General pathway for a convenient one-pot synthesis of trifluoromethyl- containing 2-amino-7-alkyl(aryl/heteroaryl)- 1,8-naphthyridines and fused cycloalkane analogues

Article abstract of DOI:10.3390/molecules16042817

A convenient and general method for the synthesis in 26-73% yields of a new series of 7-alkyl(aryl/heteroaryl)-2-amino-5-trifluoromethyl-1,8-naphthyridines from direct cyclocondensation reactions of 4-alkoxy-1,1,1-trifluoroalk-3-en-2- ones [CF₃

Full text of DOI:10.3390/molecules16042817

Molecules 2011, 16, 2817-2832; doi:10.3390/molecules16042817
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
General Pathway for a Convenient One-Pot Synthesis of
Trifluoromethyl-Containing 2-amino-7-alkyl(aryl/heteroaryl)-
1,8-naphthyridines and Fused Cycloalkane Analogues
Helio G. Bonacorso *, Rosália Andrighetto, Nícolas Krüger, Nilo Zanatta and
Marcos A. P. Martins
Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal
de Santa Maria, 97105-900 Santa Maria, RS, Brazil
* Author to whom correspondence should be addressed; E-Mail: heliogb@base.ufsm.br;
Tel.: +55(55)-3220-8867; Fax: +55(55)-3220-8031.
Received: 15 February 2011; in revised form: 24 March 2011 / Accepted: 28 March 2011 /
Published: 30 March 2011
Abstract: A convenient and general method for the synthesis in 26–73% yields of a new
series of 7-alkyl(aryl/heteroaryl)-2-amino-5-trifluoromethyl-1,8-naphthyridines from direct
cyclocondensation reactions of 4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones [CF3C(O)CH=C(R1)OR,
where R1 = H, Me, Ph, 4-MePh, 4-OMePh, 4-FPh, 4-BrPh, 4-NO2Ph, 2-furyl, 2-thienyl and
R = Me, Et] with 2,6-diaminopyridine (2,6-DAP), under mild conditions, is described.
Another synthetic route also allowed the synthesis of 2-amino-5-trifluoromethyl-
cycloalka[b][1,8]naphthyridines in 33–36% yields, from direct or indirect cyclo-
condensation reactions of five-, six- and seven-membered 2-trifluoroacetyl-1-methoxy-
cycloalkenes with 2,6-DAP.
Keywords: trifluoromethylated heterocyles; quinolines; naphthyridines; cycloalka[b][1,8]-
naphthyridines; aminonaphthyridines
1. Introduction
Among the nitrogenous heterocycles, naphthyridines and their derivatives represent an important
class of organic molecules that attract the interest of both synthetic and medicinal chemists due to their
exceptionally broad spectrum of biological activities as well as their use as important binding units in

Molecules 2011, 16
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the molecular design of synthetic receptors [1]. Naphthyridine derivatives have attracted considerable
attention primarily due to the presence of a 1,8-naphthyridine skeleton in many compounds which have
been isolated from natural substances and exhibit various biological activities [2]. As a heterocyclic
moiety, 1,8-naphthyridine also deserves special interest as in its molecule, the arrangement of the
nitrogen atoms is optimal for chelation of various metal cations, including lanthanide ions [3].
In parallel to the growing interest in the synthesis of 1,8-naphthyridines to provide biologically
active molecules, a large number of publications have reported that several of their derivatives possess
antibacterial [4], antimycobacterial [5], antitumor [6], anti-inflammatory [7,8], analgesic [8],
antiplatelet [9], gastric antisecretary [10], local anaesthetic [11], anticonvulsant [12] and
antihypertensive activity [13,14], besides being associated with β-adrenergic blocking properties [15].
Some 1,8-naphthyridine compounds have been patented as fungicides, bactericides, insecticides,
herbicides, anxiolytic, antihypertensives, antiarrhythmics and also as immunostimulants [2,16-19].
In addition, has been recognized that attachment of a trifluoromethyl group into heterocycles can be
used to modulate the physical, chemical and biological properties. It is well documented that the
influence of the trifluoromethyl substituent on physiological activity is due mainly to the increased
lipophilicity of the molecules, causing greater cell permeability and resistance to enzyme degradation
[20]. Consequently, synthetic methodology to incorporate fluorine and fluorous synthons must be
improved in order to prepare sophisticated fluoroorganic molecules on a practical scale. One of the
most satisfactory methods for introducing a CF3 group into heterocycles is via the trifluoromethylated
building block approach. The trifluoroacetylation of enol ethers or acetals provided, in one step and in
good yields, β-alkoxyvinyl trifluoromethyl ketones 1 which proved to be useful building blocks for the
syntheses of many series of heterocyclic compounds [21].
Since the 50s various diamino-ketoester condensations involving reactions of cyclic and acyclic β-
ketoesters or diketones with aminopyridines or diaminopyridines have been studied in an attempt to
develop generalized predictions regarding the direction of ring closure to form diazepinones,
naphthyridones, naphthyridines or pyrimidines [6,12-15,19,22]. Whereas a literature review shows that
the synthesis of trifluoromethylated naphthyridines and derivatives has been little explored and that
1,8-naphthyridines trifluoromethylated described are associated with satisfactory biological activities
[14], the incorporation of trifluoromethyl group in a variety of 1,8-naphthyridines would be expected
to provide highly desirable intermediates for the synthesis of new drug candidates. So, due to the great
biological importance and employment of amino-naphthyridines as starting material for the synthesis
of new tri and tetracyclic heterocycles, the development of new synthetic approaches remains an active
research area [19,23].
The use of diethyl ethoxymethylenemalonate (EMME) [24], Conrad-Limpach [25], Knorr [26] and
Skraup [27] methods have been particularly successful in the synthesis of certain quinolines. The
adaptation of these reactions to the synthesis of the corresponding naphthyridines by employing
aminopyridines instead of anilines should furnish convenient methods for the preparation of these
types of compounds since aminopyridines are readily available [19]. However, these methods have not
been as satisfactory for the preparation of 1,8-naphthyridines as they are the preparation of quinolines.
In contrast to aniline derivatives, 2-aminopyridine derivatives may cyclize in two ways, one of which
leads to the formation of 1,8-naphthyridines and the other leads to the formation of pyrimidines, and
the latter course of reaction has is observed with more frequency [28]. In both types of cyclization, the

Molecules 2011, 16
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pyridine ring functions as the electron donor and the carbonyl group in the side chain serves as the
electron acceptor.
The formation of pyrimidines should not be surprising, since the resonance structures existing in the
structure of the 2-aminopyridine derivatives strongly favor cyclization leading to the pyrimidine ring.
Nevertheless, although the formation of a pyrimidine often occurs, an investigation of the synthesis of
certain 1,8-naphthyridines from aminopyridines with diethylmalonate, ethoxymethylidenemalonate or
ethyl acetoacetate has been made [14,19,29]. It is known that the synthesis of 1,8-naphthyridines has
been performed successfully when 6-methyl-2-aminopyridine or 2,6-diaminopyridine are used as
precursors, since 6-methyl or 6-amino groups activate the 3-position leading to those molecules
[14,29]. Thus, the great difference in behavior of 2-aminopyridine and 2,6-diaminopyridine, for
example, has usually been attributed to activation of the 3-position by the electron releasing amine
group.
Recently, we reported reactivity of the endocyclic nitrogen atom of the π-deficient pyridine ring
towards the carbonyl group of the trichloroacetyl enamine derivates from the reactions employing 4-
alkoxy-4-alkyl(aryl)-1,1,1-trichloroalk-3-en-2-ones and 2-aminopyridine in a molar ratio of 1:1,
presenting a convenient method to obtain 4-oxo-4H-pyrido[1,2-a]pyrimidines in good yields (45–81%)
[28]. We also reported the synthesis of 5H-thiazolo[3,2-a]pyrimidi-5-ones from the reactions of β-
alkoxyvinyl trichloromethyl ketones and 2-aminothiazole [30]. Unfortunately, reactions using β-
alkoxyvinyl trifluoromethyl ketones and 2-aminopyridine in an attempt to obtain the respective cyclic
structure only resulted in the isolation of trifluoroacetylenamine derivatives [32]. On the other hand,
reactions using β-alkoxyvinyl trifluoro(chloro)methyl ketones and 2,3-diaminopyridine have been
successfully employed in the synthesis of 3H-pyrido[2,3-b][1,4]diazepinols [31,32] or diazepinones
[31,33].
Although the reactions of 4-alkoxy-4-alkyl(aryl/heteroaryl)-1,1,1-trifluoroalk-3-en-2-ones with
primary and secondary amines have been well documented [28,30-41], there are no reports in the
literature dealing with β-alkoxyvinyl trifluoromethyl ketones as electrophilic precursors and 2,6-
diaminopyridine (2,6-DAP) as nucleophilic precursor. Considering the importance of
trifluoromethylated heterocycles, as an extension of our research the purpose of this paper is to report
the results of a chemical behavior study of the reactions of 4-alkoxy-4-alkyl(aryl/heteroaryl)-1,1,1-
trifluoroalk-3-en-2-ones and 2-trifluoroacetyl-1-methoxycycloalkenes 1 with 2,6-DAP, a symmetrical
heteroaromatic diamine, aiming at the synthesis of new nitrogen-containing trifluoromethylated
heterocycles with conventional procedures (Scheme 1). None of methods reported to date for the
synthesis of naphthyridines employs the strategy adopted in this study. Our method allows the easier
introduction of CF3 group at position 5 and of wide scope of both electron-donor and electron-
withdrawing substituents at position 7 and fused cycloalkanes to the C6-C7 bond of the naphthyridines
ring. Furthermore, the free amino group at position 2, in both cases, allows further important
derivatizations.
2. Results and Discussion
Initially, a series of ten examples of 4-alkoxy-4-alkyl(aryl/heteroaryl)-1,1,1-trifluoroalk-3-en-2-ones
1a-j, which are readily available CCC synthetic blocks, were prepared from trifluoroacetylation

Molecules 2011, 16
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reactions of enol ethers commercially available (for 1a-b) or generated in situ from the respective
acetophenone dimethyl acetal (for 1c-j) with trifluoroacetic anhydride, respectively, in the presence of
pyridine, as described in the literature [42-45].
Fortunately, we found that trifluoromethylated ketones 1a-j when added dropwise to 2,6-DAP at a
molar ratio of 1:1 in methanol as solvent at 0 °C for 2 hours and after heating under reflux for 24
hours, produced 7-alkyl(aryl/heteroaryl)-2-amino-5-trifluoromethyl-1,8-naphthyridines 3a-j. These
compounds were easily isolated from the one-step reaction mixtures in 51–73% yields, although 3a, 3b
and 3i were obtained in lower yields 26, 39 and 38%, respectively (Scheme 1). This is not surprising
since a detailed review of the literature shows that enaminone derivatives of β-ethoxyvinyl
trifluoromethyl ketone (enone 1a) present a different chemical behavior from other enones [41],
leading to heterocycles with lower yields [34] and the absence of cyclization has been reported in
many papers [28,35]. The naphthyridine 3b was previously also synthesized in a low yield (10–23%)
by Eichler et al. from the reaction of 2,6-DAP and 1,1,1-trifluoropentane-2,4-dione [22].
As an extension of this study we also developed the synthesis of compound 3b from the
cyclocondensation reaction of enamino ketone intermediate 2b in methanol at reflux temperature for
24 hours (Scheme 1). The isolation of 2b was possible when the reaction of enone 1b with 2,6-DAP
was carried out in methanol as solvent at 0 °C for 2 hours. Unfortunately, the enamino ketones 2a, 2c-j
could be not isolated as pure compounds, under the same or similar reaction conditions.
Scheme 1. Synthesis of 7-alkyl(aryl/heteroaryl)-2-amino-5-trifluoromethyl-1,8-naphthyridines.
CF3
O
OMe(Et)
R1
i
H
ii
NH2
N
N
O
26-73 %
F3C
NH2
N
N
R1
R1
CF3
1a-j
3a-j
2a, 2c-j (not isolated)
2b (isolated, 58 %)
1-3
R1
a
H
b
c
d
e
f
g
h
i
j
Me Ph 4-MePh 4-OMePh 4-FPh 4-BrPh 4-NO2Ph 2-Furyl 2-Thienyl
Reagents and Conditions: (i) = 2,6-Diaminopyridine, MeOH, 0 °C, 2 h; (ii) = MeOH, reflux, 24 h.
1
The structures of 3a-j were established on the basis of H- and 13C-NMR spectroscopy and
literature data for similar compounds (chemical shifts and spin ± spin coupling constants)
[5,9,12,14,22,41,46]. According to the literature, it is well known that the proton in the 4-position of
the naphthyridine nucleus shows long-range coupling with fluorine atoms of the 5-trifluoromethyl
substituent, but in some cases the outer signals of the quartets can appear as shoulders on the inner
signals instead of as clearly resolved quartets [22]. This splitting of the H-4 signal is seen in all of the
compounds having this structural feature and was clearly seen in 1H-NMR spectral data of compounds
3a-j.

Molecules 2011, 16
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Furthermore, some examples of compounds 3 were converted in good yields (82–93%) to the
corresponding 2-acetamide derivatives 4, by reaction with acetic anhydride under high temperature
[14] (Scheme 2).
Scheme 2. Synthesis of 2-acetamide derivatives.
CF3
N
CF3
i
O
82-93 %
R1
H3C
N
N
R1
H2N
N
N
H
3
4
3,4
c
f
g
i
j
R1 Ph 4-FPh 4-BrPh 2-Furyl 2-Thienyl
Reagents and Conditions: (i) = Acetic anhydride, 160 °C, 4h.
As a second extension, applying a similar cyclization method to that previously described by us for
the preparation of some trifluoromethyl-substituted benzo[h]quinolines [35], dihydrobenzo[c]acridines
[36], cycloalka[b]quinolines [37], 1,2,3,4-tetrahydroacridines [38], 7-aminoquinolines and 1,7-
phenanthrolines [41], to investigate the chemical behavior of enamino ketone intermediate 2b in
polyphosphoric acid medium (PPA), we found that a 1:1 mixture of isomers 3b:5b is obtained when
2b is heated at 90 °C for 20 h (Scheme 3). These compounds were easily identified since CH3 and CF3
groups have different chemical shifts in the 13C-NMR spectra of each of the isomers. Thus, 7-methyl-
2-amino-5-trifluoromethyl-1,8-naphthyridine (3b) showed chemical shifts at 133.8 ppm (C5, q, 2JCF 31
Hz) and 24.6 ppm for the CH3 group, while the isomer 5-methyl-2-amino-7-trifluoromethyl-1,8-
2
naphthyridine (5b) showed chemical shifts at 148.1 ppm (C7, q, JCF 34 Hz) and 17.5 ppm for the
CH3 group.
Scheme 3. Synthesis of isomers 3b:5b.
CF3
CH3
i
H
NH2
N
N
O
87 %
H2N
N
N
CH3
H2N
N
N
CF3
H3C
CF3
2b
3b (44 %)
Reagents and Conditions: (i) = PPA, 90 °C, 20 h.
5b (43 %)
As an second extension of this study, we also developed the synthesis of trifluoromethyl substituted
cycloalka[b][1,8]naphthyridines 3 from the reactions of 2-trifluoroacetyl-1-methoxycycloalkenes 1
with 2,6-DAP (Scheme 4). Firstly, three examples of methoxycycloalkenes 1k-m were obtained by a
direct acylation reaction of the cycloalkane dimethyl acetals with trifluoracetic anhydride in the
presence of pyridine, as described in the literature [47,48]. Subsequently, the intramolecular
cyclization reactions of trifluoroacetylated cycloalkenes 1k-m were carried out, applying the same

Molecules 2011, 16
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conditions described for the preparation of 3a-j. This reaction condition allows to isolate, in one-pot,
only the respective cycloalka[b][1,8]naphthyridines 3l, 3m in 30–33% yields because the cyclization
of 1k did not take place. This reaction condition allowed the isolation of enaminone 2k in 43% yield,
derived from 2-trifluoroacetyl-1-methoxycyclopentene. The synthesis of 3k, in 78% yield, was only
possible from intramolecular cyclization reaction of enaminone 2k in polyphosphoric acid medium
(PPA), as shown in Scheme 4. The structures of compounds 2k, 3k-m were easily established on the
1
basis of H- and 13C-NMR spectroscopy and literature data for similar compounds, such as
trifluoromethyl-containing cycloalka[b]quinolines [37].
Scheme 4. Synthesis of trifluoromethyl substituted cycloalka[b][1,8]naphthyridines.
CF3
iii
H2N
N
N
H
43 %
H2N
N
N
O
CF3
OMe
O
i,ii
2k
3k
CF3
CF3
n
1k-m
30-33 %
n
H2N
N
N
3l-m
1-3
k
l
m
n
1
2
3
Reagents and Conditions: (i) = 2,6-Diaminopyridine, MeOH, 0 °C, 2 h; (ii) = MeOH, reflux, 24 h;
(iii) = PPA, 90 °C, 20 h.
Any attempt to explain the low yield for the synthesis of compounds 3l and 3m and the absence of
cyclization for 1k requires an examination of the structural effects on internal cycloalkenes 1k-m.
Information from the literature for precursors of these compounds [47], obtained by calculation
using AM1 semi-empirical method, indicate the possibility of non-planar conformations for these
molecules, which would explain the difficulty in achieving [3+3] intramolecular cyclization in the case
of 1k [37,48].
3. Experimental
3.1. General
Unless otherwise indicated all common reagents and solvents were used as obtained from
commercial suppliers without further purification. The melting points were determined using a Kofler
1
Reichert-Thermovar and Electrothermal Mel-Temp 3.0 apparatus. H- and 13C-NMR spectra were
acquired on a Bruker DPX 200 spectrometer (1H at 200.13 MHz) and Bruker DPX 400 (1H at
400.13 MHz, 13C at 100.32 MHz) spectrometer, 5 mm sample tubes, 298 K, digital resolution
±0.01 ppm, in DMSO-d6, in CDCl3 for 3a, 3m, 4i, 4j and CDCl3 + TFA for 4g, using TMS as internal

Molecules 2011, 16
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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 (São Paulo
University, USP/Brazil).
3.2. General procedure for the synthesis of (Z)-N(5,5,5-Trifluoro-4-oxo-2-penten-2-yl)-2,6-diamino-
pyridine (2b)
To a magnetically stirred solution of 2,6-diaminopyridine (0.54 g, 5 mmol) in methanol (25 mL), a
solution of 1b (0.84 g, 5 mmol) in methanol (25 mL) was added dropwise at 0 °C over a period of 2 h.
After the end of the reaction, the solvent was evaporated under reduced pressure. Then, the crude oily
product was dissolved in hot ethanol and subsequently cooled (4–8 °C, 24 h) to give the title
compound 2b (0.28 g, 58% yield) as a brown solid, m.p. 130–132 °C. 1H-NMR (200 MHz, DMSO-d6):
δ = 12.69 (s, 1H, NH), 7.40 (t, J = 8 Hz, 1H, H-10), 6.33 (d, J = 8 Hz, 1H, H-9), 6.34 (d, J = 8 Hz, 1H,
13
H-11), 5.49 (s, 1H, H-3), 5.20 (s, 2H, NH2), 2.53 (s, 3H, CH3). C-NMR (100 MHz, DMSO-d6): δ =
175.3 (q, 2J = 31 Hz, C=O), 166.5 (C-2), 157.7 (C-8), 149.0 (C-6), 138.7 (C-10), 116.6 (q, 1J = 288 Hz,
CF3), 104.5, 103.8 (C-9, C-11), 91.8 (C-3), 21.7 (CH3). GC-MS (EI, 70 eV) m/z: 245 (M+, 100), 228
(15), 176 (22), 148 (15), 69 (5%). Anal. Calcd. For C10H10F3N3O (245.08): C, 48.98; H, 4.11; N,
17.14%. Found: C, 48.82; H, 4.03; N, 17.28%.
3.3. General procedure for the synthesis of 2-(6-Aminopyridin-2-ylamino)1-trifluoroacetyl-cyclopent-
1-ene (2k)
To a magnetically stirred solution of 2,6-diaminopyridine (0.22 g, 2 mmol) in methanol (20 mL), a
solution of 1k (0.38 g, 2 mmol) in methanol (20 mL) was added dropwise at 0 °C over a period of 2 h.
The mixture was refluxed for an additional 24 h. After the end of the reaction, the solvent was
evaporated under reduced pressure. Then, the crude oily product was dissolved in hot ethanol and
subsequently cooled (4–8 °C, 24 h) to give the title compound 2k (0.22 g, 43% yield) as a brown solid,
m.p. 139–141 °C. 1H-NMR (200 MHz, DMSO-d6): δ = 11.85 (s, 1H, NH), 6.03 (s, 2H, NH2); Py: 7.39
(t, J = 8 Hz, 1H, H-4), 6.32 (d, J = 8 Hz, 1H, H-5), 6.27 (d, J = 8 Hz, 1H, H-3); c-Pent: 3.28–3.24 (m,
2H, CH2), 2.67–2.64 (m, 2H, CH2), 1.96–1.88 (m, 2H, CH2). 13C-NMR (100 MHz, DMSO-d6):
δ = 172.5 (q, 2J = 33 Hz, C=O), 171.3 (C-2), 101.0 (C-1), 117.2 (q, 1J = 289 Hz, CF3); Py: 158.8 (C-6),
4
149.6 (C-2), 139.0 (C-4), 104.1, 103.5 (C-3, C-5); c-Pent: 34.1 (CH2), 26.3 (q, J = 3 Hz, CH2), 22.1
(CH2). GC-MS (EI, 70 eV) m/z: 271 (50), 256 (5), 202 (25), 174 (M+, 100%). Anal. Calcd. For
C12H12F3N3O (271.09): C, 53.14; H, 4.46; N, 15.49%. Found: C, 53.02; H, 4.38; N, 15.61%.
3.4. General procedure for the synthesis of 7-alkyl(aryl/heteroaryl)-2-amino-5-trifluoromethyl-1,8-
naphthyridines 3a-j
To a magnetically stirred solution of 2,6-diaminopyridine (1.08 g, 10 mmol) in methanol (40 mL), a
solution of 1a-j (10 mmol) in methanol (40 mL) was added dropwise at 0 °C over a period of 2 h. The
mixture was refluxed for an additional 24 h. After the end of the reaction, the solvent was evaporated

Molecules 2011, 16
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under reduced pressure. The crude product was dissolved in ethanol and cooled (4–8 °C, 24 h). The
solids 3b-j were isolated from the cooled solution by filtration under reduced pressure. The compound
3a was purified by flash chromatography eluting with ethyl acetate/n-hexane (1:2); yields: 26–73%.
1
2-Amino-5-trifluoromethyl-1,8-naphthyridine (3a): Brown solid; yield 26%; m.p. 126–128 °C. H-
NMR (200 MHz, CDCl3): δ = 8.91 (d, J = 5 Hz, 1H, H-7), 8.08 (dq, J1 = 2, J2 = 9 Hz, 1H, H-4), 7.41
(d, J = 5 Hz, 1H, H-6), 6.94 (d, J = 9 Hz, 1H, H-3), 6.43 (s, 2H, NH2). 13C-NMR (100 MHz, CDCl3):
2
δ = 159.9 (C-7), 156.8 (C-8a), 152.0 (C-2), 135.1 (q, J = 31 Hz, C-5), 134.2 (C-4), 123.1 (q,
1J = 275 Hz, CF3), 114.8 (C-3), 114.5 (q, 3J = 5 Hz, C-6), 112.5 (C-4a). GC-MS (EI, 70 eV) m/z: 214
(M+, 100), 194 (52), 69 (10%). Anal. Calcd. For C9H6F3N3 (213.05): C, 50.71; H, 2.84; N, 19.71%.
Found: C, 50.77; H, 2.92; N, 19.81%.
2-Amino-5-trifluoromethyl-7-methyl-1,8-naphthyridine (3b): Yellow solid; yield 39%; m.p.
200–202 °C (lit. [22] 195–197 °C). 1H-NMR (200 MHz, DMSO-d6): δ = 8.01 (dq, J1 = 2, J2 = 9 Hz,
13
1H, H-4), 7.43 (s, 1H, H-6), 7.16 (s, 2H, NH2), 6.97 (d, J = 9 Hz, 1H, H-3), 2.64 (s, 3H, CH3). C-
2
NMR (100 MHz, DMSO-d6): δ = 160.8 (C-7), 160.7 (C-8a), 157.0 (C-2), 132.9 (q, J = 31 Hz, C-5),
1
3
132.4 (C-4), 123.5 (q, J = 275 Hz, CF3), 114.1 (C-3), 113.6 (q, J = 5 Hz, C-6), 108.8 (C-4a), 24.8
(CH3). GC-MS (EI, 70 eV) m/z 227 (M+, 100), 210 (3), 200 (37), 158 (3), 131 (5%).
2-Amino-5-trifluoromethyl-7-phenyl-1,8-naphthyridine (3c): Beige solid; yield 69%; m.p. 255–257 °C.
1H-NMR (200 MHz, DMSO-d6): δ = 8.28 (dd, J1 = 2, J2 = 8 Hz, 2H, Ph), 8.06 (dq, J1 = 2, J2 = 9 Hz,
1H, H-4), 8.03 (s, 1H, H-6), 7.58-7.53 (m, 3H, Ph), 7.18 (s, 2H, NH2), 7.05 (d, J = 9 Hz, 1H, H-3). 13C-
NMR (100 MHz, DMSO-d6): δ = 161.0 (C-7), 157.5 (C-8a), 157.2 (C-2), 137.7 (C-Ph), 134.0 (q,
2J = 31 Hz, C-5), 132.3 (q, 4J = 2 Hz, C-4), 129.8, 128.5, 127.0 (5 C-Ph), 123.2 (q, 1J = 275 Hz, CF3),
3
3
114.8 (C-3), 110.2 (q, J = 5 Hz, C-6), 110.0 (q, J = 2 Hz, C-4a). GC-MS (EI, 70 eV) m/z: 290 (M+,
100), 270 (23%). Anal. Calcd. For C15H10F3N3 (289.08): C, 62.28; H, 3.48; N, 14.53%. Found: C,
62.12; H, 3.60; N, 14.30%.
2-Amino-5-trifluoromethyl-7-(4-methylphenyl)-1,8-naphthyridine (3d): Yellow solid; yield 51%; m.p.
1
219–221 °C. H-NMR (200 MHz, DMSO-d6): δ = 8.19 (d, J = 8 Hz, 2H, Ph), 8.09 (dd, J1 = 2,
J = 9 Hz, 1H, H-4), 7.98 (s, 1H, H-6), 7.35 (d, J = 8 Hz, 2H, Ph), 7.20 (s, 2H, NH2), 7.08 (d, J = 9 Hz,
13
1H, H-3), 2.40 (s, 3H, CH3). C-NMR (100 MHz, DMSO-d6): δ = 160.9 (C-7), 157.4 (C-8a), 157.2
(C-2), 139.5, 134.9 (2 C-Ph), 133.8 (q, 2J = 31 Hz, C-5), 132.1 (C-4), 129.1, 126.8 (4 C-Ph), 123.2 (q,
1J = 275 Hz, CF3), 114.5 (C-3), 109.8 (q, 3J = 5 Hz, C-6), 99.5 (C-4a), 20.5 (CH3). GC-MS (EI, 70 eV)
m/z: 303 (M+, 100), 276 (12), 234 (14%). Anal. Calcd. For C16H12F3N3 (303.1): C, 63.36; H, 3.99; N,
13.86%. Found: C, 63.44; H, 4.06; N, 14.01%.
2-Amino-5-trifluoromethyl-7-(4-methoxyphenyl)-1,8-naphthyridine (3e): Beige solid; yield 53%; m.p.
210–212 °C. 1H-NMR (200 MHz, DMSO-d6): δ = 8.32 (d, J = 8 Hz, 2H, Ph), 8.10 (dq, J1 = 2, J2 = 9 Hz,
1H, H-4), 8.03 (s, 1H, H-6), 7.44 (s, 2H, NH2), 7.13 (d, J = 8 Hz, 2H, Ph), 7.10 (d, J = 9 Hz, 1H, H-3),
3.89 (s, 3H, CH3). 13C-NMR (100 MHz, DMSO-d6): δ = 161.2 (C-7), 160.9 (C-8a), 157.4 (C-Ph),
2
1
157.3 (C-2), 134.0 (q, J = 31 Hz, C-5), 132.5 (C-4), 130.2, 128.7 (3 C-Ph), 123.4 (q, J = 275 Hz,
CF3), 114.5 (C-3), 114.1 (2 C-Ph), 109.8 (q, 3J = 5 Hz, C-6), 109.6 (C-4a), 55.2 (OCH3). GC-MS (EI,

Molecules 2011, 16
2825
70 eV) m/z: 320 (M+, 100), 300 (22%). Anal. Calcd. For C16H12F3N3O (319.09): C, 60.19; H, 3.79; N,
13.16%. Found: C, 59.90; H, 3.89; N, 13.07%.
2-Amino-5-trifluoromethyl-7-(4-fluorophenyl)-1,8-naphthyridine (3f): Yellow solid; yield 73%; m.p.
260–262 °C. 1H-NMR (200 MHz, DMSO-d6): δ = 8.36–8.32 (m, 2H, FPh), 8.06 (dq, J1 = 2, J2 = 9 Hz,
1H, H-4), 8.01 (s, 1H, H-6), 7.38–7.33 (m, 2H, FPh), 7.14 (s, 2H, NH2), 7.02 (d, J = 9 Hz, 1H, H-3).
13C- NMR (100 MHz, DMSO-d6): δ = 163.4 (d, 1J = 247 Hz, C-FPh), 161.2 (C-7), 157.3 (C-8a), 156.5
2
(C-2), 134.2 (d, 4J = 3 Hz, C-FPh), 134.1 (q, J = 31 Hz, C-5), 132.4 (C-4), 129.5 (d, 3J = 9 Hz, 2 C-
FPh), 123.3 (q, 1J = 275 Hz, CF3), 115.6 (d, 2J = 21 Hz, 2 C-FPh), 115.1 (C-3), 110.2 (q, 3J = 5 Hz, C-
3
6), 110.0 (q, J = 2 Hz, C-4a). GC-MS (EI, 70 eV) m/z: 307 (M+, 100), 238 (25), 164 (2), 143 (4%).
Anal. Calcd. For C15H9F4N3 (307.07): C, 58.64; H, 2.95; N, 13.68%. Found: C, 58.48; H, 3.11; N,
13.24%.
2-Amino-7-(4-bromophenyl)-5-trifluoromethyl-1,8-naphthyridine (3g): Yellow solid; yield 73%; m.p.
285–287 °C. 1H-NMR (200 MHz, DMSO-d6): δ = 8.23 (dd, J1 = 2, J2 = 8 Hz, 2H, Ph), 8.08 (dq, J1 = 2,
J2 = 9 Hz, 1H, H-4), 8.02 (s, 1H, H-6), 7.72 (dd, J1 = 2, J2 = 8 Hz, 2H, Ph), 7.18 (s, 2H, NH2), 7.07 (d,
J = 9 Hz, 1H, H-3). 13C-NMR (100 MHz, DMSO-d6): δ = 161.3 (C-7), 157.3 (C-8a), 156.4 (C-2),
2
136.9 (C-Ph), 134.2 (q, J = 31 Hz, C-5), 132.5 (C-4), 131.7, 129.2, 123.9 (5 C-Ph), 123.4 (q,
1J = 275 Hz, CF3), 115.3 (C-3), 110.4 (C-4a), 110.2 (q, 3J = 5 Hz, C-6). GC-MS (EI, 70 eV) m/z: 367
(M+, 100), 298 (12), 288 (50), 144 (17%). Anal. Calcd. For C15H9BrF3N3 (366.99): C, 48.94; H, 2.46;
N, 11.41%. Found: C, 49.04; H, 2.54; N, 11.37%.
2-Amino-5-trifluoromethyl-7-(4-nitrophenyl)-1,8-naphthyridine (3h): Yellow solid; yield 63%; m.p. >
1
340 °C. H-NMR (200 MHz, DMSO-d6): δ = 8.53 (d, J = 8 Hz, 2H, Ph), 8.35 (d, J = 8 Hz, 2H, Ph),
8.06 (dd, J1 = 2, J = 9 Hz, 1H, H-4), 8.02 (s, 1H, H-6), 7.20 (s, 2H, NH2), 7.06 (d, J = 9 Hz, 1H, H-3).
13C-NMR (100 MHz, DMSO-d6): δ = 161.1 (C-7), 157.1 (C-8a), 155.0 (C-2), 148.0, 143.4 (2 C-Ph),
134.3 (q, 2J = 31 Hz, C-5), 132.1 (C-4), 128.2, 123.5 (4 C-Ph), 123.0 (q, 1J = 275 Hz, CF3), 115.7 (C-
3
3), 110.9 (C-4a), 109.8 (q, J = 2 Hz, C-6). GC-MS (EI, 70 eV) m/z: 334 (M+, 100), 288 (97), 144
(17%). Anal. Calcd. For C15H9F3N4O2 (334.07): C, 53.90; H, 2.71; N, 16.76%. Found: C, 53.85; H,
2.78; N, 16.52%.
2-Amino-5-trifluoromethyl-7-(2-furyl)-1,8-naphthyridine (3i): Yellow solid, yield 38%; m.p. 230–232
°C. 1H-NMR (200 MHz, DMSO-d6): δ = 7.98 (d, J = 4 Hz, 1H, furyl), 7.89 (dq, J1 = 2, J2 = 9 Hz, 1H,
H-4), 7.80 (s, 1H, H-6), 7.40 (d, J = 5 Hz, 1H, furyl), 7.17 (s, 2H, NH2), 7.04 (d, J = 9 Hz, 1H, H-3),
13
6.75 (t, J = 4 Hz, 1H, furyl). C-NMR (100 MHz, DMSO-d6): δ = 160.9 (C-7), 157.0 (C-8a), 152.3
2
4
1
(C-2), 149.5, 145.1, (2 C-furyl), 133.9 (q, J = 31 Hz, C-5), 132.3 (q, J = 2 Hz, C-4), 123.0 (q, J =
275 Hz, CF3), 114.5 (C-3), 112.4, 111.1 (2 C-furyl), 109.8 (q, 3J = 2 Hz, C-4a), 108.6 (q, 3J = 5 Hz, C-
6). GC-MS (EI, 70 eV) m/z: 279 (M+, 100), 251 (25), 223 (12%). Anal. Calcd. For C13H8F3N3O
(279.06): C, 55.92; H, 2.89; N, 15.05%. Found: C, 55.48; H, 2.88; N, 14.72%.
2-Amino-5-trifluoromethyl-7-(2-thienyl)-1,8-naphthyridine (3j): Yellow solid; yield 60%; m.p. 260–
262 °C. 1H-NMR (200 MHz, DMSO-d6): δ = 8.12 (d, J = 4 Hz, 1H, thienyl), 8.07 (dq, J1 = 2, J2 = 9 Hz,
1H, H-4), 8.04 (s, 1H, H-6), 7.78 (d, J = 5 Hz, 1H, thienyl), 7.26 (t, J = 4 Hz, 1H, thienyl), 7.23 (s, 2H,

Molecules 2011, 16
NH2), 7.07 (d, J = 9 Hz, 1H, H-3). C-NMR (100 MHz, DMSO-d6): δ = 161.1 (C-7), 157.0 (C-8a),
2826
13
2
4
153.2 (C-2), 143.9 (C-thienyl), 133.9 (q, J = 31 Hz, C-5), 132.3 (q, J = 2 Hz, C-4), 130.0, 128.3,
127.5 (3 C-thienyl), 123.1 (q, 1J = 275 Hz, CF3), 114.3 (C-3), 109.9 (q, 3J = 2 Hz, C-4a), 109.3 (q, 3J =
5 Hz, C-6). GC-MS (EI, 70 eV) m/z: 295 (M+, 100), 268 (25), 226 (4%). Anal. Calcd. For C13H8F3N3S
(295.04): C, 52.88; H, 2.73; N, 14.23%. Found: C, 52.94; H, 2.85; N, 14.10%.
3.5. General procedure for the synthesis of 2-amino-5-trifluoromethyl-7,8-dihydro-6H-
cyclopenta[b][1,8]-naphthyridine (3k)
To a stirred mixture of H3PO4 (0.8 mL) and P2O5 (1.2 g) (PPA) at 90 °C, 2k (0.27 g, 1 mmol) was
added. The reaction mixture was stirred for an additional 20 h. After cooling, the reaction mixture was
treated with crushed ice and with concentrated NH4OH until the pH was 8. The compound 3k was
isolated of the solution by filtration at reduced pressure as a brown solid, in 78% yield, m.p. 172–174
ºC. 1H-NMR (200 MHz, DMSO-d6): δ = 8.00 (dq, J1 = 2, J2 = 9 Hz, 1H, H-4), 6.91 (d, J = 9 Hz, 1H,
H-3), 6.80 (s, 2H, NH2), 3.18–3.14 (m, 2H, CH2), 3.02 (t, J = 9 Hz, 2H, CH2), 2.15–2.07 (m, 2H, CH2).
13C-NMR (100 MHz, DMSO-d6): δ = 170.0 (C-9a), 159.8 (C-2), 156.5 (C-10a), 132.5 (q, 4J = 3 Hz, C-
3
2
1
4), 128.0 (q, J = 3 Hz, C-5a), 127.6 (q, J = 30 Hz, C-5), 124.2 (q, J = 276 Hz, CF3), 113.0 (C-3),
109.2 (q, 3J = 2 Hz, C-4a), 33.7, 29.7 (q, 4J = 2 Hz), 21.9 (3 CH2). GC-MS (EI, 70 eV) m/z: 253 (M+,
100), 237 (5), 184 (20%). Anal. Calcd. For C12H10F3N3 (253.08): C, 56.92; H, 3.98; N, 16.59%.
Found: C, 56.80; H, 3.84; N, 16.73%.
3.6. General procedure for the synthesis of 2-amino-5-trifluoromethyl-cycloalka[b][1,8]-
naphthyridines 3l, 3m
To a magnetically stirred solution of 2,6-diaminopyridine (0.22 g, 2 mmol) in methanol
(20 mL), a solution of 1k-l (2 mmol) in methanol (20 mL) was added drop wise at 0 °C over a period
of 2 h. The mixture was refluxed for an additional 24 h. After the end of the reaction, the solvent was
evaporated under reduced pressure. The compounds 3k-l were purified by flash chromatography
eluting with ethyl acetate/n-hexane (1:2); yields: 30–33%.
2-Amino-5-trifluoromethyl-6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridine (3l): Brown solid, yield
33%; m.p. 128–130 °C. 1H-NMR (200 MHz, DMSO-d6): δ = 8.07 (dq, J1 = 2, J2 = 9 Hz, 1H, H-4),
6.93 (d, J = 9 Hz, 1H, H-3), 6.85 (s, 2H, NH2), 2.99–2.96 (m, 4H, CH2), 1.90–1.78 (m, 4H, CH2). 13C-
NMR (100 MHz, DMSO-d6): δ = 160.9 (C-2), 159.8 (C-10a), 154.6 (C-9a), 132.7 (q, 4J = 3 Hz, C-4),
130.3 (q, 2J = 28 Hz, C-5), 124.7 (q, 1J = 278 Hz, CF3), 124.5 (C-5a), 114.0 (C-3), 110.5 (q, 3J = 2 Hz,
C-4a), 33.8, 25.6, 22.0, 21.2 (4 CH2). GC-MS (EI, 70 eV) m/z: 268 (M+, 100), 248 (20), 198 (9%).
Anal. Calcd. For C13H12F3N3 (267.1): C, 58.42; H, 4.53; N, 15.72%. Found: C, 58.59; H, 4.65; N,
15.61%.
2-Amino-5-trifluoromethyl-7,8,9,10-tetrahydro-6H-cyclohepta[b][1,8]naphthyridine (3m): Brown
solid; yield 30%; m.p. 93–95 °C. 1H-NMR (200 MHz, CDCl3): δ = 8.20 (d, J = 9 Hz, 1H, H-4), 7.75
(d, J = 9 Hz, 1H, H-3), 7.19 (s, 2H, NH2), 3.21–3.00 (m, 4H, CH2), 1.79–1.68 (m, 6H, CH2). 13C-NMR
(100 MHz, CDCl3): δ = 158.8 (C-2), 156.5 (C-11a), 154.5 (C-10a), 140.7 (C-5a), 134.6 (C-4), 131.2

Molecules 2011, 16
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(q, 2J = 30 Hz, C-5), 123.9 (q, 1J = 278 Hz, CF3), 113.5 (C-3), 97.3 (C-4a), 39.0, 38.9, 29.3, 27.5, 26.2
(5 CH2). GC-MS (EI, 70 eV) m/z: 281 (M+, 100), 265 (15), 252 (30), 212 (4%). Anal. Calcd. For
C14H14F3N3 (281.1): C, 59.78; H, 5.02; N, 14.94%. Found: C, 59.69; H, 4.88; N, 15.01%.
3.7. General procedure for the synthesis of 2-acetylamino-7-(aryl/heteroaryl)-5-trifluoromethyl-1,8-
naphthyridines 4
A suspension of 2 mmol of amino derivatives 3c, 3f, 3g, 3i or 3j in 5 mL of acetic anhydride was
refluxed at 160 °C for 2 h. After cooling, the solids were collected and washed with water to give their
acetamide derivatives 4, in 82–93% yields.
2-Acetylamino-5-trifluoromethyl-7-phenyl-1,8-naphthyridine (4c): Beige solid; yield 74%; m.p. 224–
226 °C. 1H-NMR (200 MHz, DMSO-d6): δ = 11.34 (s, 1H, NH), 8.54-850 (m, 2H, H-3, H-4), 8.40 (s,
13
1H, H-6), 8.37-835 (m, 2H, Ph), 760-7.58 (m, 3H, Ph), 2.22 (CH3). C-NMR (100 MHz, DMSO-d6):
2
δ = 171.6 (C=0), 170.0 (C-8a), 158.7 (C-7), 155.5 (C-2), 136.9 (C-Ph), 135.4 (q, J = 33 Hz, C-5),
134.4 (C-4), 130.4, 128.7, 127.3 (5 C-Ph), 122.9 (q, 1J = 275 Hz, CF3), 115.9 (C-3), 114.4 (q, 3J = 5 Hz,
C-6), 113.1 (C-4a), 23.9 (CH3). GC-MS (EI, 70 eV) m/z: 331 (40), 288 (M+, 100), 262 (15), 219 (9%).
Anal. Calcd. For C17H12F3N3O (331.09) C, 61.63; H, 3.65; N, 12.68%. Found: C, 61.49; H, 3.50; N,
12.78%.
2-Acetylamino-5-trifluoromethyl-7-(4-fluorophenyl)-1,8-naphthyridine (4f): Beige solid; yield 83%;
1
m.p. 263–265 °C. H-NMR (200 MHz, CDCl3): δ = 11.21 (s, 1H, NH), 8.50 (d, J = 9 Hz, 1H, H-3),
8.45 (d, J = 9 Hz, 1H, H-4), 8.40-8.37 (m, 2H, FPh), 8.33 (s, 1H, H-6), 7.39-7.35 (m, 2H, FPh), 2.23
(s, 3H, CH3). 13C-NMR (100 MHz, DMSO-d6): δ = 170.0 (C=0), 163.6 (d, 1J = 248 Hz, C-FPh), 157.6
(C-8a), 155.0 (C-7), 154.9 (C-2), 135.5 (q, 2J = 33 Hz, C-5), 134.3 (C-4), 133.4 (d, 4J = 3 Hz, C-FPh),
1
2
129.6 (d, 3J = 9 Hz, 2 C-FPh), 122.7 (q, J = 275 Hz, CF3), 115.8 (C-6), 115.6 (d, J = 21 Hz, 2 C-
FPh), 114.2 (C-3), 113.0 (C-4a), 23.8 (CH3). GC-MS (EI, 70 eV) m/z: 349 (45), 307 (M+, 100), 280
(25), 238 (15%). Anal. Calcd. For C17H11F4N3O (349.08): C, 58.46; H, 3.17; N, 12.03%. Found: C,
58.28; H, 3.02; N, 12.15%.
2-Acetylamino-7-(4-bromophenyl)-5-trifluoromethyl-1,8-naphthyridine (4g): Beige solid; yield 93%;
m.p. 222–224°C. 1H-NMR (200 MHz, CDCl3 + TFA): δ = 11.34 (s, 1H, NH), 8.90 (d, J = 9 Hz, 1H, H-
3), 8.45 (s, 1H, H-6), 8.18 (d, J = 9 Hz, 2H, Ph), 7.80 (d, J = 9 Hz, 2H, Ph), 7.74 (d, J = 9 Hz, 1H, H-
13
4), 2.54 (s, 3H, CH3). C-NMR (100 MHz, CDCl3 + TFA): δ = 176.0 (C=0), 169.8 (C-8a), 152.1 (C-
2
7), 145.4 (C-2), 143.0 (C-Ph), 137.7 (q, J = 33 Hz, C-5), 133.5 (C-4), 133.0, 129.7, 128.8, (5 C-Ph),
121.6 (q, 1J = 275 Hz, CF3), 118.2 (q, 3J = 5 Hz, C-6), 114.1 (C-3), 113.3 (C-4a), 24.2 (CH3). GC-MS
(EI, 70 eV) m/z: 409 (42), 367 (M+, 100), 339 (5), 296 (6), 288 (42%). Anal. Calcd. For
C17H11BrF3N3O (409.1): C, 49.78; H, 2.70; N, 10.24%. Found: C, 49.61; H, 2.58; N, 10.33%.
2-Acetylamino-5-trifluoromethyl-7-(2-furyl)-1,8-naphthyridine (4i): Yellow solid; yield 82%; m.p.
221–223 °C. 1H-NMR (200 MHz, CDCl3): δ = 9.74 (s, 1H, NH), 8.60 (d, J = 9 Hz, 1H, H-3), 8.41 (d,
J = 9 Hz, 1H, H-4), 8.10 (s, 1H, H-6), 7.65 (s, 1H, furyl), 7.45 (d, J = 3 Hz, 1H, furyl), 6.62 (t,
J = 2 Hz, 1H, furyl), 2.29 (s, 3H, CH3). 13C-NMR (100 MHz, CDCl3): δ = 176.2 (C=0), 169.8 (C-8a),

Molecules 2011, 16
2828
2
152.5 (C-7), 151.8 (C-2), 145.3 (2 C-furyl), 136.0 (q, J = 32 Hz, C-5), 135.9 (C-4), 122.8 (q,
1J = 275 Hz, CF3), 115.8 (C-3), 114.3 (C-4a), 113.8 (q, 3J = 5 Hz, C-6), 112.9, 112.7 (2 C-furyl), 24.5
(CH3). GC-MS (EI, 70 eV) m/z: 321 (50), 306 (5), 279 (M+, 100), 251 (10%). Anal. Calcd. For
C15H10F3N3O2 (321.07) C, 56.08; H, 3.14; N, 13.08%. Found: C, 56.00; H, 3.03; N, 13.18%.
2-Acetylamino-5-trifluoromethyl-7-(2-thienyl)-1,8-naphthyridine (4j): Beige solid; yield 90%; m.p.
225–227 °C. 1H-NMR (200 MHz, CDCl3): δ = 9.76 (s, 1H, NH), 8.59 (d, J = 9 Hz, 1H, H-3), 8.40 (d,
J = 9 Hz, 1H, H-4), 7.98 (s, 1H, H-6), 7.84 (s, 1H, thienyl), 7.54 (d, J = 4 Hz, 1H, thienyl), 7.16 (d,
13
J = 3 Hz, 1H, thienyl), 2.29 (s, 3H, CH3). C-NMR (100 MHz, CDCl3): δ = 176.1 (C=0), 169.8 (C-
8a), 155.3 (C-7), 154.9 (C-2), 143.4 (C-thienyl), 135.9 (q, 2J = 33 Hz, C-5), 135.7 (C-4), 130.9, 128.4,
127.9 (3 C-thienyl), 122.9 (q, 1J = 275 Hz, CF3), 115.8 (C-3), 114.3 (C-4a), 114.1 (q, 3J = 5 Hz, C-6),
24.7 (CH3). GC-MS (EI, 70 eV) m/z: 337 (43), 322 (5), 295 (M+, 100), 268 (25%). Anal. Calcd. For
C15H10F3N3OS (337.05): C, 53.41; H, 2.99%; N, 12.46. Found: C, 53.33; H, 2.81; N, 12.54%.
3.8. General procedure for the synthesis of 2-amino-5-trifluoromethyl-7-methyl-1,8-naphthyridine (3b)
and 2-amino-7-trifluoromethyl-5-methyl-1,8-naphthyridine (5b)
These compounds were obtained as a yellow solid, a 1:1 mixture of 3b:5b in 87% yield, m.p. 179–
181 °C. To a stirred mixture of H3PO4 (0.8 mL) and P2O5 (1.2 g) (PPA) at 90 °C, 2b (0.24 g, 1 mmol)
was added. The reaction mixture was stirred for an additional 20 h. After cooling, the reaction mixture
was treated with crushed ice and with concentrated NH4OH until the pH was 8. The solution was then
extracted with ethyl acetate (3 × 20 mL), the combined extracts were dried (MgSO4) and evaporated to
dryness under a vacuum to obtain the solid mixture of isomers 3b:5b.
2-Amino-5-trifluoromethyl-7-methyl-1,8-naphthyridine (3b): Yield 44%. 1H-NMR (200 MHz, CDCl3):
δ = 8.08 (d, J = 9 Hz, 1H, H-4), 7.36 (s, 1H, H-6), 6.98 (d, J = 9 Hz, 1H, H-3), 6.19 (s, 2H, NH2), 2.74
13
(s, 3H, CH3). C-NMR (100 MHz, DMSO-d6): δ = 160.5 (C-7), 159.8 (C-8a), 156.5 (C-2), 133.8 (q,
1
3
2J = 31 Hz, C-5), 133.0 (C-4), 122.6 (q, J = 275 Hz, CF3), 114.2 (C-3), 113.8 (q, J = 5 Hz, C-6),
112.9 (C-4a), 24.6 (CH3). GC-MS (EI, 70 eV) m/z 227 (M+, 100), 210 (3), 200 (37), 158 (3), 131 (5%).
2-amino-7-trifluoromethyl-5-methyl-1,8-naphthyridine (5b): Yield 43%.1H-NMR (200 MHz, CDCl3):
δ = 8.08 (d, J = 9 Hz, 1H, H-4), 7.33 (s, 1H, H-6), 6.90 (d, J = 9 Hz, 1H, H-3), 5.98 (s, 2H, NH2), 2.67
(s, 3H, CH3). 13C-NMR (100 MHz, DMSO-d6): δ = 160.3 (C-7), 159.8 (C-8a), 155.2 (C-2), 148.1 (q, 2J
= 34 Hz, C-7), 146.9 (C-5), 132.7 (C-4), 120.8 (q, 1J = 275 Hz, CF3), 114.2 (C-3), 113.8 (q, 3J = 5 Hz,
C-6), 112.9 (C-4a), 17.5 (CH3). GC-MS (EI, 70 eV) m/z: 227 (M+, 100), 210 (3), 200 (37), 158 (3),
131 (5%).
4. Conclusions
In summary, we have developed a new, simple and convenient route for the preparation of a new
series of 7-alkyl(aryl/heteroaryl)-2-amino-5-trifluoromethyl-1,8-naphthyridines 3a-j in moderate to
good yields, derived from direct cyclocondensation reactions employing acyclic β-alkoxyvinyl
trifluoromethyl ketones 1a-j and 2,6-DAP, under mild conditions by a conventional one-pot procedure.

Molecules 2011, 16
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We also developed the synthesis of new 2-amino-5-trifluoromethyl-cycloalka[b][1,8]naphthyridines
3l-m as fused heteropolycycles from direct or indirect cyclocondensation reactions of 2-trifluoroacetyl-
1-methoxycycloalkenes 1l-m and 2,6-DAP. Furthermore, we have been able to use acyclic and cyclic
ketones 1, for the first time, in the synthesis of trifluoromethylated 2-amino-1,8-naphthyridines, which
possess a free amino group for further important derivatizations.
Acknowledgements
The authors thank the Conselho Nacional de Desenvolvimento Científico, CNPq, for the financial
support (Proc. Nr. 303.296/2008-9). Fellowships from CAPES and CNPq are also acknowledged.
References and Notes
1. Goswami, S.; Mukherjee, R.; Mukherjee, R.; Jana, S.; Maity, A.C.; Adak, A.K. Simple and
efficient synthesis of 2,7-difunctionalized-1,8-naphthyridines. Molecules 2005, 10, 929–936.
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Sample Availability: Samples of the compounds 2b, 2k, 3a-m, 4c, 4f, 4g, 4i, 4j are available from the
authors.
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