Synthesis of new fluorine-containing 1,2,3,4-tetrahydroacridines

Article abstract of DOI:10.1080/00397910902803692

A convenient method for the synthesis of a novel series of four 5-trilfluoromethyl-1,2,3,4-tetrahydroacridines, by intramolecular cyclization reactions of 2-trifluoroacetyl-1-(arylamino)-cyclohexene using polyphosphoric acid (PPA), is described. The six n

Full text of DOI:10.1080/00397910902803692

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Synthesis of New Fluorine-
Containing 1,2,3,4-
Tetrahydroacridines
Helio Gauze Bonacorso a , Tatiana Soldati de Moraes
a , Nilo Zanatta a & Marcos Antonio Pinto Martins a
a Research Group of Heterocyclic Chemistry
(NUQUIMHE), Chemistry Department , Federal
University of Santa Maria , Santa Maria, Brazil
Published online: 08 Sep 2009.
To cite this article: Helio Gauze Bonacorso , Tatiana Soldati de Moraes , Nilo
Zanatta & Marcos Antonio Pinto Martins (2009) Synthesis of New Fluorine-Containing
1,2,3,4-Tetrahydroacridines, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 39:20, 3677-3686, DOI:
10.1080/00397910902803692
To link to this article: http://dx.doi.org/10.1080/00397910902803692
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Synthetic Communications1, 39: 3677–3686, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902803692
Synthesis of New Fluorine-Containing
1,2,3,4-Tetrahydroacridines
Helio Gauze Bonacorso, Tatiana Soldati de Moraes, Nilo Zanatta,
and Marcos Antonio Pinto Martins
Research Group of Heterocyclic Chemistry (NUQUIMHE), Chemistry
Department, Federal University of Santa Maria, Santa Maria, Brazil
Abstract: A convenient method for the synthesis of a novel series of four
5-trilfluoromethyl-1,2,3,4-tetrahydroacridines, by intramolecular cyclization
reactions of 2-trifluoroacetyl-1-(arylamino)-cyclohexene using polyphosphoric
acid (PPA), is described. The six new enaminoketone intermediates were obtained
by an oxygen–nitrogen exchange reaction from 2-trifluoroacetyl-1-methoxycyclo-
hexene with six 4-substituted anilines.
Keywords: Acridines, cyclohexene, PPA, tetrahydroacridines
INTRODUCTION
It is well documented that acridines have a wide range of biological
applications, including antitumor properties,[1] but carcinogenic activity
has also been documented. Because of its planar structure, the acridine
chromophore moiety sometimes has excellent DNA binding properties.
Moreover, a new acridine (tetrahydroacridine) skeleton fused with a
six-membered ring yields polycyclic derivatives, which also play an
important role against Alzheimer’s disease, as for example, the first
AChE inhibitor, tetrahydroaminoacridine (Cognex).[2,3] In particular,
the chemistry and biological activities of numerous compounds related
Received October 8, 2008.
Address correspondence to Helio Gauze Bonacorso, Research Group of
Heterocyclic Chemistry (NUQUIMHE), Chemistry Department, Federal
University of Santa Maria, 97105-900 Santa Maria, RS, Brazil. E-mail: heliogb@
base.ufsm.br
3677

3678
H. G. Bonacorso et al.
to the benzo[a]- and benzo[b]acridine families have been widely investigated
for the past 50 years, and carcinogenic activities have been detected.[4,5]
Acridines have been prepared from improvements of the classical
methods developed by Skraup, Conrad–Limpach, Do¨bner–von Miller,
and Friedla¨nder.[6] On the other hand, it has been observed that the intro-
duction of a trifluoromethyl and its higher homologue CnF2nþ1 groups
into a heterocycle may result in greater activity than that of the parent
compound, which is probably a result of the high lipophylicity of per-
fluoroalkyl substituents.[7,8] Moreover, the inclusion of fluorine atoms
in a drug molecule can influence both the disposition of the drug and
the interaction of the drug with its pharmacological target.
There are few studies available on the synthesis of trifluoromethy-
lated acridines and derivatives. In one study, De and Gibbs developed
a very simple and efficient but very expensive new method to obtain
polycyclic acridines by a Friedla¨nder condensation involving 2-aminoar-
ylketones with cyclic ketones in the presence of itrium triflate.[9] Other
methods have included the use of microwave (Muscia et al.)[10] and
ruthenium catalysis (Cho et al.).[11] Recently, Banwell et al.[12] reported
the synthesis of some acridines by an Ullmann coupling mediated by
palladium catalysis.
Herein, the present study shows a general method to regiospecifically
synthesize b-enaminoketones (3) and 5-trifluoromethyl-1,2,3,4-tetrahy-
droacridines (4) from the reaction of a cyclic b-methoxyvinyl trifluoro-
methyl ketone (1) with six substituted anilines (2) without use of heavy
metals as catalysts (Scheme 1).
Although there are many methods for the synthesis of acridines (4) in
the literature, none have used the strategy adopted in this study. Our
Scheme 1. Route for the synthesis of 1,2,3,4-tetrahydroacridines.

1,2,3,4-Tetrahydroacridines
3679
strategy has the following advantages: (i) it is easier to introduce the
substituent at position 7 of the acridine ring, and (ii) the reactivity of
the b-carbon in 1 and the carbonyl carbon in 3 allows the regiospecific
introduction of a wide scope of anilines bearing both electron-donating
and electron-withdrawing substituents.
RESULTS AND DISCUSSION
The b-methoxyvinyl trifluoromethyl ketone (1) derived from the
trifluoroacetylation reaction of cyclohexanonedimethyl acetal was
prepared previously.[13–16]
First, a novel series of six 2-trifluoroacetyl-1-(arylamino)-cyclohexenes
(3a–f) was isolated in 37–71% yields by the O,N-exchange reaction of
2-trifluoroacetyl-1-methoxycyclohexene with 4-substituted anilines (2).
The reactions were carried out in acetonitrile under reflux for 24 h, by
a methodology similar to that described by Bonacorso et al.[17,18] The best
results were obtained when a solution of 2 in anhydrous acetonitrile was
added dropwise to 1, also diluted in the same solvent.
Second, the intramolecular cyclization reactions of 2-trifluoroacetyl-
1-(arylamino)-cyclohexene (3a–f) were carried out in polyphosphoric acid
(PPA) in the absence of solvent according to the method described by
Bonacorso et al.[17,18] At first, PPA (P2O5 þ H3PO4) was prepared at
90ꢀC, and compounds 3a–f were added in small portions to the acid
mixture. The cyclization of 3a–f proceeded at only 90–110ꢀC for 24 h
to afford the corresponding new series of four 5-trifluoromethyl-1,2,3,4-
tetrahydroacridines (4a, 4b, 4d–e) in 20–85% yields. To search for better
reaction conditions and results, we tested some Lewis acids and reactions
under microwave conditions. Unfortunately, POCl3,[19] P2O5=
POCl3,[20] and trifluoroacetic acid,[21] as well as microwave conditions,
produced no positive results for the synthesis of all acridines, especially
for nitro- (4c) and iodo- (4f) derivatives, which could be not isolated.
An explanation for the wide differences in yields or no isolated
products in the presented cyclizations can be found in a comprehensive
study of the Combes quinoline synthesis. Roberts and Turner[22] studied
the Combes synthesis and observed that anilines substituted in the meta
position by electron-donating groups readily cyclized, generally leading
exclusively to 7-substituted quinolines, whereas ortho or para electron-
donating-group substitutents inhibited or prevented cyclization. Similar
results have been observed by Linderman and Kirollos,[23] where the reac-
tion conditions required to obtain a series of trifluoromethyl-substituted
quinolines from the respective enamine precursors reflected the activation
of the aniline ring.

3680
H. G. Bonacorso et al.
1
The unambiguous H and 13C NMR chemical shift assignments of
compounds 1, 3a–f, and 4a, 4b, 4d, and 4e were carried out with the help
of HETCORR and COLOQ two-dimensional-NMR experiments and by
comparison with NMR data of similar compounds previously
reported.[17,18]
CONCLUSION
In conclusion, we have developed a convenient and greener procedure
(without heavy metals) to obtain new 5-trifluoromethyl-1,2,3,4-
tetrahydroacridines as heteropolycycles derived from cyclohexanone
and 4-substituted anilines involving the isolation of 2-trifluoroacetyl-
arylamino-cyclohexene intermediates. Furthermore, we have been able
to synthesize and use for the first time 1-methoxy-2-trifluoroacetyl-
cyclohexenes in the synthesis of acridines. We hope that the new
trifluoromethyl-substituted acridines described here contribute to a
combinatorial library of acridine derivatives with the aim of determining
a more potent drug and its action pathway as an anticancer agent.
EXPERIMENTAL
Unless otherwise indicated, all common reagents and solvents were used
as obtained from commercial suppliers without further purification. The
melting points were determined on a Reichert Thermovar apparatus and
are uncorrected. 1H and 13C NMR spectra were acquired on Bruker DPX
200 (1H at 200.13 MHz) and Bruker DPX 400 (1H at 400.13 MHz and
13C at 100.61 MHz) spectrometers, 5-mm sample tubes, at 298 K, with
a digital resolution of ꢁ0.01 ppm, in CDCl3, and using tetramethylsilane
(TMS) as internal reference. Mass spectra were registred in a HP 6890
gas chromatograph (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 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).
1-(Arylamino)-2-trifluoroacetyl-cyclohexenes (3a–f): General Procedure
A solution of aniline 2a–f (5 mmol) in anhydrous acetonitrile (5 ml) was
added dropwise to a magnetically stirred solution of 1 (1.04 g, 5 mmol)

1,2,3,4-Tetrahydroacridines
3681
in anhydrous acetonitrile (12 ml) at room temperature. The mixture was
stirred under reflux for 24 h. The solvent was evaporated under reduced
pressure, and the solid products 3a–f were recrystallized from ethanol
(yields 37–71%).
Data
2-Trifluoroacetyl-1-(4-methylphenylamino)-cyclohexene (3a)
1
Yellow solid, yield 37%, mp 87–89ꢀC. H NMR (CDCl3): d ¼ 13.2 (bs,
1H, NH); 7.18 (d, 2H, J ¼ 7.9, Ar); 7.01 (d, 2H, J ¼ 8.2, Ar);
2.56–2.36 (m, 7H, CH2 e Me) 1.67–1.62 (m, 4H, CH2).13C NMR
2
(CDCl3): d ¼ 175.5 (q, JC-F ¼ 31.4, C¼O); 167.8 (C1); 136.8; 134.5;
1
129.7; 125.6 (6C, Ar); 118.2 (q, JC-F ¼ 289.5, CF3); 98.2 (C2); 28.4
4
(CH2); 22.3 (CH2); 22.1(q, JC-F ¼ 3.3, C3); 21.0 (CH2); 20.8 (Me).
CG-MS (EI, 70 eV): m=z (%) ¼ 283 (Mþ, 43); 214 (100); 199 (3);
186 (17); 172 (5); 91 (21); 69 (6). Anal. calcd. for C15H16F3NO
(283.12): C, 63.60; H, 5.69; N, 4.94%. Found: C, 63.42; H, 5.52;
N, 4.81%.
2-Trifluoroacetyl-1-(4-methoxyphenylamino)-cyclohexene (3b)
1
Brown solid, yield 51%, mp 83–85ꢀC. H NMR (CDCl3): d ¼ 13.14 (bs,
1H, NH); 7.07 (d, 2H, J ¼ 8.7, Ar); 6.90 (d, 2H, J ¼ 9.0, Ar); 3.82
(s, 3H, OMe); 2.56–2.35 (m, 4H, CH2); 1.66–1.63 (m, 4H, CH2).
13C NMR (CDCl3): d ¼ 175.5 (q, 2JC-F ¼ 31.4, C¼O); 168.3 (C1); 158.4;
1
130.0; 127.2; 114.3 (6C, Ar); 118.3 (q, JC-F ¼ 289.5, CF3); 98.1 (C2);
4
55.3 (OMe); 28.5 (CH2); 22.4 (CH2); 22.1 (q, JC-F ¼ 2.5, C3); 21.1
(CH2). CG-MS (EI, 70 eV): m=z (%) ¼ 299 (Mþ, 99); 230 (100); 202
(32); 107 (13); 77 (19); 69 (7). Anal. calcd. for C15H16F3NO2
(299.11): C, 60.20; H, 5.39; N, 4.68%. Found: C, 60.19; H, 5.33; N,
4.72%.
2-Trifluoroacetyl-1-(4-nitrophenylamino)-cyclohexene (3c)
Yellow solid, yield 40%, mp 115–117ꢀC. 1H NMR (CDCl3): d ¼ 13.35 (bs,
1H, NH); 8.25 (d, 2H, J ¼ 9.0, Ar); 7.27 (d, 2H, J ¼ 9.0, Ar); 2.59 (m, 4H,
CH2); 1.73–1.70 (m, 4H, CH2). 13C NMR (CDCl3): d ¼ 177.8 (q,
2JC-F ¼ 32.3, C¼O); 165.3 (C1); 143.7; 126.3; 125.0; 113.3 (6C, Ar);
1
117.7 (q, JC-F ¼ 289.6, CF3); 101.1 (C2); 29.1 (CH2); 22.3 (CH2); 22.2

3682
H. G. Bonacorso et al.
4
(q, JC-F ¼ 3.7, C3); (CH2); 21.1 (CH2). CG-MS (EI, 70 eV): m=z
(%) ¼ 314 (Mþ, 97); 245 (87); 217 (31); 199 (100); 170 (30); 69 (85). Anal.
calcd. for C14H13F3N2O3 (314.09): C, 53.51; H, 4.17, N, 8.91%. Found:
C, 53.45; H, 3.88; N, 8.67%.
1-(4-Chlorophenylamino)-2-trifluoroacetyl-cyclohexene (3d)
1
Yellow solid, yield 43%, mp 96–97ꢀC. H NMR (CDCl3): d ¼ 13.18 (bs,
1H, NH); 7.35 (d, 2H, J ¼ 8.5, Ar); 7.08 (d, 2H, J ¼ 8.7, Ar); 2.56–2.38
(m, 4H, CH2); 1.75–1.64 (m, 4H, CH2).13C NMR (CDCl3): d ¼ 176.4
2
(q, JC-F ¼ 31.7, C¼O); 167.1 (C1); 135.9; 132.5; 129.3; 127.0 (6C, Ar);
1
118.1 (q, JC-F ¼ 289.6, CF3); 99.0 (C2); 28.5 (CH2); 22.2 (CH2); 22.1
4
(q, JC-F ¼ 3.7, C3); 21.0 (CH2). CG-MS (EI, 70 eV): m=z (%) ¼ 303
(Mþ, 50); 234 (100); 206 (16); 111 (13); 75 (11); 69 (4). Anal. calcd. for
C14H13ClF3NO (303.06): C, 55.37; H, 4.31; N, 4.61%. Found: C, 55.14;
H, 4.10; N, 4.56%.
1-(4-Bromophenylamino)-2-trifluoroacetyl-cyclohexene (3e)
Yellow solid, yield 71%, mp 127–128ꢀC. 1H NMR (CDCl3): d ¼ 13.17 (bs,
1H, NH); 7.50 (d, 2H, J ¼ 8.5, Ar); 7.02 (d, 2H, J ¼ 8.5, Ar); 2.56–2.38
(m, 4H, CH2); 1.67–1.64 (m, 4H, CH2).13C NMR (CDCl3): d ¼ 176.4
2
(q, JC-F ¼ 33.0, C¼O); 166.9 (C1); 136.5; 132.3; 127.3; 120.3 (6C, Ar);
1
118.1 (q, JC-F ¼ 288.9, CF3); 99.0 (C2); 28.5 (CH2); 22.2 (CH2); 22.1
4
(q, JC-F ¼ 3.7, C3); 21.0 (CH2). CG-MS (EI, 70 eV): m=z (%) ¼ 347
(Mþ, 81); 278 (88); 250 (16); 199 (100); 171(22); 76 (22); 69 (9). Anal.
calcd. for C14H13BrF3NO (347.01): C, 48.03; H, 3.76; N, 4.02%. Found:
C, 48.23; H, 3.74; N, 3.82%.
2-Trifluoroacetyl-1-(4-iodophenylamino)-cyclohexene (3f)
1
Orange solid, yield 43%, mp 152–153ꢀC. H NMR (CDCl3): d ¼ 13.18
(bs, 1H, NH); 7.69 (d, 2H, J ¼ 8.7, Ar); 6.88 (d, 2H, J ¼ 8.2, Ar);
2.56–2.39 (m, 4H, CH2); 1.68–1.64 (m, 4H, CH2).13C NMR (CDCl3):
2
d ¼ 176.4 (q, JC-F ¼ 31.8, C¼O); 166.9 (C1); 138.3; 137.1; 127.5; 91.4
1
(6C, Ar); 118.1 (q, JC-F ¼ 289.5, CF3); 99.1 (C2); 28.6 (CH2); 22.2
4
(CH2); 22.0 (q, JC-F ¼ 3.5, C3); 21.0 (CH2). CG-MS (EI, 70 eV): m=z
(%) ¼ 395 (Mþ, 96); 326 (36); 298 (14); 199 (100); 170 (28); 76 (39); 69
(15). Anal. calcd. for C14H13F3INO (395): C, 42.55; H, 3.32; N, 3.54%.
Found: C, 42.30; H, 3.24; N, 3.52%.

1,2,3,4-Tetrahydroacridines
3683
5-Trifluoromethyl-1,2,3,4-tetrahydroacridines (4a, 4b, 4d–e):
General Procedure
To a magnetically stirred solution of H3PO4 (2 ml) and P2O5 (3 g) (PPA)
at 90ꢀC, 3a–f (5 mmol) were added at room temperature. The mixture
was stirred for 24 h at 110ꢀC. 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) and distilled water (three times, 10 ml) and dried over anhydrous
sodium sulfate, and the solvent was removed under reduced pressure.
The resulting solid products were recrystallized from ethanol (yields
20–85%).
Data
9-Trifluoromethyl-7-methyl-1,2,3,4-tetrahydroacridine (4a)
1
Yellow solid, yield 85%, mp 63–65ꢀC. H NMR (CDCl3): d ¼ 7.91–7.89
(m, 2H, Ar); 7.50 (m, 1H, Ar); 3.18–3.15 (m, 4H, CH2); 2.54 (s, 3H,
Me); 2.0–1.87 (m, 4H, CH2).13C NMR (CDCl3): d ¼ 158.2 (C4a); 145.2
2
(C10a); 136.8 (C7); 131.1 (C5); 130.4 (q, JC-F ¼ 28.9, C9); 130.3
3
1
(q, JC-F ¼ 1.8, C8); 125.2 (q, JC-F ¼ 278.8, CF3); 126.6 (C6); 122.9 (q,
3JC-F ¼ 4.9, C8a); 122.7 (q, 4JC-F ¼ 1.4, C9a); 34.3 (CH2); 27.1 (q, 4JC-F ¼ 4.9,
C1); 22.6 (CH2) 22.1 (CH2); 21.9 (Me). CG-MS (EI, 70 eV): m=z (%) ¼ 265
(Mþ, 100); 250 (19); 196 (36); 181 (15); 90 (4); 77(4); 69 (5). Anal. calcd. for
C15H14F3N (265.11): C, 67.91; H, 5.32; N, 5.28%. Found: C, 67.52; H, 5.02;
N, 5.20%.
9-Trifluoromethyl-7-methoxy-1,2,3,4-tetrahydroacridine (4b)
1
White solid, yield 20%, mp 147–149ꢀC. H NMR (CDCl3): d ¼ 8.04 (d,
1H, J ¼ 9.2, Ar); 7.35 (dd, 1H, J ¼ 2.5, J ¼ 2.5, Ar); 7.15 (d, 1H,
J ¼ 2.5, Ar) 3.9 (s, 3H, OMe); 3.14–3.01 (m, 4H, CH2); 2.0–1.87 (m,
2
4H, CH2).13C NMR (CDCl3): d ¼ 159.0 (C7); 143.6 (q, JC-F ¼ 31.4,
C9); 142.6 (C4a); 139.7 (C10a); 131.8 (C9a); 129.4 (C8a); 127.5 (C5);
1
122.4 (q, JC-F ¼ 276.0, CF3); 121.3 (C6); 100.4 (C8); 55.3 (OMe); 25,8
4
(CH2); 24.8 (q, JC-F ¼ 3.0, C1); 21.8 (CH2); 21.6 (CH2). CG-MS (EI,
70 eV): m=z (%) ¼ 281 (Mþ, 100); 250 (7); 212 (17); 181 (6); 77 (8); 69
(23). Anal. calcd. for C15H14F3NO (281.1): C, 64.05; H, 5.02; N,
4.98%. Found: C, 64.12; H, 4.74; N, 4.67%.

3684
H. G. Bonacorso et al.
7-Chloro-9-trifluoromethyl-1,2,3,4-tetrahydroacridine (4d)
1
Brown solid, yield 40%, mp 131–133ꢀC. H NMR (CDCl3): d ¼ 8.06 (d,
1H, J ¼ 8.7, Ar); 7.93 (d, 1H, J ¼ 2.0, Ar); 7.63 (dd, 1H, J ¼ 2.0,
J ¼ 2.3, Ar); 3.15–3.03 (m, 4H, CH2); 1.99–1.90 (m, 4H, CH2). 13C
2
NMR (CDCl3): d ¼ 146.4 (q, JC-F ¼ 32.0, C9); 143.8 (C4a); 142.3
(10a); 134.4 (C7); 132.1 (C6); 129.9 (C5); 129.1 (9a); 128.4 (C8a); 122.0
1
(q, JC-F ¼ 276.9, CF3); 121.7 (C8); 30.8 (CH2); 25.8 (CH2); 24.8
(q, 4JC-F ¼ 3.1, C1); 21.7 (CH2). CG-MS (EI, 70 eV): m=z (%) ¼ 285 (Mþ,
100); 250 (37); 216 (16); 181 (10); 69 (7). Anal. calcd. for C14H11ClF3N
(285.05): C, 58.86; H, 3.88; N, 4.90%. Found: C, 58.57; H, 3.72, N, 4.83%.
7-Bromo-9-trifluoromethyl-1,2,3,4-tetrahydroacridine (4e)
1
Beige solid, yield 52%, mp 133–134ꢀC. H NMR (CDCl3): d ¼ 8.11 (d,
1H, J ¼ 2.0, Ar); 7.98 (d, 1H, J ¼ 8.7, Ar); 7.76 (dd, 1H, J ¼ 2.0,
J ¼ 2.0, Ar); 3.15–3.04 (m, 4H, CH2); 1.99–1.85 (m, 4H, CH2).
2
13C NMR (CDCl3): d ¼ 146.5 (q, JC-F ¼ 32.0, C9); 143.7 (C4a); 142.5
(C10a); 132.5 (C6); 132.1 (C5); 129.4 (C9a); 128.4 (C8a); 125.0 (C8);
1
122.0 (q, JC-F ¼ 276.9, CF3); 122.8 (C7); 25.8 (CH2); 24.8 (q,
4JC-F ¼ 3.0, C1); 21.7 (CH2); 21.4 (CH2). CG-MS (EI, 70 eV): m=z (%) ¼
329 (Mþ, 100); 260 (7); 250 (36); 181 (14); 152 (20); 69 (5); 75 (7). Anal.
calcd. for C14H11BrF3N (329): C, 50.93; H, 3.36; N, 4.24%. Found: C,
50.92; H, 3.17; N, 4.17%.
ACKNOWLEDGMENTS
´
The authors thank Conselho Nacional de Desenvolvimento Cientıfico
e Tecnologico (CNPq) for financial support. Fellowships from the
ꢀ
´
Coordenac¸a˜o de Aperfeic¸oamento de Pessoal de Nıvel Superior (CAPES)
(T. S. M.) and Fundac¸a˜o de Apoio a Tecnologia e Ciencia (FATEC) are
ˆ
also acknowledged.
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