Synthesis of 1-Arylethyl-2-arylethylamino-5-trifluoroacetyl-1,2,3,4-tetrahydropyridines and Related Compounds with Potential Cell Efflux Pump Inhibition

Article abstract of DOI:10.1002/jhet.2271

This study reports a simple, fast, and efficient method for the synthesis of a new series of 1-arylethyl-2-arylethylamino-5-trifluoroacetyl-1,2,3,4-tetrahydropyridines and related compounds from the reaction of 2-alkoxy-5-trifluoroacetyl-3,4-dihydro-2H-py

Full text of DOI:10.1002/jhet.2271

Month 2014
Synthesis of 1-Arylethyl-2-arylethylamino-5-trifluoroacetyl-1,2,3,4-
tetrahydropyridines and Related Compounds with Potential Cell Efflux
Pump Inhibition
*
Nilo Zanatta, Marcio M. Lobo, Josiane M. dos Santos, Laura de A. Souza, Valquiria P. de Andrade,
Helio G. Bonacorso, and Marcos A. P. Martins
Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria,
97.105-900, Santa Maria, RS, Brazil
*
E-mail: zanatta@base.ufsm.br
Received April 8, 2014
DOI 10.1002/jhet.2271
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
This study reports a simple, fast, and efficient method for the synthesis of a new series of 1-arylethyl-2-
arylethylamino-5-trifluoroacetyl-1,2,3,4-tetrahydropyridines and related compounds from the reaction of
2-alkoxy-5-trifluoroacetyl-3,4-dihydro-2H-pyrans with 2-arylethanamines and related 2-ethanamines.
The desired tetrahydropyridines were obtained in excellent yields (90–98%), through a reaction that
can be described as an AAB′ three-component reaction protocol following an ANRORC-type
mechanism.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
lead to the desired tetrahydropyridines at low yields and
with the formation of byproducts.
Nitrogen heterocycles such as pyridines are present as
basic skeleton of a series of compounds that exhibit signif-
icant medicinal properties [1,2]. Tetrahydropyridines, for
example, are an important class of heterocycles that have
potential therapeutic applications in the treatment of
Parkinson’s and Alzheimer’s diseases [3]. Besides this,
they possess anti-hyperglycemic [4], muscarinic [5],
antipsychotic [6], antiproliferative [7], and antimalarial ac-
tivity [8], and are also calcium ion efflux pump inhibitors [9].
Calcium channel antagonists [10] represent a heteroge-
neous group of drugs divided into four main families:
dihydropyridine [11], phenylalkylamines [12], benzothi-
azepines [13], and tetralol [14]. Verapamil®, (shown in
Fig. 1) [15], which belongs to the group known as phenylalky-
lamines, can inhibit P-glycoprotein mediated efflux and thus
increase oral absorption of some compounds. In a previous
study, we discovered a compound, which was designated
as THP 124 (Fig. 1) that combines both phenylalkylamine
and tetrahydropyridine scaffold and exhibited efflux pump
inhibition four times higher than verapamil [16].
Although the syntheses of tetrahydropyridines have
been reported since the late 19th century, methods to
obtain 2-amino substituted tetrahydropyridines are scarce
[22,22(a),22(b),23,24].
The introduction of a trifluoromethyl group into potentially
bioactive compounds has become an important strategy to
increase biological response [25] because the trifluoromethyl
group has high electro-negativity, electron density, steric
hindrance, and hydrophobic character, which can improve
the pharmacokinetic profiles of potential drugs [26].
Although, many methods for trifluoromethylation of
organic compounds have been developed [27], still the best
methods for introducing a trifluoromethyl group into a mol-
ecule is through reactants containing the trifluoromethyl
group, such as 4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones
(enones), which are easily obtained from the trifluoro-
acetylation of enol ethers or acetals [28]. The enones have
proven to be useful precursor for the synthesis of a series
of heterocycles [29] and other aliphatic compounds [30].
However, the synthetic potential of 2-alkoxy-5-
trifluoroacetyl-3,4-dihydro-2H-pyrans as the starting
material in organic synthesis has been explored very little
[31,32]. Recently, our research group used 2-alkoxy-5-
trifluoroacetyl-3,4-dihydro-2H-pyrans for the synthesis
of an extensive series of tetrahydropyridines [23] and
6-trifluoroacetyl tetrahydropyridine oxa-geminated and
aza-geminated heterocycles [24]. Many compounds of
The most commonly used methods to synthesize
tetrahydropyridines consist of reactions of imines with
carbonyl compounds [17], the cyclocondensation of
δ-haloimines [18], the hydrogenation of pyridine salts
[19], Hantzsch cyclization reactions [20], and Diels-Alder
reactions, as well as Michael Mukaiama reactions
[20,21], which often consist of multistage reactions that
© 2014 HeteroCorporation

N. Zanatta, M. M. Lobo, J. M. dos Santos, L. d. A. Souza,
V. P. de Andrade, H. G. Bonacorso, and M. A. P. Martins
Vol 000
Scheme 1
Figure 1. Structure of verapamil and tetrahydropyran-2-yl 124.
these two series showed cell efflux inhibition double that of
the control drug verapamil and, in particular, the compound
known as THP 124 (shown in Fig. 1) exhibited cell efflux
inhibition four times higher than the control drug [16].
Thus, we decide to investigate how different substituents on
the phenyl ring of the 2-arylethanamines and related
2-ethanamines portion could affect both the reactivity of the
reaction and the biological response. Thus, in this study, we
focus on a specific class of compounds that have similar
structure of the model compound THP 124. This study
allowed optimizing the reaction conditions and yields for the
reaction of this specific class of amines with 2-alkoxy-5-
trifluoroacetyl-3,4-dihydro-2H-pyrans that in the previous
paper [23] was described, as a general procedure and carried
out in 24 h. In the present study, the reaction time was
optimized to 5 min. at room temperature and rendering
excellent yields (≥90%).
Table 1
Optimized yields for the synthesis of tetrahydropyridines 6a–m.
Ethanamines (R1)b
Yieldc
(%)
Entry Enonea
(3a–m)
Product
1
2
3
4
5
6
7
8
3
4
3
4
3
4
3
4
3
4
3
4
3
4
3
4
3
4
3
4
3
4
3
4
3
4
2-OMeC6H4
2-OMeC6H4
4-OMeC6H4
4-OMeC6H4
3,4-OMeC6H3
3,4-OMeC6H3
4-FC6H4
4-FC6H4
2-ClC6H4
2-ClC6H4
3-ClC6H4
90
92
97
98
91
92
90
91
98
92
93
93
92
97
95
94
94
90
94
94
95
92
95
96
92
90
6a
6a
6b
6b
6c
6c
6d
6d
6e
6e
6f
RESULTS AND DISCUSSION
9
The cyclic enones 3 and 4 were obtained by acylation
of 2-methoxy(ethoxy)-3,4-dihydro-2H-pyran (1 and 2)
by trifluoroacetic anhydride under basic conditions as
described by Okada et al. [30] and more recently by
our research group [23,24]. The reaction of cyclic
enones 3 and 4 with 2-substituted ethanamines was
carried out in either methanol (for enone 3) or ethanol
(for enone 4), at a molar ration 1:2 (enone:amine, re-
spectively) at room temperature for 5 min, as shown in
Scheme 1. The choosing of the solvent was carried
out according to previous work reported by Zanatta
et al., [23] in which methanol or ethanol was used as
the ideal solvent. To avoid the mixture of products,
methanol was used for the reaction of enone 3, and eth-
anol was used for enone 4. When a low polar solvent
such as chloroform was used, the reaction time in-
creased by approximately 75%. We speculate that polar
solvents such as methanol and ethanol, besides solubi-
lizing all the amines and enones used, increase the reac-
tion rate by stabilizing the polar transition state.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
3-ClC6H4
4-ClC6H4
4-ClC6H4
6f
6g
6g
6h
6h
6i
6i
6j
6j
6k
6k
6l
6l
6m
6m
2,4-ClC6H3
2,4-ClC6H3
4-OHC6H4
4-OHC6H4
2-Cyclohexenyl
2-Cyclohexenyl
N-morpholyl
N-morpholyl
N(CH2CH3)2
N(CH2CH3)2
1H-Indol-3-yl
1H-Indol-3-yl
a3: R = Me; 4: R = Et.
bReaction conditions: enone (1 equiv.), amine (2 equiv.), ROH, RT, 5 min.
cYield of isolated products.
The reaction that furnishes the compounds 6 can be de-
scribed as an AAB′ three-component reaction protocol
[33], which follows an ANRORC-type mechanism [34].
The detailed mechanism of a similar reaction has been
presented elsewhere and will not be discussed further in
this study [23].
Excellent yields of the expected 1-arylethyl-2-
arylethylamino-5-trifluoroacetyl-1,2,3,4-tetrahydropyridines
and related compounds 6a–m was obtained for both enones
3 and 4 as shown in Table 1.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Synthesis of 1-Arylethyl-2-arylethylamino-5-trifluoroacetyl-1,2,3,4-
tetrahydropyridines with Potential Cell Efflux Pump Inhibition
Month 2014
methane as the ionizing gas, on an Agilent 5975B GC-MSD
spectrometer. The GC was equipped with a split-splitless in-
jector, auto-sampler, cross-linked HP-5 capillary column
(30 m, 0.32 mm of internal diameter), and helium was used
as the carrier gas. High resolution mass spectra were recorded
using a Bruker Q-TOF spectrometer in ESI mode. 1H-NMR
and 13C-NMR spectra were acquired using a Bruker DPX
200 spectrometer (1H at 200.13 MHz and 13C at 50.32 MHz) or
a Bruker DPX 400 (1H at 400.13 MHz and 13C at 100.62 MHz)
in CDCl3 or DMSO-d6 and using tetramethylslane as the internal
reference.
General
1-arylethyl-2-arylethylamino-5-trifluoroacetyl-1,2,3,4-tetrahy-
dropyridi-nes and related compounds. Ethanamines 5a–m
(2.0 mmol) were added to a solution of either enone 3
(1.0 mmol, 0.210 g) in methanol (3 mL) or enone 4 (1.0 mmol,
0.224 g) in ethanol (3 mL), and the solution was stirred at room
temperature for 5 min. The solvent was evaporated, the solid
products were purified by recrystallization from a mixture of
chloroform and methanol (5:1), and the oils were purified by
The products 6 were isolated by evaporation of the
solvent on a rotary evaporator, and the resulting materials
showed very good purity. The solid compounds were
further purified by recrystallization from a mixture of
chloroform and methanol (5:1), and the oils were purified
by filtration through a multilayer chromatography column
composed (from the bottom to the top) of sodium sulfate,
neutral alumina, active charcoal, and neutral alumina.
1
Tetrahydropyridines 6a–m were identified by H-NMR
and 13C-NMR techniques, liquid chromatography–mass
spectrometry (LC-MS) [electrospray ionization (ESI)
mode], gas chromatography–mass spectrometry [chemical
ionization (CI) mode], and high resolution mass spectrom-
etry analysis. The gas chromatography–mass spectrometry
spectra registered in CI mode did not show the molecular
ion, but instead showed a positive fragment originated
from the loss of the 2-amino group. The LC-MS registered
in ESI mode furnished the expected (M + H) ion and a
main positive fragment assigned to the loss of the 2-amino
group. The resonance signal of the N–H was not assigned
because it is probably underneath to other hydrogens.
The structures of the tetrahydropyridines 6 were
examined by 1H-NMR spectroscopy. The interpretation
procedure
for
the
synthesis
of
filtration through
a
multilayer chromatography column
composed (from the bottom to the top) of sodium sulfate,
neutral alumina, active charcoal, and neutral alumina. A mixture
of chloroform and methanol 5:1 was used as the eluent. The
solvent was evaporated, and the product was stored in a
desiccator, under vacuum, for the complete removal of solvent.
Compounds 6a–m were obtained in 90–98% yields. Compounds
6a–m are hygroscopic, and they require storage under
refrigeration to prevent decomposition.
1
of the coupling constants in the H-NMR spectra showed
that the structures of compounds 6 are consistent with a
half-chair conformation for the tetrahydropyrimidine ring
with the 2-amino group located at the axial position [23].
The position of the 2-amino group at the axial position
was assigned by the coupling constant between H-2 and
the vicinal H-3 and H-3′, in which both coupling con-
stants are very small and usually only a broad peak was
observed for H-2. All compounds obtained showed the
same structural trend.
In conclusion, we have developed a simple, fast, and
efficient ABB′ three-component protocol based on
ANRORC-type mechanism for the preparation of a new
series of 1-arylethyl-2-arylethylamino-5-trifluoroacetyl-
1,2,3,4-tetra-hydropyridines and related compounds. The
convenience of the reactions presented in this paper, in
terms of: (i) requiring short reaction time (5 min.), (ii) mild
reaction conditions (RT), (iii) easy isolation and purifica-
tion, (iv) rendering high yields, and (v) wide scope of
ethanamines that can be used in this reaction, call the
attention for the potential of this chemistry for future
developments of library of compounds through combinato-
rial chemistry.
5-Trifluoroacetyl-2-N-(2-methoxyphenethylamino)-1-(2-
methoxyphenethyl)-1,2,3,4-tetrahydropyridine (6a).
This
compound was obtained as a yellow oil in 90% yield from 3
and 92% from 4. 1H-NMR (CDCl3, 400 MHz): δ = 7.24–7.10
(m, 3H, H-6, Ar), 7.01–6.82 (m, 6H, Ar), 4.01 (t, 1H,
J = 2.6 Hz, H-2), 3.76–3.78 (s, 6H, OMe), 3.72–3.68 (m, 1H,
H-7), 3.48–3.41 (m, 1H, H-7), 2.87–2.78 (m, 8H, H-7′, H-8,
H-8′), 2.49–2.45 (m, 1H, H-4), 2.03–2.01 (m, 1H, H-3), 1.92–
1.83 (m, 1H, H-4), 1.45–1.41 (m, 1H, H-3). 13C-NMR (CDCl3,
2
100 MHz): δ = 174.4 (q, JC–F = 31.4, C¼O), 157.3, 157.2,
130.6, 130.1, 128.3, 127.6, 125.3, 120.5, 120.4, 110.2 (12C,
1
Ar), 150.4 (C-6), 119.5 (q, JC–F = 292.0, CF3), 102.0 (C-5),
69.6 (C-2), 55.0 (2C, OMe), 54.5 (C-7) 45.9 (C-7′), 31.4 (C-8),
31.1 (C-8′), 25.3 (C-3), 14.1 (C-4). MS (ESI): m/z: 463
[M + H]+. HRMS (ESI): m/z calcd for C25H30F3N2O3 [M + H]:
463.2208; found: 463.2205.
5-Trifluoroacetyl-2-N-(4-methoxyphenethylamino)-1-(4-
methoxyphenethyl)-1,2,3,4-tetrahydropyridine (6b).
This
compound was obtained as a yellow solid in 97% yield from 3
and 98% from 4, mp 72–75°C. 1H-NMR (CDCl3, 400 MHz):
δ = 7.27 (s, 1H, H-6), 7.07 (d, 2H, J = 7.6, Ar), 6.98 (d, 2H,
J = 7.6, Ar), 6.81 (d, 4H, J = 8.0, Ar), 3.90 (t, 1H, J = 3.2, H-2),
3.75 (s, 6H, OMe), 3.64–3.59 (m, 1H, H-7), 3.42–3.7 (m, 1H,
H-7), 2.90–2.82 (m, 2H, H-7′), 2.78–2.73 (m, 2H, H-8), 2.68
(t, 2H, J = 6.8, H-8′), 2.49–2.45 (m, 1H, H-4), 2.07–1.99
(m, 1H, H-3), 1.90–1.86 (m, 1H, H-4), 1.54–1.45 (m, 1H, H-3).
EXPERIMENTAL
2
13C-NMR (CDCl3, 100 MHz): δ = 174.7 (q, JC–F = 31.2,
The 2-alkoxy-5-trifluoroacetyl-3,4-dihydro-2H-pyrans (3 and
4) were prepared according to the literature [23,30]. All melting
points were determined using a Kofler Reichert Thermovar or
on an MQAPF-301 apparatus and are uncorrected. LC mass
spectra were registered on an LC-MS/MS Agilent 6460 in ESI
mode. GC mass spectra were registered in CI mode, using
C¼O), 158.6, 158.2, 131.3, 129.5, 129.3, 114.2, 113.9 (12C,
1
Ar), 150.1 (C-6), 118.0 (q, JC–F = 296.2, CF3), 102.0 (C-5),
69.6 (C-2), 55.9 (C-7), 55.1, 55.0 (2C, OMe), 47.2 (C-7′), 35.6
(C-8), 35.2 (C-8′), 25.3 (C-3), 14.8 (C-4). MS (ESI): m/z: 463
[M + H]+. HRMS (ESI): m/z calcd for C25H30F3N2O3 [M + H]:
463.2208; found: 463.2205.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. Zanatta, M. M. Lobo, J. M. dos Santos, L. d. A. Souza,
V. P. de Andrade, H. G. Bonacorso, and M. A. P. Martins
Vol 000
5-Trifluoroacetyl-2-N-(3,4-dimethoxyphenethylamino)-1-(3,4-
dimethoxyphenethyl)-1,2,3,4-tetrahydropyridine (6c). This
5-Trifluoroacetyl-2-N-(4-chlorophenethylamino)-1-(4-
chlorophenethyl)-1,2,3,4-tetrahydropyridine (6g). This
compound was obtained as a yellow oil in 91% yield from 3 and
92% from 4. H-NMR (CDCl3, 400 MHz): δ = 7.28 (s, 1H, H-6),
compound was obtained as a light yellow oil in 92% yield from 3
and 97% from 4. 1H-NMR (CDCl3, 200 MHz): δ = 7.38–7.02
(m, 9H, H-6, Ar), 3.95 (t, 1H, J = 3.2 Hz, H-2), 3.78–3.64 (m, 1H,
H-7), 3.51–3.37 (m, 1H, H-7), 2.98–2.85 (m, 6H, H-7′, H-8,
H-8′), 2.58–2.48 (m, 1H, H-4), 2.17–2.05 (m, 1H, H-3), 2.01–
1.89 (m, 1H, H-4), 1.65–1.49 (m, 1H, H-3). 13C-NMR (CDCl3,
1
6.80–6.63 (m, 6H, Ar), 3.95 (t, 1H, J= 2.8, H-2), 3.84 (brs, 12H,
OMe), 3.81–3.76 (m, 1H, H-7), 3.50–3.43 (m, 1H, H-7), 2.93–2.86
(m, 2H, H-7′), 2.79 (t, J= 6.8, 2H, H-8), 2.73 (t, 2H, J=7.2, H-8′),
2.52–2.48 (m, 1H, H-4), 2.08–2.01 (m, 1H, H-3), 1.97–1.93
(m, 1H, H-4), 1.55–1.46 (m, 1H, H-3). 13C-NMR (CDCl3,
2
100 MHz): δ = 175.7 (q, JC–F = 31.4, C¼O), 159.4 (C-6), 135.2,
2
100 MHz): δ = 174.9 (q, JC–F = 32.2, C¼O), 150.0 (C-6), 149.1,
134.8, 134.6, 133.9, 133.6, 132.2, 130.8, 130.5, 129.6, 129.3,
1
148.9, 148.0, 147.5, 131.6, 129.7, 122.2, 120.8, 120.3, 111.9, 111.5,
111.2 (12C, Ar), 119.3 (q, 1JC–F = 289.8, CF3), 102.1 (C-5), 69.5 (C-
2), 56.0 (C-7), 55.7 (4C, OMe), 47.3 (C-7′), 35.9 (C-8), 35.7 (C-8′),
25.1 (C-3), 14.6 (C-4). MS (ESI): m/z: 523 [M + H]+. HRMS (ESI):
m/z calcd for C27H34F3N2O5 [M + H]+: 523.2420; found: 523.2418.
5-Trifluoroacetyl-2-N-(4-fluorophenethylamino)-1-(4-
fluorophenethyl)-1,2,3,4-tetrahydropyridine (6d). This
compound was obtained as a light yellow oil in 90% yield from 3
and 91% from 4. 1H-NMR (CDCl3, 400 MHz): δ = 7.26 (s, 1H, H-
6), 7.14–6.93 (m, 8H, Ar), 3.90 (t, 1H, J = 3.6, H-2), 3.68–3,51
(m, 1H, H-7), 3.45–3.38 (m, 1H, H-7), 2.93–2.91 (m, 2H, H-7′),
2.84–2.79 (m, 2H, H-8), 2.73 (t, 2H, J = 6.8, H-8′), 2.51–2.46
(m, 1H, H-4), 2.08–2.01 (m, 1H, H-3), 1.94–1.88 (m, 1H, H-4),
1.55–1.48 (m, 1H, H-3). 13C-NMR (CDCl3, 100 MHz): δ = 175.1
127.2, 127.0 (12C, Ar), 119.8 (q, JC–F = 289.2, CF3), 101.5 (C-
5), 69.7 (C-2), 53.3 (C-7), 45.4 (C-7′), 34.1 (C-8), 33.6 (C-8′),
25.2 (C-3), 14.6 (C-4). MS (ESI): m/z: 471 [M + H]+, 473
[M+ H + 2]+, 475 [M + H + 4]+. HRMS (ESI): m/z calcd for
C23H24Cl2F3N2O [M+ H]+: 471.1218; found: 471.1215.
5-Trifluoroacetyl-2-N-(2,4-dichlorophenethylamino)-1-(2,4-
dichlorophenethyl)-1,2,3,4-tetrahydropyridine (6h).
This
compound was obtained as a light yellow oil in 95% yield from 3
1
and 94% from 4. H-NMR (CDCl3, 200 MHz): δ =7.37–7.09, (m,
7H, H-6, Ar), 3.98 (t, 1H, J= 3.4, H-2), 3.87–3.68 (m, 1H, H-7),
3.53–3.39 (m, 1H, H-7), 3.00–2.87 (m, 6H, H-7′, H-8, H-8′), 2.57–
2.45 (m, 1H, H-4), 2.15–2.06 (m, 1H, H-3), 1.98–1.87 (m, 1H, H-
4), 1.62–1.51 (m, 1H, H-3). 13C-NMR (CDCl3, 100 MHz):
2
δ = 175.3 (q, JC–F = 32.9, C¼O), 159.8 (C-6), 135.7, 134.6, 134.5,
2
1
(q, JC–F = 30.0, C¼O), 161.9 (d, J C–F = 246.0 , Ar), 161.6 (d,
133.7, 133.5, 132.8, 131.7, 131.5, 129.6, 129.3, 127.4, 127.0 (12C,
Ar), 119.4 (q, 1JC–F = 291.2, CF3), 102.5 (C-5), 69.6 (C-2), 53.5 (C-
7), 45.4 (C-7′), 34.0 (C-8), 33.7 (C-8′), 25.4 (C-3), 14.8 (C-4). MS
(ESI): m/z: 541 [M + H]+, 543 [M + H + 2]+, 545 [M + H + 4]+, 547
[M+H+6]+, 549 [M+H+8]+. HRMS (ESI): m/z calcd for
C23H22Cl4F3N2O [M+ H]+: 541.2403; found: 541.0417.
1J C–F = 247.0, Ar), 149.9 (C-6), 135.2, 133.3, 130.2–129.9, (6C,
Ar), 116.0–113.0 (4C, Ar) 119.4 (q, JC–F = 290.1, CF3), 102.4
1
(C-5), 69.8 (C-2), 55.7 (C-7), 47.3 (C-7′), 35.9 (C-8), 35.3 (C-8′),
25.4 (C-3), 14.9 (C-4). MS (ESI): m/z: 439 [M+ H]+. HRMS
(ESI): m/z calcd for C23H24F5N2O: [M+ H]+: 439.1809; found:
439.1808.
5-Trifluoroacetyl-2-N-(4-hydroxyphenethylamino)-1-(4-
5-Trifluoroacetyl-2-N-(2-chlorophenethylamino)-1-(2-
hydroxyphenethyl)-1,2,3,4-tetrahydropyridine (6i).
This
chlorophenethyl)-1,2,3,4-tetrahydropyridine (6e).
This
compound was obtained as a light yellow solid, hygroscopic, in
94% yield: from 3 and 90% from 4. 1H-NMR (DMSO-d6,
400 MHz): δ = 7.32 (s, 1H, H-6), 7.01–6.96 (m, 4H, Ar), 6.69 (d,
4H, Ar) 4.09 (t, 1H, J = 3.2, H-2), 3.69–3.63 (m, 1H, H-7) 3.56–
3.49 (m, 1H, H-7), 3.19 (s, 2H, OH), 2.79–2.70 (m, 4H, H-7′, H-
8), 2.60 (t, 2H, J = 7.2, H-8′), 2.31–2.27 (m, 1H, H-4), 2.10–2.03
(m, 1H, H-3), 1.88–1.84 (m, 1H, H-4), 1.48–1.40 (m, 1H, H-3).
compound was obtained as a light yellow oil in 98% yield from 3
and 92% from 4. 1H-NMR (CDCl3, 200 MHz): δ = 7.25–6.95
(m, 9H, H-6, Ar), 3.90 (t, 1H, J = 3.6, H-2), 3.73–3.59 (m, 1H, H-
7), 3.49–3.36 (m, 1H, H-7), 2.97–2.91 (m, 2H, H-7′), 2.85–2.69
(m, 4H, H-8, H-8′), 2.56–2.45 (m, 1H, H-4), 2.10–2.02 (m, 1H,
H-3), 1.90–1.88 (m, 1H, H-4), 1.59–1.51 (m, 1H, H-3). 13C-NMR
2
2
13C-NMR (DMSO-d6, 100 MHz): δ = 172.5 (q, JC–F = 30.0,
(CDCl3, 50MHz): δ = 175.7 (q, JC–F = 31.4, C¼O), 150.1 (C-6),
141.4, 139.4, 134.4, 134.1, 129.9, 129.6, 128.7, 128.6, 127.0,
C¼O), 155.7, 155.3, 130.0, 129.5, 129.1, 127.0, 115.0, 114.9
(12C, Ar), 150.7 (C-6), 119.3 (q, 1JC–F = 292.7, CF3), 100.6 (C-5),
68.5 (C-2), 55.2 (C-7), 47.2 (C-7′), 35.1 (C-8), 34.1 (C-8′), 24.9
(C-3), 14.7 (C-4). MS (ESI): m/z: 435 [M + H]+. HRMS (ESI): m/z
calcd for C23H26F3N2O3 [M + H]+: 435.1895; found: 435.1893.
5-Trifluoroacetyl-2-N-(2-cyclohexenylethylamino)-1-(2-
1
126.8, 126.7, 126.4 (12C, Ar), 120.7 (q, JC–F = 292.0, CF3),
102.1 (C-5), 69.6 (C-2), 55.4 (C-7), 46,8 (C-7′), 36.2 (C-8), 35.7
(C-8′), 25.0 (C-3), 14.7 (C-4). MS (ESI): m/z: 471 [M+ H]+, 473
[M+ H + 2]+, 475 [M+ H + 4]+. HRMS (ESI): m/z calcd for
C23H24Cl2F3N2O [M+ H]+: 471.1218; found: 471.1209.
5-Trifluoroacetyl-2-N-(3-chlorophenethylamino)-1-(3-
cyclohexenylethyl)-1,2,3,4-tetrahydropyridine (6j).
This
chlorophenethyl)-1,2,3,4-tetrahydropyridine (6f).
This
compound was obtained as an orange oil in 95% yield from 3
and 93% from 4. H-NMR (CDCl3, 400 MHz): δ = 7.44 (s, 1H,
1
compound was obtained as a light yellow oil in 93% yield
from both 3 and 4. 1H-NMR (CDCl3, 200MHz): δ = 7.24–6.95
(m, 9H, H-6, Ar), 3.89 (t, 1H, J = 3.4, H-2), 3.73-3.49 (m,
1H, H-7) 3.50-3.36 (m, 1H, H-7), 2.99–2.89 (m, 2H, H-7′),
2.84–2.72 (m, 4H, H-8, H-8′), 2.58–2.44 (m, 1H, H-4),
2.11–1.89 (m, 2H, H-3, H-4), 1.65–1.44 (m, 1H, H-3). 13C-
H-6), 5.43 (s, 2H, ¼CH cyclohexenyl), 4.06 (t, 1H, J = 3.2,
H-2), 3.59–3,54 (m, 1H, H-7), 3.36–3.29 (m, 1H, H-7), 2.73–
2.69 (m, 2H, H-7′), 2.58–2.53 (m, 1H, H-4), 2.20 (t, 2H,
J = 6.8, H-8), 2.11 (t, 2H, J = 6.4, H-8′), 2.05–1.88 (m, 9H, H-
4, cyclohexenyl), 1.64–1.22 (m, 9H, H-3, cyclohexenyl). 13C-
2
2
NMR (CDCl3, 100 MHz): δ = 174.3 (q, JC–F = 32.7, C¼O),
NMR (CDCl3, 100 MHz): δ = 174.7 (q, JC–F = 30.02, C¼O),
158.8 (C-6), 137.7, 135.6, 135.3, 134.7, 133.1, 132.8, 131.0, 129.9,
150.4 (C-6), 134.0, 133.0 (2C, ¼C cyclohexenyl), 125.2, 123.3
1
1
129.6, 129.3, 127.4, 126.9 (12C, Ar), 119.4 (q, JC–F = 290.2,
(2C, ¼CH cyclohexenyl), 119.5 (q, JC–F = 298.5, CF3), 101.8
CF3), 101.9 (C-5), 68.6 (C-2), 54.5 (C-7), 44.4 (C-7′), 33.9
(C-8), 33.5 (C-8′), 25.4 (C-3), 14.6 (C-4). MS (ESI): m/z:
471 [M + H]+, 473 [M + H + 2]+, 475 [M + H + 4]+. HRMS
(ESI): m/z calcd for C23H24Cl2F3N2O [M+H]+: 471.1218;
found: 471.1211.
(C-5), 69.0 (C-2), 53.1 (C-7), 43.4 (C-7′), 38.2 (C-8), 37.9
(C-8′), 27.9, 27.8, 25.0, 22.7, 22.4, 22.2, 21.9 (7C, CH2
cyclohexenyl), 25.0 (C-3), 14.7, (C-4). MS (ESI): m/z: 411
[M+ H]+. HRMS (ESI): m/z calcd for C23H34F3N2O [M+ H]+:
411.2623; found: 411.2630.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Synthesis of 1-Arylethyl-2-arylethylamino-5-trifluoroacetyl-1,2,3,4-
tetrahydropyridines with Potential Cell Efflux Pump Inhibition
Month 2014
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Panzer, S.; Kopp, C. W. Heart 2010, 96, 186; (b) Zahradník, I.;
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5-Trifluoroacetyl-2-N-(2-(N-morpholyl)-ethylamino)-1-(2-(N-
morpholyl)-ethyl)-1,2,3,4-tetrahydropyridine (6k). This
compound was obtained as an orange oil in 95% yield from 3
1
and 92% from 4. H-NMR (CDCl3, 400 MHz): δ = 7.61 (s, 1H,
H-6), 4.14 (t, 1H, J = 3.2, H-2), 3.69–3.65 (m, 8H, CH2-O
morpholyne) 3.59–3.51 (m, 1H, H-7), 3.39–3.36 (m, 1H, H-7),
2.79–2.68 (m, 2H, H-7′), 2.61–2.60 (m, 1H, H-4), 2.56 (t, 2H,
J = 6.0 Hz H-8), 2.50–2.45 (m, 10H, H-8′, CH2-N morpholyne),
2.20–2.02 (m, 1H, H-4), 1.69–1.60 (m, 1H, H-3). 13C-NMR
2
(CDCl3, 100 MHz): δ = 175.0 (q, JC–F = 31, C¼O), 150.7 (C-6),
119.5 (q, 1JC–F = 288.7, CF3), 102.2 (C-5), 69.8 (C-2), 66.8, 66.6
(2C, OCH2 morpholyne), 58.0 (2C, C-7 e C-8), 53.6, 53.4 (2C,
CH2-N morpholyne), 51.2 (C-7′), 41.8 (C-8′), 25.2 (C-3), 14.7
(C-4). MS (ESI): m/z: 421 [M + H]+. HRMS (ESI): m/z calcd for
C19H32F3N4O3 [M + H]+: 421.2426; found: 421.2424.
5-Trifluoroacetyl-2-N-(2-(1-N2,N2-diethylamino) (ethylamino)-
1-(2-(1-N1,N1-diethylamino)ethyl)-1,2,3,4-tetrahydropyridine
(6l). This compound was obtained as an orange oil in 95% yield
1
from 3 and 96% from 4. H-NMR (CDCl3, 400MHz): δ = 7.59
(s, 1H, H-6), 4.16 (s, 1H, J = 3.2, H-2), 3.53–3.50 (m, 1H, H-7),
3.32–3.27 (m, 1H, H-7), 2.69–2.67 (m, 2H, H-7′), 2.59–2.46
(m, 16H, H-8, H-8′, H-9, H-9′), 2.18–2.14 (m, 2H, H-4, H-3),
2.06–2.02 (m, 1H, H-4), 1.70–1.61 (m, 1H, H-3), 1.60–1.71
(m, 12H, CH3). 13C-NMR (CDCl3, 100 MHz): δ = 174.8
2
1
(q, JC–F = 31.3, C¼O), 150.0 (C-6), 119.6 (q, JC–F = 290.4,
CF3), 102.0 (C-5), 70.0 (C-2), 53.1 (C-8), 53.0 (C-7), 52.7 (C-8′),
46.9 (C-9), 46.7 (C-9′), 43.4 (C-7′), 25.9 (C-3), 14.8 (C-4), 11.7,
11.6 (2C, CH3). MS (ESI): m/z: 393 [M + H]+. HRMS (ESI): m/z
calcd for C27H34F3N2O5 [M+ H]+: 523.2420; found: 523.2418.
5-Trifluoroacetyl-2-N-(1H-indol-3-yl-ethylamino)-1-(1H-indol-
3-yl-ethyl)-1,2,3,4-tetrahydropyridine (6m). This compound was
obtained as a brown solid, hygroscopic, in 92% yield from 3 and
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1
90% from 4. H-NMR (CDCl3, 400 MHz): δ = 8.45, 8.34 (s, 2H,
NH indole), 7.56–6.76 (m, 11H, H-6, Ar), 3.89 (t, 1H, J= 3.2,
H-2), 3.71–3.62 (m, 1H, H-7), 3.44–3.38 (m, 1H, H-7), 2.99–2.87
(m, 6H, H-7′, H-8, H-8′), 2.40–2.40 (m, 1H, H-4), 2.00–1.94
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2
13C-NMR (CDCl3, 100 MHz): δ = 174.8 (q, JC–F =30.5, C¼O),
150.8 (C-6), 136.3, 127.1, 126.5, 122.6, 122.1, 122.0, 121.9,
119.4, 191.1, 118.5, 117.9, 112.9, 111.5, 111.3, 111.2, 110.9
[16] Study under development.
1
(16C, Ar), 118.6 (q, JC–F = 292.0, CF3), 102.0 (C-5), 69.6 (C-2),
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54.8 (C-7), 45.9 (C-7′), 25.9 (C-8), 25.8 (C-8′), 25.2 (C-3), 14.8
(C-4). MS (ESI): m/z: 481 [M + H]+. HRMS (ESI): m/z calcd for
C27H28F3N4O [M + H]+: 481.2215; found: 481.2211.
Acknowledgments. The authors thank the financial support from
the Fundação de Apoio à Tecnologia e Ciência do Estado do Rio
Grande do Sul (FAPERGS, PRONEX No. 10/0037-8 and
PqGaucho 11/1608-8) and Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq – Universal grant No. 473512/
2009-2), and fellowships from CAPES (F. M. S.) and CNPq
(E. C. A).
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet