Iron(III) phosphate-catalyzed synthesis of 7,10,11,12-tetrahydrobenzo[c]acridin-8(9H)-ones

Article abstract of DOI:10.1007/s11172-015-0835-4

One-pot FePO₄-catalyzed three-component reaction of 1-naphthylamine, aldehydes, and cyclic 1,3-dicarbonyl compounds affords 7,10,11,12-tetrahydrobenzo[c]acridines in high yields.

Full text of DOI:10.1007/s11172-015-0835-4

Russian Chemical Bulletin, International Edition, Vol. 64, No. 1, pp. 151—153, January, 2015
151
Iron(III) phosphateꢀcatalyzed synthesis
of 7,10,11,12ꢀtetrahydrobenzo[c]acridinꢀ8(9H)ꢀones
F. K. Behbahani and M. Farahani
Department of Chemistry, Karaj Branch, Islamic Azad University,
Karaj, Iran.
Fax: +026 (344) 181 56. Eꢀmail: Farahnazkargar@yahoo.com
Oneꢀpot FePO4ꢀcatalyzed threeꢀcomponent reaction of 1ꢀnaphthylamine, aldehydes, and
cyclic 1,3ꢀdicarbonyl compounds affords 7,10,11,12ꢀtetrahydrobenzo[c]acridines in high yields.
Key words: benzo[c]acridines, naphthylamine, aldehydes, oneꢀpot reaction.
Lately, extensive research on the synthesis of tricyclic
compounds containing acridine moieties has been reportꢀ
ed. Acridine derivatives possess antitumor,1 carcinogenic,2
and antiꢀmalaria activities,3 and, therefore, they can be
used for heart defibrillation.4 Owing to its planar strucꢀ
ture, acridine chromophore sometimes has excellent DNA
binding properties. Recently, the synthesis of new polyꢀ
acridines promising as bisꢀintercalating agents has been
described.5 Moreover, acridine skeleton fused with a five
or sixꢀmembered ring yields polycyclic derivatives playing
an important role as DNAꢀintercalating anticancer drugs.6
Acridine derivatives are also of increasing interest due to
the industrial production of synthetic fuels, that may
contain nitrogen analogs of polycyclic aromatic hydroꢀ
carbons.4 Thus, the synthesis of acridine derivatives is an
important and principal task in modern organic chemistry.
Many methods are available for the preparation of
benzoacridine derivatives: reactions of Nꢀarylideneꢀ1ꢀ
naphthylamine with 1,3ꢀdicarbonyl compounds in ethaꢀ
nol7 or water using benzyltriethylammonium bromide as
a catalyst8,9 and threeꢀcomponent reactions of naphꢀ
thylamine, dimedone, and aldehyde in ethanol carried out
either on heating10,11 or under microwave12,13 and ultraꢀ
sonic14,15 irradiation.
These methods despite some merits have their shortꢀ
comings, such as low yield, high reaction temperature,
and long reaction time. Herein we present a synthetic proꢀ
cedure to access dibenzo[c]acridine derivatives via FePO4ꢀ
catalyzed threeꢀcomponent reaction of 1ꢀnaphthylamine
(1), aromatic aldehydes 2, and dimedone 3 (Scheme 1)
and a comparison of the efficiency of this procedure with
known conventional methods.
Results and Discussion
To optimize the reaction conditions for the synthesis
of dibenzo[c]acridines 4a—g, the FePO4ꢀcatalyzed threeꢀ
component condensation of 1ꢀnaphthylamine (1), benzꢀ
aldehyde (2a), and dimedone 3 was carried out in differꢀ
ent solvents at room temperature. We examined the effect
of the solvents (water, CHCl3, MeCN, EtOH) on the yield
of compound 4а in this model reaction (Table 1). The
highest yield of 4a (90%) was achieved with EtOH as
a solvent (see Table 1, entry 4). When the reaction was
Scheme 1
Table 1. Effect of different solvents on the
yield of compound 4a*
Entry
Solvent
Yield (%)
1
2
3
4
Water
CHCl3
MeCN
EtOH
25
46
63
90
R = Ph (a), 4ꢀClC6H4 (b), 2,4ꢀCl2C6H3 (c), 3,4ꢀ(MeO)2C6H3 (d),
2ꢀMeC6H4 (e), 3ꢀHOC6H4 (f), CH=CHPh (g)
* Reaction time 1 h, temperature 20 C.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 0151—0153, January, 2015.
1066ꢀ5285/15/6401ꢀ0151 © 2015 Springer Science+Business Media, Inc.

152
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 1, January, 2015
Behbahani and Farahani
Table 2. One pot synthesisa of benzo[c]acridine derivaꢀ
tives 4a—g
In summary, we have developed a novel modified proꢀ
cedure to synthesize benzo[c]acridine derivatives in high
yields. The advantages of this method are mild reaction
conditions, easiness of the product isolation, availability of
the starting compounds, and noticeable environmental
benefits as compared with the known procedures.
Product
t/min
Yield (%)
M.p./C
4a
4b
4c
4d
4e
4f
60
60
75
90
50
90
45
90
85
83
95
88
90
88
262—26414
269—27114
284—28814
253—25913
2 7 0 — 2 7 4 7
1 8 7 — 1 9 5 b
175—180b
Experimental
Melting points were measured using the open capillary with
an Electro Thermal 9200 apparatus. IR spectra were recorded on
a Bruker FTꢀIR spectrometer in the KBr pellets with the scanꢀ
ning range of 4000—400 cm–1. The products were identified by
a comparison of their physicochemical and spectral data with those
reported for the authentic samples. 1H and 13C NMR spectra
were obtained on a Bruker DRXꢀ500 instrument in CD3Cl. Mass
spectra were recorded on an Agilent 5973 Network Mass Selecꢀ
tive Detector. Elemental analyses were performed on a Carlo
Erba 106 Perkin—Elmer model 240 analyzer.
7,10,11,12ꢀTetrahydrobenzo[c]acridinꢀ8(9H)ꢀones 4a—g
(general procedure). A 50 mlꢀflask was charged with a mixture of
1ꢀnaphthylamine (1 mmol), dimedone (1 mmol), aldehyde
(1 mmol), FePO4 (10 mol.%), and EtOH (10 mL). The reaction
mixture was stirred at 20 C for the time given in Table 2. After
completion of the reaction (TLC monitoring), the mixture was
poured into iceꢀwater (50 mL), the precipitate was collected by
filtration. Recrystallization from EtOH gave pure product.
10,10ꢀDimethylꢀ7ꢀphenylꢀ7,10,11,12ꢀtetrahydrobenzo[c]ꢀ
acridinꢀ8(9H)ꢀone (4a). White crystals, m.p. 262—264 C. IR,
/cm–1: 3301 (NH); 2956, 2868 (CH aliph.); 1689 (C=O); 1595
(C=C arom.); 1072 (C—O). 1H NMR, : 1.03, 1.08 (both s,
3 H each, CH3); 2.05 (d, 1 H, CH, J = 10.0 Hz); 2.07 (d, 1 H,
CH, J = 10.0 Hz); 2.58 (d, 1 H, CH, J = 15.0 Hz); 2.61 (d, 1 H,
CH, J = 15.0 Hz); 5.82 (s, 1 H, CH); 6.87—7.07 (m, 9 H, ArH);
7.71 (d, 1 H, ArH, J = 8.6 Hz); 8.45 (d, 1 H, ArH, J = 8.5 Hz);
9.26 (s, 1 H, NH). MS, m/z: 353.46 [M]+.
4g
a Solvent EtOH, temperature 20 C.
b Compounds 4f and 4g were first synthesized in the
present work.
performed in water, CHCl3, and MeCN (entries 1—3),
product 4a was obtained in the yields from poor to moderate.
To generalize this reaction to a library synthesis, we
extended it to various aldehydes (see Scheme 1) to synꢀ
thesize the corresponding derivatives 4b—g. As seen from
Table 2, in all cases the yields were high. The described
procedure is suitable for aromatic aldehydes bearing both
electronꢀreleasing and electronꢀwithdrawing substituents
in the benzene ring. The reaction proceeds with relativeꢀ
ly high rate. However, it is worthy to note that the electꢀ
ronꢀwithdrawing substituents favor the transformaꢀ
tion. The described method towards benzo[c]acridine deꢀ
rivatives is convincingly superior to the reported methꢀ
ods7,13,14 with respect to the yield, reaction time, simpꢀ
licity, and safety.
To show the merits of this catalytic method in comꢀ
parison with the previously reported protocols, we comꢀ
pared the yields of compound 4a achieved under various
conditions (Table 3). The advantages of our method are
evident regarding the catalyst loading and easiness of catꢀ
alyst separation, which are both very important in chemiꢀ
cal industry.
7ꢀ(4ꢀChlorophenyl)ꢀ10,10ꢀdimethyꢀ7,10,11,12ꢀtetrahydroꢀ
benzo[c]acridinꢀ8(9H)ꢀone (4b). White crystals, m.p. 269—271 C.
IR, /cm–1: 3530 (NH), 2950 (CH aliph.); 1630 (C=O); 1579
(C=C arom.); 1080 (C—O). 1H NMR, : 0.99, 1.07 (both s,
3 H each, CH3); 2.01 (d, 1 H, CH, J = 10.0 Hz); 2.03 (d, 1 H,
Table 3. A comparison of different synthetic procedures to access compound 4a
Entry
Initiation
m/g
t/min
Solvent
Yield (%)
a
1
2
3
4
5
6
7
BNBTS
NBS
Ultrasound irradiation
MW/neutral aluminum oxide
MW/basic aluminum oxide
MW
0.10
0.08
132
184
120
119
8.5
—
—
8216
8416
9114
7517
8017
8717
90с7
a
b
—
EtOH
EtOH
EtOH
b
—
b
—
b
a
—
112
160
—
FePO4
0.022
EtOH
Note: m is the amount of catalyst used in the reaction; t is the reaction time; MW is microwave irradiation;
BNBTS is N,N´ꢀdibromoꢀN,N´ꢀethaneꢀ1,2ꢀdiylbis(4ꢀtoluenesulfonamide); NBS is Nꢀbromosuccinimide.
a Reaction was carried out without solvent.
b Reaction was carried out without catalyst.
c Present work.

Tetrahydrobenzo[c]acridinꢀ8(9H)ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 1, January, 2015
153
CH, J = 10.0 Hz); 2.58 (d, 1 H, CH, J = 15.0 Hz); 2.61 (d, 1 H,
CH, J = 15.0 Hz); 5.30 (s, 1 H, CH); 7.14—7.31 (m, 5 H, ArH);
7.45—7.59 (m, 2 H, ArH); 7.45—7.63 (m, 2 H, ArH); 8.43 (d, 1 H,
ArH, J = 8.7 Hz); 9.35 (s, 1 H, NH). MS, m/z: 387.9 [M]+.
7ꢀ(2,4ꢀDichlorophenyl)ꢀ10,10ꢀdimethylꢀ7,10,11,12ꢀtetraꢀ
hydrobenzo[c]acridinꢀ8(9H)ꢀone (4c). White crystals, m.p.
284—288 C. IR, /cm–1: 3306 (NH); 2956 (CH aliph.); 1684
(C=O); 1587 (C=C arom.); 1086 (C—O). 1H NMR, : 1.03,
1.08 (both s, 3 H each, CH3); 2.03 (d, 1 H, CH, J = 15.0 Hz);
2.06 (d, 1 H, CH, J = 15.0 Hz); 2.65 (d, 1 H, CH, J = 10.0 Hz);
2.67 (d, 1 H, CH, J = 10.0 Hz); 5.71 (s, 1 H, CH); 7.14—7.37
(m, 7 H, ArH); 7.82 (d, 1 H, ArH, J = 8.1 Hz); 8.48 (d, 1 H,
ArH, J = 8.1 Hz); 9.29 (s, 1 H, NH). MS, m/z: 422.35 [M]+.
7ꢀ(3,4ꢀDimethoxyphenyl)ꢀ10,10ꢀdimethylꢀ7,10,11,12ꢀtetraꢀ
hydrobenzo[c]acridinꢀ8(9H)ꢀone (4d). White crystals, m.p.
253—259 C. IR, /cm–1: 3368 (NH); 2955 (CH aliph.); 1597
(C=C arom.); 1026 (C—O). 1H NMR, : 1.03, 1.08 (both s,
3 H each, CH3); 2.05 (d, 1 H, CH, J = 15.0 Hz); 2.08 (d, 1 H,
CH, J = 15.0 Hz); 2.65 (d, 1 H, CH, J = 10.0 Hz); 2.67 (d, 1 H,
CH, J = 10.0 Hz); 3.65, 3.68 (both s, 3 H each, OCH3); 5.17
(s, 1 H, CH3); 6.56—6.78 (m, 2 H, ArH); 6.81 (s, 1 H, ArH); 7.35
(d, 1 H, ArH, J = 8.5 Hz); 7.61—7.63 (m, 3 H, ArH); 8.15 (d, 1 H,
ArH, J = 8.4 Hz); 9.27 (s, 1 H, NH). MS, m/z: 413.51 [M]+.
10,10ꢀDimethylꢀ7ꢀ(2ꢀmethylphenyl)ꢀ7,10,11,12ꢀtetrahydroꢀ
benzo[c]acridinꢀ8(9H)ꢀone (4e). White crystals, m.p. 167—170 C.
IR, /cm–1: 3290 (NH); 2955, 2834 (CH aliph.); 1688 (C=O);
1591 (C=C); 1028 (C—O). 1H NMR, : 1.02, 1.09 (both s,
3 H each, CH3); 2.06 (d, 1 H, CH, J = 10.0 Hz); 2.08 (d, 1 H,
CH, J = 10.0 Hz); 2.57 (d, 1 H, CH, J = 15.0 Hz); 2.58 (d, 1 H,
CH, J = 15.0 Hz); 2.7 (s, 3 H, CH3); 5.82 (s, 1 H, CH); 6.79—7.01
(m, 8 H, ArH); 7.86 (d, 1 H, ArH, J = 8.0 Hz); 8.45 (d, 1 H,
ArH, J = 8.4 Hz); 9.26 (s, 1 H, NH). MS, m/z: 367.48 [M]+.
7ꢀ(3ꢀHydroxyphenyl)ꢀ10,10ꢀdimethylꢀ7,10,11,12ꢀtetrahydroꢀ
benzo[c]acridinꢀ8(9H)ꢀone (4f). White crystals, m.p. 187—195 C.
IR, /cm–1: 3314 (NH); 3070 (C—H aliph.); 2956 (CH aliph.);
1640 (C=O); 1468 (C=C arom.); 1047 (C—O). 1H NMR, : 0.95,
1.07 (both s, 3 H each, CH3); 2.06 (d, 1 H, CH, J = 10.5 Hz);
2.17 (d, 1 H, CH, J = 10.5 Hz); 2.52 (d, 1 H, CH, J = 15.5 Hz);
2.64 (d, 1 H, CH, J = 15.5 Hz); 5.75 (s, 1 H, CH); 6.80 (d, 1 H,
ArH, J = 10.0 Hz); 6.93—7.01 (m, 3 H, ArH); 7.13 (d, 2 H, ArH,
J = 5.0 Hz); 7.31 (s, 1 H, ArH); 7.36—7.53 (m, 1 H, ArH); 7.69
(d, 1 H, ArH, J = 10.0 Hz); 7.75 (s, 1 H, NH); 7.85 (d, 1 H,
ArH, J = 10.0 Hz); 8.95 (s, 1 H, OH). MS, m/z: 369.46 [M]+.
Found (%): C, 81.21; H, 6.22; N, 3.71. C25H23NO2. Calculatꢀ
ed (%): C, 81.27; H, 6.27; N, 3.79.
J = 10.5 Hz); 2.34 (d, 1 H, CH, J = 15.5 Hz); 2.35 (d, 1 H, CH,
J = 15.5 Hz); 5.06 (d, 1 H, CH, J = 5.0 Hz); 6.30 (d, 1 H, CH,
J = 15.0 Hz); 6.36 (dd, 1 H, CH, J = 15.0 Hz, J = 5.0 Hz); 6.90
(s, 1 H, NH); 7.16—7.22 (m, 5 H, ArH); 7.32 (d, 2 H, ArH,
J = 5.0 Hz); 7.55 (m, 2 H, ArH); 7.77 (d, 1 H, ArH, J = 10.0 Hz);
7.85 (d, 1 H, ArH, J = 10.0 Hz). MS, m/z: 379.49 [M]+. Found (%):
C, 85.39; H, 6.58; N, 3.57. C27H25NO. Calculated (%): C, 85.45;
H, 6.64; N, 3.69.
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10,10ꢀDimethylꢀ7ꢀ(2ꢀphenylethenyl)ꢀ7,10,11,12ꢀtetrahydroꢀ
benzo[c]acridinꢀ8(9H)ꢀone (4g). Yellow crystals, m.p. 175—180 C.
IR, /cm–1: 3342 (NH); 2956 (CH aliph.); 1635 (C=O); 1590,
1557 (C=C arom. and aliph.). 1H NMR, : 1.11, 1.16 (both s,
3 H each, CH3); 2.16 (d, 1 H, CH, J = 10.5 Hz); 2.7 (d, 1 H, CH,
Received June 3, 2014;
in revised form July 3, 2014