Highly chemoselective synthesis of 6-Alkoxy-l-aIkyl(aryl)-3- trifluoroaeetyl-1,4,5,6 tetrahydropyridlines and 1-Alkyl(aryl)-6-anino-3- trifluoroacetyl-1,4,5,6-tetrahydropyridines

Article abstract of DOI:10.1002/ejoc.200801119

A simple and highly chemoselective method for the synthesis of a large series of novel 6-alkoxy-1-alkyl (aryl)-3-trifluoro-acetyl-1,4,5,6- tetrahydropyridines and l-alkyl(aryl)-6-amino-3-trifluoroacetyl-l,4,5,6- tetrahydropyridines, from the reaction of 6

Full text of DOI:10.1002/ejoc.200801119

FULL PAPER
DOI: 10.1002/ejoc.200801119
Highly Chemoselective Synthesis of 6-Alkoxy-1-alkyl(aryl)-3-trifluoroacetyl-
1,4,5,6-tetrahydropyridines and 1-Alkyl(aryl)-6-amino-3-trifluoroacetyl-1,4,5,6-
tetrahydropyridines
Nilo Zanatta,*[a] Liana da S. Fernandes,[a] Fabiane M. Nachtigall,[a] Helena S. Coelho,[a]
Simone S. Amaral,[a] Alex F. C. Flores,[a] Helio G. Bonacorso,[a] and
Marcos A. P. Martins[a]
Keywords: Heterocycles / Halogenated heterocycles / Antimicrobial activity / Tetrahydropyridines
A simple and highly chemoselective method for the synthesis
of a large series of novel 6-alkoxy-1-alkyl(aryl)-3-trifluoro-
3-trifluoroacetyl-1,4,5,6-tetrahydropyridine series was as-
sessed against a variety of microorganisms including yeast-
acetyl-1,4,5,6-tetrahydropyridines and 1-alkyl(aryl)-6-amino- like fungi, bacteria and algae, and some of these compounds
3-trifluoroacetyl-1,4,5,6-tetrahydropyridines, from the reaction exhibit significant antimicrobial activity.
of 6-alkoxy-3-trifluoroacetyl-4,5-dihydro-6H-pyrans with pri-
mary alkyl and arylamines, in good yields, is reported. Prelimi- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
nary in vitro antimicrobial activity of the 1-alkyl(aryl)-6-amino-
Germany, 2009)
a mixture of products in low yields. Additionally, only few
1,4,5,6-tetrahydropyridines are described in the litera-
ture.[18]
Introduction
Tetrahydropyridines constitute an important class of or-
ganic compounds usually reported as potential therapeutic
and pharmacological agents against Alzheimer’s and Park-
inson’s[1] diseases and are used as experimental models for
studying neurodegeneration.[2] In addition, tetrahydropyr-
idines have been reported to exhibit important muscarin-
ic,[1a,3] nicotinic,[4] analgesic,[5] hyperglycaemic,[5] antipsy-
chotic[6] and antiproliferative[7] activity, as well as calcium
ion flux regulation[4,8] and GABA inhibition.[6,9] Two tetra-
hydropyridines, 2-acetyl-1,4,5,6-tetrahydropyridine and 2-
acetyl-3,4,5,6-tetrahydropyridine, reported as tautomeric
structures and responsible for producing a mousy taint in
wines, have been isolated from Brettanomyces and Lacto-
bacillus yeasts.[10] Curiously enough, the same tautomeric
tetrahydropyridines were recently identified as the major
components of the cracker-like flavour in freshly baked
bread.[11]
Cyclic enones have been extensively used for the last few
decades for obtaining a series of heterocyclic compounds
such as isoxazoles,[19] pyrazoles,[20] pyrimidines,[21] 3-amino-
methylene-dihydrofuran-2-ones,[22] analogues of cyclophos-
phamide,[23] furan-3-carboxamides[24] and 3-alkoxy-3-cyano
carboxylic acids.[25] Although both the synthesis and appli-
cations of enones have been the subject of recent reviews,[26]
6-alkoxy-3-trifluoroacetyl-4,5-dihydro-6H-pyrans have been
very little explored as starting reagents in organic synthesis.
In a review of the literature, only four references were
found. Three of them report Grignard reactions carried out
with 6-alkoxy-3-trifluoroacetyl-4,5-dihydro-6H-pyrans
1
and 2 to obtain different compounds, depending on the na-
ture of the Grignard reagent and the reaction conditions[27]
and one reference reports the reactions of compounds 1 and
2 with hydroxylamine hydrochloride to selectively give flu-
orine-containing 4H-pyrano[3,2-d]isoxazoles or 4-(cyano-
ethyl)dihydroisoxazole in moderate to high yields.[28]
The use of cyclic enones such as 3-trihaloacetyl-4,5-dihy-
drofuran and 3-trihaloacetyl-5,6-dihydro-4H-pyran has
been attracting much attention because these compounds
can easily react with nucleophiles, generating new aliphatic
or heterocyclic systems by a process that involves the open-
ing of the furan or pyran ring by the nucleophile and
the subsequent closure of the alkyl-hydroxy side
chain.[9,27b,28,29] The two most widespread methods of in-
troducing a trifluoroacetyl group in heterocycles are by di-
rect trifluoroacetylation[30] and through a cyclocondensa-
Tetrahydropyridines are usually prepared from the cy-
clocondensation of amines and carbonyl compounds,[12] cy-
clocondensation of δ-haloimines,[13] hydrogenation of pyr-
idine salts,[14] Hantzsch’s cyclisation[8a,15] as well as Diels–
Alder[16] and Mukaiyama Michael reactions.[17] Most of
these methods involve extensive synthetic routes, furnishing
[a] Núcleo de Química de Heterociclos (NUQUIMHE), De-
partamento de Química, Universidade Federal de Santa Maria,
97.105-900, Santa Maria, RS, Brazil
Fax: +55-55-220-8031
E-mail: zanatta@base.ufsm.br
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Nilo Zanatta et al.
FULL PAPER
tion reaction of a bis(trifluoroacetyl)vinyl ether[31] or
For the synthesis of compounds 4a–o, reactions were car-
amine[32] with dinucleophiles. Other methods include oxi- ried out by stirring a mixture of enones 1 or 2 with primary
dative dimerisation of 1,1,1-trifluoro-4-arylbut-3-yn-2-one, amines in an appropriate solvent according to the condi-
carried out by treatment with lead dioxide in a dichloro- tions specified in Table 1. All reactions were tested with dif-
methane/trifluoroacetic acid mixture,[33] dipolar cycload- ferent solvents and reaction times and the yields and reac-
dition of diazo compounds[34] and azides[35] with α,β-unsat- tion conditions reported in Table 1 are the optimised
urated trifluoromethyl ketones,[36] photo-induced cycli- results. The reactions were monitored by thin-layer
sation of sulfimino uracil substituted with α,β-unsaturated chromatography by following the disappearance of the en-
trifluoromethyl ketones and intramolecular cyclisation of ones and formation of the products. It was observed that
trifluoro(dimethoxyethylamino)alkenones.[37] Advances in the more basic and volatile amines, such as methyl-, ethyl-
the chemistry of α,β-unsaturated trifluoromethylketones and propylamines, gave better results in hexane while less
have been the subject of a recent review.[26b]
reactive or bulkier amines furnished better results in more
In this study, a very simple and highly chemoselective polar solvents, as shown in Table 1. Yields were very good
method has been proposed for the synthesis of a wide range for all amines tested. Table 1 shows that changing the 6-
of 6-alkoxy-1-alkyl(aryl)-3-trifluoroacetyl-1,4,5,6-tetrahy- methoxy group to a 6-ethoxy group (compounds 1 and 2)
dropyridines and 1-alkyl(aryl)-6-amino-3-trifluoroacetyl- did not affect the reaction yields. Products 4 were isolated
1,4,5,6-tetrahydropyridines from the reaction of the readily by evaporation of the solvent on a rotary evaporator and
available 6-alkoxy-3-trifluoroacetyl-4,5-dihydro-6H-pyrans the resultant materials showed very good purity. The solid
(cyclic enones) with primary alkyl and arylamines. In ad- compounds were purified by recrystallisation from a mix-
dition, a series of 1-alkyl(aryl)-6-amino-3-trifluoracetyl- ture of dichloromethane and hexane and the oils were puri-
1,4,5,6-tetrahydropyridines were assessed against a series of fied by filtration through a multilayer chromatography col-
microorganisms including yeast-like fungi, bacteria and al- umn composed (from the bottom to the top) of sodium
gae.
sulfate, neutral alumina, active charcoal and neutral alu-
mina. Although the solid compounds are stable, oily prod-
ucts are not very stable and they decomposed when purifi-
cation was carried out using a silica gel chromatography
column or if they were kept unrefrigerated for a few days.
Compound 4i exhibited significant in vitro antimicrobial
activity for most of the screened fungi and bacteria. In ad-
dition some compounds, such as 4f, 4h, 4j, 4k and 4l, also
exhibited relevant in vitro antimicrobial activity, though
more selectively than compound 4i for some kinds of fungi
and/or bacteria.[39]
The structures of the 1-alkyl(aryl)-6-amino-3-trifluoro-
acetyl-1,4,5,6-tetrahydropyridines were examined by 1H
NMR spectroscopy and single-crystal X-ray diffraction.
The interpretation of the coupling constants in the 1H
NMR spectra showed that the structure of 4d is consistent
with a half-chair conformation with the 6-amino group lo-
cated at the axial position.[40] The position of the 6-amino
group at the axial position is indicated by the coupling con-
stant between H-6 and the vicinal H-5 and H-5Ј, where
both coupling constants are very small and usually only a
broad peak was observed for H-6. All other compounds
obtained showed the same structural trend. The structure
of 4d was confirmed by single-crystal X-ray diffraction.[41]
Reactions of 1 or 2 with primary amines carried out in
the same molar ratio furnished a mixture of disubstituted
products 4, monosubstituted compounds [6-alkoxy-1-
alkyl(aryl)-3-trifluoroacetyl-1,4,5,6-tetrahydropyridines] as
well as the starting enones. In this reaction, the formation
of 6-amino-3-trifluoroacetyl-1,4,5,6-tetrahydropyrans was
not observed. Much effort was made to stop the reaction at
the first substitution in order to isolate pure 6-alkoxy-1-
alkyl(aryl)-3-trifluoroacetyl-1,4,5,6-tetrahydropyridines. How-
ever, when the reaction of 1 or 2 with a series of pyridinyl-
methylamines (entries 13–18, Table 2) was carried out in an
equivalent amount, the desired 6-alkoxy-1-(pyridinyl)-
Results and Discussion
Scheme 1 outlines the synthesis of 1-alkyl(aryl)-6-amino-
3-trifluoroacetyl-1,4,5,6-tetrahydropyridines 4 and 6-alk-
oxy-1-alkyl(aryl)-3-trifluoroacetyl-1,4,5,6-tetrahydropyridines
5 and 6 from the reaction of 6-alkoxy-3-trifluoroacetyl-4,5-
dihydro-6H-pyrans 1 and 2 with primary alkyl and aryl-
amines. In 2003, Zhu et al[38] reported the synthesis of pyr-
ans 1 and 2 from a cyclocondensation reaction of β-alk-
oxyvinyl trifluoromethyl ketones with α,β-unsaturated car-
bonyl compounds. This reaction was carried out at high
temperatures in a sealed tube for 8 hours and furnished low
yields (30–42%). In this study, cyclic enones 1 and 2 were
synthesised through the trifluoroacetylation of the parent
2-alkoxy-3,4-dihydro-2H-pyrans, in 75–80% yields, by a
procedure similar to that described by Martins et al.[19]
Scheme 1. General scheme for the synthesis of all compounds.
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Highly Chemoselective Synthesis of 1,4,5,6-Tetrahydropyridines
Table 1. Optimised reaction conditions for the synthesis of 4a–o.
raphy column as described for the purification of com-
pounds 4. The column was eluted with methanol or ethanol
according to the alkoxy group present in the product 5 and
6, respectively. Products 5 and 6 were obtained as oils and
in good yields. The structures of the compounds 5 and 6
1
were confirmed by CG-MS as well as H and 13C NMR.
Entry
Enone[a] R1[b] and reaction
conditions[c]
% Yield[d] Product
Table 2. Optimised reaction conditions for the synthesis of 5 and
6.
1
2
3
4
5
6
7
8
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
Me
Me
Et
Et
Pr
Pr
C6H5
C6H5
85
82
89
86
95
95
90
87
98
95
80
81
95
92
92
87
89
90
94
93
85
82
75
76
82
96
87
95
80
90
4a
4a
4b
4b
4c
4c
4d
4d
4e
4e
4f
9
C6H5CH2
C6H5CH2
C6H5(CH2)2
C6H5(CH2)2
2-Me-C6H5
2-Me-C6H5
4-Me-C6H5
4-Me-C6H5
2-OH-C6H5
2-OH-C6H5
4-MeO-C6H5
4-MeO-C6H5
4-Cl-C6H5
4-Cl-C6H5
pyridin-2-yl
pyridin-2-yl
(pyridin-2-yl)-CH2
(pyridin-2-yl)-CH2
(pyridin-3-yl)-CH2
(pyridin-3-yl)-CH2
(pyridin-4-yl)-CH2
(pyridin-4-yl)-CH2
Entry
Enone[a] R1[b] and reaction
conditions[c]
% Yield[d] Product
10
11
12
13
14
13
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
4f
1
2
3
4
5
6
7
8
1
2
2
1
2
1
1
2
2
1
2
2
1
2
1
2
1
2
Me
Me
Pr
C6H5
C6H5
C6H5CH2
C6H5(CH2)2
2-Me-C6H5
4-Me-C6H5
4-MeO-C6H5
4-MeO-C6H5
4-Cl-C6H5
(pyridin-2-yl)-CH2
(pyridin-2-yl)-CH2
(pyridin-3-yl)-CH2
(pyridin-3-yl)-CH2
(pyridin-4-yl)-CH2
(pyridin-4-yl)-CH2
65
62
67
69
68
82
71
73
62
70
67
68
82
96
87
95
80
90
5a
6a
6c
5d
6d
5e
5f
4g
4g
4h
4h
4i
4i
4j
6g
6h
5j
4j
9
4k
4k
4l
10
11
12
13
14
15
16
17
18
6j
6k
5m
6m
5n
6n
5o
6o
4l
4m
4m
4n
4n
4o
4o
[a] 1: R = Me; 2: R = Et. [b] Molar ratio enone/amine/Py 1:1:1. [c]
Reaction conditions: entries 1, 4, 6, 7 and 10: MeOH, Py, reflux,
48 h; entries 2, 3, 5, 8, 9, 11 and 12: EtOH, Py, reflux, 48 h; entries
13, 15 and 17: MeOH, reflux, 48 h; entries 14, 16 and 18: EtOH,
reflux, 48 h. [d] Yield of isolated product.
[a] 1: R = Me; 2: R = Et. [b] Molar ratio enone/amine is 1:2, respec-
tively. [c] Reaction conditions: entries 1–6: hexane, room temp., 4 h;
entries 7–22: MeOH, room temp., 24 h; entries 23–24: MeCN, re-
flux, 24 h; entries 25, 27 and 29: EtOH, reflux, 24 h; entries 26, 28
and 30: MeOH, reflux, 24 h. [d] Yield of isolated product.
In further experiments, several compounds, 5, were used
as starting materials with the intention of carrying out sub-
methyl-3-trifluoroacetyl-1,4,5,6-tetrahydropyridines 5m–o stitution of the 6-methoxy group with alcohols and amines.
and 6m–o were isolated as pure compounds and in good First, we tried transetherification reactions in order to sub-
yields. Amines 3m–o bear a pyridine moiety which can cap- stitute the 6-methoxy group by other alkoxy groups. These
ture an ionised hydrogen and act as a proton transfer agent. reactions were carried out using alcohols such as 2-propa-
We therefore realised that in order to stop the reaction at nol, tert-butyl alcohol and propargyl alcohol as solvents
the first substitution, when using amines 3a–k, the addition and reflux times up to 70 hours. Similar reactions of com-
of pyridine was necessary. Triethylamine was also used but pounds 5 with primary and secondary amines were carried
failed to give the desired products 5 or 6. Thus, when the out with solvents such as chloroform, methanol and aceto-
reaction of 6-alkoxy-3-trifluoroacetyl-4,5-dihydro-6H- nitrile, under reflux for up to 70 hours. Additionally, many
pyrans 1 or 2 with the other amines, such as 3a–k, were reactions of compounds 5 with alcohols or primary and
carried out in the presence of an equivalent of pyridine, the secondary amines were carried out in an appropriate sol-
corresponding products 5 or 6 were isolated, in good yields. vent and in the presence of each one of these catalysts: p-
Table 2 shows the optimised reaction conditions and yields toluenesulfonic acid, sulfuric acid, zinc chloride, zinc bro-
for the synthesis of products 5 and 6. Products 5 and 6 were mide, pyridine and triethylamine. In all these reactions, the
isolated by evaporation of the solvent and the oils obtained desired products were not obtained and starting materials
were purified by filtration through a multilayer chromatog- were always recovered.
Eur. J. Org. Chem. 2009, 1435–1444
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Nilo Zanatta et al.
FULL PAPER
Reaction Mechanism
For the mechanism of formation of compounds 5 or 6,
shown in Scheme 3, we speculate that the aldehyde VI in
the presence of a protonated pyridine, the alcohol, used as
solvent, adds to the carbonyl of the aldehyde to give the
hemiacetal VII which tautomerises to form the structure
VIII. This eliminates a water molecule to give the oxonium
ion XIV, which undergoes intramolecular attack at the en-
amino group furnishing compounds 5 or 6, in good yields.
We believe that the pyridine works as a proton transfer
agent.
A possible mechanism for the formation 1-alkyl(aryl)-6-
amino-3-trifluoroacetyl-1,4,5,6-tetrahydropyridines is shown
in Scheme 1. Presumably the reaction starts with the
Michael addition of the primary amine at the carbon-2 of
the 6-alkoxy-3-trifluoroacetyl-4,5-dihydro-6H-pyran giving
the addition intermediate I which is in equilibrium with the
acyclic structure II.[28] The hemiacetal II eliminates an
alcohol molecule to form a more stable aldehyde III[28]
which is attacked by the second amine nitrogen to give the
corresponding hemiaminal IV that eliminates a water mole-
cule to give the imine V. Subsequent attack of the enamine
nitrogen on the imino group, followed by a 1,3-H shift, fur-
nishes compounds 4 in high yields (Scheme 2).
Conclusions
In summary, we have shown a simple and highly chemo-
selective method for the synthesis of a large series of 6-
alkoxy-1-alkyl(aryl)-3-trifluoroacetyl-1,4,5,6-tetrahydropyr-
idines and 1-alkyl(aryl)-6-amino-3-trifluoroacetyl-1,4,5,6-
tetrahydropyridines, from the reaction of 6-alkoxy-3-trifluo-
roacetyl-4,5-dihydro-6H-pyrans with primary alkyl and
arylamines in good yields. In addition, some of the 1-
alkyl(aryl)-6-amino-3-trifluoroacetyl-1,4,5,6-tetrahydropyr-
idines exhibited significant in vitro antimicrobial activity.[39]
Experimental Section
Unless otherwise indicated, all commercial reagents and solvents
were obtained from commercial suppliers and used without further
purification. Thin-layer chromatography (TLC) was performed
using silica gel plates GF254, 0.25 mm thickness. For visualisation,
TLC plates were either placed under ultraviolet light, or stained
with iodine vapour. All melting points were determined on a
Reichert Thermovar apparatus and are uncorrected. Elemental
analyses were performed on a Vario EL Elementar Analysensys-
teme. High resolution mass spectra were recorded in ESI-mode.
Mass spectra were registered on EI mode (70 eV) on an HP 5973
MSD instrument connected to an HP 6890 GC and interfaced with
a Pentium PC. The GC was equipped with a split-splitless injector,
autosampler, cross-linked HP-5 capillary column (30 m, 0.32 mm
ID) and helium was used as the carrier gas. 1H and 13C NMR
spectra were recorded on a Bruker DPX 400 spectrometer (1H at
400.13 MHz and 13C at 100.62 MHz) in [D6]DMSO or CDCl3
using TMS as the internal reference. Crystallographic measure-
ments were made on a Bruker Kappa Apex II CCD area detector
with graphite-monochromated Mo-Kα radiation (λ = 0.71073 Å).
The structure was solved by direct methods (SHELXS-97) and ad-
ditional atoms were located in the difference Fourier map and re-
fined on F2 (SHELXL-97).
Scheme 2. Reaction mechanism for the formation of compounds 4.
General Procedure for the Synthesis of 6-Alkoxy-3-trifluoroacetyl-
4,5-dihydro-6H-pyrans 1 and 2: A solution of trifluoroacetic anhy-
dride (21.2 mL; 165 mmol) in anhydrous dichloromethane (70 mL)
was poured into a two-necked round-bottomed flask equipped with
an addition funnel, drying tube and under argon atmosphere. To
the stirred solution, cooled to 0 °C, a solution of the appropriate
6-alkoxy-4,5-dihydro-6H-pyran (150 mmol) in anhydrous pyridine
(13.4 mL, 165 mmol) was added dropwise. After the addition was
completed, the reaction mixture was kept stirring for 16 h while
being allowed to warm to room temperature. The reaction mixture
was washed with distilled water (4ϫ30 mL) and the combined
water phases were extracted with dichloromethane (1ϫ30 mL).
The dichloromethane layers were combined, dried with anhydrous
Scheme 3. Reaction mechanism for the formation of compounds 5
or 6.
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Highly Chemoselective Synthesis of 1,4,5,6-Tetrahydropyridines
sodium sulfate, filtered and the solvent removed using a rotary
evaporator. Products 1 and 2 were obtained as colourless oils in
yields of 80 and 75%, respectively. Subsequent purification was not
required for compounds 1 and 2.
(m, 1 H), 2.68–2.58 (m, 3 H), 2.22–2.03 (m, 2 H), 1.74–1.41 (m, 5
H), 0.94 (t, J = 7.4 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3):
2
1
δ = 174.7 (q, JC,F = 30.0 Hz), 150.3, 118.1 (q, JC,F = 289.4 Hz),
101.8, 69.3, 56.6, 48.0, 25.4, 23.5, 22.7, 14.7, 11.5, 10.8 ppm. GC-
MS (EI 70 eV): m/z (%) = 278 (30) [M]+; 249 (5), 220 (100), 181
(43), 150 (25), 122 (27). HRMS (ESI) m/z calcd. for C13H21F3N2O
[M + H]+ 279.1684, found 279.1678.
3-Trifluoroacetyl-6-methoxy-4,5-dihydro-6H-pyran (1): This prod-
1
uct was obtained as a colourless oil, yield 25.2 g (80%). H NMR
(400 MHz, CDCl3): δ = 7.72 (s, 1 H), 5.15 (t, J = 3.6 Hz, 1 H),
3.54 (s, 3 H), 2.38–2.33 (m, 2 H), 2.05–2.00 (m, 1 H) ppm. 13C
General Procedure for the Synthesis of Tetrahydropyridines 4d–k: To
a stirred solution of pyran 1 or 2 (2.0 mmol) in methanol (15 mL),
amines 3d–k (4.0 mmol) were added dropwise. Amines such as 3j
and 3k (4.0 mmol), which are solid, were dissolved in methanol
(5 mL) and added to the solution of pyran through an addition
funnel. The reactions were stirred at room temperature for 24 h.
The solvent was removed using a rotary evaporator and the residue
was dissolved in dichloromethane (20 mL) and washed with water
(1ϫ20 mL). The organic phase was dried with anhydrous sodium
sulfate and the solvents evaporated. Product 4e was obtained as an
orange oil and products 4d, 4f–k were obtained as solids and were
purified by recrystallisation from a mixture of hexane and dichloro-
methane. Compound 4e was 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. The column was eluted with methanol or ethanol.
2
NMR (100 MHz, CDCl3): δ = 179.3 (q, JC,F = 34.6 Hz), 159.2,
117.7 (q, 1JC,F = 290.4 Hz), 112.4, 100.2, 56.2, 25.1, 14.3 ppm. GC-
MS (EI 70 eV): m/z (%) = 210 (14) [M]+, 179 (15), 141 (16), 69
(21), 58 (100). C8H9F3O3 (210.15): calcd. C 45.72, H 4.32; found
C 45.98, H 4.47.
6-Ethoxy-3-trifluoroacetyl-4,5-dihydro-6H-pyran (2): This product
was obtained as a colourless oil, yield 25.2 g (75%). 1H NMR
(400 MHz, CDCl3): δ = 7.71 (s, 1 H), 5.24 (t, J = 6.4 Hz, 1 H),
3.94–3.87 (m, 1 H), 3.71–3.65 (m, 1 H), 2.37 (dd, J = 6.0, J =
5.6 Hz, 2 H), 2.03–1.97 (m, 1 H), 1.88–1.82 (m, 1 H), 1.23 (t, J =
7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 179.2 (q,
1
2JC,F = 34.7 Hz), 159.4, 116.7 (q, JC,F = 290.1 Hz), 111.9, 99.1,
64.9, 25.4, 14.9, 14.5 ppm. GC-MS (EI 70 eV): m/z (%) = 224 (22)
[M+], 178 (54), 127 (15), 72 (100). C9H11F3O3 (224.17): calcd. C
48.22, H 4.95; found C 48.53, H 5.10.
General Procedure for the Synthesis of Tetrahydropyridines 4a–c:
To a stirred solution of 6-alkoxy-3-trifluoroacetyl-4,5-dihydro-6H-
pyran 1 or 2 (2.0 mmol) in hexane (15 mL), amines 3b–c (4.0 mmol)
were added dropwise and the reaction was stirred at room tempera-
ture for 4 h. For methylamine (3a) an excess (4.0 mmol) was used
because this amine is volatile and marketed as an aqueous solution.
For this reaction, the solvent used was methanol (15 mL). At the
end of the reaction, the solvent was removed using a rotary evapo-
rator and the residue was dissolved in dichloromethane (20 mL)
and washed with water (1ϫ20 mL) and the organic phase was
dried with anhydrous sodium sulfate and the solvents evaporated.
Products were obtained as red oils in yields of 85% to 95%.
1-Phenyl-6-phenylamino-3-trifluoroacetyl-1,4,5,6-tetrahydropyridine
(4d): This compound was obtained as a white solid, yield 0.56 g
(81%) (from 1) and 0.52 g (75%) (from 2), mp. 144–145 °C. 1H
NMR (CDCl3, 200 MHz): δ = 7.90 (s, 1 H), 7.37–7.33 (m, 2 H),
7.24–7.16 (m, 5 H), 6.78 (t, J = 7.6 Hz, 1 H), 6.64 (d, J = 7.6 Hz,
2 H), 5.47 (br. s, 1 H), 2.71 (dd, J1 = 14.0, J2 = 5.3 Hz, 1 H),
2.39–2.31 (m, 2 H), 1.92–1.83 (m, 1 H) ppm. 13C NMR (CDCl3,
2
100 MHz): δ = 176.8 (q, JC,F = 32.3 Hz), 146.4, 144.7, 144.4,
1
129.8, 129.5, 126.1, 120.9, 119.1, 114.1, 117 ppm. 7 (q, JC,F
=
289.2 Hz), 105.7, 66.9, 25.1, 14.4. GC-MS (EI 70 eV): m/z (%) =
346 (9) [M]+; 277 (0.05), 254 (100), 184 (3), 173 (0.02), 156 (33), 93
(11), 77 (35). C19H17F3N2O (346.35): calcd. C 65.89, H 4.95, N
8.09; found C 65.68, H 5.00, N 8.22.
3-Trifluoroacetyl-1-methyl-6-methylamino-1,4,5,6-tetrahydropyr-
idine (4a): This compound was obtained as a red oil; yield 0.38 g
(85%) (from 1) and 0.37 g (82%) (from 2). 1H NMR (200 MHz,
CDCl3): δ = 7.48 (s, 1 H), 3.95 (t, J = 3.1 Hz, 1 H), 3.23 (s, 3 H),
2.63–2.50 (m, 4 H), 2.22–2.02 (m, 2 H), 1.76–1.58 (m, 1 H) ppm.
1-Benzyl-6-benzylamino-3-trifluoroacetyl-1,4,5,6-tetrahydropyridine
(4e): This compound was obtained as a yellow solid, yield 0.67 g
(90%) (from 1) and 0.65 g (87%) (from 2), mp. 103–104 °C. 1H
NMR (CDCl3, 200 MHz): δ = 7.64 (s, 1 H), 7.38–7.24 (m, 8 H),
7.06–7.02 (m, 2 H), 4.59 (d, J = 15.0 Hz, 1 H), 4.48 (d, J = 15.0 Hz,
1 H), 3.98 (t, J = 2.9 Hz, 1 H), 3.88 (d, J = 13.4 Hz, 1 H), 3.75 (d,
J = 13.4 Hz, 1 H), 2.67–2.58 (m, 1 H), 2.27–1.98 (m, 2 H), 1.60–
1.43 (m, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 175.21 (q,
2JC,F = 31.6 Hz), 150.6, 139.3, 135.6, 128.9, 128.5, 128.2, 128.0,
2
13C NMR (100 MHz, CDCl3): δ = 174.54 (q, JC,F = 32.0 Hz),
1
151.17, 118.00 (q, JC,F = 289.8 Hz), 102.2, 72.2, 42.54, 32.5, 24.4,
14.5 ppm. GC-MS (EI 70 eV): m/z (%) = 222 (24) [M]+; 207 (0.02),
192 (94), 176 (5), 153 (7), 125 (24), 110 (5), 94 (44), 57 (100).
HRMS (ESI) m/z calcd. for C9H13F3N2O [M + H]+: 223.1058,
found 223.1053.
1
127.5, 127.3, 118.0 (q, JC,F = 289.7 Hz), 102.4, 67.2, 58.2, 49.9,
24.7, 14.6 ppm. CGϪMS (EI, 70 eV): m/z (%) = 374 (1) [M]+; 305
(0.02), 283 (18), 198 (2), 176 (11), 108 (17), 91 (100). C21H21F3N2O
(374.40): calcd. C 67.37, H 5.65, N 7.48; found C 67.30, H 5.58, N
7.40.
1-Ethyl-6-ethylamino-3-trifluoroacetyl-1,4,5,6-tetrahydropyridine
(4b): This compound was obtained as a red oil; yield 0.45 g (89%)
(from 1) and 0.43 g (86%). (from 2). 1H NMR (200 MHz, CDCl3):
δ = 7.53 (s, 1 H), 4.13 (t, J = 2.9 Hz, 1 H), 3.60–3.32 (m, 2 H),
2.78–2.56 (m, 3 H), 2.24–2.02 (m, 2 H), 1.71–1.54 (m, 1 H), 1.30–
1.00 (m, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.5 (q,
1-(2-Phenylethyl)-6-(2-phenylethylamino)-3-trifluoroacetyl-1,4,5,6-
tetrahydropyridine (4f): This compound was obtained as an orange
oil, yield 0.79 g (98 %) (from 1) and 0.76 g (95 %) (from 2). 1H
NMR (CDCl3, 200 MHz): δ = 7.34–7.16 (m, 9 H), 7.11–7.07 (m, 2
H), 3.89 (br. s, 1 H), 3.67 (dd, J = 14.0, J = 7.0 Hz, 1 H), 3.44 (dd,
J = 14.0, J = 7.0 Hz, 1 H), 2.95–2.72 (m, 6 H), 2.48 (m, 1 H,),
2.08–1.83 (m, 2 H), 1.56–1.38 (m, 1 H) ppm. 13C NMR (CDCl3,
1
2JC,F = 33.5 Hz), 149.8, 118.1 (q, JC,F = 289.5 Hz), 102.3, 68.8,
49.5, 40.4, 27.9, 25.5, 15.3, 14.6 ppm. GC-MS (EI 70 eV): m/z (%)
= 250 (28) [M]+; 206 (100), 176 (30), 153 (27), 136 (21), 108 (42).
HRMS (ESI) m/z calcd. for C11H17F3N2O [M + H]+ 251.1371,
found 251.1375
2
3-Trifluoroacetyl-1-propyl-6-propylamino-1,4,5,6-tetrahydropyridine
100 MHz): δ = 174.7 (q, JC,F = 31.7 Hz), 150.1, 139.3, 137.3,
(4c): This compound was obtained as a red oil; yield 0.53 g (95%)
128.6, 128.6, 128.4, 128.4, 126.8, 126.3, 117.9 (q, 1JC,F = 289.8 Hz),
102.1, 69.5, 55.8, 47.1, 36.5, 36.1, 25.1, 14.7 ppm. GC-MS (EI,
70 eV): m/z (%) = 402 (3) [M]+; 333 (2), 305 (13), 282 (96), 212 (2),
1
(from 1) and 0.53 g (95%) (from 2). H NMR (200 MHz, CDCl3):
δ = 7.50 (s, 1 H), 4.10 (br. s, 1 H), 3.58–3.44 (m, 1 H), 3.30–3.16
Eur. J. Org. Chem. 2009, 1435–1444
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1439

Nilo Zanatta et al.
FULL PAPER
105 (100), 91 (50), 79 (21). C23H25F3N2O (402.45): calcd. C 68.64,
H 6.26, N 6.96; found C 68.23, H 5.82, N 7.03.
2 H), 5.38 (br. s, 1 H), 2.74–2.64 (m, 1 H), 2.37–2.25 (m, 2 H),
1.95–1.83 (m, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 176.8
(q, 2JC,F = 31.3 Hz), 146.1, 143.1, 142.9, 129.9, 129.4, 129.0, 123.8,
1-(2-Methylphenyl)-6-(2-methylphenylamino)-3-trifluoroacetyl-
1,4,5,6-tetrahydropyridine (4 g): This compound was obtained as a
white solid, yield 0.71 g (95%) (from 1) and 0.69 (92%) (from 2),
mp. 108–109 °C. 1H NMR (CDCl3, 200 MHz): δ = 7.54 (s, 1 H),
7.21 (dd, J = 10.3, J = 3.3 Hz, 4 H), 7.02 (d, J = 7.4 Hz, 1 H), 6.86
(t, J = 7.5 Hz, 1 H), 6.63 (t, J = 7.3 Hz, 1 H), 6.22 (d, J = 8.0 Hz,
1
122.3, 115.1, 117.5 (q, JC,F = 289.8 Hz), 106.0, 66.9, 25.1,
14.3 ppm. GC-MS (EI, 70 eV): m/z (%) = 414 (3) [M]+; 288 (100),
207 (2), 190 (26), 111 (21). C19H15Cl2F3N2O (415.24): calcd. C
54.96, H 3.64, N 6.75; found C 54.94, H 3.75, N 6.79.
General Procedure for the Synthesis of Tetrahydropyridine 4l: To a
1 H), 5.31 (d, J = 9.6 Hz, 1 H), 4.02 (d, J = 9.4 Hz, 1 H), 2.92–2.83 stirred solution of pyran 1 or 2 (2.0 mmol) in acetonitrile (15 mL)
(m, 1 H), 2.46–2.07 (m, 9 H) ppm. 13C NMR (CDCl3, 100 MHz): δ was added a solution of amine 3l (4.0 mmol) in acetonitrile (5 mL)
2
= 176.2 (q, JC,F = 32.1 Hz), 149.8, 143.8, 142.7, 134.2, 131.6, dropwise and the reaction was heated to reflux for 24 h. The sol-
130.5, 128.3, 127.2, 127.0, 126.8, 122.5, 118.6, 111.4, 117.7 (q, 1JC,F
vent was removed using a rotary evaporator and the residue was
= 289.70 Hz), 103.0, 67.3, 26.3, 17.6, 17.3, 14.5 ppm. GC-MS (EI, dissolved in dichloromethane (20 mL), washed with water
70 eV): m/z (%) = 374 (5) [M]+; 345 (0.02), 305 (0.05), 268 (100),
198 (3), 170 (29), 91 (40). C21H21F3N2O (374.40): calcd. C 67.37,
H 5.65, N 7.48; found C 67.34, H 5.36, N 7.04.
(1ϫ20 mL) and the organic phase was dried with anhydrous so-
dium sulfate and the solvents evaporated. Product 4l was obtained
as a solid and purified by recrystallisation from a mixture of hexane
and dichloromethane.
1-(4-Methylphenyl)-6-(5-methylphenylamino)-3-trifluoroacetyl-
1,4,5,6-tetrahydropyridine (4h): This compound was obtained as a
yellow solid, yield 0.69 g (92%) (from 1) and 0.65 g (87%) (from
2), mp. 101–102 °C. 1H NMR (CDCl3, 200 MHz): δ = 7.86 (s, 1
H), 7.14 (s, 4 H), 6.99 (d, J = 8.0 Hz, 2 H), 6.55 (d, J = 8.2 Hz, 2
6-(Aminopyrid-2-yl)-1-(pyrid-2-yl)-3-trifluoroacetyl-1,4,5,6-tetra-
hydropyridine (4l): This compound was obtained as a yellow solid,
yield 0.57 g (82%) (from 1) and 0.58 g (84%) (from 2), mp. 150–
1
152 °C. H NMR (CDCl3, 200 MHz): δ = 9.15 (s, 1 H), 8.36–8.34
H), 5.39 (br. s, 1 H), 3.93 (s, 1 H), 2.71 (m, 1 H), 2.33–2.24 (m, 8 (m, 1 H), 8.17 (d, J = 4.0 Hz, 1 H), 7.68–7.59 (m, 1 H), 7.48–7.40
H), 1.92–1.76 (m, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = (m, 1 H), 7.27 (d, J = 8.2 Hz, 1 H), 7.05–7.00 (m, 1 H), 6.71–6.65
2
176.5 (q, JC,F = 32.0 Hz), 146.7, 142.4, 142.0, 136.1, 130.3, 130.0,
(m, 1 H), 6.53–6.49 (m, 2 H), 5.14 (d, J = 8.8 Hz, 1 H), 2.80–2.70
1
128.5, 120.9, 114.4, 117.7 (q, JC,F = 289.8 Hz), 105.2, 67.4, 25.0,
(m, 1 H), 2.40–2.28 (m, 2 H), 2.00–1.82 (m, 1 H) ppm. 13C NMR
20.7, 20.3, 14.3 ppm. GC-MS (EI, 70 eV): m/z (%) = 374 (5) [M]+;
345 (0.02), 268 (100), 198 (2), 170 (37), 91 (39). C21H21F3N2O
(374.40): calcd. C 67.37, H 5.65, N 7.48; found C 67.21, H 5.42, N
7.11.
(CDCl3, 100 MHz): δ = 178.1 (q, JC,F = 32.8 Hz), 155.9, 152.5,
2
148.2, 147.7, 138.8, 137.7, 119.5, 114.2, 110.6, 109.2, 142.8, 117.5
1
(q, JC,F = 289.7 Hz), 107.5, 59.8, 25.79, 14.8 ppm. GC-MS (EI,
70 eV): m/z (%) = 348 (3) [M]+, 254 (98), 157 (48), 78 (100).
C17H15F3N4O (348.32): calcd. C 58.62, H 4.34, N 16.08; found C
58.60, H 4.20, N 15.68.
1-(2-Hydroxyphenyl)-6-(2-hydroxyphenylamino)-3-trifluoroacetyl-
1,4,5,6-tetrahydropyridine (4i): This compound was obtained as a
brown solid, yield 0.67 g (89%) (from 1) and 0.68 g (90%) (from
General Procedure for the Synthesis of Tetrahydropyridines 4m–o:
2), mp. 143–144 °C. 1H NMR (DMSO–d6, 200 MHz): δ = 10.07 (s, To a stirred solution of pyran 1 (0.42 g, 2.0 mmol) in methanol
1 H), 9.34 (s, 1 H), 7.59 (s, 1 H), 7.28 (d, J = 7.8 Hz, 1 H), 7.12 (t,
J = 7.6 Hz, 1 H), 6.93 (d, J = 8.0 Hz, 1 H), 6.78 (t, J = 7.5 Hz, 1
H), 6.64 (d, J = 7.0 Hz, 1 H), 6.47 (s, 3 H), 5.53 (d, J = 8.8 Hz, 1
(8 mL) or pyran 2 (0.45 g, 2.0 mmol) in ethanol (8 mL), amines
3m–o (0.43 g, 4.0 mmol) were added dropwise and the reaction was
stirred at room temperature for 24 h. The solvent was removed
H), 4.94 (d, J = 9.4 Hz, 1 H), 2.63–2.55 (m, 1 H), 2.34–2.09 (m, 2 using a rotary evaporator and the products were purified by fil-
H), 2.00–1.85 (m, 1 H) ppm. 13C NMR ([D6]DMSO, 100 MHz): δ tration through a multilayer chromatography column composed
2
= 174.0 (q, JC,F = 30.9 Hz), 152.0, 144.3, 134.0, 131.6, 128.6, (from the bottom to the top) of sodium sulfate, neutral alumina,
126.84, 119.5, 119.4, 117.7, 116.6, 114.1, 111.9, 151.1, 117.8 (q, J
= 288.8 Hz), 102.4, 66.3, 25.5, 14.5 ppm. GC-MS (EI, 70 eV): m/z
(%) = 377 (1) [M – 1]+; 269 (100), 200 (99), 172 (25), 93 (9).
C19H17F3N2O3 (378.35): calcd. C 60.32, H 4.53, N 7.40; found C
60.12, H 4.67, N 7.23.
active charcoal and neutral alumina and the column was eluted
with methanol or ethanol. Products 4m–o should be stored in a
refrigerator to avoid decomposition.
2-(Aminopyrid-2-yl)methyl-1-(pyrid-2-yl)methyl-3-trifluoroacetyl-
1,4,5,6-tetrahydropyridine (4m): This compound was obtained as a
brown oil, yield 0.62 g (82%) (from 1) and 0.68 g (90%) (from 2).
1H NMR (DMSO–d6, 400 MHz): δ = 8.54 (d, J = 1.2 Hz, 1 H),
8.47 (d, J = 0.8 Hz, 1 H), 7.78–7.74 (m, 4 H), 7.44 (s, 1 H), 7.31–
7.24 (m, 4 H), 4.82 (s, 2 H), 4.16 (br. s, 1 H), 3.94 (d, J = 14 Hz, 1
1-(4-Methoxyphenyl)-6-(4-methoxyphenylamino)-3-trifluoroacetyl-
1,4,5,6-tetrahydropyridine (4j): This compound was obtained as a
white solid, yield 0.76 g (94%) (from 1) and 0.75 g (93%) (from 2),
mp. 110–111 °C. 1H NMR (CDCl3, 200 MHz): δ = 7.78 (s, 1 H),
7.13 (d, J = 8.0 Hz, 2 H), 6.85 (d, J = 8.2 Hz, 2 H), 6.74 (d, J = H); 3.89 (d, J = 4.0 Hz, 1 H), 2.36–2.35 (m, 1 H), 2.25–2.21 (m, 1
7.8 Hz, 2 H), 6.57 (d, J = 8.2 Hz, 2 H), 5.27 (br. s, 1 H), 3.78 (s, 3
H), 1.98–1.93 (m, 1 H), 1.52–1.49 (m, 1 H) ppm. 13C NMR ([D6]-
2
H), 3.73 (s, 3 H), 2.78–2.67 (m, 1 H), 2.38–2.26 (m, 2 H), 1.94–1.81
DMSO, 100 MHz): δ = 174.2 (q, JC,F = 31.6 Hz), 150.2, 150.0,
2
1
(m, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 176.3 (q, JC,F
=
149.8, 146.3, 122.3, 146.3, 117.7 (q, JC,F = 292.7 Hz), 103.5, 85.1,
32.3 Hz), 158.1, 153.4, 138.5, 138.3, 123.4, 116.4, 115.0, 114.9,
56.3, 55.1, 23.6, 13.7 ppm. GC-MS (EI, 70 eV): m/z (%) = 376 (3)
[M]+, 284 (13), 268 (10), 176 (9), 92 (100). HRMS (ESI) m/z calcd.
for C19F3H19N4O [M + H]+ 377.1589, found 377.1580.
1
147.4, 117.8 (q, JC,F = 290.0 Hz), 104.6, 69.0, 55.6, 55.5, 25.4,
14.3 ppm. GC-MS (EI, 70 eV): m/z (%) = 406 (7) [M]+, 284 (100),
186 (34), 123 (73), 107 (13), 92 (9), 77 (17). C21H21F3N2O3 (406,40):
calcd. C 62.06, H 5.21, N 6.89; found C 61.85, H 5.24, N 6.86.
2-(Aminopyrid-3-yl)methyl-1-(pyrid-3-yl)methyl-3-trifluoraocetyl-
1,4,5,6-tetrahydropyridine (4n): This compound was obtained as a
1-(4-Chlorophenyl)-6-(4-chlorophenylamino)-3-trifluoroacetyl- brown oil, yield 0.62 g (83%) (from 1) and 0.63 g (84%) (from 2).
1,4,5,6-tetrahydropyridine (4k): This compound was obtained as a
white solid, yield 0.71 g (85%) (from 1) and 0.66 g (80%) (from 2),
mp. 128–129 °C. 1H NMR (CDCl3, 200 MHz): δ = 7.79 (s, 1 H),
1H NMR (DMSO-d6, 400 MHz): δ = 8.54 (s, 1 H), 8.52 (d, J =
4.0 Hz, 1 H), 8.42 (s, 1 H), 3.71–7.77 (d, J = 7.2 Hz, 2 H), 7.60 (s,
1 H), 7.39–7.35 (m, 2 H), 4.82 (d, J = 15.6 Hz, 1 H), 4.70 (d, J =
7.32 (d, J = 9.0 Hz, 2 H), 7.17–7.10 (m, 4 H), 6.58 (d, J = 8.6 Hz, 15.4 Hz, 1 H), 4.01 (br. s, 1 H), 3.86 (d, J = 13.6 Hz, 1 H), 3.76 (d,
1440
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1435–1444

Highly Chemoselective Synthesis of 1,4,5,6-Tetrahydropyridines
J = 13.6 Hz, 1 H), 2.40–2.25 (m, 2 H), 2.24–1.98 (m, 1 H), 1.44
(br. s, 1 H) ppm. 13C NMR ([D6]DMSO, 100 MHz): δ = 173.1 (q,
2JC,F = 30.6 Hz), 151.4, 149.3, 148.9, 135.8, 135.6, 135.3, 132.4,
291.7 Hz), 104.5, 84.6, 58.5, 55.4, 23.9, 13.9 ppm. GC-MS (EI,
70 eV): m/z (%) = 299 (30) [M]+, 268 (17), 230 (30), 208 (14), 176
(10), 108 (10), 91 (100). HRMS (ESI) m/z calcd. for C15H16F3NO2
[M + H]+ 300.1211, found 300.1208.
1
123.6, 123.2, 147.9, 117.9 (q, JC,F = 292.1 Hz), 102.2, 67.9, 54.0,
46.4, 24.7, 14.6 ppm. GC-MS (EI, 70 eV): m/z (%) = 376 (3) [M]+,
284 (11), 268 (5), 176 (10), 92 (100). HRMS (ESI) m/z calcd. for
C19F3H19N4O [M + H]+ 377.1589, found 377.1576.
1-Phenetyl-6-methoxy-3-trifluoroacetyl-1,4,5,6-tetrahydropyridine
(5f): This compound was obtained as a brown oil, yield 0.51 g
(82%). 1H NMR (CDCl3, 200 MHz): δ = 7.32–7.24 (m, 4 H), 7.17–
7.13 (m, 2 H), 4.28 (br. s, 1 H), 3.69–3.58 (m, 2 H), 3.36 (s, 3 H),
2.91 (t, J = 7.0 Hz, 2 H), 2.55–2.46 (m, 1 H), 2.12–2.06 (m, 2 H),
1.42–1.26 (m, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 175.6
(q, J = 31.8 Hz), 149.53, 137.3, 128.7, 126.9, 117.7 (q, J =
291.7 Hz), 104.1, 86.1, 56.7, 55.1, 36.4, 23.7, 13.7 ppm. GC-MS
(EI, 70 eV): m/z (%) = 281 (74); 105 (100), 77 (48). C16H18F3NO2
(313.13): calcd. C 61.33, H 5.79, N 4.47; found C 61.34, H 5.68, N
4.36.
6-(Aminopyrid-4-yl)methyl-1-(pyrid-4-yl)methyl-3-trifluoroacetyl-
1,4,5,6-tetrahydropyridine (4o): This compound was obtained as a
brown oil, yield 0.56 g (74%) (from 1) and 0.57 g (76%) (from 2).
1H NMR ([D6]DMSO, 400 MHz): δ = 8.54 (d, J = 1.6 Hz, 2 H),
8,46 (d, J = 1.2 Hz, 2 H), 7.79 (s, 1 H), 7.33 (d, J = 4.0 Hz, 2 H),
7.19 (d, J = 4.0 Hz, 2 H), 4.83 (d, J = 16.0 Hz, 1 H), 4.73 (d, J =
16.2 Hz, 1 H), 3.99 (br. s, 1 H), 3.85 (d, J = 15.2 Hz, 1 H), 3.75 (d,
J = 15.2 Hz, 1 H), 2.43–2.28 (m, 2 H), 2.02–2.00 (m, 1 H), 1.56
(br. s, 1 H) ppm. 13C NMR ([D6]DMSO, 50 MHz): δ = 173.8 (q,
2JC,F = 31.0 Hz), 151.7, 150.9, 149.9, 149.3, 122.9, 122.3, 146.3,
117.9 (q, 1JC,F = 290.1 Hz), 103.6, 85.1, 68.4, 56.4, 23.6, 13.7 ppm.
GC-MS (EI, 70 eV): m/z (%) = 376 (3) [M]+, 284 (24), 268 (28),
176 (12), 107 (16), 92 (100). HRMS (ESI) m/z calcd. for
C19F3H19N4O [M + H]+ 377.1589, found 377.1580.
1-(4-Methoxyphenyl)-6-methoxy-3-trifluoroacetyl-1,4,5,6-tetrahydro-
pyridine (5j): This compound was obtained as a brown oil, yield
1
0.48 g (77%). H NMR (CDCl3, 200 MHz): δ = 7.73 (s, 1 H), 7.17
(d, J = 9.0 Hz, 2 H), 6.94 (d, J = 9.0 Hz, 2 H), 4.92 (br. s, 1 H),
3.83 (s, 3 H), 3.35 (s, 3 H), 2.69–2.59 (m, 1 H), 2.37–2.30 (m, 2 H),
1.68–1.64 (m, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 176.7
(q, J = 31.8 Hz), 147.3, 150.1, 138.8, 123.3, 116.4, 117.7 (q, J =
291.05 Hz), 106.6, 87.02, 55. 6, 24.12, 13.93 ppm. GC-MS (EI,
70 eV): m/z (%) = 315 (72) [M]+, 300 (6), 284 (69), 122 (89), 107
(24), 58 (100). C15H16F3NO3 (315.11): calcd. C 57.14, H 5.12, N
4.44; found C 57.07, H 5.21, N 4.48.
General Procedure for the Synthesis of Tetrahydropyridines 5a, 5d–
f, 5j and 6a, 6c–d, 6 g–h, 6j–k: To a stirred solution of pyran 1
(0.42 g, 2.0 mmol) in methanol (8 mL) or pyran 2 (0.45 g,
2.0 mmol) in ethanol (8 mL) and pyridine (0.17 mL, 2.0 mmol), the
desired amines 3 (2.0 mmol) were added and the reaction was
stirred and heated to reflux for 48 h. The solvent was partially evap-
orated and the residue was dissolved in chloroform (20 mL) and
washed with water (2ϫ20 mL). The combined organic phases were
dried with anhydrous sodium sulfate and evaporated with a rotary
evaporator. Products 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 and the column was eluted with methanol or etha-
nol.
6-Ethoxy-1-methyl-3-trifluoroacetyl-1,4,5,6-tetrahydropyridine (6a):
This compound was obtained as an orange oil, yield 0.29 g (62%).
1H NMR (CDCl3, 400 MHz): δ = 7.41 (s, 1 H), 4.45 (br. s, 1 H),
3.61 (m, 2 H,), 3.21 (s, 3 H), 2.58–2.54 (m, 1 H), 2.16–2.12 (m, 2
H), 1.57–1.53 (m, 1 H) e 1.25 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 174.9 (q, J = 31.7 Hz), 150.4, 117.7 (q, J
= 291.7 Hz), 103.5, 85.3, 63.6, 42.0, 24.3, 15.0, 13.4 ppm. GC-MS
(EI, 70 eV): m/z (%) = 237 (22) [M]+, 208 (9), 192 (60), 168 (22),
140 (8), 94 (100), 69 (51). C10H14F3NO2 (237.22): calcd. C 50.63,
H 5.95, N 5.90; found C 50.36, H 5.53, N 5.45.
6-Methoxy-1-methyl-3-trifluoroacetyl-1,4,5,6-tetrahydropyridine
(5a): This compound was obtained as a orange oil, yield 0.29 g
1
6-Ethoxy-1-propyl-3-trifluoroacetyl-1,4,5,6-tetrahydropyridine (6c):
This compound was obtained as an orange oil, yield 0.37 g (70%).
1H NMR (CDCl3, 200 MHz): δ = 7.46 (s, 1 H), 4.53 (br. s, 1 H),
3.63–3.5 (m, 2 H), 3.45–3.38 (m, 1 H), 3.30–3.23 (m, 1 H), 2.64–
2.54 (m, 1 H), 2.25–2.06 (m, 2 H), 1.70–1.64 (m, 2 H), 1.53–1.44
(m, 1 H), 1.24 (t, J = 7.0 Hz, 3 H), 0.94 (t, J = 7.0 Hz, 3 H) ppm.
13C NMR (CDCl3, 50 MHz): δ = 175.2 (q, J = 31.7 Hz), 150.2,
117.8 (q, J = 291.4 Hz), 103.5, 84.0, 63.2, 56.8, 24.41, 22.6, 15.1,
13.7, 10.62 ppm. GC-MS (EI, 70 eV): m/z (%) = 265 (29) [M]+, 236
(11), 220 (100), 196 (29), 177 (28), 69 (57). HRMS (ESI) m/z calcd.
for C12H18F3NO2 [M + H]+ 266.1368, found 266.1361.
(65%). H NMR (CDCl3, 400 MHz): δ = 7.42 (s, 1 H), 4.38 (br. s,
1 H), 3.44 (s, 3 H), 3.23 (s, 3 H), 2.57–2.53 (m, 1 H), 2.20–2.16 (m,
2 H), 1.57–1.49 (m, 1 H,) ppm. 13C NMR (CDCl3, 100 MHz): δ =
175.2 (q, J = 32.2 Hz), 150.3, 117.7 (q, J = 292.1 Hz), 103.8, 86.8,
55.5, 43.3, 26.6, 13.4 ppm. GC-MS (EI, 70 eV): m/z (%) = 223 (23)
[M]+, 208 (3), 192 (46), 154 (43), 94 (100), 69 (63). HRMS (ESI)
m/z calcd. for C9H12F3NO2 [M + H]+ 224.0898, found 224.0887.
6-Methoxy-1-phenyl-3-trifluoroacetyl-1,4,5,6-tetrahydropyridine
(5d): This compound was obtained as a brown oil, yield 0.38 g
1
(67%). H NMR (CDCl3, 400 MHz): δ = 7.83 (s, 1 H), 7.44–7.38
(m, 2 H), 7.32–7.26 (m, 3 H), 5.02 (br. s, 1 H), 3.37 (s, 3 H), 2.67–
2.59 (m, 1 H), 2.39–2.32 (m, 2 H), 1.78–1.63 (m, 1 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 177.0 (q, J = 32.5 Hz), 146.5 (C-2),
145.3, 129.9, 126.1, 121.1, 117.5 (q, J = 291.7 Hz), 107.5, 86.5,
55.32, 23.95, 14.08 ppm. GC-MS (EI, 70 eV): m/z (%) = 285 (14)
[M]+, 270 (4), 192 (46), 254 (20), 216 (4), 184 (9), 156 (29), 77 (100).
HRMS (ESI) m/z calcd. for C14H14F3NO2 [M + H]+ 286.1055,
found 286.1051.
6-Ethoxy-1-phenyl-3-trifluoroacetyl-1,4,5,6-tetrahydropyridine (6d):
This compound was obtained as a brown oil, yield 0.41 g (69%).
1H NMR (CDCl3, 200 MHz): δ = 7.83 (s, 1 H), 7.46–7.39 (m, 2
H), 7.32–7.22 (m, 3 H), 5.10 (s, 1 H), 3.60–3.49 (m, 2 H), 2.69–2.57
(m, 1 H), 2.43–2.28 (m, 2 H), 1.77–1,61 (m, 1 H), 1.21 (t, J =
7.0 Hz, 3 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 176.9 (q, J =
32.3 Hz), 145.3, 146.7, 129.8, 126.1, 121.1, 117.6 (q, J = 291.7 Hz),
107.3, 85.2, 63.4, 24.6, 15.3, 14.14 ppm. GC-MS (EI, 70 eV): m/z
(%) = 299 (90) [M]+, 270 (28), 254 (100), 230 (22), 202 (7), 177
(57), 77 (98). HRMS (ESI) m/z calcd. for C15H16F3NO2 [M + H]+
300.1211, found 300.1207.
1-Benzyl-6-methoxy-3-trifluoroacetyl-1,4,5,6-tetrahydropyridine
(5e): This compound was obtained as a orange oil, yield 0.40 g
1
(68%). H NMR (CDCl3, 200 MHz): δ = 7.56 (s, 1 H), 7.36 (m, 3
H), 4.64 (d, J = 15.2 Hz, 1 H), 4.50 (d, J = 15.2 Hz, 1 H), 4.36 (br.
s, 1 H), 3.37 (s, 3 H), 2.63–2.51 (m, 1 H,), 2.30–2.11 (m, 2 H), 1.54– 6-Ethoxy-1-(2-tolyl)-3-trifluoroacetyl-1,4,5,6-tetrahydropyridine
1.38 (m, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 175.9 (q, J
= 32.5 Hz), 149.9, 135.5, 129.1, 128.4, 127.6, 117.8 (q, J =
(6g): This compound was obtained as an orange oil, yield 0.52 g
(83%). H NMR (CDCl3, 400 MHz): δ = 7.45 (s, 1 H), 7.29–7.26
1
Eur. J. Org. Chem. 2009, 1435–1444
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1441

Nilo Zanatta et al.
FULL PAPER
(m, 4 H), 4.80 (br. s, 1 H), 3.47 (m, 2 H), 2.71–2.66 (m, 1 H), 2.41– 55.0, 23.7, 13.8 ppm. GC-MS (EI, 70 eV): m/z (%) = 300 (24)
2.33 (m, 1 H), 2.28 (s, 3 H), 1.80–1.69 (m, 2 H), 1.10 (t, J = 7.0 Hz,
3 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 176.5 (q, J = 32.3 Hz),
149.5, 144.3, 134.3, 131.7, 128.2, 127.2, 126.9, 117.7 (q, J =
291.7 Hz), 105.2, 86.4, 64.6, 25.6, 17.9, 15.3, 14.0 ppm. GC-MS
(EI, 70 eV): m/z (%) = 313 (27) [M]+, 284 (7), 268 (45), 244 (6), 108
(100), 91 (43). HRMS (ESI) m/z calcd. for C16H18F3NO2 [M +
H]+ 314.1367, found 314.1364.
[M]+, 269 (15), 231 (19), 208 (20), 176 (54), 92 (100), 80 (5). HRMS
(ESI) m/z calcd. for C14F3H15N2O2 [M + H]+ 301.1164, found
301.1159.
6-Methoxy-1-(pyrid-3-yl)methyl-3-trifluoroacetyl-1,4,5,6-tetrahydro-
pyridine (5n): This compound was obtained as a brown oil, yield
1
0.49 g (87%). H NMR ([D6]DMSO, 200 MHz): δ = 8.57 (s, 1 H),
8.53 (d, J = 1.4 Hz, 1 H), 7.76 (d, J = 4.0 Hz, 1 H), 7.71 (s, 1 H),
7.42 (dd, J = 7.6, J = 4.6 Hz, 1 H), 4.87 (d, J = 15.4 Hz, 1 H), 4.74
(d, J = 15.4 Hz, 1 H), 4.60 (br. s, 1 H), 3.31 (s, 3 H), 2.49–2.33 (m,
1 H), 2.13–1.97 (m, 2 H), 1.44–1.34 (m, 1 H,) ppm. 13C NMR ([D6]-
6-Ethoxy-1-(4-tolyl)-3-trifluoroacetyl-1,4,5,6-tetrahydropyridine
(6h): This compound was obtained as an orange oil, yield 0.44 g
1
(71%). H NMR (CDCl3, 400 MHz): δ = 7.78 (s, 1 H), 7.22 (d, J
2
= 8.8 Hz, 2 H), 7.12 (d, J = 8.4 Hz, 2 H), 5.07 (br. s, 1 H), 3.54–
3.50 (m, 2 H), 2.66–2.61 (m, 1 H), 2.37 (s, 3 H), 2.33–2.29 (m, 1
DMSO, 100 MHz): δ = 173.9 (q, JC,F = 31.9 Hz), 150.3, 139.5,
1
132.5, 123.6, 149.0, 117.6 (q, JC,F = 292.6 Hz), 103.4, 84.8, 55,
H), 1.71–1,63 (m, 2 H), 1.20 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR 54.9, 23.5, 13.7 ppm. GC-MS (EI, 70 eV): m/z (%) = 300 (28)
(CDCl3, 100 MHz): δ = 176.7 (q, J = 32.5 Hz), 147.0, 143.0, 136.1,
130.3, 121.3, 117.6 (q, J = 291.7 Hz), 106.8, 85.3, 63.6, 24.74, 20.7,
15.3, 14.1 ppm. GC-MS (EI, 70 eV): m/z (%) = 313 (31) [M]+, 298
(2), 284 (9), 268 (47), 170 (39), 107 (100). HRMS (ESI) m/z calcd.
for C16H18F3NO2 [M + H]+ 314.1367, found 314.1361.
[M]+, 268 (29), 231 (21), 208 (18), 176 (13), 92 (100). HRMS (ESI)
m/z calcd. for C14F3H15N2O2 [M + H]+ 301.1164, found 301.1156.
6-Methoxy-1-(pyrid-4-yl)methyl-3-trifluoroacetyl-1,4,5,6-tetrahydro-
pyridine (5o): This compound was obtained as a brown oil, yield
1
0.48 g (80%). H NMR ([D6]DMSO, 200 MHz): δ = 8.57 (d, J =
6-Ethoxy-1-(4-methoxyphenyl)-3-trifluoroacetyl-1,4,5,6-tetrahydro- 5.8 Hz, 2 H), 7.75 (s, 1 H), 7.28 (d, J = 5.4 Hz, 2 H), 4.92 (d, J =
pyridine (6j): This compound was obtained as a brown oil, yield 16.2 Hz, 1 H), 4.76 (d, J = 16.0 Hz, 1 H), 4.56 (br. s, 1 H), 3.30 (s,
1
0.41 g (63%). H NMR (CDCl3, 400 MHz): δ = 7.72 (s, 1 H), 7.17 3 H), 2.39–2.36 (m, 1 H), 2.16–1.91 (m, 2 H), 1.53–1.44 (m, 1
2
(d, J = 9 Hz, 2 H), 6.93 (d, J = 9 Hz, 2 H), 5.00 (br. s, 1 H), 3.83
H) ppm. 13C NMR ([D6]DMSO, 100 MHz): δ = 174.1 (q, JC,F
=
1
(s, 3 H), 3.56–3.48 (m, 2 H), 2.66–2,61 (m, 1 H), 2.38–2.26 (m, 2 31.9 Hz), 150.6, 149.8, 122.2, 146.2, 117.4 (q, JC,F = 291.8 Hz),
H), 1.72–1.63 (m, 1 H), 1.19 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR 103.5, 84.9, 56.3, 54.9, 23,5, 13.7 ppm. GC-MS (EI, 70 eV): m/z
(CDCl3, 100 MHz): δ = 176.6 (q, J = 32.5 Hz), 147.6, 158, 138.7,
123.4, 114.8, 117.7 (q, J = 291.7 Hz), 106.4, 85.7, 63.7, 55.5, 24.8,
15.4, 14.0 ppm. GC-MS (EI, 70 eV): m/z (%) = 329 (55) [M]+, 300
(13), 284 (53), 123 (100), 107 (9), 77 (20). HRMS (ESI) m/z calcd.
for C16H18F3NO3 [M + H]+ 330.1317, found 330.1308.
(%) = 300 (23) [M]+, 268 (29), 231 (21), 208 (18), 176 (13), 92 (100).
HRMS (ESI) m/z calcd. for C14F3H15N2O2 [M + H]+ 301.1164,
found 301.1156.
6-Ethoxy-1-(pyrid-2-yl)methyl-3-trifluoroacetyl-1,4,5,6-tetrahydro-
pyridine (6m): This compound was obtained as a brown oil, yield
0.60 g (96%). H NMR ([D6]DMSO, 400 MHz): δ = 8.58 (d, J =
1
1-(4-Chlorophenyl)-6-ethoxy-3-trifluoroacetyl-1,4,5,6-tetrahydropyr-
idine (6k): This compound was obtained as an orange oil, yield
0.49 g (73%). H NMR (CDCl3, 400 MHz): δ = 7.74 (s, 1 H), 7.39 4.90 (d, J = 15.6 Hz, 1 H), 4.79 (d, J = 15.6 Hz, 1 H), 4.72 (br. s,
0.8 Hz, 1 H), 7.86–7.81 (m, 2 H), 7.42 (s, 1 H), 7.40–7.34 (m, 1 H),
1
(d, J = 9.2 Hz, 2 H), 7.17 (d, J = 8.8 Hz, 2 H), 5.04 (br. s, 1 H),
3.59–3.49 (m, 2 H), 2.65–2,60 (m, 1 H), 2.39–2.32 (m, 2 H), 1.72–
1,64 (m, 1 H), 1.22 (t, J = 6.8 Hz, 3 H,) ppm. 13C NMR (CDCl3,
100 MHz): δ = 177.1 (q, J = 32.7 Hz), 146.0, 143.8, 131.6, 129.9,
122.4, 117.5 (q, J = 289.9 Hz), 107.8, 85.2, 63., 24.5, 15.3,
14.0 ppm. GC-MS (EI, 70 eV): m/z (%) = 333 (24) [M]+, 304 (8),
288 (46), 264 (6), 127 (100) [PB], 111 (34). HRMS (ESI) m/z calcd.
for C15H15ClF3NO3 [M + H]+ 334.0821, found 334.0812.
1 H), 3.61–3.50 (m, 2 H), 2.43–2.38 (m, 1 H), 2.08–2.00 (m, 2 H,
4-H), 1.49–1.44 (m, 1 H) e 1.07 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR
2
([D6]DMSO, 100 MHz): δ = 174.2 (q, JC,F = 30.9 Hz), 154.7,
151.7, 137.4, 123.2, 122.6, 149.7, 118.1 (q, 1JC,F = 292.7 Hz), 103.3,
84.3, 63.3, 59.4, 24.7, 15.5, 14.2 ppm. GC-MS (EI, 70 eV): m/z (%)
= 314 (14) [M]+, 269 (15), 245 (7), 222 (18), 177 (15), 92 (100).
HRMS (ESI) m/z calcd. for C15F3H17N2O2 [M + H]+ 315.1320,
found 315.1325.
General Procedure for the Synthesis of Tetrahydropyridines 5m–o,
6m–o: To a stirred solution of pyran 1 (0.42 g, 2.0 mmol) in meth-
anol (8 mL) or pyran 2 (0.45 g, 2.0 mmol) in ethanol (8 mL), 0.60 g (95%). H NMR ([D6]DMSO, 400 MHz): δ = 8.57 (s, 1 H),
6-Ethoxy-1-(pyrid-3-yl)methyl-3-trifluoroacetyl-1,4,5,6-tetrahydro-
pyridine (6n): This compound was obtained as a brown oil, yield
1
amines 3m–o (0.22 g, 2.0 mmol) were added and the reaction was
stirred and heated to reflux for 24 h for the compounds 5m–o and
for 48 h for the compounds 6m–o. The solvent was partially evapo-
rated and the products were purified by filtration through a
multilayer chromatography column composed upwards from so-
dium sulfate, neutral alumina, active charcoal and neutral alumina
and the column was eluted with methanol or ethanol. Compounds
5m–o and 6m–o must be stored in a refrigerator to avoid decompo-
sition.
8.54 (d, J = 4.8 Hz, 1 H), 7.74 (d, J = 7.6 Hz, 1 H), 7.43 (t, J =
8 Hz, 1 H), 6.66 (s, 1 H), 4.82–4.78 (m, 2 H), 4.67 (br. s, 1 H),
3.59–3.43 (m, 2 H), 2.41–2.37 (m, 2 H), 1.51–1.39 (m, 2 H), 1.05
(t, J = 7.0 Hz, 3 H) ppm. 13C NMR ([D6]DMSO, 100 MHz): δ =
2
173.5 (q, JC,F = 30.3 Hz), 150.4, 150.3, 135.4, 132.4, 123.5, 148.9,
1
117.7 (q, JC,F = 292.0 Hz), 103.0, 83.6, 62.6, 54.8, 27.2, 14.9,
13.8 ppm. GC-MS (EI, 70 eV): m/z (%) = 314 (15) [M]+, 269 (12),
245 (7), 222 (15), 177 (12), 92 (100). HRMS (ESI) m/z calcd. for
C15F3H17N2O2 [M + H]+ 315.1320, found 315.1324.
6-Methoxy-1-(pyrid-2-yl)methyl-3-trifluoroacetyl-1,4,5,6-tetrahydro- 6-Ethoxy-1-(pyrid-4-yl)methyl-3-trifluoroacetyl-1,4,5,6-tetrahydro-
pyridine (5m): This compound was obtained as a brown oil, yield
0.49 g (82%). H NMR ([D6]DMSO, 200 MHz): δ = 8.57 (d, J =
pyridine (6o): This compound was obtained as a brown oil, yield
0.57 g (90%). H NMR ([D6]DMSO, 400 MHz): δ = 8.57 (d, J =
1
1
3.8 Hz, 1 H), 7.83 (dd, J = 7.6, J = 1.6 Hz, 2 H), 7.37 (s, 1 H), 7.33
5.6 Hz, 2 H), 7.75 (s, 1 H), 7.29 (d, J = 5.2 Hz, 2 H), 4.87 (d, J =
(t, J = 7.8 Hz, 1 H), 4.92 (d, J = 15.4 Hz, 1 H), 4.78 (d, J = 15.6 Hz, 16.4 Hz, 1 H), 4.77 (d, J = 16.4 Hz, 1 H), 4.63 (br. s, 1 H), 3.59–
1 H), 4.64 (br. s, 1 H), 3.32 (s, 3 H), 2.42–2.35 (m, 1 H), 2.10–
3.45 (m, 2 H), 2.44–2.40 (m, 1 H), 2.10–2.06 (m, 2 H), 1.53–1.47
2.02 (m, 2 H), 1.44–1.40 (m, 1 H) ppm. 13C NMR ([D6]DMSO,
(m, 1 H), 1.06 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR ([D6]DMSO,
2
2
100 MHz): δ = 173.8 (q, JC,F = 31.1 Hz), 156.3, 151.2, 137.0,
100 MHz): δ = 173.9 (q, JC,F = 31.3 Hz), 150.4, 149.6, 122.2,
1
1
122.8, 122.1, 151.1, 117.7 (q, JC,F = 292.3 Hz), 103.0, 85.3, 59.1,
145.8, 117.4 (q, JC,F = 292.6 Hz), 102.5, 83.7, 62.8, 56.0, 24.2,
1442
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1435–1444

Highly Chemoselective Synthesis of 1,4,5,6-Tetrahydropyridines
14.8, 13.7 ppm. GC-MS (EI, 70 eV): m/z (%) = 314 (31) [M]+, 269
(46), 245 (15), 222 (32), 177 (26), 92 (100). HRMS (ESI) m/z calcd.
for C15F3H17N2O2 [M + H]+ 315.1320, found 315.1317.
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Biological Assays: The in vitro antimicrobial activity of the 1-alk-
yl(aryl)-6-amino-3-trifluoroacetyl-1,4,5,6-tetrahydropyridines was
assessed against a selection of microorganisms including yeast-like
fungi, algae and bacteria. The minimal inhibitory concentration
(MIC) and minimal fungicidal, bactericidal and algacidal concen-
trations were determined by broth microdilution methods accord-
ing to NCCLS standards.[42–44] Compounds were dissolved in
DMSO and the solutions were diluted with a culture medium. By
further progressive dilutions with the test medium, the required
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concentrations (320, 160, 80, 40, 20, 10, 5, 2.5 and 1.25 µgmLϪ1
)
were obtained. The antimicrobial activities were evaluated based
on the minimal inhibitory concentration (MIC) according to the
NCCLS M27-A2 procedures[42] for yeast-like fungi and algae. For
bacteria, the procedures described in NCCLS M7-A4[44] were em-
ployed. Bacteria were initially inoculated into Mueller-Hinton agar
and, after overnight growth, four or five colonies were directly sus-
pended in saline solution until the turbidity matched the turbidity
of the McFarland standard (approximately 108 cfumLϪ1). The sus-
pensions were diluted to 1:100 in saline followed by a new dilution
to 1:20 in Mueller-Hinton broth, resulting in a final inoculum con-
centration of 5ϫ104 cfumLϪ1 per well. Yeasts and P. zopfii were
inoculated on potato dextrose agar and the procedures of inoculum
standardisation were similar; the test medium was RPMI 1640
broth. Briefly, each well of the microdilution tray was filled with
100 µL of compound diluted in 100 µL of the inoculum. The plates
were incubated at 35 °C / 24 h for the bacteria and Candida species;
S. cerevisae, C. neoformans and P. zopfii required up to 72 h of
incubation. Growth or a lack of growth in the wells containing the
antimicrobial agent was determined by comparison with the growth
control, indicated by turbidity. The lowest concentration that com-
pletely inhibited visible growth of the organism was recorded as the
MIC. All tests were carried out in duplicate and accepted when
coincident. When the tests were not coincident they were repeated
in duplicate once more. The minimal fungicidal, bactericidal and
algacidal concentrations were determined by subculture of 20 µL
of the content of each well that remained clear. The media em-
ployed were Sabouraud dextrose agar for fungi and P. zopfii and
Mueller–Hinton agar for bacteria. The plates were incubated at
35 °C during the same time periods for MIC determination and
the lowest concentration required to demonstrate complete growth
absence was named cidal. The interpretation of the results was
based on fluconazole and amphotericin B breakpoints for the fungi
and based on imipenem for bacterial pathogens all according to
M27-A2,[42] M38-A[43] and M7-A4[44] techniques, respectively.
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Acknowledgments
The authors thank the financial support from the Conselho Na-
cional de Desenvolvimento Científico e Tecnológico Universal
(CNPq), grant no. 476634/06-7 and fellowships from CAPES (to
F.M.N.) and CNPq (to L.d.S. F., H. S. Coelho, and S. S. A.).
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Received: November 11, 2008
Published Online: February 3, 2009
1444
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Eur. J. Org. Chem. 2009, 1435–1444