) spectrum of 3a shows the presence of 19 carbon
signals.
In demonstrating efficiency and scope of Eaton’s reagent for the synthesis of
quinolines, cyclic ketones such as 1,3-cyclohexanedione and 5,5-dimethyl-1,3-cyclo-
hexanedione smoothly condensed with 2-aminoaryl ketones to afford the respective
polycyclic quinolines (Scheme 2). In most cases, the products were isolated by simple
filtration and the crude products were purified by recrystallization from a mixture of
ethylacetate and acetonitrile. All compounds (Table 1) were isolated by recrystalliza-
tion only and no chromatographic workup was required to obtain pure products.
The structures of 3a, 3c, and 3f were confirmed by single-crystal x-ray diffraction
(Figs. 2–4).
Pyrazolo[3,4-a]acridines were synthesized from precursor polycyclic quino-
lones (3) and ethylformate. Sodium methoxide initiated the reaction, which took
Scheme 2. Synthesis of 3,4-dihydroacridin-1(2H)-ones (3).

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R. SATHEESHKUMAR ET AL.
Table 1. Synthesis of 3,4-dihydroacridin-1(2H)-one derivatives (3a–f)
Entry
R1
R2
R3
H
Product
Yield (%)a
3a
3b
3c
3d
3e
3f
NO2
H
89
NO2
H
H
CH3
90
93
93
85
87
Cl
H
Cl
H
CH3
Cl
Cl
Cl
H
Cl
CH3
Notes. Reaction conditions: 5-chloro-2-aminobenzophenone 1a (1 mmol) and 1,3-cyclohexanedione 2a
(1.2 mmol, 1.2 equiv.) in the presence of Eaton's reagent as a catalyst without solvent at 90 °C.
aRecrystallized pure products.
4–5 h at room temperature, yielding exclusively 4, as confirmed by thin-layer
chromatographic (TLC) analysis (Scheme 3). After completion of the reaction,
quenching with water dissolved the excess of sodium methoxide. Further purifi-
cation via column chromatography was found to be unnecessary (Table 2). The

PYRAZOLO[3,4-a]ACRIDINES
2207
Figure 2. X-ray crystal structure of 3a. Thermal ellipsoids are depicted at the 50% probability level.
structures of the derivatives 4a and 4b were confirmed by single-crystal x-ray
diffraction (Figs. 5 and 6).
2-(Hydroxymethylene)-9-phenyl-3,4-dihydroacridin-1(2H)-one (4) was reacted
with hydrazine hydrate in ethanol for 2–3 h (Scheme 4), quenched with water, and
recrystallized in ethanol. The crude product obtained was recrystallized by using
ethanol to give the pure product (5a). The IR spectrum of 5a showed an absorption
band at 3385 cmꢀ1 due to the presence of the NH group and two sharp bands at
Figure 3. Room-temperature structure of 3c with ellipsoids depicted at the 50% probability level. The
material underwent a destructive phase transition upon cooling. The structure exhibits disorder in the
phenyl ring (C14-C19) and (C8-C13) ring.

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R. SATHEESHKUMAR ET AL.
Figure 4. X-ray structure of 3f with ellipsoids depicted at the 50% probability level. Only one position of
the disordered (C14-C19) Cl2 ring has been shown for clarity.
1
1625 cmꢀ1 and 1554 cmꢀ1 associated with the presence of the C=N group. The H
NMR (CDCl3, 400 MHz) spectrum of 5a shows a multiplet at d 2.610–2.642 due
to the C4-CH2 protons, a multiplet at d 3.083–3.267 due to the C5-CH2 protons, a
singlet at d 7.191 due to the C3-H proton, and the remaining aromatic protons in
the region of d 7.109–7.867. The 13C NMR (CDCl3, 100 MHz) spectrum of 5b
showed the presence of 20 carbon signals. Based on the spectral data, we have
assigned the obtained product as 9-nitro-11-phenyl-4,5-dihydro-2H-pyrazolo[3,4-a]
acridine (5a). The identities of all of the compounds (Table 3) were verified by IR
and NMR spectroscopic methods and elemental analysis. The structures of pyra-
zolo[3,4-a]acridine derivatives 5a and 5b were unambiguously confirmed by single-
crystal x-ray diffraction (Figs. 7 and 8).
CONCLUSION
A simple and efficient method for the synthesis of pyrazolo[3,4-a]acridine deri-
vatives, which does not require high temperatures or harsh conditions, has been
Scheme 3. Synthesis of hydroxymethylene derivatives of 3,4-dihydroacridin-1(2H)-ones (4).

PYRAZOLO[3,4-a]ACRIDINES
2209
Table 2. Synthesis of hydroxymethylene derivatives of 3,4-dihydroacridin-1(2H)-one
Entry
R1
R2
R3
H
Product
Yield (%)a
4a
NO2
H
73
4b
4c
4d
NO2
H
H
H
CH3
70
75
77
Cl
H
Cl
CH3
4e
Cl
Cl
Cl
Cl
H
75
73
4f
CH3
Notes. Reaction conditions: 7-chloro-9-phenyl-3,4-dihydroacridin-1(2H)-one (3a) (1 mmol) and
ethylformate (1.2 mmol, 1.2 equiv.) in the presence of sodium methoxide at 4–5 h in rt.
aRecrystallized pure products.
reported. The significant features of this reaction are the mild reaction conditions,
the operational simplicity, good to high yields, and the use of an inexpensive and
commercially available reagent.

2210
R. SATHEESHKUMAR ET AL.
Figure 5. X-ray crystal structure of 4c. Thermal ellipsoids depicted at the 50% probability level.
Figure 6. X-ray crystal structure of 4d. Thermal ellipsoids depicted at the 50% probability level.
Scheme 4. Synthesis of pyrazolo[3,4-a]acridine derivatives (5).

PYRAZOLO[3,4-a]ACRIDINES
2211
Yield (%)a
63
Table 3. Synthesis of pyrazolo[3,4-a]acridine derivatives (5a–f)
Entry
R1
R2
R3
H
Product
5a
NO2
H
5b
5c
5d
NO2
H
H
H
CH3
60
65
63
Cl
H
Cl
CH3
5e
5f
Cl
Cl
Cl
Cl
H
60
62
CH3
Notes. Reaction conditions: (Z)-7-chloro-2-(hydroxymethylene)-9-phenyl-3,4-dihydroacridin-1(2H)-one
(4a) (1 mmol) and hydrazine hydrate (1.2 mmol, 1.2 equiv.) in the presence of ethanol at reflux temperature.
aRecrystallized pure products.
EXPERIMENTAL
Melting points (mp) were determined on a Mettler FP 51 apparatus (Mettler
Instruments, Switzerland) and are uncorrected. They are expressed in degree

2212
R. SATHEESHKUMAR ET AL.
Figure 7. X-ray crystal structure of 5c. Thermal ellipsoids is depicted at the 50% probability level.
centigrade (°C). A Nicolet Avatar model FT-IR spectrophotometer was used to rec-
ord the IR spectra (4000–400 cmꢀ1). 1H NMR and 13C NMR spectra were recorded
on Bruker AV 400 [400 MHz (1H) and 100 MHz (13C)] spectrometers using tetra-
methylsilane (TMS) as an internal reference. The chemical shifts are expressed in
parts per million (ppm). Coupling constants (J) are reported in hertz (Hz). The terms
Jo and Jm refer to ortho coupling constant and metacoupling constant. The terms s,
d, t, and dd refer to singlet, doublet, triplet, and doublet of doublet, respectively, and
bs refers to a broad singlet. Microanalyses were performed on a Vario EL III model
CHNS analyzer (Vario, Germany) at the Department of Chemistry, Bharathiar
University. Eaton’s reagent was purchased from Sigma Aldrich. Unless otherwise
Figure 8. X-ray crystal structure of 5d. Thermal ellipsoids depicted at the 50% probability level.

PYRAZOLO[3,4-a]ACRIDINES
2213
specified, other reagents were obtained from commercial suppliers. When known
compounds had to be prepared according to literature procedures, pertinent refer-
ences are given. The purity of the products was tested by TLC with plates
coated with silica gel G using petroleum ether and ethyl acetate in the ratio of
75:25 as developing solvents.
General Procedure for Synthesis of 9-Phenyl-3,4-dihydroacridin-1
(2H)-ones (3)
A mixture of an appropriate 2-aminobenzophenone (1, 1 mmol) and 1,3-cyclo-
hexanedione (2a=2b, 1.2 mmol) was heated for 3 h in the presence of freshly prepared
Eaton’s reagent (phosphorus pentoxide–methanesulfonic acid) as a catalyst without
any solvent at 90 °C. Then the reaction mass was transferred to an excess saturated
sodium carbonate solution (30 mL). The solid obtained was filtered and washed with
sufficient water, extracted with EtOAc (2 × 10 mL), and dried over anhydrous
magnesium sulfate. Evaporation of the solvent followed by purification on recrystal-
lization from ethyl acetate to yield pure 9-phenyl-3,4-dihydroacridin-1(2H)-one (3).
7-Nitro-9-phenyl-3,4-dihydroacridin-1(2H)-one (3a)
Yellow solid; mp 186–188 °C. Yield ¼ 89%; IR (KBr, cmꢀ1) nmax: 1694, 1552;
1H NMR (CDCl3 400 MHz) (ppm) d: 2.187–2.251 (m, 2H, C3-CH2), 2.665–2.698
(m, 2H, C2-CH2), 3.334–3.366 (m, 2H, C4-CH2), 7.109–7.129 (m, 2H, C3', C5'-H),
7.475–7.490 (m, 3H, C2', C4', C6'-H), 8.112 (d, 1H, J ¼ 9.20 Hz, C5-H), 8.350 (d, 1H,
J ¼ 2.40 Hz, C8-H), 8.435 (dd, 1H, Jm ¼ 2.40 Hz, Jo ¼ 9.20 Hz, C6-H); 13C NMR
(CDCl3, 100 MHz) (ppm) d: 21.02 (C3), 34.84 (C4), 40.46 (C2), 124.89 (C13), 125.02
(C10), 125.31 (C6), 126.77 (C2', C6'), 128.05 (C3', C4', C5'), 128.55 (C8), 130.48 (C5),
135.80 (C1'), 145.53 (C9), 150.45 (C7), 153.21 (C12), 166.15 (C11), 197.12 (C1). Anal.
calcd. for C19H14N2O3: C, 71.69; H, 4.43; N, 8.80. Found: C, 71.66; H, 4.47; N,
8.84%.
General Procedure for Synthesis of (Z)-2-(Hydroxymethylene)-9-
phenyl-3,4-dihydroacridin-1(2H)-ones (4)
A mixture of an appropriate 9-phenyl-3,4-dihydroacridin-1(2H)-one (3,
1 mmol) and ethylformate (1.2 mmol) was added to freshly prepared sodium methox-
ide (1 g sodium in 10 mL methanol) at 0 °C to room temperature for 4–5 h. Subse-
quently the reaction mixture was quenched with ice water (45 mL) and extracted
with EtOAc (2 × 10 mL) and dried over anhydrous magnesium sulphate. Evapor-
ation of the solvent afforded yellow solid, which was recrystallized from ethyl acetate
to give (Z)-2-(hydroxymethylene)-9-phenyl-3,4-dihydroacridin-1(2H)-one (4).
(Z)-7-Nitro-2-(hydroxymethylene)-9-phenyl-3,4-dihydroacridin-1(2H)-
one (4a)
Brownish yellow solid; mp 124–126 °C; yield 73%; IR (KBr, cmꢀ1) nmax: 3435,
1
1693, 1563; H NMR (CDCl3 400 MHz) (ppm) d: 2.610–2.642 (m, 2H, C3-CH2),

2214
R. SATHEESHKUMAR ET AL.
3.261–3.291 (m, 2H, C4-CH2), 7.074–7.093 (m, 3H, CHOH, C3', C5'-H), 7.338
(d, 1H, J ¼ 2.00 Hz, C9-H), 7.428–7.440 (m, 3H, C2', C4', C6'-H), 7.597 (dd, 1H,
Jm ¼ 2.00 Hz, Jo ¼ 8.80 Hz, C6-H), 7.910 (d, 1H, Jo ¼ 8.80 Hz, C5-H), 14.240 (s, 1H,
CHOH); 13C NMR (CDCl3, 100 MHz) (ppm) d: 29.471 (C3), 34.525 (C4), 113.845
(C2), 122.654 (C13), 125.463 (C8), 127.783 (C7), 128.847 (C4'), 129.336 (C3', C5'),
129.549 (C2', C6'), 130.439 (C10), 131.467 (C5), 132.352 (C6), 134.023 (C9), 146.312
(C1'), 150.457 (C12), 153.210 (C11), 166.154 (CHOH), 180.120 (C1). Anal. calcd. for
C20H14N2O4: C, 69.36; H, 4.07; N, 8.09. Found: C, 69.41; H, 4.02; N, 8.13%.
General Procedure for Synthesis of 11-Phenyl-4,5-dihydro-2H-
pyrazolo[3,4-a]acridines (5)
A mixture of an appropriate (Z)-2-(hydroxymethylene)-9-phenyl-3,4-dihydroa-
cridin-1(2H)-one (4, 1 mmol) and hydrazine hydrate (1.2 mmol) was refluxed in
20 mL ethanol for 2–3 h. Then the reaction mixture was quenched with water and
1:1 HCl afforded a yellow solid, which was recrystallized from ethanol to furnish
11-phenyl-4,5-dihydro-2H-pyrazolo[3,4-a]acridine (5).
9-Nitro-11-phenyl-4,5-dihydro-2H-pyrazolo[3,4-a]acridine (5a)
Brownish yellow solid; mp 186–188 °C; yield ¼ 63%; IR (KBr, cmꢀ1) nmax
:
3385, 1625, 1554; 1H NMR (CDCl3 400 MHz) (ppm) d: 2.610–2.642 (m, 2H,
C4-CH2), 3.083–3.267 (m, 2H, C5-CH2), 7.109 (d, 1H, J ¼ 2.40 Hz, C10-H), 7.191
(s, 1H, C3-H), 7.269–7.323 (m, 2H, C2', C6'-H), 7.399–7.561 (m, 4H, C3', C4', C5',
C8-H), 7.867 (d, 1H, J ¼ 8.80 Hz, C7-H); 13C NMR (CDCl3, 100 MHz) (ppm) d:
21.27 (C4), 34.08 (C5), 120.45 (C7), 125.84 (C10), 127.27 (C13), 127.94 (C12), 128.08
(C8), 128.60 (C14), 128.84 (C3', C4', C5'), 129.02 (C2', C6'), 130.21 (C7), 131.35 (C3),
132.39 (C9), 137.40 (C1'), 145.98 (C11), 146.77 (C16), 152.68 (C15). Anal. calcd. for
C20H14N4O2: C, 70.17; H, 4.12; N, 16.37. Found: C, 70.12; H, 4.17; N, 16.33%.
ACKNOWLEDGMENT
Our sincere thanks go to the SIF, VIT University, Vellore, for providing access
to their NMR spectral facilities.
FUNDING
R. Satheeshkumar is thankful to the University Grant Commission–SAP, New
Delhi, for a BSR Junior Research Fellowship, which is gratefully acknowledged.
K. J. Rajendra Prasad greatly acknowledges a UGC-BSR one-time grant for
research.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
Complete CIF files for compounds 3a, 3c, 3f, 4c, 4d, 5c, and 5d have been deposited
with the Cambridge Crystallographic Data Centre as CCDC Nos. 1009510, 984318,

PYRAZOLO[3,4-a]ACRIDINES
2215
1047623, 1009511, 1046857, 1019265, and 1046856 respectively. Copies of the data can
be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge,
CB2 1EZ, UK. [Fax: þ44 (0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk.]
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