Cyclobutene ring-opening of bicyclo[4.2.0]octa-1,6-dienes: Access to CF3-substituted 5,6,7,8-tetrahydro-1,7-naphthyridines

Article abstract of DOI:10.1021/jo301501r

An efficient method for the synthesis of novel CF₃-substituted tetrahydro-1,7-naphthyridines including cyclic α-amino acid derivatives has been developed. The method is based on unusual cyclobutene ring-opening of bicyclo[4.2.0]octa-1,6-dienes with pyrrolidine to afford the corresponding 1,5-diketones followed by their heterocyclization. A convenient one-pot procedure has been also elaborated starting from readily available trifluoromethylated 1,6-allenynes.

Full text of DOI:10.1021/jo301501r

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Article
Cyclobutene Ring Opening of Bicyclo[4.2.0]octa-1,6-dienes:
Access to CF3-substituted 5,6,7,8-Tetrahydro-1,7-naphthyridines
Artur K Mailyan, Alexander S Peregudov, Pierre H Dixneuf, Christian Bruneau, and Sergey N. Osipov
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo301501r • Publication Date (Web): 05 Sep 2012
Downloaded from http://pubs.acs.org on September 8, 2012
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Cyclobutene Ring Opening of Bicyclo[4.2.0]octa-1,6-dienes:
Access to CF3-substituted 5,6,7,8-Tetrahydro-1,7-naphthyridines
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Artur K. Mailyana, Alexander S. Peregudova, Pierre H. Dixneufb*, Christian Bruneaub,
Sergey N. Osipova*
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aA.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov str.
28, 119991, Moscow, Russia
Tel.: +7 499 1359306, Fax: +7 499 1355085, E-mail: osipov@ineos.ac.ru
bCentre of Catalysis and Green Chemistry, UMR 6226 CNRS-Universite de Rennes 1, Campus de
Beaulieu, 35042 Rennes Cedex, France, E-mail: E-mail: pierre.dixneuf@univ-rennes1.fr
Abstract:
An efficient method for the synthesis of novel CF3-substituted tetrahydro-1,7-naphthyridines including
cyclic α-amino acid derivatives has been developed. The method is based on unusual cyclobutene ring
opening of bicyclo[4.2.0]octa-1,6-dienes with pyrrolidine to afford the corresponding 1,5-diketones
followed by their heterocyclization. A convenient one pot procedure has been also elaborated starting
from readily available trifluoromethylated 1,6-allenynes.
Introduction
Nitrogen heterocycles equipped with diverse functionalities are important structural motifs
widely distributed in natural products and pharmaceuticals. Among them, 1,7-naphthyridines
represent a special class of dinitrogen-containing heterocycles that are found in the structure of
many bioactive compounds.1 During the past decade a particular attention has focused on their
partially reduced derivatives, the 5,6,7,8-tetrahydro-1,7-naphthyridines (THNs). Being
conformationally constrained counterparts of well-known pharmacophore 2-(3-
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pyridyl)ethylamine2, THNs have been shown to function as highly potential agents for the
treatment of depressions,3 Alzheimer disease,4 multiple sclerosis,5 and various skin diseases.6
Several synthetic strategies have been developed to access 1,7-THN framework due to its
medicinal and synthetic usefulness. They include the partial hydrogenation of 1,7-
naphthyridine,7 the conjugative addition of organometallic reagents with chloroformates to C=N-
bond of 1,7-naphthyridine,7c,8 the annulation of a piperidine ring onto a functionalized pyridine,9
the elaboration of a pyridine core from a preformed piperidine derivative,10 multicomponent
synthesis of epoxy-tetrahydronaphthyridine with subsequent fragmentation.11 More recent
approach involves the cobalt-catalyzed [2+2+2]-cycloaddition of orthogonally protected diyne
nitriles.12 These synthetic routes often consist of multistep procedures and have consequently
low overall yields. Moreover, most of them are not applicable for the preparation 1,7-THNs with
functional groups in the piperidine ring.
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On the other hand, it is well established that the introduction of trifluoromethyl (CF3) groups
into specific positions of organic molecules can substantially alter their chemical and metabolic
stability, lipophilicity, and binding selectivity due to the strongly electron withdrawing nature
and large hydrophobic domain of trifluoromethyl groups.13 Indeed, many biologically active
compounds, such as the antidepressant Prozac, the anti-inflammatory drug Celebrex and the
anticancer agent Casodex contain the CF3 group as a key structural motif.14 Therefore, the
development of efficient synthetic methodologies aimed at the rapid construction of new
nitrogen-containing heterocyclic systems bearing different functionalities, including CF3 groups,
is of great importance to sustain pharmaceutical innovation.
Results and Discussion
We have recently elaborated an efficient one-step protocol for the synthesis of functionalized
allenynes via [2,3]-sigmatropic rearrangement of propargyl-containing nitrogen and sulfur ylides
generated in situ from CF3-containing diazocompounds 1.15 The synthetic potential of allenynes
2 as the unique building blocks for the construction of functionally substituted heterocycles has
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been demonstrated by the intramolecular carbocyclizations such as cobalt-mediated Pauson-
Khand reaction and thermal [2+2]-cycloaddition to access the functionally substituted
heterocyclic compounds fused with cyclopentenone 315 and cyclobutene 416 rings, respectively
(Scheme 1).
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Scheme 1. Synthesis and carbocyclizations of CF3-substituted 1,6-allenynes
In this context, along with our interest in CF3-containing heterocyclic compounds including
cyclic α-amino acid derivatives17, we now wish to disclose a convenient route to functionalized
5,6,7,8-tetrahydro-1,7-naphthyridines based on unusual cyclobutene ring opening of acyl-
substituted bicyclo[4.2.0]octa-1,6-dienes with amines followed by intramolecular
heterocyclization (Scheme 2).
Scheme 2. Transformation of bicycloocta-1,6-dienes into tetrahydro-1,7-naphthyridines
Despite the fact that the compounds containing bicyclo[4.2.0]octa-1,6-diene framework are
well documented in the literature18, to the best of our knowledge, the ring opening of
cyclobutene unit was not previously described.
The synthesis of starting bicyclodienes 6 comprising the keto-function on double bond of
cyclobutene ring has been accomplished using the same methodology as for their arylated
analogues 416 (Scheme 1). First, allenynes 5 a-h were prepared by means of Pd-catalyzed cross-
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coupling of terminal allenyne 2a with different aromatic and aliphatic acylchlorides. The
reactions were performed in THF at room temperature at the presence of 5 mol% of
PdCl2(PPh3)2/CuI and 1.5-fold excess of NEt3 to furnish the corresponding allenynes 5 a-h in
good isolated yields. Then we found that intramolecular [2+2]-cycloaddition of 5 smoothly
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o
proceeds in toluene at 110 C for 1-2 hours affording the desired bicyclic products 6 in good to
excellent yields. It is noteworthy that the formation of cyclobutene ring proceeds upon distal
double bond of allene system exclusively (Table 1).
Table 1. Synthesis of acylated bicyclo[4.2.0]octa-1,6-dienes
Sonogashira step,
Yield, %
5a - 75
[2+2]-Cycloaddition,
Yield, %
6a - 75
Entry
R
1
2
3
4
5
6
7
8
C6H5
4-MeO-C6H4
2-MeO-C6H4
4-Me-C6H4
2-Me-C6H4
4-NO2-C6H4
Cy
5b - 78
6b - 89
5c - 78
6c - 91
5d - 83
6d - 91
5e - 73
6e - 88
5f - 64
6f - 82
5g - 68
6g - 78
t-Bu
5h - 57
6h – 85
Bicyclo[4.2.0]octa-1,6-dienes 6 contain in their structure the unique combination of
constrained cyclobutene ring with carbonyl group coincidently featuring the activated alkene
system. Thus, examining their properties, we have unexpectedly found that derivatives 6
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comprising aroyl groups on double bond of cyclobutene unit, in contrast to their aryl analogues
4, readily undergo four member ring opening at the presence of piperidine or pyrrolidine to
afford the corresponding cyclic 1,5-diketones 7 (Scheme 3).
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Scheme 3. Cyclobutene ring opening of bicyclo[4.2.0]octa-1,6-dienes
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excess of
O
secondary amine,
F3C
MeO2C
F3C
MeO2C
rt, few minutes,
then 1N HCl
Ar
N
N
Ar
Me
Me
O
7
6
O
In order to investigate this interesting transformation in details, a number of primary and
secondary amines, such as diethyl- and diisopropyl amines, benzyl amine, aniline, piperidine and
pyrrolidine, have been tested using benzoyl-substituted cyclobutene 6a as a model compound.
As a result, we found that the highest yields of cyclic 1,5-diketone 7a can be achieved on
treatment of 6a with twofold excess of pyrrolidine. The full conversion of starting bicycle occurs
in dry dioxane at room temperature for 20 min (monitoring by 19F NMR-spectroscopy).
Subsequent treatment of the reaction mixture with 1N HCl, needed for the removing of the
remaining amine, affords 7a in 68 % yield.
The proposed mechanism of 1,5-diketone formation includes: i) nucleophilic addition of
pyrrolidine to the activated double bond of cyclobutene ring to give the corresponding Michael
adduct 6aa; ii) ring opening of cyclobutene to form zwitterionic intermediate B; iii) hydrolysis of
the latter yielding the final product 7a (Scheme 4).
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Scheme 4. Proposed mechanism of cyclobutene ring opening
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We have succeeded to isolate and characterize the adduct 6aa (NR2 = pyrrolidinyl) formed as
a mixture of diastereomers in a ratio of 1:2. In the case of primary amines the similar adduct A
has proved to be unstable; the reaction rapidly leads to the formation of imine 8. This fact
implicitly confirms the existence of the intermediate B. One more evidence can be considered in
favor of the proposed mechanism: the stable dihydropyridine 9 is formed as a result of proton
migration of CH2N-group in zwitterionic intermediate B under exposure of reaction mixture in
dry dioxane for 48 hours. Therefore, the usage of secondary amine, especially pyrrolidine, with
subsequent rapid water treatment is a critical point for the successful formation of the desired
compound 7a. At the same time, 1,5-diketone 7a can be also obtained by acidic hydrolysis of
imine 8 when primary amine is utilized.
The found regularities are also implemented for the other bicyclo[4.2.0]octa-1,6-dienes 6 (see
the Supporting Info). However, in order to simplify the synthetic procedure and to improve the
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yields of 1,5-diketones, we have developed a convenient method consisted of thermal [2+2]-
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cycloaddition of allenynes 5 and cyclobutene ring opening in one pot. Thus, the cycloaddition
5
6
7
o
step has been accomplished by heating in dioxane at 110 C until the full conversion of starting
8
9
material (control by TLC). The reaction usually has gone to completion for 4 hours. Then, after
cooling till the room temperature, the resulting solution has been treated with twofold excess of
pyrolidine and in 20 min with 1 N HCl to yield 7 (Table 2).
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Table 2. One pot synthesis of 1,5-diketones 7
Entry
X
CF3
Y
R
Product
7a
Yield, %
70
1
2
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CF3
C6H5
CF3
4-MeO-C6H4
2-MeO-C6H4
4-Me-C6H4
2-Me-C6H4
4-NO2-C6H4
Cy
71
7b
7c
3
CF3
73
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CF3
70
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7e
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CF3
74
6
CF3
77
7f
7
CF3
87
7g
8
CF3
t-Bu
25a
7h
7i
9
CF3
C6H5
70
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CF3
CF3
2-MeO-C6H4
C6H5
76
7j
CO2Et
CO2Et
CO2Et
CO2Et
65
7k
7l
2-MeO-C6H4
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a ring opening step was performed under heating at 50°C for 2 hours; there was no conversion of
[2+2]-cycloadduct at rt.
To extend a scope of the reaction, terminal 1,6-allenynes 2 b,c containing two
trifluoromethyl- (X = Y = CF3) and two ethoxycarbonyl - (X = Y = CO2Et) groups have been
specially synthesized from (CF3)2C=N2 or (MeO2C)2C=N2 by analogy with 2a15 (see Exp.
Section). Then, 2b,c were transformed into 5 i-l using the same protocol as for 5 a-h (Table 1)
and directly involved into one pot process affording the corresponding diketones 7 i-l (entries 9-
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12, Table 2). It should be noted, that the nature of substituents (R, X and Y) did not essentially
affect the outcome of the process; in all cases, diketones 7 were isolated in good yields after
column chromatography on silica gel. The only exception was the case of pivaloyl-containing
allenyne 5h. Low yield of the corresponding diketone 7h (entry 8) can be addressed to steric
effect of bulky t-Bu-group.
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The 1,5-diketones obtained have proved to be convenient synthons for the preparation of
functional 5,6,7,8-tetrahydro-1,7-naphthyridines 10. Thus, we found that 1,5-diketones 7 have
selectively undergone heterocyclization under heating with excess of ammonia acetate in glacial
acetic acid at 100 °С for 1 h to afford the corresponding heterocycles 10 a-l in good to high
yields (Table 3).
Table 3. Synthesis of functional 5,6,7,8-tetrahydro-1,7-naphthyridines 10
O
8 eq. NH4OAc
AcOH
100°C, 1h
X
X
Y
Y
R
N
N
Me
N
R
Me
O
10
7
Entry
X
Y
R
Product
10a
10b
10c
Yield, %
75
1
2
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CF3
C6H5
4-MeO-C6H4
2-MeO-C6H4
4-Me-C6H4
2-Me-C6H4
4-NO2-C6H4
Cy
85
3
89
4
90
10d
10e
5
84
6
86
10f
7
88
10g
10h
10i
8
t-Bu
93
9
C6H5
76
10
11
12
CF3
2-MeO-C6H4
C6H5
51
10j
CO2Et
CO2Et
CO2Et
CO2Et
70
10k
10l
2-MeO-C6H4
68
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The structure of derivative 10i was confirmed by single-crystal X-ray diffraction analysis
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(see the Supporting Info).
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Conclusion
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In conclusion, the present study first demonstrated that bicyclo[4.2.0]octa-1,6-dienes derived
by thermal [2+2]-cycloaddition of functional acylated 1,6-allenynes can regioselectively undergo
four member ring opening by treating with pyrrolidine to afford the corresponding
dehydropiperidine-containing 1,5-diketones. A convenient one pot procedure for their
preparation involved both of cycloaddition and ring opening processes has been also performed
starting from 1,6-allenynes. The 1,5-diketones obtained were further successfully converted into
functionally substituted tetrahydro-1,7-naphthyridines including cyclic α-amino acid derivatives
via intramolecular cyclization performed under heating with excess of ammonia acetate in acetic
acid. This straightforward method would extend the potential application of novel 1,7-
naphthyridine derivatives in synthetic and medicinal chemistry.
Experimental section
General experimental methods
All solvents were freshly distilled from appropriate drying agents before use. All other reagents
were
recrystallized
or
distilled
as
necessary.
Sonogashira
reactions
and
[2+2] cycloaddition reactions were performed under an argon atmosphere. Analytical TLC was
performed with Merck silica gel 60 F254 plates. Visualization was accomplished by UV light,
spraying by Ce(SO4)2 solution in 5% H2SO4 or KMnO4 solution in water. Column
chromatography was carried out using Merck silica gel 60 (230-400 mesh ASTM) and ethyl
acetate/hexanes as eluent. NMR spectra were recorded at room temperature on
NMR spectrometers operating at 200 MHz, 300 MHz, 600 MHz, respectively (TMS reference)
1
13
19
for H; 50, 75 and 151 MHz for C; 282 MHz for F (CFCl3) reference). 1,6-Allenyne 2a15,
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1,1,1,3,3,3-hexafluoromethyl-2-diazopropane19, diethyl diazomalonate20 and N,N-dipropargyl-N-
methylamine21 were prepared using the literature protocols.
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7
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General procedure for Sonogashira coupling. A solution of the corresponding acyl
chloride (1.05 mmol) and 1,6-allenyne 2 (0.81mmol) in degassed THF (3 ml) was placed in dried
Schlenk tube. Then PdCl2(PPh3)2 (28 mg, 0.04 mmol) and CuI (8 mg, 0.04 mmol) were added
sequentially in an argon flow. The resulting mixture was warmed up to room temperature and
dry triethylamine (0.16 ml, 1.13 mmol) was added via septum rubber. The reaction mixture was
vigorously stirred for 2-3 hours until disappearance of starting 1,6-allenyne (TLC control). The
precipitate of triethylamine hydrochloride was filtered off. A solvent was removed under reduced
pressure and the crude product was purified by column chromatography on silica gel (hexanes:
EtOAc = 8:1) to give pure 5.
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Methyl
2-[methyl(4-oxo-4-phenylbut-2-yn-1-yl)amino]-2-(trifluoromethyl)penta-3,4-
1
dienoate, (5a). Yield: 215 mg, 75% (yellowish oil). Rf 0.4; H NMR (200 MHz, C6D6) δ 8.18
(d, J = 6.5 Hz, 2H, Harom.), 7.25 – 6.96 (m, 3H, Harom.), 5.22 (t, J = 6.8 Hz, 1H, CHallene), 4.60 (d,
J = 6.8 Hz, 2H, CH2allene), 3.65 (s, 2H, CH2), 3.33 (s, 3H, COOCH3 ), 2.52 (s, 3H, NCH3). 13C
NMR (50 MHz, C6D6) δ 208.2, 175.8, 165.2, 135.9, 132.6, 128.3, 127.4, 124.0 (q, J = 290.5 Hz)
89.8, 86.3 (q, J = 1.4 Hz), 81.5, 77.9, 72.5 (q, J = 25.5 Hz), 50.8, 41.4 (q, J = 1.9 Hz), 36.5 (q, J
= 2.0 Hz). 19F NMR (188 MHz, C6D6) δ: -68.50 (s, 3F, CF3). Anal. Calcd for C18H16F3NO3 (%):
C, 61.54; H, 4.59; N, 3.99. Found: C, 61.47; H, 4.65; N, 3.81.
Methyl
2-[[4-(4-methoxyphenyl)-4-oxobut-2-yn-1-yl](methyl)amino]-2-(trifluoro-
1
methyl)penta-3,4-dienoate, (5b). Yield: 240 mg, 78% (yellowish oil). Rf 0.35; H NMR (200
MHz, C6D6) δ 8.21 (d, J = 8.8 Hz, 2H, Harom.), 6.64 (d, J = 8.8 Hz, 2H, Harom.), 5.25 (t, J = 6.8
Hz, 1H, CHallene), 4.60 (d, J = 6.8 Hz, 2H, CH2allene), 3.67 (s, 2H, CH2), 3.33 (s, 3H, COOCH3),
3.19 (s, 3H, OCH3), 2.56 (s, 3H, NCH3). 13C NMR (50 MHz, C6D6) δ 209.9, 176.2, 166.9, 164.9,
132.4, 131.0, 125.6 (q, J = 298.3 Hz), 114.4, 90.4, 88.0 (q, J = 1.6 Hz), 83.3, 79.5, 74.1 (q, J =
25.2 Hz), 55.3, 52.4, 43.0 (q, J = 1.7 Hz), 38.1 (q, J = 2.1 Hz). 19F NMR (188 MHz, C6D6) δ: -
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68.42 (s, 3F, CF3). Anal. Calcd for C19H18F3NO4 (%): C, 59.84; H, 4.76; N, 3.67. Found: C,
60.05; H, 4.69; N, 3.79.
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methyl)penta-3,4-dienoate, (5c). Yield: 240 mg, 78% (yellowish oil). Rf 0.35; 1H NMR (600
MHz, C6D6) δ 8.19 (dd, J = 7.7, 1.7 Hz, 1H, Harom.), 7.21 – 7.16 (m, 1H, Harom.), 6.85 – 6.80 (m,
1H, Harom.), 6.54 (t, J = 8.0 Hz, 1H, Harom.), 5.34 (t, J = 6.8 Hz, 1H, CHallene), 4.68 (d, J = 6.8 Hz,
2H, CH2allene), 3.77 (s, 2H, NCH2), 3.46 (s, 3H, OCH3), 3.41 (s, 3H, CO2CH3), 2.66 (s, 3H,
NCH3). 13C NMR (151 MHz, C6D6) δ 209.3, 175.6, 166.4, 159.8, 134.4, 132.1, 127.3, 125.0 (q, J
= 289.5 Hz), 120.2, 112.2, 89.2, 87.6, 85.3, 79.0, 73.7 (q, J = 25.4 Hz), 55.1, 51.8, 42.7, 37.5. 19F
NMR (188 MHz, C6D6) δ: -68.30 (s, 3F, CF3). Anal. Calcd for C19H18F3NO4 (%): C, 59.84; H,
4.76; N, 3.67. Found: C, 59.72; H, 4.88; N, 3.55.
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Methyl
2-{methyl[4-(4-methylphenyl)-4-oxobut-2-yn-1-yl]amino}-2-(trifluoro-
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methyl)penta-3,4-dienoate, (5d). Yield: 245 mg, 83% (yellowish oil). Rf 0.4; H NMR (200
MHz, CDCl3) δ 8.02 (d, J = 8.0 Hz, 2H, Harom.), 7.27 (d, J = 8.0 Hz, 2H, Harom.), 5.39 (t, J = 6.8
Hz, 1H, CHallene), 5.05 (d, J = 6.8 Hz, 2H, CH2allene), 3.95 (s, 2H, CH2), 3.81 (s, 3H, COOCH3),
2.71 (s, 3H, NCH3), 2.41 (s, 3H, CH3). 13C NMR (50 MHz, CDCl3) δ 208.4, 176.4, 165.8, 144.3,
133.3, 128.7, 128.3, 123.5 (q, J = 289.7 Hz), 89.8, 86.3 (q, J = 1.5 Hz), 81.3, 78.5, 72.5 (d, J =
25.3 Hz), 51.7, 41.6 (q, J = 1.8 Hz), 36.8 (q, J = 2.1 Hz), 20.7. 19F NMR (188 MHz, CDCl3) δ: -
68.41 (s, 3F, CF3). Anal. Calcd for C19H18F3NO3 (%): C, 62.46; H, 4.97; N, 3.83. Found: C,
62.40; H, 4.89; N, 3.98.
Methyl
2-{methyl[4-(2-methylphenyl)-4-oxobut-2-yn-1-yl]amino}-2-(trifluoro-
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methyl)penta-3,4-dienoate, (5e). Yield: 216 mg, 73% (yellowish oil). Rf 0.4; H NMR (200
MHz, CDCl3) δ 8.22 (d, J = 7.5 Hz, 1H, Harom.), 7.56 – 7.12 (m, 3H, Harom.), 5.39 (t, J = 6.8 Hz,
1H, CHallene), 5.05 (d, J = 6.7 Hz, 2H, CH2allene), 3.94 (s, 2H, CH2), 3.82 (s, 3H, COOCH3), 2.71
(s, 3H, NCH3), 2.62 (s, 3H, CH3). 13C NMR (50 MHz, CDCl3) δ 209.8, 179.7, 167.2, 140.9,
135.7, 133.8, 133.4, 132.5, 126.3, 124.9 (q, J = 289.8 Hz), 90.3, 87.7, 84.0, 79.9, 73.9 (q, J =
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25.3 Hz), 53.1, 43.0 (q, J = 1.6 Hz), 38.2 (q, J = 1.7 Hz), 22.3. 19F NMR (188 MHz, CDCl3) δ: -
68.37 (s, 3F, CF3). Anal. Calcd for C19H18F3NO3 (%): C, 62.46; H, 4.97; N, 3.83. Found: C,
62.53; H, 5.05; N, 3.75.
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2-{methyl[4-(4-nitrophenyl)-4-oxobut-2-yn-1-yl]amino}-2-(trifluoro-
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methyl)penta-3,4-dienoate, (5f). Yield: 205 mg, 64% (yellowish oil). Rf 0.45; H NMR (200
MHz, C6D6) δ 7.86 (d, J = 8.7 Hz, 2H, Harom.), 7.71 (d, J = 8.7 Hz, 2H, Harom.), 5.23 (t, J = 6.8
Hz, 1H, CHallene), 4.60 (d, J = 6.8 Hz, 2H, CH2allene), 3.65 (s, 2H, CH2), 3.31 (s, 3H, COOCH3),
2.53 (s, 3H, NCH3). 13C NMR (50 MHz, C6D6) δ 209.7, 175.4, 166.6, 150.9, 140.7, 130.3, 125.4
(q, J = 290.3 Hz), 123.7, 93.4, 87.7 (q, J = 2.2 Hz), 82.3, 79.5, 73.9 (q, J = 25.6 Hz), 52.3, 42.8,
37.9 (d, J = 2.3 Hz). 19F NMR (188 MHz, C6D6) δ: -68.31 (s, 3F, CF3). Anal. Calcd for
C18H15F3N2O5 (%): C, 54.55; H, 3.81; N, 7.07. Found: C, 54.70; H, 3.65; N, 6.89.
Methyl 2-[(4-cyclohexyl-4-oxobut-2-yn-1-yl)(methyl)amino]-2-(trifluoro-methyl)penta-
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3,4-dienoate, (5g). Yield: 197 mg, 68% (yellowish oil). Rf 0.5; H NMR (200 MHz, C6D6) δ
5.20 (t, J = 6.8 Hz, 1H, CHallene), 4.59 (d, J = 6.8 Hz, 2H, CH2allene), 3.60 (s, 2H, CH2), 3.32 (s,
3H, COOCH3), 2.50 (s, 3H, NCH3), 2.26 – 2.09 (m, 1H, CH), 1.98 – 1.73 (m, 2H, CH2), 1.61 –
1.25 (m, 6H, 3CH2), 1.14 – 0.91 (m, 2H, CH2). 13C NMR (50 MHz, C6D6) δ 209.6, 189.8, 166.6,
125.4 (q, J = 301.9 Hz), 88.8, 87.8 (q, J = 1.5 Hz), 83.4, 79.2, 73.9 (d, J = 25.4 Hz), 52.3, 52.2,
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42.6 (q, J = 2.2 Hz), 37.7 (q, J = 2.3 Hz), 28.4, 26.1, 25.6. F NMR (188 MHz, C6D6) δ: -68.36
(s, 3F, CF3). Anal. Calcd for C18H22F3NO3 (%): C, 60.50; H, 6.21; N, 3.92. Found: C, 60.41; H,
6.34; N, 3.81.
Methyl 2-[(5,5-dimethyl-4-oxohex-2-yn-1-yl)(methyl)amino]-2-(trifluoro-methyl)penta-
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3,4-dienoate, (5h). Yield: 153 mg, 57% (yellowish oil). Rf 0.5; H NMR (200 MHz, CDCl3) δ
5.35 (t, J = 6.8 Hz, 1H, CHallene), 5.03 (d, J = 6.8 Hz, 2H, CH2allene), 3.84 (s, 2H, CH2), 3.81 (s,
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3H, COOCH3), 2.64 (s, 3H, NCH3), 1.20 (s, 9H, 3CH3). C NMR (50 MHz, CDCl3) δ 208.3,
192.9, 165.8, 123.5 (q, J = 290.2 Hz), 89.3, 86.3, 80.5, 78.5, 72.5 (q, J = 25.4 Hz), 51.7, 43.7,
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41.4 (q, J = 1.6 Hz), 36.6 (q, J = 2.0 Hz), 24.9. F NMR (188 MHz, CDCl3) δ: -68.36 (s, 3F,
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CF3). Anal. Calcd for C16H20F3NO3 (%):C, 58.00; H, 6.08; N, 4.23. Found: C, 58.11; H, 6.17; N,
4.12.
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General procedure for [2+2] cycloaddition. A solution of the corresponding allenyne (200
mg) in dry toluene (4 ml) was placed in dried Schlenk tube. The reaction mixture was heated at
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110°C for 2 hours under argon. Then a resulting solution was cooled to rt, a solvent was
removed under reduced pressure, and the residual oil was chromatographed with mixture of
hexanes:EtOAc = 8:1 furnishing the desired bicyclic product 6.
Methyl 8-benzoyl-3-methyl-4-(trifluoromethyl)-3-azabicyclo[4.2.0]octa-1(8),5-diene-4-
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carboxylate, (6a). Yield: 150 mg, 75% (yellowish oil). Rf 0.25; H NMR (200 MHz, C6D6) δ
7.68 (dd, J = 8.0, 1.5 Hz, 2H, Harom.), 7.21 – 7.00 (m, 3H, Harom.), 5.47 (s, 1H, CH), 3.58 (s, 2H,
CH2), 3.29 (s, 3H, COOCH3), 3.15 (t, J = 2.7 Hz, 2H, CH2), 2.31 (q, J = 1.5 Hz, 3H, NCH3). 13C
NMR (50 MHz, C6D6) δ 186.5, 166.3, 148.1, 139.3, 137.0, 134.5, 131.2, 127.4, 127.2, 124.6 (q,
J = 292.1 Hz), 110.1 (d, J = 2.3 Hz), 68.7 (q, J = 25.5 Hz), 51.0, 47.8, 38.7 (d, J = 2.1 Hz), 35.9.
19F NMR (188 MHz, C6D6) δ: -67.23 (s, 3F, CF3). Anal. Calcd for C18H16F3NO3 (%): C, 61.54;
H, 4.59; N, 3.99. Found: C, 61.40; H, 4.71; N, 4.07.
Methyl
8-(4-methoxybenzoyl)-3-methyl-4-(trifluoromethyl)-3-azabicyclo[4.2.0]octa-
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1(8),5-diene-4-carboxylate, (6b). Yield: 178 mg, 89% (yellowish oil). Rf 0.23; H NMR (200
MHz, C6D6) δ 7.76 (d, J = 8.8 Hz, 2H, Harom.), 6.65 (d, J = 8.8 Hz, 2H, Harom.), 5.49 (s, 1H, CH),
3.69 (s, 2H, CH2), 3.32 (s, 3H, COOCH3), 3.26 (s, 3H, COOCH3), 3.22 (t, J = 2.6 Hz, 2H, CH2),
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2.36 (q, J = 1.2 Hz, 3H, NCH3). C NMR (50 MHz, C6D6) δ 184.9, 166.4, 162.3, 147.6, 139.5,
134.9, 129.8, 129.6, 124.7 (q, J = 292.1 Hz), 112.8, 109.5 (q, J = 2.4 Hz), 68.8 (q, J = 25.3 Hz),
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53.6, 51.0, 47.9, 38.8 (q, J = 2.1 Hz), 36.2. F NMR (188 MHz, C6D6) δ: -67.25 (s, 3F, CF3).
Anal. Calcd for C19H18F3NO4 (%):C, 59.84; H, 4.76; N, 3.67. Found: C, 59.93; H, 4.88; N, 3.40.
Methyl
8-(2-methoxybenzoyl)-3-methyl-4-(trifluoromethyl)-3-azabicyclo[4.2.0]octa-
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1(8),5-diene-4-carboxylate, (6c). Yield: 182 mg, 91% (yellowish oil). Rf 0.23; H NMR (200
MHz, C6D6) δ 7.34 (dd, J = 7.5, 1.7 Hz, 1H, Harom.), 7.07 (td, J = 7.5, 1.7 Hz, 1H, Harom.), 6.73 (t,
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J = 7.4 Hz, 1H, Harom.), 6.44 (d, J = 8.3 Hz, 1H, Harom.), 5.46 (s, 1H, CH), 3.45 (s, 2H, CH2), 3.27
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(s, 3H, COOCH3), 3.20 - 3.14 (m, 5H, OCH3+CH2), 2.25 (q, J = 1.4 Hz, 3H, NCH3). C NMR
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(50 MHz, C6D6) δ 187.9, 166.3, 156.1, 147.5, 139.4, 136.0, 131.0, 128.7, 128.3, 124.7 (q, J =
292.1 Hz), 119.5, 110.1, 110.0, 68.8 (q, J = 25.6 Hz), 53.7, 51.0, 47.1, 38.7 (q, J = 1.8 Hz), 35.0.
19F NMR (188 MHz, C6D6) δ: -67.24 (s, 3F, CF3). Anal. Calcd for C19H18F3NO4 (%):C, 59.84;
H, 4.76; N, 3.67. Found: C, 59.67; H, 4.73; N, 3.80.
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Methyl
3-methyl-8-(4-methylbenzoyl)-4-(trifluoromethyl)-3-azabicyclo[4.2.0]octa-
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1(8),5-diene-4-carboxylate, (6d). Yield: 182 mg, 91% (yellowish oil). Rf 0.22; H NMR (200
MHz, C6D6) δ 7.66 (d, J = 7.9 Hz, 2H, Harom.), 6.91 (d, J = 7.9 Hz, 2H, Harom.), 5.48 (s, 1H, CH),
3.63 (s, 2H, CH2), 3.32 (s, 3H, COOCH3), 3.19 (s, 2H), 2.33 (s, 3H, NCH3), 2.03 (s, 3H, CH3).
13C NMR (50 MHz, C6D6) δ 186.1, 166.4, 147.8, 142.0, 139.4, 134.8, 134.5, 128.1, 127.4, 124.6
(q, J = 292.1 Hz), 109.8 (q, J = 2.3 Hz), 68.7 (q, J = 25.3 Hz), 51.0, 47.8, 38.8 (q, J = 1.8 Hz),
36.0, 20.0. 19F NMR (188 MHz, C6D6) δ: -67.26 (s, 3F, CF3). Anal. Calcd for C19H18F3NO3 (%):
C, 62.46; H, 4.97; N, 3.83. Found: C, 62.33; H, 4.85; N, 3.94.
Methyl
3-methyl-8-(2-methylbenzoyl)-4-(trifluoromethyl)-3-azabicyclo[4.2.0]octa-
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1(8),5-diene-4-carboxylate, (6e). Yield: 176 mg, 88% (yellowish oil). Rf 0.22; H NMR (200
MHz, C6D6) δ 7.21 – 6.85 (m, 4H, Harom.), 5.46 (s, 1H, CH), 3.34 (s, 2H, CH2), 3.28 (s, 3H,
COOCH3), 3.16 (s, 2H, CH2), 2.37 (s, 3H, NCH3), 2.22 (s, 3H, CH3). 13C NMR (50 MHz, C6D6)
δ 189.6, 166.2, 147.7, 139.0, 137.2, 136.2, 135.7, 130.4, 129.6, 127.1, 126.7, 124.6 (q, J = 292.0
Hz), 110.5 (q, J = 2.3 Hz), 68.7 (q, J = 25.3 Hz), 51.0, 47.2, 38.7 (q, J = 2.1 Hz), 35.0, 18.6. 19F
NMR (188 MHz, C6D6) δ: -67.21 (s, 3F, CF3). Anal. Calcd for C19H18F3NO3 (%): C, 62.46; H,
4.97; N, 3.83. Found: C, 62.58; H, 5.09; N, 3.99.
Methyl 3-methyl-8-(4-nitrobenzoyl)-4-(trifluoromethyl)-3-azabicyclo[4.2.0]octa-1(8),5-
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diene-4-carboxylate, (6f). Yield: 164 mg, 82% (yellowish oil). Rf 0.20; H NMR (200 MHz,
C6D6) δ 7.73 (d, J = 8.7 Hz, 2H, Harom.), 7.31 (d, J = 8.7 Hz, 2H, Harom.), 5.52 (s, 1H, CH), 3.49
(s, 2H, CH2), 3.30 (s, 3H, COOCH3), 3.07 (t, J = 2.7 Hz, 2H, CH2), 2.35 (q, J = 1.3 Hz, 3H,
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NCH3). 13C NMR (50 MHz, C6D6) δ 184.7, 166.1, 149.6, 148.7, 141.0, 138.9, 133.5, 127.6,
124.5 (q, J = 292.0 Hz), 122.4, 111.5 (q, J = 2.6 Hz), 68.7 (q, J = 25.2 Hz), 51.1, 47.6, 38.8 (q, J
= 2.1 Hz), 35.7. 19F NMR (188 MHz, C6D6) δ: -67.17 (s, 3F, CF3). Anal. Calcd for
C18H15F3N2O5 (%): C, 54.55; H, 3.81; N, 7.07. Found: C, 54.70; H, 3.74; N, 7.19.
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Methyl 8-(cyclohexylcarbonyl)-3-methyl-4-(trifluoromethyl)-3-azabicyclo[4.2.0]octa-
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1(8),5-diene-4-carboxylate, (6g). Yield: 156 mg, 78% (yellowish oil). Rf 0.35; H NMR (200
MHz, C6D6) δ 5.44 (s, 1H, CH), 3.60 (s, 2H, CH2), 3.29 (s, 3H, COOCH3), 2.98 (t, J = 2.8 Hz,
2H. CH2), 2.39 (q, J = 1.5 Hz, 3H, NCH3), 2.30 – 2.13 (m, 1H, HCy), 1.73 – 1.23 (m, 8H, Hcy),
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1.18 – 0.99 (m, 2H, HCy). C NMR (50 MHz, C6D6) δ 197.2, 166.3, 145.6, 138.9, 134.8, 124.6
(q, J = 292.0 Hz), 109.8 (q, J = 2.4 Hz), 68.6 (q, J = 25.6 Hz), 51.0, 47.4, 47.2, 38.9 (q, J = 2.0
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Hz), 34.3, 27.3 (d, J = 3.0 Hz), 24.7, 24.6. F NMR (188 MHz, C6D6) δ: -67.30 (s, 3F, CF3).
Anal. Calcd for C18H22F3NO3 (%):C, 60.50; H, 6.21; N, 3.92. Found: C, 60.63; H, 6.35; N, 4.04.
Methyl
8-(2,2-dimethylpropanoyl)-3-methyl-4-(trifluoromethyl)-3-azabicyclo-
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[4.2.0]octa-1(8),5-diene-4-carboxylate, (6h). Yield: 170 mg, 85% (yellowish oil). Rf 0.35; H
NMR (200 MHz, C6D6) δ 5.47 (s, 1H, CH), 3.78 (s, 2H, CH2), 3.25 (s, 3H, COOCH3), 3.02 (t, J
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= 2.8 Hz, 2H, CH2), 2.36 (q, J = 1.4 Hz, 3H, NCH3), 0.95 (s, 9H, 3CH3). C NMR (50 MHz,
C6D6) δ 200.6, 167.8, 149.5, 140.9, 135.1, 126.1 (q, J = 292.2 Hz), 110.9 (q, J = 2.4 Hz), 70.1 (q,
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J = 25.8 Hz), 52.3, 49.6, 42.6, 40.2 (q, J = 2.3 Hz), 38.2, 26.0. F NMR (188 MHz, C6D6) δ: -
67.34 (s, 3F, CF3). Anal. Calcd for C16H20F3NO3 (%): C, 58.00; H, 6.08; N, 4.23. Found: C,
57.89; H, 6.21; N, 4.11.
Typical procedure for cyclobutene ring opening of bicyclo[4.2.0]octa-1,6-diene.
Pyrrolidine (81 mg, 0.12mmol) was added to solution of 6a (200 mg, 0.6 mmol) in dry dioxane
(4 ml). At that, a color of the reaction mixture was changed from light yellow to red, and the
resulting solution was stirred for 20 min (TLC control). Then, the reaction mixture was poured
into 50 ml of 1N HCl (water solution), extracted with EtOAc. Combined organic fractions were
washed with water, dried over anhydrous MgSO4. A solvent was removed under reduced
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pressure, and the residue was chromatographed with a mixture of EtOAc:hexanes = 1:6
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furnishing 7a. Yield: 143 mg (68%).
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methyl)piperidine-2-carboxylate, (8). To solution of compound 7a (100 mg, 0.28 mmol) in dry
dioxane (2 ml) aniline (52 mg, 0.56 mmol) was added and the resulting mixture was vigorously
stirred at ambient temperature for 24 hours. Then a solvent was removed under reduced pressure
and the crude product was purified by flash chromatography on silica gel (eluent:
EtOAc/hexanes =1/5) to give compound 8 as yellow oil (purity ∼ 80 % determined by 19F NMR-
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spectroscopy, partially hydrolyzed on column). Yield: 57 mg (45%). Rf = 0.4; H NMR (300
MHz, C6D6) δ 7.97 (d, J = 7.2 Hz, 2H, 2CHarom), 7.29 – 7.11 (m, 5H, 5CHarom), 7.04 (t, J = 7.3
Hz, 1H, CHarom), 6.75 (d, J = 7.6 Hz, 2H, 2CHarom), 6.50 (s, 1H, CH), 3.69 (m, 2H, CH2), 3.38 (s,
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3H, CO2CH3), 3.26 – 3.05 (m, 4H, 2CH2), 2.30 (s, 3H, NCH3). F NMR (282 MHz, C6D6) δ -
67.96 (s, 3F, CF3).
Transformation of 8 to 7a. Imine 8 (50 mg) was hydrolyzed by treating with a mixture of
3N HCl (1.5 ml) / dioxane (0.5 ml) at ambient temperature for 1 hour. The resulting mixture was
poured into 20 ml of cold water, extracted twice with EtOAc. Combined organic solution was
washed with water, dried over anhydrous MgSO4. A solvent was removed under reduced
pressure, and the residue was chromatographed with a mixture of EtOAc/hexanes = 1/6
furnishing products 7a. Yield: 26 mg (63%).
Methyl 8-benzoyl-3-methyl-1-pyrrolidin-1-yl-4-(trifluoromethyl)-3-azabicyclo[4.2.0]oct-5-
ene-4-carboxylate 6aa (mixture of diastereomers in a ratio of 1:2). Pyrrolidine (40 mg, 0.58
mmol) was added to solution of 6a (100 mg, 0.29 mmol) in dry dioxane (2 ml) at rt. The
resulting mixture was stirred for 20 min, solvent was removed under reduced pressure to give the
crude product (purity ∼ 87 % determined by 19F NMR-spectroscopy). All attempts to purify 6aa
were unsuccessful and led to formation of 9 under column chromatography conditions. 1H NMR
(300 MHz, CDCl3) 7.65 (m, 2H, CHarom), 7.37 (m, 3H, CHarom), 5.90 and 5.86 (1H, =CH), 5.57
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(m, 1H, CHC(O)), 3.85 and 3.83 (s, 2H, NCH2), 3.64 (s, 3H, CO2CH3), 3.54 (d, J = 12.9 Hz, 1H,
CH2) and 3.49 (d, J = 12.1 Hz, 1H, CH2), 3.16-3.27 (m, 1H, CH2), 3.05-2.85 (m, 4H, 2NCH2),
2.64 (q, J = 2.2 Hz, 3H, NCH3) and 2.60 (s, 3H, NCH3), 1.77-1.69 (m, 4H, 2CH2); 19F NMR (282
MHz, CDCl3) δ -66.73 (s, 3F, CF3), -70.33 (s, 3F, CF3).
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Methyl 1-methyl-4-(3-oxo-3-phenylpropyl)-5-pyrrolidin-1-yl-2-(trifluoromethyl)-1,2-
dihydropyridine-2-carboxylate, (9). Obtained by exposure of 6a and pyrrolidine (2 equiv.) in
dry dioxane at room temperature for 48 h and purified by column chromatography. Rf = 0.42
(EtOAc/hexanes = 1/6); 1H NMR (600 MHz, C6D6) δ 7.90 (d, J = 7.7 Hz, 2H, Harom.), 7.21 (d, J
= 6.8 Hz, 1H, Harom.), 7.13 (t, J = 7.6 Hz, 2H, Harom.), 5.72 (s, 1H, CH), 5.19 (s, 1H, CH), 3.41 (s,
3H, CO2CH3), 3.15 – 3.07 (m, 1H, CH2), 3.02 – 2.95 (m, 1H, CH2), 2.93 – 2.86 (m, 1H, CH2),
2.82 (s, 3H, NCH3), 2.81 – 2.75 (m, 1H, CH2), 2.75 – 2.68 (m, 2H, NCH2), 2.62 – 2.53 (m, 2H,
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NCH2), 1.66 – 1.52 (m, 4H, 2CH2). C NMR (151 MHz, C6D6) δ 198.1, 167.3, 141.8, 137.3,
132.3, 128.3, 128.1, 126.8, 125.2 (q, J = 294.5 Hz), 122.3, 104.9, 71.4 (q, J = 27.1 Hz), 53.0,
52.2, 39.1, 38.4, 26.9, 23.8. 19F NMR (282 MHz, C6D6) δ -73.23 (s). Anal. Calcd for
C22H25F3N2O3 (%): C, 62.55; H, 5.96; N, 6.63. Found: C, 62.43; H, 6.12; N, 6.82
General procedure for one pot synthesis of 1,5-diketons 7 from 1,6-allenynes 6. A
solution of the corresponding allenyne (200 mg) in dry dioxane (4 ml) was refluxed for 4 hours
under argon atmosphere. After completion of [2+2]-cycloaddition (TLC control), the reaction
mixture was cooled to rt and pirrolidine (2 equiv.) was added. The reaction was stirred at rt for
20 min. The resulting red solution was poured into 50 ml of 1N HCl, extracted with EtOAc.
Combined organic solution was washed with water, dried over anhydrous MgSO4. A solvent was
removed under reduced pressure, and the residue was chromatographed with a mixture of
hexanes:EtOAc = 6:1 furnishing desired products.
Methyl
1-methyl-5-oxo-4-(3-oxo-3-phenylpropyl)-2-(trifluoromethyl)-1,2,5,6-
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tetrahydropyridine-2-carboxylate, (7a). Yield: 148mg, 70% (yellowish oil). Rf = 0.37; H
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NMR (200 MHz, CDCl3) δ 7.94 (d, J = 7.0 Hz, 2H, Harom.), 7.64 – 7.39 (m, 3H, Harom.), 6.71 (s,
1H), 3.84 (s, 3H, COOCH3), 3.60 (s, 2H, CH2), 3.17 (t, J = 7.5 Hz, 2H, CH2), 2.76 (t, J = 7.5 Hz,
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2H, CH2), 2.57 (q, J = 0.9 Hz, 3H, NCH3). C NMR (50 MHz, CDCl3) δ 198.9, 193.7, 166.3,
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140.9, 137.0, 136.8 (q, J = 2.1 Hz), 133.6, 129.0, 128.4, 124.8 (q, J = 292.1 Hz), 70.5 (q, J =
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25.8 Hz), 59.2, 53.7, 40.2 (q, J = 2.1 Hz), 37.1, 24.5. F NMR (188 MHz, CDCl3) δ: -67.65 (s,
3F, CF3). Anal. Calcd for C18H18F3NO4 (%): C, 58.54; H, 4.91; N, 3.79. Found: C, 58.41; H,
4.70; N, 3.55.
Methyl
4-[3-(4-methoxyphenyl)-3-oxopropyl]-1-methyl-5-oxo-2-(trifluoromethyl)-
1,2,5,6-tetrahydropyridine-2-carboxylate, (7b). Yield: 149 mg, 71% (colorless solid). M.p. =
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86-89°C; Rf = 0.25; H NMR (200 MHz, CDCl3) δ 7.94 (d, J = 8.8 Hz, 2H, Harom.), 6.95 (d, J =
8.8 Hz, 2H, Harom.), 6.71 (s, 1H, CH), 3.89 (s, 2H, COOCH3), 3.86 (s, 3H, OCH3), 3.61 (s, 2H,
CH2), 3.12 (t, J = 7.3 Hz, 2H, CH2), 2.76 (t, J = 7.2 Hz, 2H, CH2), 2.59 (s, 3H, NCH3). 13C NMR
(50 MHz, CDCl3) δ 196.0, 192.3, 164.9, 162.5, 139.6, 135.3 (q, J = 2.2 Hz), 129.3, 128.7, 123.4
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(q, J = 292.4 Hz), 112.7, 69.1 (q, J = 25.6 Hz), 57.8, 54.4, 52.3, 38.8, 35.4, 23.2. F NMR (188
MHz, CDCl3) δ: -67.60 (s, 3F, CF3). Anal. Calcd for C19H20F3NO5 (%): C, 57.14; H, 5.05; N,
3.51. Found: C, 57.01; H, 5.18; N, 3.44.
Methyl
4-[3-(2-methoxyphenyl)-3-oxopropyl]-1-methyl-5-oxo-2-(trifluoromethyl)-
1,2,5,6-tetrahydropyridine-2-carboxylate, (7c). Yield: 154 mg, 73% (yellowish oil). Rf = 0.25;
1H NMR (200 MHz, CDCl3) δ 7.64 (dd, J = 7.6, 1.6 Hz, 1H, Harom.), 7.45 (t, J = 7.6 Hz, 1H,
Harom.), 7.04 - 6.91 (m, 2H, Harom.), 6.65 (s, 1H, CH), 3.88 (s, 3H, COOCH3), 3.83 (s, 3H, OCH3),
3.58 (s, 2H, CH2), 3.16 (t, J = 7.1 Hz, 2H, CH2), 2.72 (t, J = 7.1 Hz, 2H, CH2), 2.56 (s, 3H,
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NCH3). C NMR (50 MHz, CDCl3) δ 199.7, 192.2, 165.0, 157.5, 139.8, 134.8 (q, J = 2.1 Hz),
132.6, 129.2, 127.0, 123.4 (q, J = 292.3 Hz), 119.6, 110.5, 69.1 (q, J = 25.7 Hz), 57.8, 54.4, 52.3,
40.5, 38.8 (q, J = 2.1 Hz), 22.7. 19F NMR (188 MHz, CDCl3) δ: -67.74 (s, 3F, CF3). Anal. Calcd
for C19H20F3NO5 (%): C, 57.14; H, 5.05; N, 3.51. Found: C, 56.99; H, 4.82; N, 3.81.
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Methyl 1-methyl-4-[3-(4-methylphenyl)-3-oxopropyl]-5-oxo-2-(trifluoromethyl)-1,2,5,6-
tetrahydropyridine-2-carboxylate, (7d). Yield: 147 mg, 70% (colorless solid). M.p. = 74-
75C°C; Rf = 0.36; 1H NMR (200 MHz, CDCl3) δ 7.85 (d, J = 8.2 Hz, 2H, Harom.), 7.26 (d, J = 7.7
Hz, 2H, Harom.), 6.71 (s, 1H, CH), 3.86 (s, 3H, COOCH3), 3.61 (s, 2H, CH2), 3.13 (t, J = 7.4 Hz,
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2H, CH2), 2.76 (t, J = 7.3 Hz, 2H, CH2), 2.59 (s, 3H, NCH3), 2.42 (s, 3H, CH3). C NMR (50
MHz, CDCl3) δ 196.6, 191.8, 164.4, 142.5, 139.1, 134.8 (q, J = 2.0 Hz), 132.6, 127.8, 126.6,
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122.9 (q, J = 292.1 Hz), 68.6 (q, J = 25.7 Hz), 57.3, 51.8, 38.3, 35.1, 22.6, 20.1. F NMR (188
MHz, CDCl3) δ: -67.61 (s, 3F, CF3). Anal. Calcd for C19H20F3NO4 (%):C, 59.53; H, 5.26; N,
3.65. Found: C, 59.41; H, 5.35; N, 3.77.
Methyl 1-methyl-4-[3-(2-methylphenyl)-3-oxopropyl]-5-oxo-2-(trifluoromethyl)-1,2,5,6-
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tetrahydropyridine-2-carboxylate, (7e). Yield: 156 mg, 74% (yellowish oil). Rf = 0.36; H
NMR (200 MHz, CDCl3) δ 7.62 (d, J = 7.2 Hz, 1H, Harom.), 7.42 – 7.20 (m, 3H, Harom.), 6.71 (s,
1H, CH), 3.85 (s, 3H, COOCH3), 3.59 (s, 2H, CH2), 3.11 (t, J = 7.2 Hz, 2H, CH2), 2.74 (t, J =
7.2 Hz, 2H, CH2), 2.57 (q, J = 1.2 Hz, 3H, NCH3), 2.48 (s, 3H, CH3). 13C NMR (50 MHz,
CDCl3) δ 202.5, 193.7, 166.4, 140.9, 138.6, 137.8, 136.7 (q, J = 2.1 Hz), 132.4, 131.9, 128.9,
126.1, 124.8 (q, J = 292.4 Hz), 70.5 (q, J = 25.6 Hz), 59.2, 53.7, 40.2 (q, J = 2.1 Hz), 39.7, 24.3,
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21.7. F NMR (188 MHz, CDCl3) δ: -67.61 (s, 3F, CF3). Anal. Calcd for C19H20F3NO4 (%): C,
59.53; H, 5.26; N, 3.65. Found: C, 59.69; H, 5.33; N, 3.77.
Methyl 1-methyl-4-[3-(4-nitrophenyl)-3-oxopropyl]-5-oxo-2-(trifluoromethyl)-1,2,5,6-
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tetrahydropyridine-2-carboxylate, (7f). Yield: 162 mg, 77% (yellowish oil). Rf = 0.24; H
NMR (200 MHz, CDCl3) δ 8.31 (d, J = 8.8 Hz, 2H, Harom.), 8.09 (d, J = 8.8 Hz, 2H, Harom.), 6.73
(s, 1H, CH), 3.87 (s, 3H, COOCH3), 3.60 (s, 2H, CH2), 3.22 (t, J = 7.2 Hz, 2H, CH2), 2.77 (t, J =
7.2 Hz, 2H, CH2), 2.57 (s, 3H, NCH3). 13C NMR (50 MHz, CDCl3) δ 195.9, 192.4, 164.8, 149.4,
139.9, 139.0, 135.9 (q, J = 2.1 Hz), 128.0, 123.4 (q, J = 292.1 Hz), 122.9, 69.1 (q, J = 25.7 Hz),
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57.8, 52.4, 38.8 (q, J = 2.2 Hz), 36.4, 23.0. F NMR (188 MHz, CDCl3) δ: -67.60 (s, 3F, CF3).
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Anal. Calcd for C18H17F3N2O6 (%): C, 52.18; H, 4.14; N, 6.76. Found: C, 52.33; H, 4.35; N,
6.56.
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Methyl
4-(3-cyclohexyl-3-oxopropyl)-1-methyl-5-oxo-2-(trifluoromethyl)-1,2,5,6-
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tetrahydropyridine-2-carboxylate, (7g). Yield: 184 mg, 87% (yellowish oil). Rf 0.33; 1H NMR
(200 MHz, CDCl3) δ 6.60 (s, 1H, CH), 3.85 (s, 3H, COOCH3), 3.56 (s, 2H, CH2), 2.67 – 2.48
(m, 7H, 2CH2+ NCH3 ), 2.28 (br. s, 1H, HCy), 2.70 - 2.47 (m, 5H, HCy ), 1.40 – 1.14 (m, 5H,
HCy). 13C NMR (50 MHz, CDCl3) δ 211.2, 192.2, 165.0, 139.6, 135.1 (q, J = 2.0 Hz), 123.4 (q, J
= 292.0 Hz), 69.1 (q, J = 25.4 Hz), 57.8, 52.3, 49.8, 38.8 (q, J = 1.9 Hz), 37.5, 27.3, 24.8, 24.6,
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22.2. F NMR (188 MHz, CDCl3) δ: -67.73 (s, 3F, CF3). Anal. Calcd for C18H24F3NO4 (%): C,
57.59; H, 6.44; N, 3.73. Found: C, 57.41; H, 6.12; N, 3.78.
Methyl
4-(4,4-dimethyl-3-oxopentyl)-1-methyl-5-oxo-2-(trifluoromethyl)-1,2,5,6-
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tetrahydropyridine-2-carboxylate, (7h). Yield: 53 mg, 25% (yellowish oil). Rf 0.34; H NMR
(200 MHz, CDCl3) δ 6.62 (s, 1H, CH), 3.87 (s, 3H, COOCH3), 3.56 (s, 2H, CH2), 2.79 – 2.48
(m, 7H, 2CH2+ NCH3), 1.09 (s, 9H, 3CH3). 13C NMR (151 MHz, CDCl3) δ 214.2, 193.3, 166.0,
140.6, 136.3, 124.4 (q, J = 292.3 Hz), 70.1 (q, J = 26.0 Hz), 58.8, 53.3, 44.1, 39.8, 34.8, 26.2,
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23.6. F NMR (188 MHz, CDCl3) δ: -67.68 (s, 3F, CF3). Anal. Calcd for C16H22F3NO4 (%): C,
55.01; H, 6.35; N, 4.01. Found: C, 54.85; H, 6.05; N, 4.23.
[1,1-Bis(trifluoromethyl)buta-2,3-dien-1-yl]methyl(prop-2-yn-1-yl)amine, (2b).
A mixture of N,N-dipropargyl-N-methylamine (2.4 g, 22.4 mmol), liquefied 1,1,1,3,3,3-
hexafluoromethyl-2-diazopropane (4 g, 22.4 mmol), copper trifluoroacetylacetonate (0.4 g, 1,12
mmol, 5 mol %) in dry benzene (30 ml) was placed into preliminarily cooled (0 °C) steel bomb
and shuttled at 100 °C for 1 hour. Then the bomb was cooled to rt. The reaction mixture was
filtered through a short pad of silica gel to remove copper residue. The solvent was removed
under atmospheric pressure and the crude product was re-condensed under reduced pressure (1
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Torr) into cold receiver (-78°C) to give 2.9 g of colorless liquid. Yield: 50%. H NMR (600
MHz, CDCl3) δ 5.24 (t, J = 6.9 Hz, 1H, CHallene), 5.14 (d, J = 6.8 Hz, 2H, CH2allene), 3.71 (s, 2H,
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NCH2), 2.77 (s, 3H, NCH3), 2.26 (t, J = 2.4 Hz, 1H, CH). 13C NMR (151 MHz, CDCl3) δ 209.7,
124.6 (q, J = 293.8 Hz), 85.5, 80.08, 80.07, 71.9, 71.0 (sept, J = 26 Hz), 42.1, 36.8. 19F NMR
(282 MHz, CDCl3) δ -67.33 (s). Anal. Calcd for C10H9F6N (%):C, 46.70; H, 3.53; N, 5.45.
Found: C, 46.81; H, 3.43; N, 5.59.
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Diethyl
[methyl(prop-2-yn-1-yl)amino](propa-1,2-dien-1-yl)malonate,
(2c).
A mixture of N,N-dipropargyl-N-methylamine 1.6 g (15mmol), diethyl diazomalonate 2.8 g
(15mmol) and copper trifluoroacetylacetonate 0.55 g (0.15 mmol, 10 mol %) in anhydrous
toluene (30 mL) was refluxed for 1.5 h. After the reaction completion (TLC control) the solvent
was removed under reduced pressure and the crude product was purified by column
chromatography on silica gel (hexanes : EtOAc – 4:1) to give 2.8 g of yellowish oil. Yield: 70%.
Rf 0.44; 1H NMR (600 MHz, CDCl3) δ 5.72 (t, J = 6.8 Hz, 1H, CHallene), 4.93 (d, J = 6.8 Hz, 2H,
CH2allene), 4.29 – 4.21 (m, 4H, 2OCH2), 3.58 (s, 2H, NCH2), 2.58 (s, 3H, NCH3 ), 2.21 (t, J = 2.4
Hz, 1H, CH), 1.27 (t, J = 7.4 Hz, 6H). 13C NMR (151 MHz, CDCl3) δ 208.7, 167.7, 89.1, 80.0,
78.6, 74.5, 72.5, 61.8, 41.9, 37.3, 14.1. Anal. Calcd for C14H19NO4 (%): C, 63.38; H, 7.22; N,
5.28. Found: C, 63.28; H, 7.38; N, 5.53.
4-[[1,1-Bis(trifluoromethyl)buta-2,3-dien-1-yl](methyl)amino]-1-phenylbut-2-yn-1-one,
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(5i). Yield: 228 mg, 78% (yellowish oil). Rf 0.5 (hexanes:EtOAc = 15:1); H NMR (300 MHz,
CDCl3) δ 8.19 (d, J = 7.2 Hz, 2H, Harom.), 7.68 (t, J = 7.2 Hz, 1H, Harom.), 7.55 (t, J = 7.2 Hz, 2H,
Harom.), 5.36 – 5.28 (m, 1H, CHallene), 5.21 (d, J = 6.4 Hz, 2H, Hallene), 4.09 (s, 2H, NCH2), 2.90
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(s, 1H, NCH3). C NMR (151 MHz, CDCl3) δ 209.9, 177.7, 136.6, 134.3, 129.6, 128.7, 123.8
(q, J = 291.0 Hz), 90.8, 85.2, 82.1, 80.4, 70.9 (sept, J = 26 Hz), 42.7, 37.4. 19F NMR (282 MHz,
CDCl3) δ -67.46 (s, 6F, 2CF3). Anal. Calcd for C17H13F6NO (%): C, 56.52; H, 3.63; N, 3.88.
Found: C, 56.70; H, 3.55; N, 3.71.
4-[[1,1-Bis(trifluoromethyl)buta-2,3-dien-1-yl](methyl)amino]-1-(2-methoxyphenyl)-
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but-2-yn-1-one, (5j). Yield: 190 mg, 60% (yellowish oil). Rf 0.45 (hexanes:EtOAc = 15:1); H
NMR (300 MHz, CDCl3) δ 8.05 (dd, J = 7.8, 1.8 Hz, 1H, Harom.), 7.59 (ddd, J = 8.4, 7.8, 1.8 Hz,
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1H, Harom.), 7.14 – 7.02 (m, 2H, Harom.), 5.38 – 5.24 (m, 1H, CHallene), 5.23 – 5.06 (m, 2H,
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CH2allene), 4.03 (s, J = 3.8 Hz, 2H, NCH2), 3.97 (s, 3H, OCH3), 2.86 (s, 3H, NCH3). C NMR
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112.1, 89.4, 85.3, 84.2, 80.4, 70.9 (sept, J = 26 Hz), 55.8, 42.7, 37.3. 19F NMR (282 MHz,
CDCl3) δ -67.39 (s, 6F, CF3). Anal. Calcd for C18H15F6NO2 (%): C, 55.25; H, 3.86; N, 3.58.
Found: C, 55.14; H, 3.99; N, 3.71.
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Diethyl
[methyl(4-oxo-4-phenylbut-2-yn-1-yl)amino](propa-1,2-dien-1-yl)malonate,
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(5k). Yield: 209 mg, 70% (yellowish oil). Rf 0.40 (hexanes:EtOAc = 4:1); H NMR (600 MHz,
CDCl3) δ 8.16 – 8.12 (m, 2H, Harom.), 7.61 (t, J = 7.4 Hz, 1H, Harom.), 7.48 (t, J = 7.4 Hz, 2H,
Harom.), 5.78 (t, J = 6.8 Hz, 1H, CHallene), 4.98 (d, J = 6.8 Hz, 2H, CH2allene), 4.36 – 4.22 (m, 4H,
2OCH2), 3.96 (s, 2H, NCH2), 2.68 (s, 3H, NCH3), 1.29 (t, J = 7.1 Hz, 6H, 2CH3).13C NMR (151
MHz, CDCl3) δ 208.8, 177.7, 167.7, 136.6, 134.1, 129.6, 128.6, 91.4, 89.0, 82.9, 78.8, 74.4,
62.0, 42.4, 37.7, 14.1 (d, J = 8.1 Hz). Anal. Calcd for C21H23NO5 (%): C, 68.28; H, 6.28; N, 3.79.
Found: C, 68.01; H, 6.53; N, 3.97.
Diethyl
[[4-(2-methoxyphenyl)-4-oxobut-2-yn-1-yl](methyl)amino](propa-1,2-dien-1-
yl)malonate, (5l). Yield: 233 mg, 72% (yellowish oil). Rf 0.40 (hexanes:EtOAc = 4:1);
1H NMR (600 MHz, CDCl3) δ 8.00 (dd, J = 7.6, 1.6 Hz, 1H, Harom.), 7.54 – 7.48 (m, 1H, Harom.),
7.04 – 6.96 (m, 2H, Harom.), 5.75 (t, J = 6.8 Hz, 1H, CHallene), 4.95 (d, J = 6.8 Hz, 2H, CH2allene),
4.35 – 4.18 (m, 4H, 2OCH2), 3.92 (s, J = 3.9 Hz, 3H, OCH3), 3.90 (s, 2H, NCH2), 2.65 (s, 3H,
NCH3), 1.28 (t, J = 7.1 Hz, 6H, 2CH3). 13C NMR (151 MHz, CDCl3) δ 206.2, 174.0, 165.1,
157.2, 132.5, 130.5, 123.8, 117.7, 109.5, 87.4, 86.6, 82.4, 76.2, 71.9, 59.4, 53.4, 39.9, 35.1, 11.6.
Anal. Calcd for C22H25NO6 (%): C, 66.15; H, 6.31; N, 3.51. Found: C, 66.47; H, 6.05; N, 3.19.
1-Methyl-4-(3-oxo-3-phenylpropyl)-6,6-bis(trifluoromethyl)-1,6-dihydropyridin-3(2H)-
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one, (7i). Yield: 147 mg, 70% (yellowish oil). Rf 0.30 (hexanes : EtOAc – 5:1); H NMR (300
MHz, CDCl3) δ 7.98 (d, J = 7.3 Hz, 2H, Harom.), 7.60 (t, J = 7.3 Hz, 1H, Harom.), 7.49 (t, J = 7.3
Hz, 2H, Harom.), 6.73 (s, 1H, CH), 3.60 (s, 2H, NCH2), 3.22 (t, J = 7.2 Hz, 2H, CH2), 2.84 (t, J =
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7.2 Hz, 2H, CH2), 2.75 (s, 3H, NCH3 ). 13C NMR (151 MHz, CDCl3) δ 198.2, 192.4, 142.7,
136.6, 133.2, 133.1, 128.6, 128.0, 123.6 (q, J = 294.8 Hz), 67.2 (sept, J = 26.2 Hz), 59.1, 39.6,
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36.6, 24.1. F NMR (282 MHz, CDCl3) δ -68.05 (s, 6F, 2CF3). Anal. Calcd for C17H15F6NO2
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(%): C, 53.83; H, 3.99; N, 3.69. Found: C, 53.58; H, 4.21; N, 3.81.
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4-[3-(2-Methoxyphenyl)-3-oxopropyl]-1-methyl-6,6-bis(trifluoromethyl)-1,6
dihydropyridin -3(2H)-one, (7j). Yield: 160 mg, 76% (yellowish oil). Rf 0.30 (hexanes : EtOAc
– 5:1); 1H NMR (300 MHz, CDCl3) δ 7.70 (dd, J = 7.7, 1.8 Hz, 1H, Harom.), 7.51 (ddd, J = 8.3,
7.4, 1.8 Hz, 1H, Harom.), 7.10 – 6.96 (m, 2H, Harom.), 6.69 (s, 1H, CH), 3.94 (s, 3H, OCH3), 3.60
(s, 2H, NCH2), 3.24 (t, J = 7.1 Hz, 2H, CH2), 2.82 (t, J = 7.0 Hz, 2H, CH2), 2.76 (s, 3H, NCH3).
13C NMR (151 MHz, CDCl3) δ 200.5, 192.4, 158.5, 143.0, 133.7, 132.7, 130.3, 127.9, 123.7 (q,
J = 294.5 Hz), 120.7, 111.5, 67.1 (sept, J = 26.2 Hz), 59.1, 55.4, 41.4, 39.7, 23.7. 19F NMR (282
MHz, CDCl3) δ -68.06 (s, 6F, 2CF3). Anal. Calcd for C18H17F6NO3 (%): C, 52.82; H, 4.19; N,
3.42. Found: C, 52.89; H, 4.33; N, 3.52.
Diethyl
1-methyl-5-oxo-4-(3-oxo-3-phenylpropyl)-5,6-dihydropyridine-2,2(1H)-
dicarboxylate, (7k). Yield: 137 mg, 65% (yellowish oil). Rf 0.35 (hexanes : EtOAc – 3:1); 1H
NMR (300 MHz, CDCl3) δ 7.98 (d, J = 7.2 Hz, 2H, Harom.), 7.60 (t, J = 7.3 Hz, 1H, Harom.), 7.49
(t, J = 7.5 Hz, 2H, Harom.), 6.92 (s, 1H, CH), 4.32 (q, J = 7.1 Hz, 4H, 2OCH2), 3.56 (s, 2H,
NCH2), 3.20 (t, J = 7.3 Hz, 2H, CH2), 2.77 (t, J = 7.3 Hz, 2H, CH2), 2.62 (s, 3H, NCH3), 1.34 (t,
J = 7.1 Hz, 6H, 2CH3). 13C NMR (151 MHz, CDCl3) δ 198.7, 194.3, 166.6, 141.1, 138.0, 136.7,
133.1, 128.6, 128.0, 72.7, 62.4, 59.1, 40.0, 37.1, 24.0, 14.1. Anal. Calcd for C21H25NO6 (%): C,
65.10; H, 6.50; N, 3.62. Found: C, 65.00; H, 6.61; N, 3.73.
Diethyl
4-[3-(2-methoxyphenyl)-3-oxopropyl]-1-methyl-5-oxo-5,6-dihydropyridine-
2,2(1H)-dicarboxylate, (7l). Yield: 122 mg, 58% (yellowish oil). Rf 0.55 (hexanes : EtOAc –
1:1); 1H NMR (300 MHz, CDCl3) δ 7.69 (d, J = 7.6 Hz, 1H, Harom.), 7.48 (t, J = 7.8 Hz, 1H,
Harom.), 7.06 – 6.95 (m, 2H, Harom.), 6.86 (s, 1H, CH), 4.31 (q, J = 7.1 Hz, 4H, 2OCH2), 3.92 (s,
3H, OCH3 ), 3.55 (s, 2H, NCH2), 3.19 (t, J = 7.4 Hz, 2H, CH2), 2.72 (t, J = 7.4 Hz, 2H, 2CH2),
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2.61 (s, 3H, NCH3), 1.33 (t, J = 7.1 Hz, 6H, 2CH3). 13C NMR (151 MHz, CDCl3) δ 201.0, 194.2,
166.7, 158.6, 140.5, 138.4, 133.5, 130.3, 128.0, 120.6, 111.5, 72.7, 62.3, 59.1, 55.5, 41.9, 40.0,
23.8, 14.1. Anal. Calcd for C22H27NO7 (%): C, 63.30; H, 6.52; N, 3.36. Found: C, 63.11; H, 6.85;
N, 3.22.
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General procedure for synthesis of 5,6,7,8-tetrahydro-1,7-naphthyridines 10. A solution
of corresponding 1,5-diketone (0.5 mmol) in glacial acetic acid (4 ml) was plased into round-
bottomed flask, equipped with reflux condenser, magnetic stirrer and tube for argon bubling.
Then 0.31 g NH4OAc (4 mmol) was added and reaction mixtre was heated at 100°C in constant
argon flow for 1 hour. The resuling mixture was poured into 50 ml of cold water, extracted with
EtOAc. The combinied organic fractions were washed with water and dryed over anhydrous
MgSO4. The solvent was removed under reduced pressure and the crude product was purified by
column chromatography on silica gel (petroleum ether : EtOAc = 6/1) to give pure product.
Methyl 7-methyl-2-phenyl-6-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-6-
carboxylate, (10a). Yield: 131 mg, 75% (white solid). M. p. = 83-85°C. Rf 0.50; 1H NMR (200
MHz, CDCl3) δ 7.98 (dd, J = 7.8, 1.4 Hz, 2H, Harom.), 7.63 – 7.33 (m, 5H, Harom.), 4.21 (s, 2H,
CH2), 3.80 (s, 3H, COOCH3), 3.53 (d, J = 16.3 Hz, 1H, CH2), 3.28 (d, J = 16.3 Hz, 1H, CH2),
2.78 (q, J = 0.9 Hz, 3H, NCH3). 13C NMR (50 MHz, CDCl3) δ 168.6, 156.1, 153.6, 139.5, 136.9,
129.3, 129.1, 127.3, 125.3 (q, J = 288.5 Hz), 124.4, 119.2, 68.9 (q, J = 25.6 Hz), 57.1, 53.3, 40.4
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(q, J = 2.0 Hz), 32.5 (q, J = 2.2 Hz). F NMR (188 MHz, CDCl3) δ: -69.78 (s, 3F, CF3). Anal.
Calcd for C18H17F3N2O2 (%): C, 61.71; H, 4.89; N, 8.00. Found: C, 61.55; H, 4.77; N, 8.25.
Methyl
2-(4-methoxyphenyl)-7-methyl-6-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-
naphthyridine-6-carboxylate, (10b). Yield: 162 mg, 85% (white solid). M. p. = 94-95°C. Rf
0.45; 1H NMR (200 MHz, CDCl3) δ 7.93 (d, J = 8.7 Hz, 2H, Harom.), 7.56 – 7.42 (m, 2H, Harom.),
7.00 (d, J = 8.7 Hz, 2H, Harom.), 4.29 – 4.07 (m, 2H, CH2), 3.88 (s, 3H, COOCH3), 3.80 (s, 3H,
OCH3), 3.51 (d, J = 16.2 Hz, 1H, CH2), 3.26 (d, J = 16.2 Hz, 1H, CH2), 2.77 (s, 3H, NCH3). 13C
NMR (50 MHz, CDCl3) δ 168.6, 160.8, 155.8, 153.4, 136.8, 132.2, 128.5, 125.3 (q, J = 288.5
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Hz), 123.6, 118.5, 114.5, 68.9 (q, J = 25.3 Hz), 57.1, 55.7, 53.3, 40.3 (q, J = 1.9 Hz), 32.5 (q, J =
2.2 Hz). 19F NMR (188 MHz, CDCl3) δ: -69.79 (s, 3F, CF3). Anal. Calcd for C19H19F3N2O3 (%):
C, 60.00; H, 5.03; N, 7.36. Found: C, 60.15; H, 4.74; N, 7.14.
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naphthyridine-6-carboxylate, (10c). Yield: 169 mg, 89% (colorless oil). Rf 0.45; 1H NMR (200
MHz, CDCl3) δ 7.76 (dd, J = 7.5, 1.6 Hz, 1H, Harom.), 7.67 (d, J = 8.2 Hz, 1H, Harom.), 7.47 (d, J
= 8.2 Hz, 1H, Harom.), 7.38 (td, J = 8.2, 1.7 Hz, 1H, Harom.), 7.08 (t, J = 8.2 Hz, 1H, Harom.), 7.00
(d, J = 8.3 Hz, 1H, Harom.), 4.34 – 4.09 (m, 2H, CH2), 3.86 (s, 3H, COOCH3), 3.81 (s, 3H,
OCH3), 3.53 (d, J = 16.3 Hz, 1H, CH2), 3.28 (d, J = 16.3 Hz, 1H, CH2), 2.76 (q, J = 1.0 Hz, 3H,
NCH3). 13C NMR (50 MHz, CDCl3) δ 167.2, 155.9, 153.2, 151.7, 134.3, 130.1, 128.9, 127.7,
123.9 (q, J = 288.4 Hz), 122.4, 122.3, 120.1, 110.3, 67.4 (q, J = 25.4 Hz), 55.6, 54.5, 51.8, 38.9
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(q, J = 2.0 Hz), 31.0 (q, J = 2.2 Hz). F NMR (188 MHz, CDCl3) δ: -69.79 (s, 3F, CF3). Anal.
Calcd for C19H19F3N2O3 (%): C, 60.00; H, 5.03; N, 7.36. Found: C, 60.19; H, 5.21; N, 7.15.
Methyl
7-methyl-2-(4-methylphenyl)-6-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-
naphthyridine-6-carboxylate, (10d). Yield: 164 mg, 90% (white solid). M. p. = 83-85°C. Rf
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0.50; H NMR (200 MHz, CDCl3) δ 7.88 (d, J = 8.1 Hz, 2H, Harom.), 7.54 (d, J = 8.1 Hz, 1H,
Harom.), 7.48 (d, J = 8.1 Hz, 1H, Harom.), 7.28 (d, J = 8.1 Hz, 2H, Harom.), 4.39 – 4.02 (m, 2H,
CH2), 3.80 (s, 3H, COOCH3), 3.52 (d, J = 16.3 Hz, 1H, CH2), 3.27 (d, J = 16.3 Hz, 1H, CH2),
2.77 (s, 3H, NCH3), 2.42 (s, 3H, CH3). 13C NMR (50 MHz, CDCl3) δ 168.6, 156.1, 153.4, 139.3,
136.8, 136.7, 129.9, 127.1, 125.3 (q, J = 288.6 Hz), 124.0, 119.0, 68.9 (q, J = 25.4 Hz), 57.1,
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53.3, 40.3 (q, J = 2.0 Hz), 32.5 (q, J = 2.1 Hz), 21.7. F NMR (188 MHz, CDCl3) δ: -69.79 (s,
3F, CF3). Anal. Calcd for C19H19F3N2O2 (%): C, 62.63; H, 5.26; N, 7.69. Found: C, 62.29; H,
5.33; N, 7.55.
Methyl
7-methyl-2-(2-methylphenyl)-6-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-
naphthyridine-6-carboxylate, (10e). Yield: 153 mg, 84% (colorless oil). Rf 0.50; 1H NMR (200
MHz, CDCl3) δ 7.50 (d, J = 7.9 Hz, 1H, Harom.), 7.45 – 7.18 (m, 5H, Harom.), 4.31 – 4.07 (m, 2H,
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CH2), 3.81 (s, 3H, COOCH3), 3.55 (d, J = 16.3 Hz, 1H, CH2), 3.30 (d, J = 16.3 Hz, 1H, CH2),
2.77 (s, 3H, NCH3), 2.36 (s, 3H, CH3). 13C NMR (50 MHz, CDCl3) δ 168.6, 158.5, 153.1, 140.4,
136.3, 136.2, 131.2, 129.9, 128.7, 126.3, 125.3 (q, J = 288.6 Hz), 123.9, 122.7, 68.8 (q, J = 25.4
Hz), 57.0, 53.3, 40.4 (q, J = 1.7 Hz), 32.6 (q, J = 2.2 Hz), 20.7. 19F NMR (188 MHz, CDCl3) δ: -
69.72 (s, 3F, CF3). Anal. Calcd for C19H19F3N2O2 (%): C, 62.63; H, 5.26; N, 7.69. Found: C,
62.77; H, 5.01; N, 7.32.
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Methyl
7-methyl-2-(4-nitrophenyl)-6-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-
naphthyridine-6-carboxylate, (10f). Yield: 170 mg, 86% (yellowish solid). Rf 0.45; M. p. =
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117-119°C. H NMR (200 MHz, CDCl3) δ 8.33 (d, J = 8.8 Hz, 2H, Harom.), 8.16 (d, J = 8.8 Hz,
2H, Harom.), 7.73 - 7.52 (m, 2H, Harom.), 4.34 – 4.04 (m, 2H, CH2), 3.82 (s, 3H, COOCH3), 3.56
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(d, J = 16.4 Hz, 1H, CH2), 3.31 (d, J = 16.5 Hz, 1H, CH2), 2.78 (s, 3H, NCH3). C NMR (50
MHz, CDCl3) δ 168.5, 154.4, 153.3, 148.5, 145.3, 137.2, 128.0, 126.4, 125.2 (q, J = 288.7 Hz),
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124.4, 119.8, 68.8 (q, J = 25.3 Hz), 56.9, 53.4, 40.4 (q, J = 2.1 Hz), 32.6 (q, J = 2.3 Hz). F
NMR (188 MHz, CDCl3) δ: -69.72 (s, 3F, CF3). Anal. Calcd for C18H16F3N3O4 (%): C, 54.69; H,
4.08; N, 10.63. Found: C, 54.79; H, 4.15; N, 10.44.
Methyl
2-cyclohexyl-7-methyl-6-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-
naphthyridine-6-carboxylate, (10g). Yield: 157 mg, 88% (colorless oil). Rf 0.55;1H NMR (200
MHz, CDCl3) δ 7.32 (d, J = 7.9 Hz, 1H, Harom.), 6.95 (d, J = 7.9 Hz, 1H, Harom.), 4.18 – 3.94 (m,
2H, CH2), 3.74 (s, 3H, COOCH3), 3.40 (d, J = 16.1 Hz, 1H, CH2), 3.15 (d, J = 16.2 Hz, 1H,
CH2), 2.80 – 2.46 (m, 4H, NCH3+CH), 1.99 – 1.65 (m, 5H, CH2cy), 1.58 – 1.17 (m, 5H, CH2Cy).
13C NMR (50 MHz, CDCl3) δ 168.6, 165.1, 152.5, 136.4, 125.3 (q, J = 288.4 Hz), 122.9, 119.2,
68.8 (q, J = 25.3 Hz), 57.0, 53.1, 46.7, 40.2 (q, J = 2.0 Hz), 33.4 (d, J = 7.4 Hz), 32.4 (q, J = 2.2
Hz), 26.9, 26.4. 19F NMR (188 MHz, CDCl3) δ: -69.90 (s, 3F, CF3). Anal. Calcd for
C18H23F3N2O2 (%): C, 60.66; H, 6.50; N, 7.86. Found: C, 60.88; H, 6.62; N, 7.99.
Methyl 2-tert-butyl-7-methyl-6-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-
6-carboxylate, (10h). Yield: 153 mg, 93% (colorless oil). Rf 0.55; 1H NMR (200 MHz, CDCl3)
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δ 7.35 (d, J = 8.1 Hz, 1H, Harom.), 7.15 (d, J = 8.1 Hz, 1H, Harom.), 4.20 – 3.98 (m, 2H, CH2), 3.79
(s, 3H, COOCH3), 3.45 (d, J = 16.2 Hz, 1H, CH2), 3.19 (d, J = 16.2 Hz, 1H, CH2), 2.74 (s, 3H,
NCH3), 1.33 (s, 9H, 3CH3). 13C NMR (50 MHz, CDCl3) δ 167.3, 166.4, 150.8, 134.6, 123.9 (q, J
= 288.6 Hz), 120.8, 116.2, 67.5 (q, J = 25.5 Hz), 55.7, 51.8, 38.9 (q, J = 2.0 Hz), 36.1, 30.9 (q, J
= 2.2 Hz), 29.1. 19F NMR (188 MHz, CDCl3) δ: -69.89 (s, 3F, CF3). Anal. Calcd for
C16H21F3N2O2 (%): C, 58.17; H, 6.41; N, 8.48. Found: C, 58.32; H, 6.35; N, 8.66.
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7-Methyl-2-phenyl-6,6-bis(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine, (10i).
Yield: 137 mg, 76% (colorless soid) M. p. = 115-117°C. Rf 0.50; 1H NMR (600 MHz, CDCl3) δ
7.99 (d, J = 7.1 Hz, 2H, Harom.), 7.61 (d, J = 8.0 Hz, 1H, Harom.), 7.55 (d, J = 8.0 Hz, 1H, Harom.),
7.49 (t, J = 7.5 Hz, 2H, Harom.), 7.43 (t, J = 7.3 Hz, 1H, Harom.), 4.17 (s, 2H, NCH2), 3.26 (s, 1H,
CH2), 2.89 (s, 3H, NCH3). 13C NMR (151 MHz, CDCl3) δ 155.5, 154.3, 139.1, 135.7, 129.0,
128.8, 126.9, 124.9 (q, J = 294.4 Hz), 123.7, 119.2, 66.1 (sept, J = 25.4 Hz), 56.4, 39.6, 30.3. 19F
NMR (282 MHz, CDCl3) δ -70.23 (s, 6F, 2CF3). Anal. Calcd for C17H14F6N2 (%): C, 56.67; H,
3.92; N, 7.78. Found: C, 56.82; H, 3.81; N, 7.65.
2-(2-Methoxyphenyl)-7-methyl-6,6-bis(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-
naphthyridine, (10j). Yield: 100mg, 51% (colorless oil). Rf 0.55; 1H NMR (300 MHz, CDCl3) δ
7.83 (dd, J = 7.6, 1.8 Hz, 1H, Harom.), 7.76 (d, J = 8.0 Hz, 1H, Harom.), 7.54 (d, J = 8.0 Hz, 1H,
Harom.), 7.48 – 7.39 (m, 1H, Harom.), 7.19 – 7.11 (m, 1H, Harom.), 7.06 (d, J = 8.3 Hz, 1H, Harom.),
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4.21 (s, 2H, NCH2), 3.91 (s, 3H, OCH3), 3.30 (s, 2H, CH2), 2.92 (s, 3H, NCH3). C NMR (151
MHz, CDCl3) δ 157.0, 154.0, 153.9, 134.7, 131.1, 130.0, 128.6, 124.9 (q, J = 294.3 Hz), 123.8,
123.2, 121.1, 111.3, 66.1 (sept, J = 25.4 Hz), 56.4, 55.5, 39.6, 30.2. 19F NMR (282 MHz, CDCl3)
δ -70.20 (s, 6F, 2CF3). Anal. Calcd for C18H16F6N2O (%): C, 55.39; H, 4.13; N, 7.18. Found: C,
55.28; H, 4.28; N, 7.01.
Diethyl 7-methyl-2-phenyl-7,8-dihydro-1,7-naphthyridine-6,6(5H)-dicarboxylate, (10k).
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CDCl3) δ 7.94 (d, J = 7.1 Hz, 2H, Harom.), 7.52 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H,
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Harom.), 7.44 (t, J = 7.5 Hz, 2H, Harom.), 7.38 (t, J = 7.3 Hz, 1H, Harom.), 4.26 (q, J = 7.1, 4H,
2CH2), 4.13 (s, 2H, NCH2), 3.44 (s, 2H, CH2), 2.76 (s, 3H, NCH3), 1.27 (t, J = 7.1 Hz, 6H,
5
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13
2CH3). C NMR (151 MHz, CDCl3) δ 169.2, 155.4, 152.8, 139.3, 136.6, 128.7, 128.7, 126.9,
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125.6, 118.7, 71.1, 61.8, 56.3, 40.5, 35.2, 14.1. Anal. Calcd for C21H24N2O4 (%): C, 68.46; H,
6.57; N, 7.60. Found: C, 68.22; H, 6.88; N, 7.88.
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Diethyl
2-(2-methoxyphenyl)-7-methyl-7,8-dihydro-1,7-naphthyridine-6,6(5H)-
1
dicarboxylate, (10l). Yield: 135 mg, 68% (colorless oil). Rf 0.50 (hexanes : EtOAc – 1:1); H
NMR (300 MHz, CDCl3) δ 7.76 (dd, J = 7.6, 1.8 Hz, 1H, Harom.), 7.66 (d, J = 8.0 Hz, 1H, Harom.),
7.47 (d, J = 8.1 Hz, 1H, Harom.), 7.38 (ddd, J = 8.1, 7.5, 1.8 Hz, 1H, Harom.), 7.09 (td, J = 7.5, 1.0
Hz, 1H, Harom.), 7.02 (t, J = 6.2 Hz, 1H, Harom.), 4.31 (q, J = 7.1 Hz, 4H, 2OCH2), 4.16 (s, 2H,
NCH2), 3.87 (s, 3H, OCH3), 3.48 (s, 2H, CH2), 2.78 (s, 3H, NCH3), 1.32 (t, J = 7.1 Hz, 6H,
2CH3). 13C NMR (151 MHz, CDCl3) δ 169.3, 156.9, 153.9, 152.4, 135.5, 131.1, 129.8, 128.9,
125.0, 123.2, 121.1, 111.4, 71.2, 61.8, 56.2, 55.6, 40.5, 35.0, 14.1. Anal. Calcd for C22H26N2O5
(%): C, 66.32; H, 6.58; N, 7.03. Found: C, 66.44; H, 6.81; N, 7.15.
Acknowledgment
This work was financially supported by RFBR-PICS and GDRI grants (No 07-03-92171, 08-03-
92504) in the frame of bilateral collaboration between CNRS France and Russian Academy of
Sciences. We thank K.I. Zamaraev International Charitable Scientific foundation for PhD grant
(A.K.M.) and Dr. I.V. Ananyev for X-Ray investigation.
Supporting Information for this article (experimental details and NMR-spectra for all new
compounds) is available online at http://www.pubs.acs.org
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