Synthesis of in vivo metabolites of the new adenosine A3 receptor PET-radiotracer[18F]Fe@SUPPY

Article abstract of DOI:10.3987/COM-07-11219

The synthesis of three expected metabolites of the new adenosine A3 receptor PET-radiotracer[¹⁸F]Fe@SUPPY is described. The target compounds - all pentasubstituted pyridines - were obtained via Hantzsch type synthesis of appropriate 1,4-dihydro

Full text of DOI:10.3987/COM-07-11219

HETEROCYCLES, Vol. 75, No. 2, 2008
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HETEROCYCLES, Vol. 75, No. 2, 2008, pp. 339 - 356. © The Japan Institute of Heterocyclic Chemistry
Received, 11th September, 2007, Accepted, 18th October, 2007, Published online, 23rd October, 2007. COM-07-11219
SYNTHESIS OF IN VIVO METABOLITES OF THE NEW ADENOSINE A3
RECEPTOR PET-RADIOTRACER [18F]FE@SUPPY
Karem Shanab,a,* Wolfgang Wadsak,c Leonhard-Key Mien,c Markus Mitterhauser,b,c
Wolfgang Holzer,a Victoria Polster,a Helmut Viernstein,b and Helmut Spreitzera,*
aDepartment of Drug and Natural Product Synthesis, University of Vienna,
Althanstrasse 14, 1090, Vienna, Austria
bDepartment of Pharmaceutical Technology and Biopharmaceutics, University of
Vienna, Althanstrasse 14, 1090, Vienna, Austria
cDepartment of Nuclear Medicine, Medical University of Vienna, Waehringer
Guertel 18-20, 1090, Vienna, Austria
Email: karem.shanab@univie.ac.at, helmut.spreitzer@univie.ac.at
Abstract – The synthesis of three expected metabolites of the new adenosine A3
receptor PET-radiotracer [18F]FE@SUPPY is described. The target compounds –
all pentasubstituted pyridines – were obtained via Hantzsch type synthesis of
appropriate 1,4-dihydropyridines, followed by oxidation to the corresponding
pyridines and subsequent modifications of the ester moieties.
INTRODUCTION
In contrast to adenosine receptor subtypes A1 and A2A, little is known about the distribution and absolute
amounts of the A3 subtype in humans. Fredholm et al found high expression of A3 mRNA in rat testes,
intermediate levels in human cerebellum and hippocampus, sheep lung and spleen and low levels in human
liver, kidney, heart, intestine, testis and rest of the brain.1 The reported data in the literature1,2,3,4 so far are
based on values of mRNA responsible for the expression rate of the A3AR but do not represent the absolute
receptor densities. For direct quantification of receptor densities autoradiography and positron emission
tomography (PET) are available, but both methods require selective radiotracers.
In the last years a variety of compounds belonging to different chemical classes has been identified as
selective A3 adenosine antagonists such as adenines, xanthenes, triazoloquinazolines, flavonoids,
thiazolopyridines, 6-phenyl-1,4-dihydropyridines, and 6-phenylpyridines.5

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HETEROCYCLES, Vol. 75, No. 2, 2008
In our efforts to develop new PET-radiotracers, we focused our interest on [18F]fluoride labeling of
pentasubstituted pyridines, which exhibit high affinity and selectivity towards the A3AR in a previous
evaluation.6 Most recently, we reported on 2-[18F]fluoroethyl 4,6-diethyl-5-[(ethylsulfanyl)carbonyl]-
-2-phenylpyridine-3-carboxylate ([18F]FE@SUPPY) (1) as the first A3 adenosine receptor radiotracer, the
establishment of its radiosynthesis, and a first biodistribution study in a rat model (Figure 1).7
O
O
18F
O
S
N
1
Figure 1. [18F]FE@SUPPY
In the course of our investigations it became obvious, that compounds (2-4) represent the expected in vivo
phase I metabolites of parent compound (1) (Figure 2). Thus, synthetic pathways to these hitherto
unknown target structures had to be developed. Whereas, 3 and 4 were needed as standards for potential
radiometabolites, compound (2) additionally, serves as a versatile precursor for further syntheses of a
variety of different pentasubstituted pyridines, for instance the alternative microwave enhanced synthesis
of 3. Detailed NMR spectroscopic studies with the target structures, including full and unambiguous
1
13
assignments of all H and C-NMR resonances, was envisaged. Hence, aims of the present study were
the preparation and structural analysis of compounds (2-4).
O
O
O
O
O
O
F
HO
SH
O
SH
HO
S
N
N
N
2
3
4
Figure 2. Expected metabolites of FE@SUPPY
RESULTS AND DISCUSSION
In all synthetic pathways, the synthesis of the pyridine core was realized by reaction of a β-enaminoester,
a β-ketoester, and an aldehyde in a straightforward Hantzsch reaction followed by oxidation of the thus
resulting 1,4-dihydropyridines with tetrachloro-1,4-benzoquinone (Scheme 1, Table 1).

HETEROCYCLES, Vol. 75, No. 2, 2008
341
O
O
Cl
Cl
Cl
Cl
O
O
O
O
O
O
O
R1
R1
R1
R2
O
H
O
R2
O
R2
+
NH2
O
N
H
N
5
6
7
8
Scheme 1
R1
R2
R1
R2
CH2CH2Si(Me)3
-
-
PMB
CH2CH2OH
PMB
OAllyl
OPMB
5a
5b
5c6
6a
6b8
6c6
7a
7b
7c
7d
8a
8b
8c
8d
PMB
CH2CH2OH
-
SCH2Me
OPMB
-
OPMB
OAllyl
SCH2Me
OPMB
CH2CH2Si(Me)3
PMB
-
OAllyl
-
CH2CH2OH
PMB
OPMB
CH2CH2Si(Me)3
SCH2Me
Table 1
β-Ketoesters (6) were prepared in a two-step route starting with the acylation of Meldrum’s acid (Scheme
2), followed by a ring opening reaction with an appropriate alcohol and decarboxylation of the
intermediately formed β-ketoacid.9 In the synthesis of β-enaminoesters (5) the first reaction step consisted
in the transesterification of the commercially available ethyl benzoylacetate into compound (9), which
was realized according to Bandgar et al using CuSO4 as catalyst.10 The subsequent enamine formation
was achieved by reaction of β-ketoesters (9) with ammonium acetate in a Dean-Stark trap in order to
maximize yields (Scheme 2).
O
O
O
O
O
O
O
ROH or RSH
Cl
O
O
6
O
O
O
O
O
ROH
CuSO4 anhy dr.
MeCO2NH4
R
O
5
O
9a11
: R = CH2CH2Si(Me)3
9b12: R = PMB
9c6: R = CH2CH2OH
Scheme 2
The different ester groups in 8 had to be chosen carefully in order to permit selective cleavage after
formation of the pyridine core, to obtain the crucial regioselective formation of the carbothioic acid group.
Therefore, the fluorine-sensitive trimethylsilylethyl (TME) and the acid-sensitive para-methoxybenzyl
esters (PMB) (8a) were selected at the first attempt to prepare title compound 2.
The para-methoxybenzylester in compound (8a) was cleaved selectively with formic acid to afford

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HETEROCYCLES, Vol. 75, No. 2, 2008
carboxylic acid (10). Established methods to convert 10 via 11, 12, or 13, respectively, to thiocarboxylic
acid (14) failed.13,14,15
The formation of the thiocarboxylic acid (14) was finally accomplished under mild conditions as
described by Nomura et al16 by direct sulfuration of the carboxylic acid (10) with P4S10 catalyzed by
Ph3SbO (Scheme 3).
O
O
O
O
Si
Si
HCO2H
O
OH
O
R
8a
N
N
10
11: R = O(CO)CH2CH(Me)2
12: R =
O
N
O
O
13: R = S(Ph)
14: R = SH
Scheme 3
Since the subsequent attempt of the fluoride-induced cleavage of the trimethylsilylethyl ester (14) to 2
failed, 8b was finally chosen as starting molecule for the synthesis of 2. The allyl ester of 8b was cleaved
first with tetrakis(triphenylphosphine)palladium(0) exploiting the sensitivity of the allyl group towards
transition metals. The resulting carboxylic acid could be easily converted to thiocarboxylic acid (15).
Subsequently, the para-methoxybenzyl group was cleaved smoothly with formic acid at room
temperature furnishing title compound (2) (Scheme 4).
O
O
O
O
O
O
1. Pd(PPh3)4; morpholine
2. (COCl)2/DMF cat.; NaSH
O
O
O
SH
HCO2H
HO
SH
O
N
O
N
N
8b
15
2
Scheme 4
Title compound (4) could be made accessible by selective cleavage of the para-methoxybenzyl ester of
8d again with formic acid.
Title compound (3) was synthesized starting from hydroxyethyl ester (8c), which was fluorinated with
diethylaminosulfur trifluoride (DAST) to give fluoroethyl ester (16). The para-methoxybenzyl ester was
treated with formic acid, thus furnishing the carboxylic acid, which was converted into carbothioic acid 3
(Scheme 5).

HETEROCYCLES, Vol. 75, No. 2, 2008
343
O
O
O
O
O
O
1. HCO2H
HO
F
F
2. (COCl)2/DMF cat.
O
O
O
O
O
SH
DAST
HF
3. NaSH
N
O
N
O
N
8c
16
3
Scheme 5
The synthesis of derivative (3) was also achieved by treatment of carboxylic/carbothioic diacid (2) with
2-fluoroethyl trifluoromethanesulfonate under microwave-enhanced conditions. Due to the low dielectric
loss (ε’’) to dielectric constant (ε’) ratio (tanδ = 0.062) of acetonitrile,17 cesium ions (Cs2CO3) were added
to improve the absorption and conversion of the microwave energy to heat by ionic conduction
mechanism.18,19 Under the investigated conditions the alkylation always occurred on the carboxylic acid
and not on the thiocarboxy moiety, which can probably be explained by the stronger electronegativity of
the oxygen atom and the higher acidity of the carboxylic acid. It should be emphasized that this approach
appears to be well qualified also for radiochemical [18F]fluoroethyl-labeling of compound 2 due to the
short reaction time of only ten minutes (Scheme 6).
O
O
O
O
F
F
HO
SH
OTf
O
SH
N
N
MW 150 °C
Cs2CO3
2
3
Scheme 6
NMR SPECTROSCOPIC INVESTIGATIONS
The NMR data of all compounds are given in the Experimental section. Complete assignment of signals
of compound (2), (3), and (4) in 1H and 13C spectra was accomplished by combination of different NMR
techniques. Figure 3 shows the 3J (13C, 1H) - correlations used in the spectral assignment of 4.
Me
O
O
HO
S
Me
N
Me
Figure 3

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EXPERIMENTAL
Melting points were determined on a Reichert-Kofler hot-stage microscope. Mass spectra were obtained
on a Shimadzu QP 1000 instrument (EI, 70 eV), a Finnigan MAT 8230 instrument (EI, 70 eV, HRMS)
and on a Finnigan MAT 900 S (ESI, 4 kV, 3 µA MeCN/MeOH, HRMS). IR spectra were recorded on a
Perkin-Elmer FTIR spectrum 1000 spectrometer. Elemental analyses were performed at the
1
13
Microanalytical Laboratory, University of Vienna. H- and C-NMR spectra were recorded on a Bruker
1
13
Avance DPX-200 spectrometer at 27 °C (200.13 MHz for H, 50.32 MHz for C), a Varian UnityPlus
300 spectrometer at 28 °C (299.95 MHz for 1H, 75.43 for 13C) or on a Bruker Avance 500 spectrometer at
1
13
293 K (500.13 MHz for H, 125.77 MHz for C). The solvent signal was used as an internal standard
which was related to TMS with δ = 7.26 ppm (1H in CDCl3), δ = 2.49 ppm (1H in DMSO-d6), δ = 77.0
ppm (13C in CDCl3), and δ = 39.5 ppm (13C in DMSO-d6). The starting materials were commercially
available and/or prepared similar to literature procedures.
2-(Trimethylsilyl)ethyl 3-oxo-3-phenylpropanoate (9a)
Ethyl benzoylacetate (1.92 g, 10.00 mmol) and 2-(trimethylsilyl)ethanol (1.18 g, 10.00 mmol) were
dissolved in 40 mL of toluene. After the addition of 100-200 mg of CuSO4 the mixture was stirred for 72
h at 100 °C. A distillation condenser was used to remove emerging EtOH. After completion of the
reaction the mixture was cooled, filtered and evaporated. The residue was chromatographed (silica gel,
light petroleum ether/EtOAc 9/1) to afford 9a as reddish liquid (2.10 g, 79 %). The spectroscopic data
were in full accordance with the literature.11
2-(Trimethylsilyl)ethyl 3-amino-3-phenylprop-2-enoate (5a)
2-(Trimethylsilyl)ethyl 3-oxo-3-phenylpropanoate (9a) (4.01 g, 15.17 mmol) and ammonium acetate
(3.51 g, 45.54 mmol) were mixed with toluene/AcOH (4/1) and refluxed for 6 h in a Dean-Stark
apparatus, followed by removal of the solvent under reduced pressure and column chromatography (silica
gel, light petroleum ether/EtOAc 9/1). The title compound (5a) was obtained as yellowish oil (3.11 g,
1
83 %). H-NMR (200 MHz, CDCl3): δ (ppm) 7.52 (m, 2H), 7.40 (m, 3H), 4.95 (s, 1H), 4.22 (t, 2H, J =
8.32 Hz) 1.03 (t, 2H, J = 8.46 Hz), 0.06 (s, 9H); 13C-NMR (50 MHz, CDCl3): δ (ppm) 170.5, 160.3, 137.7,
130.1, 128.8, 126.1, 84.8, 60.9, 17.5, -1.5. IR cm-1 (KBr): 3439, 3331, 3062, 2953, 2895, 1663, 1621,
1576, 1556, 1490, 1451, 1414, 1374, 1313, 1250, 1171, 1089, 1061. MS: m/z (%) 265 (M+ + 2, 0.53),
263 (8), 221 (13), 220 (60), 145 (94), 104 (35), 91 (28), 73 (100); Anal. Calcd for C14H21NO2Si: C, 63.84;
H, 8.04; N, 5.32. Found: C, 64.09; H, 7.93; N, 5.10.

HETEROCYCLES, Vol. 75, No. 2, 2008
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4-Methoxybenzyl 3-oxopentanoate (6a)
To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (5.00 g, 34.72 mmol) and propionyl chloride (3.53 g,
38.15 mmol) in dry CH2Cl2 (70 mL), pyridine (5.49 g, 3.6 mL, 69.41 mmol) was added dropwise at 0 °C.
After stirring for 1 h, the temperature was allowed to rise to rt and stirring was continued for 1 h. The
reaction mixture was washed with 1N HCl (70 mL), water (40 mL) and then dried with Na2SO4. The
solvent was evaporated and the crude product was used for the next step without further purification.
A solution of the crude product of the previous reaction and 4-methoxybenzyl alcohol (14.30 g, 103.50
mmol) was heated in toluene (100 mL) at 80 °C for 24 h. After removal of the solvent under reduced
pressure, the remaining oil was subjected to column chromatography (silica gel, light petroleum
ether/EtOAc 9/1) to afford 4.18 g (51 %) of 6a as yellow oil. 1H-NMR (200 MHz, CDCl3): δ (ppm) 7.29
(d, 2H, J = 6.68 Hz), 6.88 (d, 2H, J = 6.82 Hz), 5.09 (s, 2H), 3.78 (s, 3H) 3.45 (s, 2H), 2.51 (q, 2H, J =
13
7.34 Hz), 1.04 (t, 3H, J = 7.18 Hz); C-NMR (50 MHz, CDCl3): δ (ppm) 202.9, 167.0, 159.5, 130.0,
127.3, 113.7, 66.6, 55.0, 48.7, 36.0, 7.3. IR cm-1 (KBr): 2977, 2940, 2908, 2838, 1743, 1716, 1614, 1516,
1461, 1412, 1304, 1248, 1176, 1157, 1109, 1060, 1033, 965. MS: m/z (%) 236 (M+, 11), 137 (76), 122 (9),
121 (100), 91 (10), 78 (12), 77 (15), 57 (12). Anal. Calcd for C13H16O4: C, 66.09; H, 6.83; Found: C,
65.95; H, 6.81.
4-Methoxybenzyl 3-amino-3-phenylprop-2-enoate (5b)
A mixture of 4-methoxybenzyl 3-oxo-3-phenylpropanoate (9b)12 (5.80 g, 20.40 mmol) and ammonium
acetate (7.86 g, 101.97 mmol) in toluene (100 mL) was refluxed overnight using a Dean-Stark trap. The
solvent was removed in vacuo and the residue was submitted to column filtration (silica gel, light
petroleum ether/EtOAc 8/2). The resulting crude product was used for the next step without further
purification.
Allyl 3-oxopentanoate (4b)
To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (5.00 g, 34.69 mmol) and propionyl chloride (3.53 g,
38.15 mmol) in dry CH2Cl2 (70 mL), pyridine (5.49 g, 3.6 mL, 69.41 mmol) was added dropwise at 0 °C.
After stirring for 1 h, the temperature was allowed to rise to rt and stirring was continued for 1 h. The
reaction mixture was washed with 1N HCl (70 mL), water (40 mL) and was then dried with Na2SO4. The
solvent was evaporated and the residue was used for the next step without further purification.
The crude product and allyl alcohol (6.01 g, 103.48 mmol) were dissolved in toluene (100 mL) and
heated at 80 °C for 24 h. After removal of the solvent and excess allyl alcohol under reduced pressure, the
remaining oil was subjected to column chromatography (silica gel, light petroleum ether/EtOAc 9/1) to
afford 3.36 g (62 %) of 4b as liquid. The spectroscopic data were in full accordance with the literature.8

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3-(4-Methoxybenzyl) 5-[2-(trimethylsilyl)ethyl] 2,4-diethyl-6-phenyl-1,4-dihydropyridine-3,5-di-
carboxylate (7a)
A solution of 4-methoxybenzyl 3-oxopentanoate (6a) (1.35 g, 5.71 mmol), 2-(trimethylsilyl)ethyl
3-amino-3-phenylprop-2-enoate (5a) (1.51 g, 5.71 mmol) and propionaldehyde (0.32 g, 5.71 mmol) in 15
mL of absolute EtOH was stirred for 24 h in a sealed tube at 80 °C. After the solvent was removed under
reduced pressure, the obtained crude product was chromatographed (silica gel, light petroleum
ether/EtOAc 9/1) to afford 1.66 g (56 %) of 7a as viscous liquid. For spectroscopic purposes 100 mg of
this crude product were purified by preparative TLC (reversed phase C-18 silica gel MeCN/water 9/1).
1H-NMR (200 MHz, CDCl3): δ (ppm) 7.35 (m, 7H), 6.89 (m, 2H), 5.85 (s, 1H), 5.13 (m, 2H) 4.06 (t, 1H,
J = 5.42 Hz), 3.95 (m, 2H), 3.81 (s, 3H), 2.71 (m, 2H), 1.51 (m, 2H), 1.16 (t, 3H, J = 7.46 Hz), 0.87 (t, 3H,
J = 7.32 Hz), 0.67 (m, 2H),- 0.05 (s, 9H); 13C-NMR (50 MHz, CDCl3): δ (ppm) 167.4, 167.3, 159.2,
151.0, 146.6, 137.1, 129.6, 128.9, 128.2, 128.1, 113.7, 103.3, 101.2, 65.2, 61.7, 55.2, 34.3, 29.1, 25.9,
16.8, 13.0, 9.0, -1.6. IR cm-1 (KBr): 3312, 2956, 1682, 1614, 1515, 1485, 1249. MS: m/z (%) 522 (M++ 1,
0.21), 521 (0.27), 493 (17), 492 (45), 464 (13), 392 (23), 122 (10), 121 (100), 77 (10), 73 (48). HRMS
Calcd for C28H34NO5Si (M+- C2H5): 492.2201. Found: 492.2180.
3-(4-Methoxybenzyl) 5-[2-(trimethylsilyl)ethyl] 2,4-diethyl-6-phenylpyridine-3,5-dicarboxylate (8a)
Tetrachloro-1,4-benzoquinone (3.23 g, 13.14 mmol) and 3-(4-methoxybenzyl) 5-[2-(trimethylsilyl)ethyl]
2,4-diethyl-6-phenyl-1,4-dihydropyridine-3,5-dicarboxylate (7a) (1.71 g, 3.28 mmol) in THF (50 mL)
were refluxed overnight. Afterwards, the solvent was removed in vacuo and purified by column
chromatography (silica gel, light petroleum ether/EtOAc 11/1). A sample was purified for spectroscopic
purposes by reversed phase column chromatography (RP-18 silica gel, MeCN/water 8/2) giving 1.46 g
(85 %) of 8a as colorless oil. 1H-NMR (200 MHz, CDCl3): δ (ppm) 7.56 (m, 2H), 7.40 (m, 5H), 6.91 (d,
2H, J = 8.58 Hz), 5.35 (s, 2H), 4.09 (m, 2H) 3.82 (s, 3H), 2.76 (q, 2H, J = 7.48 Hz), 2.62 (q, 2H, J = 7.44
Hz), 1.25 (t, 3H, J = 7.44 Hz), 1.14 (t, 3H, J = 7.58 Hz), 0.63 (m, 2H), -0.05 (s, 9H); 13C-NMR (50 MHz,
CDCl3): δ (ppm) 168.7, 168.4, 160.1, 159.9, 156.7, 148.4, 139.8, 130.8, 128.7, 128.4, 128.3, 127.3, 127.1,
126.7, 114.0, 67.4, 63.9, 55.3, 29.7, 24.6, 16.8, 15.2, 13.8, -1.7. IR cm-1 (KBr): 2954, 1724, 1612, 1562,
1515, 1463, 1251. MS: m/z (%) 520 (M+ + 1, 1), 519 (3), 402 (2), 398 (2), 370 (3), 298 (2), 254 (3), 208
(3), 122 (10), 121 (100), 77 (5), 73 (28). Anal. Calcd for C30H37NO5Si: C, 69.33; H, 7.18; N, 2.70. Found:
C, 69.38; H, 6.95; N, 2.43. HRMS Calcd for C30H25NO5Si: 519.2441. Found: 519.2437.
2,4-Diethyl-6-phenyl-5-{[2-(trimethylsilyl)ethoxy]carbonyl}pyridine-3-carboxylic acid (10)
3-(4-Methoxybenzyl) 5-[2-(trimethylsilyl)ethyl] 2,4-diethyl-6-phenylpyridine-3,5-dicarboxylate (8a)
(1.20 g, 2.31 mmol) was stirred in formic acid (5.5 mL) for 5 h. Subsequently, formic acid was removed

HETEROCYCLES, Vol. 75, No. 2, 2008
347
under reduced pressure and the residue was purified by column chromatography (RP-18 silica gel,
MeCN/water 9/1) furnishing 734 mg (80 %) of 10 as colorless crystals. Mp 169 – 171 °C. 1H-NMR (200
MHz, DMSO): δ (ppm) 13.86 (s, 1H), 7.48 (m, 5H), 4.12 (t, 2H, J = 7.94 Hz), 2.73 (m, 4H), 1.20 (m, 6H),
0.67 (t, 2H, J = 8.20 Hz), -0.08 (s, 9H); 13C-NMR (50 MHz, DMSO): δ (ppm) 169.3, 168.0, 158.6, 155.0,
146.7, 139.3, 128.9, 128.8, 128.3, 128.1, 126.3, 63.6, 28.9, 24.2, 16.3, 15.1, 13.4, -1.7. IR cm-1 (KBr):
3420, 2951, 2878, 2451, 1959, 1720, 1562, 1454. MS: m/z (%) 399 (M+, 17), 371 (20), 356 (21), 342 (17),
326 (15), 298 (38), 282 (43), 73 (100). Anal. Calcd for C22H29NO4Si: C, 66.13; H, 7.32; N, 3.51. Found:
C, 65.99; H, 7.33; N, 3.41.
2-(Trimethylsilyl)ethyl
4,6-diethyl-5-({[(2-methylpropoxy)carbonyl]oxy}carbonyl)-2-phenylpyri-
dine-3-carboxylate (11)
To a solution of 2,4-diethyl-6-phenyl-5-{[2-(trimethylsilyl)ethoxy]carbonyl}pyridine-3-carboxylic acid
(10) (0.74 g, 1.85 mmol) in THF (40 mL), triethylamine (TEA) (0.38 g, 3.76 mmol, 0.51 mL) and
isobutyl carbonochloridate (0.25 g, 1.83 mmol, 0.24 mL) were added at -10 °C. The mixture was stirred
for 2.5 h, filtrated and concentrated in vacuo. The residue was purified by column chromatography
(RP-18 silica gel, MeCN/water 9/1) to furnish 900 mg (98 %) of 11 as colorless oil. 1H-NMR (200 MHz,
CDCl3): δ (ppm) 7.60 (m, 2H), 7.42 (m, 3H), 4.13 (m, 4H), 2.95 (q, 2H, J = 7.44 Hz) 2.80 (q, 2H, J =
7.44 Hz), 2.90 (m, 1H), 1.32 (m, 6H), 1.01 (d, 6H, J =6.70 Hz), 0.66 (m, 2H), -0.04 (s, 9H); 13C-NMR (50
MHz, CDCl3): δ (ppm) 168.3, 163.2, 160.5, 157.7, 149.3, 148.6, 139.5, 129.0, 128.4, 128.3, 126.8, 124.8,
76.1, 64.2, 29.9, 27.6, 24.7, 18.7, 16.8, 15.4, 15.2, 13.7, -1.7. IR cm-1 (KBr): 2960, 2898, 2879, 1810,
1759, 1724, 1562, 1468, 1411, 1372, 1243, 1208, 1172, 1145, 1078, 1053, 1000, 940. MS: m/z (%) 501
(M+ + 2, 0.43), 500 (2), 456 (6), 382 (57), 370 (18), 282 (33), 280 (25), 236 (25), 73 (100), 57 (58), 41
(28). Anal. Calcd for C27H37NO6Si: C, 64.90; H, 7.46; N, 2.80. Found: C, 65.11; H, 7.40; N, 2.72.
2-(Trimethylsilyl)ethyl
5-{[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}-4,6-diethyl-2-phenylpyridine-
-3-carboxylate (12)
2,4-Diethyl-6-phenyl-5-{[2-(trimethylsilyl)ethoxy]carbonyl}pyridine-3-carboxylic acid (10) (2.28
g, 5.71 mmol) was dissolved in 110 mL of abs. THF. Afterwards, N-hydroxysuccinimide (0.79 g,
6.86 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride EDC (1.42 g, 7.41
mmol) were added to the solution and the resulting mixture was stirred at rt for 2 d. The solvent was
removed by evaporation and the residue was dissolved in CH2Cl2 and washed with brine. The CH2Cl2
layer was separated, dried over anhydrous sodium sulfate, and evaporated to dryness. Recrystallization
from petroleum ether/EtOAc afforded 2.69 g (95 %) of 12 as colorless crystals. Mp 139 – 140 °C.
1H-NMR (200 MHz, CDCl3): δ (ppm) 7.62 (m, 2H), 7.42 (m, 3H), 4.13 (m, 2H), 3.07 (q, 2H, J = 7.44 Hz),

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HETEROCYCLES, Vol. 75, No. 2, 2008
13
2.88 (m, 6H), 1.33 (m, 6H), 0.67 (m, 2H), -0.04 (s, 9H); C-NMR (50 MHz, CDCl3): δ (ppm) 168.9,
168.2, 164.0, 161.6, 158.2, 150.5, 139.4, 129.0, 128.3, 126.7, 122.1, 64.2, 29.9, 25.7, 24.9, 16.8, 15.6,
14.1, -1.7. IR cm-1 (KBr): 3512, 3408, 2969, 2877, 2869, 1810, 1784, 1743, 1714, 1564, 1462, 1425,
1405, 1361, 1253. MS: m/z (%) 497 (M+ + 1, 6), 496 (1), 383 (23), 382 (85), 355 (27), 354 (100), 282
(60), 264 (41), 236 (39), 73 (96). Anal. Calcd for C26H32N2O6Si: C, 62.88; H, 6.49; N, 5.64. Found: C,
62.61; H, 6.42; N, 5.50.
2-(Trimethylsilyl)ethyl 4,6-diethyl-2-phenyl-5-[(phenylsulfanyl)carbonyl]pyridine-3-carboxylate (13)
A solution of 2,4-diethyl-6-phenyl-5-{[2-(trimethylsilyl)ethoxy]carbonyl}pyridine-3-carboxylic acid (10)
(0.62 g, 1.55 mmol) in dry CH2Cl2 (7 mL) was treated with SOCl2 (2.6 mL) and heated at reflux
overnight under argon. After cooling to rt, the reaction mixture was concentrated under reduced pressure
and the residue was dried under vacuum to remove traces of SOCl2. The resulting residue was dissolved
in CH2Cl2 (5 mL) and added to a cooled (0 °C) solution of thiophenol (0.17 g, 1.55 mmol, 0.16 mL) and
o
pyridine (0.12 g, 1.55 mmol, 0.13 mL) in CH2Cl2 (5 mL). After 5 min at 0 C the reaction mixture was
stirred at rt until completion (TLC). Then, it was washed with water and after separation of the layers, the
aqueous phase was again extracted with CH2Cl2. The combined organic extracts were dried over sodium
sulfate and after evaporation of the solvent to dryness, the residue was purified by column
chromatography (RP-18 silica gel MeCN/water 9/1) to furnish 400 mg (52 %) of 13 as yellowish oil.
1H-NMR (200 MHz, CDCl3): δ (ppm) 7.53 (m, 10H), 4.14 (m, 2H), 3.01 (q, 2H, J = 7.56 Hz), 2.86 (q, 2H,
13
J = 7.46 Hz), 1.35 (m, 6H), 0.67 (m, 2H), -0.02 (s, 9H); C-NMR (50 MHz, CDCl3): δ (ppm) 193.6,
168.5, 159.2, 157.2, 148.0, 139.7, 134.3, 132.6, 129.9, 129.5, 128.8, 128.4, 128.3, 127.1, 126.7, 64.0, 29.3,
24.3, 16.8, 15.7, 14.0, -1.7. IR cm-1 (KBr): 3057, 2968, 2876, 1730, 1713, 1689, 1558, 1449, 1403, 1378,
1314, 1272, 1248, 1217, 1165, 1144, 1074, 1044. MS: m/z (%) 491 (M+ + 1, 0.22), 449 (1), 448 (4), 383
(27), 382 (100), 354 (26), 282 (52), 264 (25), 236 (29), 109 (27), 73 (86). Anal. Calcd for C28H33NO3SSi:
C, 68.39; H, 6.67; N, 2.85. Found: C, 68.12; H, 6.87; N, 2.77.
2,4-Diethyl-6-phenyl-5-{[2-(trimethylsilyl)ethoxy]carbonyl}pyridine-3-carbothioic S-acid (14)
To a suspension of P4S10 (0.046 g, 0.13 mmol) and Ph3SbO (0.028 g, 0.06 mmol) in 10 mL of benzene,
was added 2,4-diethyl-6-phenyl-5-{[2-(trimethylsilyl)ethoxy]carbonyl}pyridine-3-carboxylic acid (10)
(0.50 g, 1.25 mmol). The mixture was refluxed for 12 h and after cooling the solvent was removed under
reduced pressure. The residue was applied onto a reversed phase silica gel column (RP-18 silica gel
1
MeCN /water 9/1) for purification to obtain 327 mg (63 %) of 14 as pinkish oil. H-NMR (200 MHz,
CDCl3): δ (ppm) 7.65 (m, 2H), 7.43 (m, 3H), 4.15 (m, 2H), 2.98 (m, 4H), 2.16 (s, 1H) 1.34 (m, 6H), 0.69
13
(m, 2H), -0.02 (s, 9H); C-NMR (50 MHz, CDCl3): δ (ppm) 190.5, 169.3, 160.9, 159.0, 150.1, 140.5,

HETEROCYCLES, Vol. 75, No. 2, 2008
349
131.5, 130.0, 129.8, 129.5, 129.4, 128.0, 65.3, 30.4, 25.3, 17.9, 16.9, 15.2, -0.68. IR cm-1 (KBr): 3423,
2953, 2897, 1723, 1557, 1451, 1404, 1378, 1278, 1250, 1166, 1144, 1075. MS: m/z (%) 416 (M+ + 1,
0.43), 415 (1), 414 (0.31), 413 (0.19), 385 (41), 383 (20), 382 (65), 354 (27), 296 (19), 282 (32), 236 (16),
73 (100). Anal. Calcd for C22H29NO3SSi: C, 68.58; H, 7.03; N, 3.37. Found: C, 63.47; H, 6.79; N, 3.29.
3-Allyl 5-(4-methoxybenzyl) 2,4-diethyl-6-phenyl-1,4-dihydropyridine-3,5-dicarboxylate (7b)
4-Methoxybenzyl 3-amino-3-phenylprop-2-enoate (5b) (2.57 g, 9.07 mmol), allyl 3-oxopentanoate (6b)
(1.42 g, 9.07 mmol) and propionaldehyde (0.53 g, 9.07 mmol) were dissolved in 20 mL of absolute EtOH.
The mixture was sealed in a Pyrex tube and stirred for 24 h at 80 °C. After cooling to rt, the solvent was
evaporated and the oily residue was purified by column chromatography (silica gel, light petroleum
1
ether/EtOAc 8/2) to give 3.61 g (86 %) of 7b as greenish-yellow oil. H-NMR (200 MHz, CDCl3): δ
(ppm) 7.31 (m, 5H), 6.93 (d, 2H, J = 8.58 Hz), 6.76 (m, 2H, J = 8.58 Hz), 5.99 (m, 2H), 5.26 (m, 2H),
4.87 (d, 2H, J = 4.16 Hz), 4.65 (m, 2H), 4.10 (t, 2H, J = 4.44 Hz), 3.80 (s, 3H), 2.73 (m, 2H), 1.57 (m,
13
2H), 1.20 (t, 3H, J = 7.44 Hz), 0.94 (t, 3H, J = 7.38 Hz); C-NMR (50 MHz, CDCl3): δ (ppm) 167.6,
167.5, 159.5, 151.5, 147.4, 137.5, 133.3, 129.9, 129.5, 128.8, 128.7, 117.7, 113.9, 103.3, 101.7, 65.8, 64.8,
55.7, 34.9, 29.5, 26.3, 13.4, 9.6. IR cm-1 (KBr): 3418, 3323, 3055, 2963, 2934, 1684, 1615, 1516, 1464,
1442, 1266, 1248, 1207, 1110, 1086, 1066. MS: m/z (%) 460 (M+ + 1, 1), 459 (2), 402 (2), 338 (1), 294
(7), 236 (1), 208 (2), 122 (19), 121 (100), 91 (3), 77 (4). Anal. Calcd for C28H31NO5·0.2 H2O: C, 72.30; H,
6.80; N, 3.01. Found: C, 72.41; H, 6.91; N, 2.91.
3-Allyl 5-(4-methoxybenzyl) 2,4-diethyl-6-phenylpyridine-3,5-dicarboxylate (8b)
A mixture of 3-allyl 5-(4-methoxybenzyl) 2,4-diethyl-6-phenyl-1,4-dihydropyridine-3,5-dicarboxylate
(7b) (3.61 g, 7.82 mmol) and tetrachloro-1,4-benzoquinone (2.13 g, 8.66 mmol) in THF (120 mL) was
refluxed overnight. After the reaction mixture was allowed to cool, the solvent was removed in vacuo and
purified by column chromatography (silica gel, light petroleum ether/EtOAc 9/1). A sample was
subjected to reversed phase column chromatography (RP-18 silica gel MeCN/water 8/2) for spectroscopic
purposes giving 1.70 g (47 %) of 8b as an orange oil. 1H-NMR (200 MHz, CDCl3): δ (ppm) 7.60 (m, 2H),
7.38 (m, 3H), 6.94 (d, 2H, J = 8.70 Hz), 6.76 (d, 2H, J = 8.72 Hz), 6.04 (m, 2H) 5.41 (m, 2H), 5.00 (s,
2H), 4.86 (d, 2H, J = 6.06 Hz), 3.77 (s, 3H), 2.84 (q, 2H, J = 7.58 Hz), 2.67 (q, 2H, J = 7.58 Hz), 1.32 (t,
13
3H, J = 7.46 Hz), 1.19 (t, 3H, J = 7.46 Hz); C-NMR (50 MHz, CDCl3): δ (ppm) 168.3, 168.1, 160.2,
159.6, 156.7, 148.6, 139.7, 131.1, 130.3, 128.7, 128.3, 128.3, 127.2, 126.6, 126.2, 119.9, 113.7, 67.3, 66.3,
55.2, 29.7, 24.6, 15.2, 13.8. IR cm-1 (KBr): 2975, 2940, 2880, 2837, 1728, 1613, 1561, 1516, 1455, 1412,
1367, 1249, 1224, 1200, 1176, 1148, 1105, 1073, 1024, 973. MS: m/z (%) 462 (M+ + 1, 0.10), 461 (0.12),

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HETEROCYCLES, Vol. 75, No. 2, 2008
433 (22), 432 (74), 326 (14), 226 (15), 121 (100), 77 (14). Anal. Calcd for C28H29NO5·0.4 H2O: C, 72.05;
H, 6.44; N, 3.00. Found: C, 72.06; H, 6.23; N, 2.94.
2,4-Diethyl-5-{[(4-methoxybenzyl)oxy]carbonyl}-6-phenylpyridine-3-carbothioic S-acid (18)
A solution of 3-allyl 5-(4-methoxybenzyl) 2,4-diethyl-6-phenylpyridine-3,5-dicarboxylate (8b) (0.93 g,
2.02 mmol) in 15 mL THF was stirred under an argon atmosphere at rt and
tetrakis(triphenylphosphine)palladium(0) (0.28 g, 0.24 mmol, 10 mol %) and morpholine (2.11 g, 24.21
mmol, 2.12 mL) were added subsequently. After 30 min. the solvent was evaporated and the residue was
dissolved in 2 N NaOH. The resulting solution was washed with CH2Cl2 and then, the aqueous phase was
acidified with 6 N HCl and again extracted with CH2Cl2. The organic extracts were dried over anhydrous
Na2SO4 and evaporated under reduced pressure. The remaining residue was chromatographed (silica gel,
light petroleum ether/EtOAc 8/2) giving 806 mg (95 %) of the carboxylic acid as yellowish crystals. Mp
1
137 – 139 °C. H-NMR (200 MHz, CDCl3): δ (ppm) 7.53 (m, 2H), 7.32 (m, 3H), 6.87 (d, 2H, J = 8.60
Hz), 6.72 (d, 2H, J = 8.58 Hz), 4.93 (s, 2H), 3.74 (s, 3H), 2.75 (m, 4H), 1.17 (m, 6H); 13C-NMR (50 MHz,
CDCl3): δ (ppm) 170.2, 168.8, 160.3, 159.8, 155.9, 147.9, 140.1, 131.4, 129.9, 129.8, 129.4, 129.0, 127.6,
126.9, 114.7, 68.0, 56.0, 29.9, 25.1, 16.1, 14.4. IR cm-1 (KBr): 3422, 2974, 2939, 2879, 1724, 1613, 1560,
1516, 1458, 1383, 1304, 1246, 1177, 1124, 1032. MS: m/z (%) 420 (M+ + 1, 3), 419 (10), 278 (14), 277
(19), 144 (15), 122 (14), 121 (100), 100 (22), 86 (20), 77 (15), 57 (41). HRMS Calcd for C25H25NO5:
419.1733. Found: 419.1727.
To 2,4-diethyl-5-{[(4-methoxybenzyl)oxy]carbonyl}-6-phenylpyridine-3-carboxylic acid (1.00 g, 2.38
mmol) from the previous reaction in benzene (10 mL) at -10 °C were added slowly oxalyl chloride (1
mL) and 1 drop of DMF. The solution was allowed to warm up to rt and stirring was continued for 2 h.
Afterwards the solvent was removed under reduced pressure and the oily residue was coevaporated with
toluene (three times). The acid chloride was used without further purification for the next reaction step.
NaSH hydrate (0.36 g, 6.45 mmol) was dissolved in absolute EtOH (10 mL) at -10 °C. Then, a solution of
the crude acid chloride (15) in THF (4 mL) was added slowly. The reaction mixture was allowed to warm
up to rt and stirring was continued for 1 h. The mixture was acidified with 6 N HCl, extracted with EtOAc,
washed with brine twice and dried over Na2SO4. After evaporation of the solvent, the solid crude product
was subjected to column chromatography (silica gel, light petroleum ether/EtOAc 8/2) to afford 480 mg
1
(46 %) of 18 as brownish crystals. Mp 59 – 60 °C. H-NMR (200 MHz, CDCl3): δ (ppm) 7.62 (m, 2H),
7.41 (m, 3H), 5.04 (s, 2H), 3.79 (s, 3H), 3.02 (q, 2H, J = 7.45 Hz), 2.88 (q, 2H, J = 7.3 Hz), 1.38 (t, 2H, J
13
= 7.44 Hz), 1.23 (t, 2H, J = 7.45 Hz); C-NMR (50 MHz, CDCl3): δ (ppm) 189.3, 168.0, 160.0, 159.7,
158.0, 149.2, 139.3, 130.4, 129.1, 128.5, 128.4, 126.5, 113.8, 67.6, 55.2, 29.4, 24.3, 15.8, 14.2. IR cm-1
(KBr): 3403, 2973, 2936, 2877, 2836, 1725, 1613, 1556, 1515, 1462, 1403, 1376, 1303, 1246, 1165, 1142,

HETEROCYCLES, Vol. 75, No. 2, 2008
351
1074, 1034, 962. MS: m/z (%) 436 (M+ + 1, 3), 435 (9), 432 (21), 402 (23), 311 (5), 121 (100), 76 (10).
HRMS Calcd for C25H25NO4S: 435.1504. Found: 435.1515.
4,6-Diethyl-2-phenyl-5-(sulfanylcarbonyl)pyridine-3-carboxylic acid (2)
2,4-Diethyl-5-{[(4-methoxybenzyl)oxy]carbonyl}-6-phenylpyridine-3-carbothioic S-acid (15) was stirred
at rt in formic acid (5 mL) for 3 h. Subsequently, the formic acid was evaporated and the residue was
dissolved in 2 N NaOH. The resulting solution was washed with CH2Cl2, acidified with 6 N HCl and
again extracted with CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4 and
evaporated in vacuo to afford the crude product, which was purified by column chromatography (RP-18
silica gel MeCN/water 9/1) giving 200 mg (27 %) of 2 as colorless crystals. Mp 191 °C (decomp.).
1H-NMR (300 MHz, DMSO-d6): δ (ppm) 13.84 (s, 1H, CO2H), 7.69 (m, 2H, Ph H-2/H-6), 7.49 (m, 3H,
Ph H-3/H-4/H-5,), 2.92 (q, 2H, J = 7.50 Hz, C-6CH2), 2.82 (q, 2H, J = 7.50 Hz, C-4CH2) 1.30 (t, 3H, J =
13
7.50 Hz, C-6CH2Me), 1.21 (t, 3H, J = 7.50 Hz, C-4CH2Me); C-NMR (75 MHz, DMSO-d6): δ (ppm)
189.8 (COSH), 168.9 (CO2), 158.3 (C-6), 156.2 (C-2), 147.4 (C-4), 138.8 (Ph C-1), 129.8 (C-5), 129.3
(Ph C-4), 128.3 (Ph C-2/C-3/C-5/C-6), 28.6 (C-6CH2), 23.9 (C-4CH2), 15.6 (C-4CH2Me), 13.7
(C-6CH2Me). IR cm-1 (KBr): 3414, 2977, 2939, 2878, 2580, 2498, 1958, 1910, 1720, 1551, 1448, 1250,
1172. MS: m/z (%) 317 (M+ + 2, 1), 315 (9), 313 (100), 284 (11), 283 (16), 282 (97), 252 (14), 180 (10),
125 (27), 77 (35), 51 (14). Anal. Calcd for C17H17NO3S•0.3 H2O: C, 63.65; H, 5.53; N, 4.37. Found: C,
63.67; H, 5.44; N, 4.31.
2,4-Diethyl-5-[(2-fluoroethoxy)carbonyl]-6-phenylpyridine-3-carbothioic S-acid (3)
To a suspension of 4,6-diethyl-2-phenyl-5-(sulfanylcarbonyl)pyridine-3-carboxylic acid (2) (0.103 g, 0.33
mmol) and Cs2CO3 (0.215 g, 0.66 mmol) in MeCN (10-15 mL) was added 2-fluoroethyl
trifluoromethanesulfonate (0.14 g, 0.72 mmol). The mixture was heated in a microwave oven to 150 °C
(300 W) for 10 min. Afterwards, the reaction mixture was concentrated and the residue was purified by
column chromatography (RP-18 silica gel, MeCN) to give 0.113 g (95 %) of 3 as colorless crystals. Mp
45 – 47 °C. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.64 (m, 2H, Ph H-2, H-6), 7.46 (m, 3H, Ph H-3, H-4,
H-5), 4.39/4.29 (m, 2H, FCH2), 4.34/4.29 (m, 2H, CH2O), 3.05 (q, 2H, J = 7.50 Hz, C-2CH2), 2.93 (q, 2H,
J = 7.50 Hz, C-4CH2) 1.40 (t, 3H, J = 7.50 Hz, C-2CH2Me), 1.29 (t, 3H, J = 7.50 Hz, C-4CH2Me);
13C-NMR (75 MHz, CDCl3): δ (ppm) 189.3 (COSH), 167.9 (CO2), 160.4 (C-2), 158.3 (C-6), 149.5 (C-4),
139.3 (Ph C-1), 130.6 (C-3), 129.3 (Ph C-4), 128.5 (Ph C-3, C-5), 128.3 (Ph C-2, C-6), 126.2 (C-5), 80.5
(d, FCH2, J = 172.0 Hz), 64.5 (d, CH2O, J = 20.2 Hz), 29.5 (C-2CH2), 24.4 (C-4CH2), 15.9 (C-4CH2Me),
14.3 (C-2CH2Me). IR cm-1 (KBr): 3439, 2975, 2938, 2877, 1731, 1556, 1495, 1448, 1403, 1377, 1278,
1250, 1166, 1144, 1077, 1060, 1033, 960. MS: m/z (%) 362 (M+ + 1, 1), 361 (3), 359 (31), 329 (21), 328

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HETEROCYCLES, Vol. 75, No. 2, 2008
(100), 312 (14), 254 (15), 236 (12), 77 (20), 47 (48). Anal. Calcd for C19H20FNO3S•0.2 H2O: C, 62.52; H,
5.63; N, 3.84. Found: C, 62.45; H, 5.44; N, 3.73.
4-Methoxybenzyl 4,6-diethyl-5-[(ethylsulfanyl)carbonyl]-2-phenyl-1,4-dihydropyridine-3-carboxyl-
ate (7d)
4-Methoxybenzyl 3-amino-3-phenylprop-2-enoate (5b) (12.00 g, 42.35 mmol), S-ethyl 3-oxopentane-
thioate (6c)9 (6.79 g, 42.35 mmol), and propionaldehyde (2.46 g, 42.35 mmol) were dissolved in absolute
EtOH and heated at 80 °C in a sealed tube for 24 h. After completion of the reaction, EtOH was removed
in vacuo and the remaining oil was purified by column chromatography (silica gel, light petroleum
ether/EtOAc 9/1) to furnish 12.60 g (64 %) of 7d as greenish-yellow oil. 1H-NMR (200 MHz, CDCl3): δ
(ppm) 7.33 (m, 5H), 6.95 (d, 2H, J = 8.58 Hz), 6.76 (d, 2H, J = 8.70 Hz), 5.91 (s, 1H), 4.90 (m, 2H), 4.22
(t, 1H, J = 5.80 Hz), 3.80 (s, 3H), 2.93 (q, 2H, J = 7.34 Hz), 2.70 (m, 2H), 1.59 (m, 2H), 1.24 (m, 6H),
13
0.92 (t, 3H, J = 7.32 Hz; C-NMR (50 MHz, CDCl3): δ (ppm) 190.8, 166.9, 159.0, 147.7, 146.6, 136.8,
129.4, 129.2, 128.4, 128.3, 113.5, 109.2, 102.9, 65.3, 55.2, 35.1, 29.4, 26.0, 23.0, 14.8, 12.8, 9.3. IR cm-1
(KBr): 3290, 2960, 2926, 2870, 1644, 1595, 1517, 1476, 1388, 1301, 1247, 1247, 1246, 1230, 1174, 1149,
1100, 1079, 1038, 973. MS: m/z (%) 466 (M+ + 1, 0.11), 465 (0.19), 437 (19), 436 (65), 404 (6), 330 (11),
218 (4), 210 (16), 182 (11), 122 (9), 121 (100), 77 (15). HRMS Calcd for C25H26NO4S: (M+ - C2H5)
436.1582. Found: 436.1587.
4-Methoxybenzyl 4,6-diethyl-5-[(ethylsulfanyl)carbonyl]-2-phenylpyridine-3-carboxylate (8d)
A mixture of 4-methoxybenzyl 4,6-diethyl-5-[(ethylsulfanyl)carbonyl]-2-phenyl-1,4-dihydropyridi-
ne-3-carboxylate (7d) (12.60 g, 27.05 mmol) and tetrachloro-1,4-benzoquinone (7.32 g, 29.77 mmol) in
THF (500 mL) was refluxed overnight. Subsequently, the solvent was evaporated and the oily residue
was subjected to column chromatography (silica gel, light petroleum ether/EtOAc 8/2) to afford 8.50 g
1
(68 %) of 8d as colorless crystals. Mp 45 – 47 °C. H-NMR (200 MHz, CDCl3): δ (ppm) 7.61 (m, 2H),
7.39 (m, 3H), 6.93 (d, 2H, J = 8.58 Hz), 6.76 (d, 2H, J = 8.58 Hz), 5.00 (s, 2H), 3.75 (s, 3H), 3.12 (q, 2H,
13
J = 7.32 Hz), 2.88 (q, 2H, J = 7.56 Hz), 2.71 (q, 2H, J = 7.44 Hz), 1.29 (m, 9H); C-NMR (50 MHz,
CDCl3): δ (ppm) 195.1, 168.2, 159.6, 159.2, 156.7, 147.9, 139.6, 133.0, 130.3, 128.7, 128.3, 126.5, 126.2,
113.7, 67.3, 55.1, 29.0, 24.4, 24.0, 15.6, 14.4, 13.9. IR cm-1 (KBr): 3428, 2973, 2935, 1725, 1663, 1613,
1560, 1517, 1463, 1411, 1372, 1278, 1245, 1170, 1150, 1076, 1076, 1034, 982. MS: m/z (%) 464 (M+ + 1,
0.25), 463 (1), 403 (13), 402 (46), 236 (9), 122 (10), 121 (100), 91 (6), 78 (5), 77 (9). HRMS Calcd for
C27H29NO4S: 463.1817. Found: 463.1826.

HETEROCYCLES, Vol. 75, No. 2, 2008
353
4,6-Diethyl-5-[(ethylsulfanyl)carbonyl]-2-phenylpyridine-3-carboxylic acid (4)
4-Methoxybenzyl 4,6-diethyl-5-[(ethylsulfanyl)carbonyl]-2-phenylpyridine-3-carboxylate (8d) (2.70 g,
5.82 mmol) was dissolved in formic acid (25 mL) and stirred for 4 h at rt, followed by gentle removal of
HCO2H by Kugelrohr distillation at rt. The obtained solid was recrystallized from Et2O to give 1.70 g
(85 %) of 4 as colorless crystals. Mp 200 – 202 °C. 1H-NMR (300 MHz, DMSO-d6): δ (ppm) 13.20 (br s,
1H, CO2H), 7.65 (m, 2H, Ph H-2/H-6), 7.45 (m, 3H, Ph H-3/H-4/H-5), 3.12 (q, 2H, J = 7.30 Hz, SCH2),
2.76 (q, 2H, J = 7.50 Hz, C-6CH2), 2.66 (q, 2H, J = 7.50 Hz, C-4CH2), 1.32 (t, 3H, J = 7.50 Hz, SCH2Me),
1.24 (t, 3H, J = 7.50 Hz, C-6CH2Me), 1.17 (t, 3H, J = 7.50 Hz, C-4CH2Me); 13C-NMR (75 MHz,
3
2
DMSO-d6): δ (ppm) 194.8 (COS, JCO,SCH = 4.90 Hz), 169.2 (CO2), 157.6 (C-6, JC-6,CH = 5.20 Hz,
2
2
2
3
3JC-6,CH = 5.20 Hz), 155.0 (C-2), 146.2 (C-4, JC-4,CH = 4.90 Hz, JC-4,Me = 4.90 Hz), 139.1 (Ph C-1),
3
2
132.6 (C-5), 132.6 (Ph C-4), 128.3 (Ph C-3/C-5), 128.2 (Ph C-2/Ph C-6), 127.9 (C-3), 28.2 (C-6CH2,
2
1
2
1JCH = 127.70 Hz, J CH
,
= 4.40 Hz), 24.2 (SCH2, JCH = 142.70 Hz, J CH ,
2
= 4.60 Hz), 23.6
Me
Me
2
2
2
1
2
1
2
(C-4CH2, JCH = 129.40 Hz, J CH
,
= 4.30 Hz), 15.5 (C-4CH2Me, JMe = 128.30 Hz, J Me,CH = 5.40
Me
2
2
2
Hz), 14.4 (SCH2Me, 1JMe = 128.30 Hz, 2J Me CH = 3.50 Hz), 13.7 (C-6CH2Me, 1JMe = 127.80 Hz, 2J Me,CH
,
2
2
= 5.10 Hz). IR cm-1 (KBr): 3443, 2977, 2491, 1925, 1711, 1661, 1555, 1453, 1413, 1376, 1260, 1184,
1149, 1078. MS: m/z (%) 344 (M+ + 1, 0.15), 343 (0.18), 327 (1), 326 (4), 283 (18), 282 (100), 236 (5),
180 (5), 126 (7), 91 (7), 77 (11). Anal. Calcd for C19H21NO3S: C, 66.45; H, 6.16; N, 4.08. Found: C,
66.18; H, 6.21; N, 3.96.
5-(2-Hydroxyethyl) 3-(4-methoxybenzyl) 2,4-diethyl-6-phenyl-1,4-dihydropyridine-3,5-dicarboxyla-
te (7c)
2-Hydroxyethyl 3-amino-3-phenylprop-2-enoate (5c)6 (2.65 g, 12.78 mmol), 4-methoxybenzyl-3-oxopen-
tanoate (6a) (3.02 g, 12.78 mmol) and propionaldehyde (0.74 g, 12.78 mmol) were dissolved in abs.
EtOH and heated in a sealed Pyrex tube at 80 °C for 24 h. After removal of the solvent, the crude product
was subjected to column chromatography (silica gel, light petroleum ether/EtOAc 1/1) to yield 2.75 g
1
(45 %) of 7c as yellow-greenish oil. H-NMR (200 MHz, CDCl3): δ (ppm) 7.43 (m, 3H), 7.32 (m, 4H),
6.88 (d, J = 8.70 Hz, 2H), 5.93 (s, 1H), 5.12 (q, J = 12.12 Hz, 2H), 4.05 (t, J = 5.56 Hz, 1H), 3.90 (m, 2H),
3.80 (s, 3H), 3.34 (m, 2H), 2.71 (m, 2H), 1.51 (m, 3H), 1.16 (t, J = 7.44 Hz, 3H), 0.87 (t, J = 7.44 Hz,
3H); 13C-NMR (50 MHz, CDCl3): δ (ppm) 167.2, 167.2, 159.3, 150.7, 147.1, 137.7, 128.8, 102.6, 101.5,
65.6, 65.4, 61.0, 55.2, 34.4, 29.0, 25.8, 13.0, 9.1. IR cm-1 (KBr): 3301, 2962, 2925, 2874, 1720, 1686,
1612, 1560, 1515, 1461. MS: m/z (%) 464 (M+ - 1, 1), 438 (1), 437 (3), 436 (10), 343 (2), 342 (5), 254 (4),
208 (4), 121 (100), 83 (17), 71 (24), 69 (24), 57 (42), 55 (28), 43 (35), 41 (19). HRMS Calcd for
C27H31NO6Na: (M+ + Na) 488.2049. Found: 488.2033

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5-(2-Hydroxyethyl) 3-(4-methoxybenzyl) 2,4-diethyl-6-phenylpyridine-3,5-dicarboxylate (8c)
A mixture of 5-(2-hydroxyethyl) 3-(4-methoxybenzyl) 2,4-diethyl-6-phenyl-1,4-dihydropyridine-3,5-di-
carboxylate (7c) (2.50 g, 5.37 mmol) and tetrachloro-1,4-benzoquinone (1.32 g, 5.37 mmol) THF (100
mL) was refluxed for 24 h. Then, THF was evaporated and the residue was purified by column
chromatography (silica gel, light petroleum ether/EtOAc 1/1) to give 1.70 g (73 %) of 8c as colorless
crystals. Mp 215 – 216 °C. 1H-NMR (200 MHz, CDCl3): δ (ppm) 7.56 (m, 2H), 7.41 (m, 5H), 6.91 (d, J =
8.58 Hz, 2H), 5.35 (s, 2H), 4.08 (t, J = 4.42 Hz, 2H), 3.81 (s, 3H), 3.43 (t, J = 4.66 Hz, 2H), 2.77 (q, J =
7.58 Hz, 2H), 2.63 (q, J = 7.58 Hz, 2H), 1.19 (m, 6H); 13C-NMR (50 MHz, CDCl3): δ (ppm) 168.8, 168.1,
160.9, 160.4, 157.3, 149.4, 140.4, 131.3, 129.5, 129.0, 128.7, 128.0, 127.5, 126.5, 114.4, 67.9, 67.4, 60.7,
55.7, 30.1, 25.1, 15.7, 14.3. IR cm-1 (KBr): 3294, 3014, 2974, 2937, 2901, 2877, 2840, 1905, 1730, 1721,
1610, 1558, 1515, 1450. MS: m/z (%) 463 (M+,3), 342 (6), 122 (9), 121 (100), 77 (8). HRMS Calcd for
C27H29NO6: 463.1995. Found: 463.2004.
5-(2-Fluoroethyl) 3-(4-methoxybenzyl) 2,4-diethyl-6-phenylpyridine-3,5-dicarboxylate (16)
5-(2-Hydroxyethyl) 3-(4-methoxybenzyl) 2,4-diethyl-6-phenylpyridine-3,5-dicarboxylate (8c) (1.60 g,
3.45 mmol) was dissolved in 90 mL of absolute CH2Cl2 under argon atmosphere and cooled to -78 °C.
Subsequently, DAST (1.10 g, 0.9 ml, 6.83 mmol) was added dropwise. The resulting solution was stirred
for 0.5 h at -78 °C, then warmed to rt and stirred until completion of the reaction, which was determined
by TLC (silica gel, light petroleum ether/EtOAc 8/2). Afterwards, 1 mL of water was added at 0 °C and
the reaction mixture was allowed to warm up to rt. The organic layer was separated and the aqueous layer
was extracted with Et2O. The combined organic phases were dried over MgSO4 and concentrated under
reduced pressure. Purification was achieved by column chromatography (silica gel, light petroleum
ether/EtOAc 8/2) to give 0.76 g (47 %) of 19 as orange oil. 1H-NMR (200 MHz, CDCl3): δ (ppm) 7.58 (m,
2H), 7.41 (m, 5H), 6.92 (d, J = 8.58 Hz, 2H), 5.36 (s, 2H), 4.36 (m, 2H), 4.17 (s, 3H), 3.82 (s, 3H), 2.79
(q, J = 7.46 Hz, 2H), 2.63 (q, J = 7.58 Hz, 2H), 1.21 (m, 6H); 13C-NMR (50 MHz, CDCl3): δ (ppm) 168.1,
160.5, 160.0, 156.8, 148.8, 139.5, 130.8, 128.9, 128.3, 128.2, 127.4, 127.0, 125.9, 114.0, 80.5 (d, J =
170.52 Hz), 67.4, 64.0 (d, J = 20.36 Hz), 55.2, 29.6, 24.7, 15.1, 13.8. IR cm-1 (KBr): 2964, 2937, 2851,
2360, 2341, 1729, 1613, 1561, 1516, 1464, 1456. MS: m/z (%) 465 (M+,5), 344 (12), 122 (10), 121 (100),
77 (6). HRMS Calcd for C27H28NO5F: 465.1952. Found: 465.1946.
2,4-Diethyl-5-[(2-fluoroethoxy)carbonyl]-6-phenylpyridine-3-carbothioic acid (3)
5-(2-Fluoroethyl) 3-(4-methoxybenzyl) 2,4-diethyl-6-phenylpyridine-3,5-dicarboxylate (16) (0.60 g, 1.30
mmol) was dissolved in formic acid (15 mL) and the solution was stirred at rt until completion of the
reaction (TLC silica gel light petroleum ether/EtOAc 2/8). The reaction solution was evaporated to

HETEROCYCLES, Vol. 75, No. 2, 2008
355
dryness using bulb-to-bulb distillation and purified through column chromatography (silica gel, light
petroleum ether/EtOAc 2/8) to furnish 0.37 g (82 %) of the carboxylic acid as colorless crystals Mp 47 –
50 °C. 1H-NMR (200 MHz, CDCl3): δ (ppm) 9.87 (s, 1H), 7.55 (m, 2H), 7.40 (m, 3H), 4.34 (m, 2H), 4.15
(s, 2H), 2.88 (d, J = 6.94, 2H), 2.68 (d, J = 6.82, 2H), 1.23 (m, 6H); 13C-NMR (50 MHz, CDCl3): δ (ppm)
172.2, 167.8, 159.4, 155.9, 140.0, 138.8, 129.1, 128.3, 126.7, 80.5 (d, J = 170.15 Hz), 64.1 (d, J = 20.36
Hz), 29.0, 24.9, 15.2, 14.1. IR cm-1 (KBr): 3441, 2978, 2941, 2879, 2506, 1956, 1732, 1559, 1448, 1382.
MS: m/z (%) 345 (M+, 75), 298 (100), 282 (36), 280 (28), 254 (65), 210 (19), 77 (20), 47 (24). HRMS
Calcd for C19H20NO4F: 345.1376. Found: 345.1372.
2,4-Diethyl-5-[(2-fluoroethoxy)carbonyl]-6-phenylpyridine-3-carboxylic acid (0.18 g, 0.52 mmol) from
the previous reaction was dissolved in 15 mL of absolute benzene under argon atmosphere and cooled to
-10 °C. Thereafter, oxalyl chloride (1.33 g, 0.9 ml, 10.48 mmol) and one drop of DMF were added. This
solution was allowed to warm to rt and was stirred for further 2 h until the reaction was completed (TLC
silica gel, light petroleum ether/EtOAc 2/8). The solvent was removed in vacuo and the oily residue
repeatedly coevaporated with toluene. The crude product was used without further purification for the
next reaction step.
To a solution of NaSH hydrate (0.08 g, 1.43 mmol) in absolute EtOH (10 mL) the crude product, obtained
by the previous reaction, dissolved in THF (5 mL) was added dropwise. The resulting solution was stirred
for 20 min. at -10 °C and further at rt until completion of the reaction (TLC, RP-18 silica gel,
MeCN/water 9/1). Subsequently, the solution was acidified with 6N HCl and extracted with EtOAc. The
organic extracts were washed with brine, dried over MgSO4 and evaporated to dryness. The solid residue
was purified by reversed phase column chromatography (RP-18 silica gel, MeCN/water 9/1) to afford
1
0.15 g (83 %) of 3 as colorless crystals. Mp 45 – 47 °C. H-NMR (300 MHz, CDCl3): δ (ppm) 7.64 (m,
2H, Ph H-2, H-6), 7.46 (m, 3H, Ph H-3, H-4, H-5), 4.39/4.29 (m, 2H, FCH2), 4.34/4.29 (m, 2H, CH2O),
3.05 (q, 2H, J = 7.50 Hz, C-2CH2), 2.93 (q, 2H, J = 7.50 Hz, C-4CH2) 1.40 (t, 3H, J = 7.50 Hz,
C-2CH2Me), 1.29 (t, 3H, J = 7.50 Hz, C-4CH2Me); 13C-NMR (75 MHz, CDCl3): δ (ppm) 189.3 (COSH),
167.9 (CO2), 160.4 (C-2), 158.3 (C-6), 149.5 (C-4), 139.3 (Ph C-1), 130.6 (C-3), 129.3 (Ph C-4), 128.5
(Ph C-3, C-5), 128.3 (Ph C-2, C-6), 126.2 (C-5), 80.5 (d, FCH2, J = 172.0 Hz), 64.5 (d, CH2O J = 20.2
Hz), 29.5 (C-2CH2), 24.4 (C-4CH2), 15.9 (C-4CH2Me), 14.3 (C-2CH2Me). IR cm-1 (KBr): 3439, 2975,
2938, 2877, 1731, 1556, 1495, 1448, 1403, 1377, 1278, 1250, 1166, 1144, 1077, 1060, 1033, 960. MS:
m/z (%) 362 (M+ + 1, 1), 361 (3), 359 (31), 329 (21), 328 (100), 312 (14), 254 (15), 236 (12), 77 (20), 47
(48). Anal. Calcd for C19H20FNO3S•0.2 H2O: C, 62.52; H, 5.63; N, 3.84. Found: C, 62.45; H, 5.44; N,
3.73.

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ACKNOWLEDGMENT
This research was funded by the Austrian Science Fund (FWF P19383-B09) awarded to M. Mitterhauser.
The authors thank Eva Schirmer and Sabine Leber for inputs and proof-reading.
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