Synthesis of new fluorine-containing dihydrobenzo[c]acridines from trifluoroacetyl dihydronaphthalene and substituted anilines

Article abstract of DOI:10.1016/j.jfluchem.2005.07.017

A convenient method for the synthesis of a novel series of 7-trifluoromethyl-5,6-dihydrobenzo[c]acridines, in 44-82% yields, by intramolecular cyclization reactions of N-aryl-2-trifluoroacetyl-3,4- dihydronaphthylamines using poly-phosphoric acid (PPA), i

Full text of DOI:10.1016/j.jfluchem.2005.07.017

Journal of Fluorine Chemistry 126 (2005) 1384–1389
www.elsevier.com/locate/fluor
Synthesis of new fluorine-containing dihydrobenzo[c]acridines from
trifluoroacetyl dihydronaphthalene and substituted anilines
*
Helio G. Bonacorso , Roberta L. Drekener, Isadora R. Rodrigues, Renata P. Vezzosi,
Michelle B. Costa, Marcos A.P. Martins, Nilo Zanatta
´ ´ ´
Nucleo de Quımica de Heterociclos (NUQUIMHE), Departamento de Quımica, Universidade Federal de Santa Maria,
97.105-900, Santa Maria, RS, Brazil
Received 8 July 2005; received in revised form 28 July 2005; accepted 28 July 2005
Available online 8 September 2005
Abstract
A convenient method for the synthesis of a novel series of 7-trifluoromethyl-5,6-dihydrobenzo[c]acridines, in 44–82% yields, by intramolecular
cyclization reactions of N-aryl-2-trifluoroacetyl-3,4-dihydronaphthylamines using poly-phosphoric acid (PPA), is described on this paper.
Naphthylamine derivatives are obtained by an oxygen-nitrogen exchange reaction from 1-methoxy-2-trifluoroacetyl-3,4-dihydronaphthalene
with substituted anilines.
# 2005 Elsevier B.V. All rights reserved.
Keywords: Acridines; Benzoacridines; Naphthylamine; Naphthalene; PPA
1. Introduction
aromatic hydrocarbons (PAH), the acridine derivatives are of
increasing concern [2]. Moreover, the development of new
synthetic methods and biological studies of fluorine-containing
nitrogen analogues of PAH and its dihydro derivatives have not
been extensively done yet. On the other hand, the introduction
of a trifluoromethyl and its higher homologues CnF2n+1 groups
into a heterocycle, frequently resulting in a much more potent
activity than that of the parent compound, has been reported, a
fact which is probably related to the high lipophylicity of
perfluoroalkyl substituents [7,8].
It is well documented that acridine derivatives have a wide
range of biological applications showing antitumor properties
[1] but carcinogenic activity has also been documented [2]. Due
to its planar structure, acridine chromophore moiety sometimes
has excellent DNA binding properties. Recently, the synthesis
of polyacridinic compounds [3] as potential bis-intercalating
agents has been extensively studied. Moreover, new acridine
(naphthalene-quinolines) skeleton fused with a five or six-
membered ring yields polycyclic derivatives, which also plays
an important role as some DNA-intercalating anticancer drugs
[4]. In particular, the chemistry and biological activity of
numerous compounds related to the benzo[a]- and benzo[c]a-
cridine families has been widely investigated for the last 50
years and carcinogenic activities were detected [5,6]. In fact,
most of the carcinogenic benzacridine family belongs to the
benzo[c]acridine series, whereas very few compounds of the
benzo[a]acridine series show such an adverse property [5]. In
the current context, due to the industrial production of synthetic
fuels, that may contain nitrogen analogues of polycyclic
Therefore, for biological evaluations, it seemed desirable to
develop a general method for the synthesis of benzo[c]acridine
derivatives (PAH analogous), which has the possibility to
introduce a trifluoromethyl, alkyl, halogen and hydroxy group
as substituent on this aza heterocyclic family. Although the
trihalomethyl substituted derivatives, dihydrobenzo[c]acridines
had been prepared based on improvements of the classical
method developed by Friedlaender-Kempter [9,10] and this
improved method was applied to substituted a-tetralone in
reaction with the appropriate 2-aminoacetophenone or 2-
nitrobenzaldehyde [2,11].
A review on the literature has shown that the synthesis of
trifluoromethylated benzo[c]acridine and derivatives were little
explored and 7-trifluoromethyl-5,6-dihydrobenzo[c]acridines
are unknown until now. As an example, Hojo et al. [12], in
* Corresponding author. Fax: +55 55 3220 8031.
E-mail address: heliogb@base.ufsm.br (H.G. Bonacorso).
0022-1139/$ – see front matter # 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2005.07.017

H.G. Bonacorso et al. / Journal of Fluorine Chemistry 126 (2005) 1384–1389
1385
Scheme 1.
1990, demonstrated that some similar compounds such as 7,12-
dihydrobenzoacridines bearing trifluoromethyl and trifluoroa-
cetyl groups can be obtained in a three step reaction in 46
to 69% yield, where the last step employs a base-catalyzed
cyclization of N-aryl-2,4-bis(trifluoroacetyl)-1-naphthyla-
mines. However, this precursor was obtained in a two step
reaction involving a bis-trifluoroacetylation of N,N-dimethyl-1-
naphthylamine and nitrogen-nitrogen exchange reaction with
para-substituted anilines.
acid in anhydrous methanol provides the dimethyl acetal
intermediate.
The acetal intermediate was distillated under reduced
pressure and the acylation reaction with trifluoroacetic
anhydride in pyridine was carried out in a molar ratio 1:2:2,
respectively, in anhydrous chloroform to reach the trifluor-
oacetyl compound 2 in 75% yield.
A novel series of nine N-aryl-2-trifluoroacetyl-3,4-dihydro-
naphthylamines 4a–i was obtained in 68–87% yields by the
methoxy-arylamino exchange reaction of 2 with anilines 3. The
reactions of compound 2 with ortho- and para-substituted
anilines 3 were carried out in acetonitrile at reflux for 6 h. The
best results were obtained when a solution of 3 in the same
solvent was added drop wise to 2, diluted in anhydrous
acetonitrile.
Herein, the present study shows a general method to
synthesize regiospecifically b-enaminoketones 4 and 5,6-
dihydrobenzo[c]acridines 5 derived from the reaction of a
new b–alkoxyvinyl trifluoromethyl ketone 2 with nine
substituted anilines 3 (Scheme 1).
The intramolecular cyclization reactions of N-aryl-2-
trifluoroacetyl-3,4-dihydro-naphthylamines 4a–i were carried
out in polyphosphoric acid (PPA) in the absence of solvent. At
first, PPA (P2O5 + H3PO4) was prepared at 90 8C and the
compounds 4a–i were added in small portions to the acid
mixture. The cyclization of 4a–i proceeded only at 110 8C for
24 h to afford the corresponding new series of nine 7-
trifluoromethyl-5,6-dihydrobenzo[c]acridines 5a–i in 44–82%
yields. To search for better reaction conditions, we tested some
Lewis acids or basic conditions and that could be used for the
synthesis of 5a. Thus, TiCl4 [15], ZnCl4 [16], P2O5/POCl3 [17],
POCl3 [18] and PPA in ethanol, produced no positive results.
The conditions used by Hojo et al. [12] for the synthesis of the
benzo[c]acridines and its dihydro derivative, which employed
triethylamine (basic condition) and trifluoroacetic acid (acid
conditions) have also failed.
2. Results and discussion
Although many methods for the synthesis of acridines 5 had
already been published, no one has used the strategy adopted in
this work. Our strategy has the following advantages: (i) It is
easier to introduce the substituent at the 7, 9 and 11 position of
the acridine ring; (ii) the reactivity of the b-carbon in 2 and the
carbonyl carbon in 4, allow the regiospecific introduction of a
wide scope of anilines bearing both electron donor and electron
withdrawing substituent; (iii) as an extension of this work, this
method also allows the use of substituted a-tetralone to
generate polysubstituted dihydrobenzo[c]acridines and (iv)
using similar reaction conditions previously reported [11], the
dihydroacridines 5 could be converted to aromatic benzo[c]a-
cridine upon heating in decaline at ꢀ190 8C in the presence of
Pd/C.
The unambiguous 1H and 13C NMR chemical shift
assignments of compounds 2, 4a–i and 5a–i were made with
the help of HMQC and HMBC 2D-NMR experiments and by
comparison with NMR data of similar compounds previously
reported. The 13C chemical shifts at position 6 and 8 for
benzoacridines 5a–i presents an interesting coupling with the
According to the methodology introduced by Hojo et al. [13]
and systematized in our laboratory [14], hereto unpublished 1-
methoxy-2-trifluoroacetyl-3,4-dihydro-naphthalene (2) could
be synthesized, in two steps. Thus, the reaction of a-tetralone
with trimethyl orthoformate in presence of p-toluenesulfonic

1386
H.G. Bonacorso et al. / Journal of Fluorine Chemistry 126 (2005) 1384–1389
fluorine atoms of the trifluoromethyl group. The carbon 6 at d
)
1H NMR (CDCl3) (400 MHz)d = 7.60–7.24(m,4H,Ar);3.85
(s, 3H, OCH3); 2.84–2.77 (m, 2H, H4); 2.67–2.59 (m, 2H, H3).
ꢀ26 ppm and 8 at d ꢀ124 ppm present coupling constant (4JCF
2
in the range of 4 and 5 Hz, respectively. As expected, the carbon
7 at d ꢀ131 ppm shows a 2JCF ꢀ29 Hz and the signal related to
the carbon of the trifluoromethyl group at d ꢀ125 ppm shows
1JCF ꢀ276 Hz.
13C NMR (CDCl3) (400 MHz) d = 180.8 (q, JCF = 36,
C=O); 140.8 (C1); 131.1, 129.0, 127.9, 126.8, 125.3, 120.9,
1
118.0 (6C, Ar); 116.6 (q, JCF = 288, CF3); 116.0 (C2); 61.6
(OCH3); 27.5 (C4); 22.9 (C3).
IR/KBr (n cmÀ1) = 1661 (C=O)
CG–MS (EI, 70 Ev): m/z (%) = 256 (M+, 24), 187 (100), 159
(6), 144 (24), 69 (18).
In conclusion, we have developed a convenient procedure to
obtain new 7-trifluoromethyl-5,6-dihydrobenzo[c]acridines as
heteropolycycles derived from tetralone and anilines involving
the isolation of N-aryl-2-trifluoroacetyl-3,4-dihydronaphthyla-
mines intermediates. Furthermore, we have been able to
synthesize and use for the first time 1-methoxy-2-trifluoroa-
cetyl-3,4-dihydro-naphthalene in enaminones synthesis and in
intramolecular cyclocondensation reactions. We hope that the
new benzoacridines described here contributes for a combi-
natorial library of acridine derivatives aiming to determine a
more potent drug and its action pathway as an anticancer agent.
Anal. Calcd. for C13H11O2F3 (256.22): C, 60.94; H, 4.33 %.
Found: C, 60.80; H, 4.34%.
3.2. Synthesis of N-aryl-2-trifluoroacetyl-3,4-dihydro-
naphthylamine (4a–i)
3.2.1. General procedure
To a magnetically stirred solution of 2 (10 mmol) in
anhydrous acetonitrile (20 ml) was added dropwise a solution
of aniline 3a–i (10 mmol) in anhydrous acetonitrile (10 ml) at
room temperature. The mixture was stirred under reflux for 6 h.
The solvent was evaporated under reduced pressure and the
solid products 4a–i were recrystallized from methanol (yields
68–87%).
3. Experimental
Unless otherwise indicated all common reagents and solvents
were used as obtainedfrom commercial suppliers without further
purification. The melting points were determined using open
capillaries on a Electrothermal Mel-Temp 3.0 apparatus and are
uncorrected. 1H and 13C NMR spectra were acquired on a Bruker
DPX 200spectrometer (1H at 200.13 MHz) and BrukerDPX 400
(1H at 400.13 MHz and 13C at 100.32 MHz) spectrometer, 5 mm
sample tubes, 298 K, digital resolution Æ0.01 ppm, in CDCl3 for
2, 4a–i and 5a–i using TMS as internal reference. Mass spectra
were registered in a HP 6890 GC connected to a HP 5973 MSD
and interfaced by a Pentium PC. The GC was equipped with a
split-splitless injector, autosampler, cross-linked HP-5 capillary
column (30 m, 0.32 mm of internal diameter), and helium was
used as the carrier gas. The CHN elemental analyses were
performed on a Perkin-Elmer 2400 CHN elemental analyzer
(Sa˜o Paulo University, USP/Brazil).
3.2.1.1. N-Phenyl-2-trifluoroacetyl-3,4-dihydro-naphthyla-
mine (4a). Yellow solid, yield 73%, Mp. 72–73 8C.
1H NMR (CDCl3) (400 MHz) d = 13.09 (s, 1H, NH); 7.26 (d,
2H, JH-H = 4, Ar); 7.23–7.19 (m, 2H, Ar); 7.14–7.10 (m, 2H,
Ar); 6.94–6.92 (m, 3H, Ar); 2.82–2.79 (m, 2H, H4); 2.61–2.58
(m, 2H, H3).
2
13C NMR (CDCl3) (400 MHz) d = 176.2 (q, JCF = 32,
C=O); 160.0 (C1); 141.9, 140.2, 131.0, 129.2, 129.1, 127.9,
1
127.7, 125.5, 125.3; 123.7 (12C, Ar); 118.1 (q, JCF = 288,
1
CF3); 103.4 (C2); 29.5 (C4); 21.5 (q, JCF = 3, C3).
CG–MS (EI, 70 Ev): m/z (%) = 317 (M+, 44), 248 (100), 220
(26), 143 (3), 128 (8), 97 (3), 92 (3), 69 (3).
Anal. Calcd. for C18H14NOF3 (317.31): C, 68.13; H, 4.45;
N, 4.45%. Found: C, 67.98; H, 4.28; N 4.31%.
3.1. Synthesis of 1-methoxy-2-trifluoroacetyl-3,4-dihydro-
naphthalene (2)
3.2.1.2. N-(4-Methylphenyl)-2-trifluoroacetyl-3,4-dihydro-
naphthylamine (4b). Yellow solid, yield 78%, Mp. 130–
133 8C.
3.1.1. General procedure
Trimethyl orthoformate (75 mmol) and p-toluenesulfonic
acid (0.39 mmol) in anhydrous methanol (30 ml) were added to
an Erlenmeyer flask (250 ml) with a-tetralone (50 mmol) and
the mixture was kept for 24 h at 60 8C. The mixture was
neutralized with sodium carbonate and filtered. The solvent was
removed under reduced pressure and the resultant oil was
distilled at 85 8C/2.2 mbar. Then, the distillate was stirred with
pyridine (100 mmol) in anhydrous chloroform (30 ml). The
mixture kept at 0 8C and trifluoroacetic anhydride (100 mmol)
was added dropwise. The mixture was stirred for 48 h at 50 8C.
The mixture was washed with a solution of hydrochloric acid
0.1 M (twice) and water (three times). The organic layer was
dried with magnesium sulfate, the solvent was removed under
reduced pressure and the product 2 was purified by distillation
under reduced pressure.
1H NMR (CDCl3) (400 MHz) d = 13.16 (s, 1H, NH); 7.26–
7.25(m,2H, Ar);7.14(d,1H, JH-H = 8,Ar);7.02(d, 2H,JH-H = 8,
Ar); 6.95–6.92 (m, 1H, Ar); 6.83 (d, 2H, JH-H = 8,Ar); 2.81–2.79
(m, 2H, H4); 2.61–2.59 (m, 2H, H3); 2.29 (s, 3H, CH3).
2
13C NMR (CDCl3) (400 MHz) d = 175.9 (q, JC-F = 32,
C=O); 160.3 (C1); 142.1, 137.6, 135.3, 131.0, 129.8, 129.2,
1
127.8, 125.6, 123.7 (12C, Ar); 118.2 (q, JC-F = 288, CF3);
4
103.0 (C2), 29.6 (C4); 21.5 (q, JC-F = 3, C3); 20.8 (CH3).
CG–MS (EI, 70 Ev): m/z (%) = 331 (M+, 62), 262 (100), 234
(29), 218 (16), 143 (2), 91 (1), 69 (2).
Anal. Calcd. for C19H16NOF3 (331.34): C, 68.88; H, 4.87;
N, 4.23%. Found: C, 68.43; H, 4.87; N, 4.11%.
3.2.1.3. N-(2-Methylphenyl)-2-trifluoroacetyl-3,4-dihydro-
naphthylamine (4c). Yellow solid, yield 77%, Mp. 98–100 8C.
Colorless liquid, yield 75%, Bp. 110 8C/1.5 mbar.

H.G. Bonacorso et al. / Journal of Fluorine Chemistry 126 (2005) 1384–1389
1387
1H NMR (CDCl3) (400 MHz) d = 13.16 (s, 1H, NH); 7.26–
7.21 (m, 3H, Ar); 7.08–7.04 (m, 1H, Ar); 6.99–6.96 (m, 2H,
Ar); 6.92–6.90 (m, 1H, Ar); 6.70 (d, 1H, JH-H = 8, Ar); 2.83–
2.80 (m, 2H, H4); 2.63–2.60 (m, 2H, H3); 2.35 (s, 3H, CH3).
Anal. Calcd. for C18H13NOF3Cl (351.75): C, 61.46; H, 3.73;
N, 3.98%. Found: C, 68.14; H, 3.69; N, 3.91%.
3.2.1.7. N-(4-Fluorophenyl)-2-trifluoroacetyl-3,4-dihydro-
naphthylamine (4g). Yellow solid, yield 71%, Mp. 105–
107 8C.
2
13C NMR (CDCl3) (400 MHz) d = 176.0 (q, JC-F = 32,
C=O); 161.1 (C1); 141.9, 139.0, 131.5, 131.0, 128.6, 128.1,
1
127.8, 126.4, 125.9, 125.6, 125.3 (12C, Ar); 118.3 (q, JC-
4
F = 288); 102.7 (C2); 29.7 (C4); 21.5 (q, JC-F = 3, C3); 18.1
1H NMR (CDCl3) (400 MHz) d = 13.04 (s, 1H, NH); 7.28–
7.27 (m, 2H, Ar); 7.09 (d, 1H, JH-H = 8, Ar); 6.98–6.91 (m, 5H,
Ar); 2.82–2.79 (m, 2H, H4); 2.61–2.58 (m, 2H, H3).
(CH3).
CG–MS (EI, 70 Ev): m/z (%) = 331 (M+, 45), 262 (100), 234
(28), 218 (24), 143 (3), 91 (17), 69 (10).
Anal. Calcd. for C19H16NOF3 (331.34): C, 68.88; H, 4.87;
N, 4.23%. Found: C, 68.69; H, 4.97; N, 4.26%.
13C NMR (CDCl3) (MHz) d = 176.5 (q, JC-F = 32, C=O);
2
1
160.1 (C1); 160.2 (d, JC-F = 246, C12); 142.1, 131.1, 129.1,
3
128.0, 127.5, 125.7 (6C, Ar); 125.4 (d, JC-F = 8, 2C, C10);
1
118.0 (q, JC-F = 288, CF3); 116.0 (d, JC-F = 23, C2, C11)
2
4
103.4 (C2); 29.5 (C4); 21.4 (q, JC-F = 3, C3).
3.2.1.4. N-(4-Bromophenyl)-2-trifluoroacetyl-3,4-dihydro-
naphthylamine (4d). Yellow solid, yield 70%, Mp. 174–
176 8C.
CG–MS (EI, 70 Ev): m/z (%) = 335 (M+, 93), 266 (100), 238
(41), 143 (5), 95 (13), 76 (4).
Anal. Calcd. for C18H13NOF4 (335.30): C, 64.48; H, 3.91;
N, 4.18%. Found: C, 64.27; H, 3.92; N, 4.16%.
1H NMR (CDCl3) (400 MHz) d = 12.89 (s, 1H, NH); 7.34–
7.27 (m, 8H, Ar); 7.12 (d, 1H, JH-H = 8, Ar); 7.01–6.97 (m, 1H,
Ar); 6.80 (d, 2H, JH-H = 8, Ar); 2.83–2.79 (m, 2H, H4); 2.62–
2.58 (m, 2H, H3).
3.2.1.8. N-(4-Methoxyphenyl)-2-trifluoroacetyl-3,4-dihydro-
naphthylamine (4h). Yellow solid, yield 87%, Mp. 165–
166 8C.
2
13C NMR (CDCl3) (MHz) d = 176.9 (q, JC-F = 32, C=O);
159.6 (C1); 141.9, 139.5, 132.2, 131.3, 129.1, 128.0, 127.4,
1
125.8, 125.1, 118.3 (12C, Ar); 117.9 (q, JC-F = 289, CF3);
1H NMR (CDCl3) (400 MHz) d = 13.23 (s, 1H, NH); 7.27 (d,
1H, JH-H = 2, Ar); 7.13 (d, 1H, JH-H = 8, Ar); 6.96–6.92 (m, 1H,
Ar); 6.89–6.87 (m, 2H, Ar); 6.76 (d, 2H, JH-H = 8, Ar); 3.76 (s,
3H, OCH3); 2.81–2.78 (m, 2H, H4); 2.60–2.57 (m, 2H, H3).
4
104.2 (C2); 29.4 (C4); 21.4 (q, JC-F = 3, C3).
CG–MS (EI, 70 Ev): m/z (%) = 397 (M+ + 1, 37), 395 (M+,
38), 326 (49), 246 (100), 218 (36), 76 (9), 69 (6).
Anal. Calcd. for C18H13NOBrF3 (396.21): C, 54.57; H, 3.31;
N, 3.54%. Found: C, 54.17; H, 3.34; N, 3.39%.
2
13C NMR (CDCl3) (400 MHz) d = 175.6 (q, JC-F = 32,
C=O); 160.4 (C1); 157.4, 142.1, 133.0, 130.9, 129.1, 127.8,
1
127.7, 125.5, 125.1, 114.4 (12C, Ar); 118.2 (q, JC-F = 288,
4
CF3); 102.5 (C2); 55.2 (OCH3); 29.6 (C4); 21.5 (q, JC-F = 3,
3.2.1.5. N-(2-Bromophenyl)-2-trifluoroacetyl-3,4-dihydro-
naphthylamine(4e). Yellow solid, yield 68%, Mp. 110–112 8C.
1H NMR (CDCl3) (400 MHz) d = 12.75 (s, 1H, NH); 7.62–
7.59 (m, 1H, Ar); 7.29–7.27 (m, 2H, Ar); 7.04–6.95 (m, 4H,
Ar); 6.70 (dd, 1H, JH-H = 8, JH-H = 1.5, Ar); 2.84–2.81 (m, 2H,
H4); 2.64–2.61 (m, 2H, H3).
C3).
CG–MS (EI, 70 Ev): m/z (%) = 347 (M+, 77), 278 (100), 250
(18), 220 (3), 143 (3).
Anal. Calcd. for C19H16NO2F3 (347.34): C, 65.70; H, 4.64;
N, 4.03%. Found: C, 65.47; H, 4.58; N, 3.98%.
2
13C NMR (CDCl3) (400 MHz) d = 177.3 (q, JC-F = 32,
3.2.1.9. N-(2-Hydroxyphenyl)-2-trifluoroacetyl-3,4-dihydro-
naphthylamine (4i). Violet solid, yield 72%, Mp. 125–126 8C.
1H NMR (CDCl3) (400 MHz) d = 12.93 (s, 1H, NH); 10.11
(s, 1H, OH); 7.36–7.33 (m, 2H, Ar); 7.14 (d, 1H, JH-H = 8, Ar);
7.04–7.01 (m, 2H, Ar); 6.78 (d, 1H, JH-H = 8, Ar); 6.65 (t, 1H,
C=O); 159.4 (C1); 141.6, 139.4, 133.3, 131.2, 128.7, 128.0,
127.9, 127.6, 126.3, 126.2, 125.8, 117.6 (12C, Ar); 117.9 (q, 1JC-
F = 290, CF3); 104.7 (C2); 29.4 (C4); 21.4 (q, 4JC-F = 3, C3).
CG–MS (EI, 70 Ev): m/z (%) = 397 (M+ + 1, 18), 395 (M+,
19), 326 (24), 316 (41), 246 (100), 219 (39), 76 (6), 69 (4).
Anal. Calcd. for C18H13NOBrF3 (396.21): C, 54.57; H, 3.31;
N, 3.54%. Found: C, 54.33; H, 3.29; N, 3.33%.
J
H-H = 8, Ar); 2.84–2.81 (m, 2H, H4); 2.52–2.49 (m, 2H, H3).
13C NMR (DMSO-d6)) (400 MHz) d = 173.7 (q, 2JC-F = 31,
C=O); 160.6 (C1); 149.9, 141.7, 131.2, 127.8, 127.7, 127.6,
127.0, 126.8, 125.5, 125.1, 119.0, 116.2 (12C, Ar); 118.1 (q, 1JC-
F = 290, CF3); 101.7 (C2); 28.7 (C4); 21.1 (q, 4JC-F = 3, C3).
CG–MS (EI, 70 Ev): m/z (%) = 333 (M+, 100), 264 (22), 236
(83), 220 (16), 143 (5), 97 (12), 69 (85).
3.2.1.6. N-(4-Chlorophenyl)-2-trifluoroacetyl-3,4-dihydro-
naphthylamine (4f). Yellow solid, yield 75%, Mp 104–105 8C.
1H NMR (CDCl3) (400 MHz) d = 12.92 (s, 1H, NH); 7.30–
7.28 (m, 2H, Ar); 7.18 (d, 2H, JH-H = 8, Ar); 7.12 (d, JH-H = 8,
Ar); 7.00–6.96 (m, 1H, Ar); 6.86 (d, 2H, JH-H = 8, Ar); 2.83–
2.79 (m, 2H, H4); 2.62–2.58 (m, 2H, H3).
Anal. Calcd. for C18H14NO2F3 (333.31): C, 64.86; H, 4.23;
N, 4.20%. Found: C, 65.26; H, 4.24; N, 4.30%.
2
13C NMR (CDCl3) (400 MHz) d = 176.9 (q, JC-F = 32,
3.3. Synthesis of 7-trifluoromethyl-5,6-dihydro-
benzo[c]acridines (5a–i)
C=O); 159.7 (C1); 141.9, 139.0, 131.3, 130.7, 129.3, 129.1,
1
128.0, 127.5, 125.8, 124.8 (12C, Ar); 117.9 (q, JC-F = 287,
4
CF3), 104.2 (C2), 29.4 (C4), 21.5 (q, JC-F = 3, C3).
3.3.1. General procedure
To a magnetically stirred mixture of H3PO4 (2 ml) and P2O5
(3 g) (PPA) at 90 8C, 4a–i (10 mmol) was added at r.t. The
CG–MS (EI, 70 Ev): m/z (%) = 351 (M+, 48), 282 (100), 254
(18), 218 (19), 143 (2), 76 (4), 69 (3).

1388
H.G. Bonacorso et al. / Journal of Fluorine Chemistry 126 (2005) 1384–1389
mixture was stirred for 24 h at 110 8C. Distilled water (10 ml)
and chloroform (10 ml) were added to the mixture at room
temperature. The solution was then extracted with chloroform
(three times, 10 ml). The combined organic layers were washed
with aq. 10% solution of NaOH (three times, 10 ml), distilled
water (three times, 10 ml), dried over sodium sulfate and the
solvent was removed under reduced pressure. The solid
products were recrystallized from ethanol (yields 44–82%).
H = 2 Hz, Ar); 8.46–8.25 (m, 3H, Ar); 4.40–4.34 (m, 2H, H6),
4.00–3.94 (m, 2H, H5).
13C NMR (CDCl3) (400 MHz) d = 153.6, 145.9, 138.8,
133.6, 132.6, 131.8, 131.5, 130.4, 127.4, 127.3, 126.6, 123.9,
2
4
121.9 (13C, Ar); 129.8 (q, JC-F = 26, C7); 126.3 (q, JC-F = 4,
C8); 124.7 (q, 1JC-F = 277, CF3); 27.1 (C5); 26,2 (q, 4JC-F = 4,
C6).
CG–MS (EI, 70 Ev): m/z (%) = 377 (M+, 100), 308 (13).
Anal. Calcd. for C18H11BrF3N (378.19): C, 57.17; H, 2.93;
N, 3.70%. Found: C, 57.68; H, 3.30; N, 3.51%.
3.3.1.1. 7-Trifluoromethyl-5,6-dihydrobenzo[c]acridine
(5a). Yellowish solid, yield 75%, Mp. 81–83 8C.
1H NMR (CDCl3) (400 MHz) d = 8.48–8.46 (m, 1H, Ar);
8.18–8.15 (m, 2H, Ar); 7.64 (t, 1H, JH-H = 4 Hz, Ar); 7.53–7.49
(m, 1H, Ar); 7.40–7.31 (m, 1H, Ar); 7.20 (d, 1H, JH-H = 8 Hz,
Ar); 3.33–3.20 (m, 2H, H6); 2.91–2.88 (m, 2H, H5).
3.3.1.5. 11-Bromo-7-trifluoromethyl-5,6-dihydrobenzo[c]acri-
dine (5e). Yellow solid, yield 44%, Mp. 144–145 8C.
1H NMR (CDCl3) (200 MHz) d = 8.65–8.60 (m, 1H, Ar);
8.18–8.03 (m., 2H, Ar); 7.48–7.35 (m, 3H, Ar); 7.27–7.25 (m,
1H, Ar); 3.44–3.36 (m, 2H, H6); 3.01–2.94 (m, 2H, H5).
13C NMR (CDCl3) (400 MHz) d = 153.7, 144.0, 138.7,
133.6, 132.8, 131.3, 130.3, 127.4, 127.1, 126.2, 124.2, 123.7
13C NMR (CDCl3) (400 MHz) d = 153.2, 147.4, 138.8,
133.9, 130.5, 130.3, 130.1, 129.0, 127.4, 127.3, 127.2, 126.7
2
1
(12C, Ar); 130.6 (q, JC-F = 29, C7); 125.1 (q, JC-F = 276,
CF3); 123.9 (q, 4JC-F = 5, C8); 123.0 (C7a); 27.3 (C5); 26.2 (q,
4JC-F = 4, C6).
2
1
(14C, Ar); 130.9 (q, JC-F = 29, C7); 124.7 (q, JC-F = 277,
CF3); 27.0 (C5); 26.0 (C6).
CG–MS (EI, 70 Ev): m/z (%) = 299 (M+, 100); 230 (33).
Anal. Calcd. for C18H12NF3 (299.29): C, 72.24; H, 4.04; N,
4.68%. Found: C, 71.72; H, 3.97; N 4.45%.
CG–MS (EI, 70 Ev): m/z (%) = 377 (M+, 100); 308 (26).
Anal. Calcd. for C18H11NBrF3 (378.19): C, 57.17; H, 2.93;
N, 3.70%. Found: C, 57.02; H, 2.93; N, 3.73%.
3.3.1.2. 9-Methyl-7-trifluoromethyl-5,6-dihydrobenzo[c]acri-
dine (5b). Yellowish solid, yield 75%, Mp. 106–108 8C.
1H NMR (CDCl3) (200 MHz) d = 8.46–8.42 (m, 1H, Ar);
8.03 (d, 1H, JH-H = 8 Hz, Ar); 7.93 (bs, 1H, Ar); 7.50–7.19 (m,
3H, Ar); 3.33–3.27 (m, 2H, H6); 2.92–2.85 (m, 2H, H5); 2.51
(s, 3H, CH3).
3.3.1.6. 9-Chloro-7-trifluoromethyl-5,6-dihydrobenzo[c]acri-
dine (5f). Biege solid, yield 61%, Mp. 130–132 8C.
1H NMR (CDCl3) (200 MHz) d = 8.42–8.39 (m, 1H, Ar);
8.14–8.01 (m, 1H, Ar); 8.03 (d, 1H, JH-H = 9 Hz, Ar); 7.58 (dd,
1H, JH-H = 2 Hz, JH-H = 9 Hz, Ar); 7.39–7.35 (m, 2H, Ar);
7.23–7.19 (m, 1H, Ar); 3.33–3.27 (m, 2H, H6); 2.94–2.87 (m,
2H, H5).
13C NMR (CDCl3) (400 MHz) d = 152.3, 146.0, 138.7,
137.5, 134.0, 131.2, 130.4, 130.0, 129.8, 127.3, 127.2, 126.5;
123.0 (13C, Ar); 129.9 (q, 2JC-F = 29, C7); 125.2 (q, 1JC-F = 277,
13C NMR (CDCl3) (400 MHz) d = 153.3, 145.6, 138.7,
133.5, 131.7, 131.4, 130.2, 129.9, 127.3, 127.2, 126.5 123.3
4
4
2
(13C); 129.7 (q, JC-F = 30, C7); 124.7 (q, JC-F = 277, CF3);
1
CF3); 122.9 (q, JC-F = 6, C8); 27.4 (C5); 26.2 (q, JC-F = 4,
C6); 22.2 (CH3).
4
123.1 (q, JC-F = 5, C8); 27.1 (C5); 26.1 (C6).
CG–MS (EI, 70 Ev): m/z (%) = 313 (M+, 100); 244 (24).
Anal. Calcd. for C19H14F3N (313.32): C, 72.84; H, 4.50; N,
4.47%. Found: C, 72.64; H, 4.55; N, 4.49%.
CG–MS (EI, 70 Ev): m/z (%) = 333 (M+, 100); 264 (20).
Anal. Calcd. for C18H11NClF3 (333.74): C, 64.78; H, 3.32;
N, 4.20%. Found: C, 64.54; H, 3.38; N, 4.13%.
3.3.1.3. 11-Methyl-7-trifluoromethyl-5,6-dihydrobenzo[c]a-
cridine (5c). Dark yellow solid, yield 67%, Mp. 132–134 8C.
1H NMR (CDCl3) (200 MHz) d = 8.53–8.48 (m, 1H, Ar);
8.03–7.99 (m, 1H, Ar); 7.52–7.29 (m, 4H, Ar); 7.22–7.18 (m,
1H, Ar); 3.36–3.29 (m, 2H, H6); 2.94–2.86 (m, 5H, H5 and
CH3).
3.3.1.7. 9-Fluoro-7-trifluoromethyl-5,6-dihydrobenzo[c]acri-
dine (5g). Brown solid, yield 59%, Mp. 116–118 8C.
1H NMR (CDCl3) (200 MHz) d = 8.44–8.39 (m, 1H, Ar);
8.16–8.09 (m, 1H, Ar); 7.81 (d, 1H, JH-H = 11 Hz, Ar); 7.48–
7.20 (m, 3H, Ar); 7.24–7.20 (m, 1H, Ar); 3.35–3.29 (m, 2H,
H6), 2.94–2.87 (m, 2H, H5).
13C NMR (CDCl3) (400 MHz) d = 151.7, 146.3, 138.7,
138.0, 134.5, 129.8, 129.2, 127.2, 126.6, 122.9, 121.9 (14C,
Ar); 130.7 (q, 2JC-F = 29, C7); 125.2 (q, 1JC-F = 276, CF3); 27.3
13C NMR (CDCl3) (400 MHz) d = 161.0 (d, JC-F = 246,
1
C9); 152.7, 144.5, 138.7, 133.7, 131.5, 130.1, 127.4, 127.3,
3
126.5, 123.6 (10C, Ar); 132.7 (d, JC-F = 8, C11); 130.0 (q,
4
1
2
(C5); 26.1 (q, JC-F = 4, C6); 18.4 (CH3).
2JC-F = 31, C7); 124.8 (q, JC-F = 277, CF3); 119.2 (d, JC-
CG–MS (EI, 70 Ev): m/z (%) = 313 (M+, 100); 244 (25).
Anal. Calcd. for C19H14NF3 (313.32): C, 72.84; H, 4.50; N,
4.47%. Found: C, 72.40; H, 4.56; N, 4.61%.
F = 25, C10); 108.3 (d, JC-F = 24, C8); 27.2 (C5); 26.2
2
(C6).
CG–MS (EI, 70 Ev): m/z (%) = 317 (M+, 100); 248 (46).
Anal. Calcd. for C18H11NF4 (317.29): C, 68.14; H, 3.49; N,
4.41%. Found: C, 68.16; H, 3.78; N, 4.43%.
3.3.1.4. 9-Bromo-7-trifluoromethyl-5,6-dihydrobenzo[c]acri-
dine (5d). Beige solid, yield 50%, Mp. 142–143 8C.
1H NMR (CDCl3) (200 MHz) d = 9.49–9.37 (m, 2H, Ar);
9.03 (d, 1H, JH-H = 9 Hz, Ar); 8.78 (d, 1H, JH-H = 9 Hz, JH-
3.3.1.8. 9-Methoxy-7-trifluoromethyl-5,6-dihydrobenzo[c]a-
cridine (5h). Salmon solid, yield 82%, Mp. 161–163 8C.

H.G. Bonacorso et al. / Journal of Fluorine Chemistry 126 (2005) 1384–1389
1389
1H NMR (CDCl3) (200 MHz) d = 8.45–8.41 (m, 1H, Ar);
8.07 (d, 1H, JH-H = 9 Hz, Ar); 7.46–7.23 (m, 5H, Ar); 3.93 (s,
3H, OCH3); 3.36–3.30 (m, 2H, H5); 2.96–2.89 (m, 2H, H6).
13C NMR (CDCl3) (400 MHz) d = 158.5, 150.9, 143.5,
138.4, 134.0, 131.6, 130.9, 129.7, 127.4, 127.2, 126.3, 124.2,
from CAPES and FATEC (R.L. Drekener) are also acknowl-
edged.
References
2
1
[1] B.C. Baguley, L. Zhuang, E.M. Marshall, Cancer Chemother. Pharmacol.
36 (1995) 244.
121.6, 102.8 (14C); 129.5 (q, JC-F = 29, C7); 125.3 (q, JC-
F = 277, CF3); 55.4 (OCH3); 27.4 (C5); 26.3 (q, 4JC-F = 3, C6).
CG–MS (EI, 70 Ev): m/z (%) = 329 (M+, 100); 260 (5).
Anal. Calcd. for C19H14NOF3 (329.32): C, 69.30; H, 4.28;
N, 4.25%. Found: C, 69.07; H, 4.55; N, 4.13%.
[2] M. Croisy-Delcey, A. Croisy, F. Zajdela, J.-M. Lhoste, J. Med. Chem. 26
(1983) 303.
[3] N. Filloux, J.-P. Galy, Synlett 7 (2001) 1137.
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(1956) 315.
3.3.1.9. 11-Hydroxy-7-trifluoromethyl-5,6-dihydrobenzo[c]a-
cridine (5i). Dark violet solid, yield 61 %, Mp. 128–130 8C.
1H NMR (DMSO-d6) (200 MHz) d = 9.91 (s, 1H, OH);
8.85–8.81 (m, 1H, Ar); 7.58–7.19 (m, 6H, Ar); 3.32 (sa, 2H,
H6); 2.99–2.93 (m, 2H, H5).
[6] N.P. Buu-Hoi, Cancer Res. 24 (1964) 1511.
[7] R. Filler, in: R.E. Banks (Ed.), Organofluorine Chemicals and Their
Industrial Applications, Ellis Horwood, London, 1979.
[8] Y. Inouye, K. Tezuka, W. Takeda, S. Sugai, J. Fluorine Chem. 35 (1987)
275.
13C NMR (CDCl3) (400 MHz) d = 153.5; 150.7; 138.6;
137.3; 133.1; 131.0; 130.0; 129.0; 127.1; 127.0; 126.9; 122.9;
111.2 (14C, Ar); 129.3 (q, 2JC-F = 29, C7) 124.8 (q, 1JC-F = 277,
[9] G. Kempter, S. Hirschberg, Ber. Dtsch. Chem. Ges. 98 (1965) 419.
[10] P. Jacquignon, A. Croisy, A. Ricci, D. Balucani, Collect. Czech. Chem.
Comm. 38 (1973) 3862.
4
4
[11] D. Makhey, C. Yu, A. Liu, L.F. Liu, E.J. LaVoie, Bio. Med. Chem. 8 (2000)
1171.
CF3); 113.3 (q, JC-F = 5, C8); 26.3 (C5); 25.5 (q, JC-F = 4,
C6).
[12] M. Hojo, R. Masuda, E. Okada, T. Tomifuji, N. Imazaki, Synthesis (1990)
1135.
CG–MS (EI, 70 Ev): m/z (%) = 329 (M+, 100); 260 (5).
Anal. Calcd. for C18H12NOF3 (315.29): C, 68.57; H, 3.84;
N, 4.44%. Found: C, 68.30; H, 3.84; N, 4.25%.
[13] M. Hojo, R. Masuda, E. Okada, Synthesis (1986) 1013.
[14] H.G. Bonacorso, M.A.P. Martins, S.R.T. Bittencourt, R.V. Lourega, N.
Zanatta, A.F.C. Flores, J. Fluorine Chem. 99 (1999) 177.
´
[15] M. Soufyane, C. Mirand, J. Levy, Tetrahedron Lett. 34 (1993) 7737.
Acknowledgements
[16] J. Chen, P.R. Selvin, J. Photochem. Photobiol. A 135 (2000) 27.
[17] V.I. Tyvorski, D.N. Bodrov, O.G. Kulinkovich, W. Aelterman, N.D.
Kimpe, Tetrahedron 56 (2000) 7313.
The authors thank for the financial support from Conselho
´
Nacional de Desenvolvimento Cientıfico – CNPq. Fellowship
[18] L. Poszavacz, G. Simig, Tetrahedron 57 (2001) 8573.