Electron-rich amino heterocycles for regiospecific synthesis of trifluoromethyl-containing fused pyridines

Article abstract of DOI:10.1055/s-2003-40520

The reaction of 4,4,4-trifluoro-3-oxobutanoates with the corresponding electron-rich amino heterocycles was investigated. A simple and flexible general procedure for the regiospecific annulation of the trifluoromethylpyridine ring to electron-rich amino heterocycles was proposed. A set of CF₃-containing fused pyridines in almost quantitative yield was obtained.

Full text of DOI:10.1055/s-2003-40520

PAPER
1531
Electron-Rich Amino Heterocycles for Regiospecific Synthesis of Trifluoro-
methyl-Containing Fused Pyridines
E
lectron-Rich
A
m
m
ino Heterocycles fo
i
r
S
ynth
t
esis of
r
Trifluoro
i
methy
y
l-Containing Fused
M
Pyridines . Volochnyuk,* Alexei O. Pushechnikov, Dmitriy G. Krotko, Dmitriy A. Sibgatulin, Svetlana A.
Kovalyova, Andrei A. Tolmachev
Research and Development Center for Chemistry and Biology, National Taras Shevchenko University, 62 Volodymyrska st., Kyiv-33,
01033, Ukraine
Fax +380(44)2696794.; E-mail: dov@fosfor.kiev.ua
Received 17 April 2003
Earlier, the regioselective interaction of 5-aminopyra-
Abstract: The reaction of 4,4,4-trifluoro-3-oxobutanoates with the
zoles 1 with 4,4,4-trifluoro-3-oxobutirates 2f forming 4-
corresponding electron-rich amino heterocycles was investigated.
A simple and flexible general procedure for the regiospecific annu-
lation of the trifluoromethylpyridine ring to electron-rich amino
CF3 pyrazolo[3,4-b]pyridones 6 (Scheme 1) has been de-
scribed.9
heterocycles was proposed. A set of CF3-containing fused pyridines
in almost quantitative yield was obtained.
Key words: electrophilic aromatic substitutions, annulations, het-
erocycles, pyridines, fluorine
Since it is known that the furnishing of bioactive molecule
with perfluoroalkyl substituents leads to an increase of
lipid solubility, and thereby enhances the absorption rate
and the transportation in vivo,1 heterocyclic compounds
bearing a trifluoromethyl group are a subject of continu-
ous interest due to their potent pharmacological proper-
ties.1,2 The most widespread method to produce
heterocycles with a trifluoromethyl group is assembly
from trifluoromethyl-containing building blocks. Recent-
Scheme 1
ly the most popular trifluoromethyl-containing building
However, the regiospecific trifluoromethylpyridine ring
blocks have been the following 1,3-electrophilic reagents:
4-triflouromethyl-1,3-diones,3 -alkoxyvinyl trifluoro-
methyl ketones,4 and -trifluoromethylsulfones.5 The
character of these approaches is the formation of mixtures
of regioisomers in a reaction with non-symmetrical binu-
cleophiles. Hence, the aim of current work within this
field is the search for experimental conditions and re-
agents to increase the regioselectivity of the cycloconden-
sation.
annulation to an amino heterocycle has been considered as
a feature only of aminopyrazoles. Nevertheless, it was es-
tablished that beside 5-aminopyrazole, other electron-rich
amino heterocyles, namely 5-aminoisooxazole 8, 6-ami-
nouraciles 9, 5-amino-2-carboethoxyfuran 10 and 5-ami-
no-2-carbomethoxythiophene 11, undergo regioselective
reaction with 4,4,4-trifluoro-3-oxobutanoates affording
CF3-containing fused pyridines and pyridones 12–18 in
high yield (Schemes 1, 2) (Tables 1, 2).
The objective of recent work has been the continuation of
our research into an electrophilic substitution of electron-
rich amino heterocycles and their derivatives.6,7 Here we
focused on the reaction of 4,4,4-trifluoro-1-(het)aryl-1,3-
butanediones with a set of electron-rich amino heterocy-
cles. The procedure allows the obtainment of various
fused pyridines, such as isooxazolo-, furo-, pyrazolo-,
thienopyridines, and pyrido[2,3-d]pyrimidines, which
have been of great interest in recent years because of the
wide variety of their biological and pharmacological
properties.2c,8
The structure elucidation of -CF3 fused pyridines was
1
based on data from H, 13C and 19F NMR spectroscopy.
The most convincing evidence of the formation of the -
CF3 isomer is the chemical shift of a CF3-group ( 19F –60)
and a chemical shift of C(4) ( 13C 130) with a coupling
2
constant JCF ca. 35 Hz, otherwise we would expect a
chemical shift of the -CF3-group at ( 19F –67) and a
chemical shift of C(2) at ( 13C 145) (Tables 4, 5).10,4a In
addition, the distant spin–spin interaction between fluo-
rine atoms of a CF3-group and hydrogen atoms of a C(5)–
CH3-group with a coupling constant 6JHF ca. 1 Hz is an in-
teresting spectral feature of pyridines 4 and 12 (Table 1).11
Synthesis 2003, No. 10, Print: 21 07 2003.
Art Id.1437-210X,E;2003,0,10,1531,1540,ftx,en;P03203SS.pdf.
© Georg Thieme Verlag Stuttgart · New York

1532
D. M. Volochnyuk et al.
PAPER
Scheme 3
out. As a result, similarly to izatins,9 the corresponding
tertiary alcohols 20 were obtained (Scheme 3).
We were interested to apply the described procedure to
anilines for the assembly of -CF3 quinolines, known to
be androgen receptor modulators,13 in a similar way. It
was found that only electron-rich anilines such as 21, 22
and 2314 could react in the same way as amino heterocy-
cles, giving -CF3 quinolines 24, 25 and 26. The reaction
of cyclocondensation with less C-nucleophilic anilines,
such as 3,4,5-trimethoxyaniline or 2,3-dihydro-1,4-ben-
zodioxin-6-amine, does not occur under analogous condi-
tions (Scheme 4) (Table 3).
Scheme 2
The synthesis of fused pyridines via cyclocondensation of
amino heterocycles with 1,3-dicarbonyl compounds is a
well-known process. However, it needs sufficiently harsh
reaction conditions. Under these conditions for non-sym-
metrical -diketones, regioselectivity has not been ob-
served.12 Nevertheless, the reaction of 4,4,4-trifluoro-3-
oxobutanoates with electron-rich amino heterocycles pro-
ceeded regiospecifically under mild conditions, refluxing
in acetic acid. The selectivity of the reaction with these
amino heterocycles can be rationalized by the strong alter-
nation of double bonds in the heterocycle ring and so the
amino group–double bond of the ring is almost fully
enamine-like. Therefore the initial attack of the active
CF3-carbonyl group occurs at the C-nucleophilic carbon
atom of the heterocycle nucleus. In the case of 5-aminopy-
razoles, the intermediates 3 or 4 were formed, which were
detected by 19F NMR spectroscopy. The intermediates 4
have been successfully isolated only when 4,4,4-trifluoro-
3-oxobutirates 2f were used,9 whereas the intermediates 3
from other diones transform spontaneously into the dihy-
drate of pyrazolopyridine 7 or into the final products 5
(Scheme 1). However, to prove our hypothesis, the reac-
tion of 5-aminopyrazole with the monoelectrophilic ana-
logue of 2 – 1,1,1-triflouroacetone (19) – has been carried
Scheme 4
In order to study pyridones as entry compounds for subse-
quent functionalizations, we attempted to transform pyri-
dones 6, 13, 16 and 18 into corresponding
chloropyridines. However, it was found that the treatment
of 4-trifluoromethyl-1H-pyrazolo[3,4-b]pyridin-6-one
(6a) and 4-trifluoromethyl-6,7-dihydrothieno[2,3-b]pyri-
din-6-one (18) with POCl3 did not allow the obtainment of
chloro derivatives.15 In our case, corresponding dichloro-
-
Scheme 5
Synthesis 2003, No. 10, 1531–1540 © Thieme Stuttgart · New York

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Electron-Rich Amino Heterocycles for Synthesis of Trifluoromethyl-Containing Fused Pyridines
1533
Scheme 6
phosphates of 4-trifluoromethyl-1H-pyrazolo[3,4-b]pyri- 33, respectively. Tosylates 29 and 33 underwent nucleo-
din-6-oxyl 27 and 4-(trifluoromethyl)thieno[2,3- philic displacement under mild conditions with aliphatic
b]pyridin-6-oxyl 31, respectively, (Schemes 5, 6) were amines17 yielding amino derivatives 30 and 34, respec-
isolated in very high yield. These dichlorophosphates tively (Schemes 5, 6), the structural analogues of seroto-
were easily transformed into derivative phosphates 28 and nin re-uptake inhibitors.8a
32. It was expected these phosphates could easily undergo
nucleophilic displacement, as a residue of phosphorus
In summary, we propose a useful and convenient proce-
dure for the synthesis of CF3-containing fused pyridines in
acid is a good leaving group. Alas it was not achieved. The
high yield with a vast variety of combinatorial modifica-
target products were prepared in a low yield by boiling
tions of fragments in the final structures.
dichlorophosphates 27 and 31 in secondary amine, e.g.
morpholine.16 Further we found that pyridones 6 and 18
could be selectively O-tosylated giving tosylates 29 and
Table 1 Yields, Melting Points and 1H NMR Data of Compounds 3, 4, 6, 11, 13, 14, 18 and 19f
N
R
R
Yield (%)a Mp, (ºC)b 1H NMR, δ (ppm), J (Hz)
5ac Ph
5bc Ph
5cd Ph
Ph
85
92
94
144
2.73 (3 H, s, CH3), 7.34 (1 H, t, 3JHH = 7.5, CH), 7.50–7.58 (5 H, m, CH), 7.91 (1 H, s, CH),
8.16 (2 H, d, 3JHH = 6.6, CH), 8.32 (2 H, d, 3JHH = 7.8, CH)
151–152 2.69 (3 H, q, 6JHF = 1.2, CH3), 7.14 (1 H, dd, 3JHH = 4.8, 3JHH = 3.9, CH), 7.31 (1 H, t,
3JHH = 7.5, CH), 7.47–7.56 (3 H, m, CH), 7.75 (2 H, s, CH), 8.32 (2 H, d, 3JHH = 7.8, CH)
142–143 2.60 (3 H, s, CH3), 7.37 (1 H, m, CH), 7.58 (3 H, br s, CH), 8.21 (3 H, br s, CH), 8.58 (1 H,
d, 3JHH = 4.8, CH), 8.71 (1 H, s, CH), 9.40 (1 H, s, CH)
5dc Ph
5ec Ph
5fc Me
CF3
Me
91
88
74
74–75
58–59
2.77 (3 H, s, CH3), 7.36 (1 H, t, 3JHH = 8.1, CH), 7.54 (2 H, t, 3JHH = 8.1, CH), 7.80 (1 H, s,
CH), 8.23 (2 H, d, 3JHH = 8.1, CH)
2.69 (3 H, q, 6JHF = 1.2, CH3), 2.76 (3 H, s, CH3), 7.27–7.31 (2 H, m, CH), 7.51 (1 H, t,
3JHH = 8.1, CH), 8.22 (2 H, d, 3JHH = 8.1, CH)
119–120 2.61 (3 H, q, 6JHF = 1.0, CH3), 4.13 (3 H, s, NCH3), 7.16 (1 H, t, 3JHH = 4.8, CH), 7.49 (1 H,
d, 3JHH = 4.8, CH), 7.68 (1 H, s, CH), 7.75 (1 H, d, 3JHH = 3.9, CH)
5gc Me
6d Ph
CF3
OH
77
86
Oil
2.68 (3 H, q, 6JHF = 1.1, CH3), 4.19 (3 H, s, NCH3), 7.70 (1 H, s, CH)
179–181 2.50 (3 H, s, CH3), 6.95 (1 H, s, CH), 7.34 (1 H, t, 3JHH = 7.6, CH), 7.53 (2 H, t, 3JHH = 7.6,
CH), 8.10 (2 H, d, 3JHH = 7.6, CH), 12.26 (1 H, br s, NH)
7e Ph
CF3
Ph
36
214
2.26 (3 H, q, 6JHF = 2.4, CH3), 2.40 (1 H, d, 2JHH = 14.1, CH2), 2.56 (1 H, d, 2JHH = 14.1,
CH2), 5.78 (1 H, br s, NH2), 6.13 (1 H, br s, OH), 6.52 (1 H, br s, OH), 7.36 (1 H, t,
3JHH = 7.5, CH), 7.47–7.57 (4 H, m, CH)
12ad
–
–
–
78
86
93
117–119 2.60 (3H, q, 6JHF = 0.9, CH3), 7.58–7.60 (3 H, m, CH), 8.29–8.32 (2 H, m, CH), 8.38 (1 H,
s, CH)
12bd
12cc
143
2.56 (3 H, q, 6JHF = 1.2, CH3), 7.28 (1 H, dd, 3JHH = 5.1, 3JHH = 3.9, CH), 7.91 (1 H, dd,
3JHH = 5.1, 3JHH = 0.6, CH), 8.31 (1 H, dd, 3JHH = 3.9, 3JHH = 0.6, CH), 8.36 (1 H, s, CH)
CF3
43–44
2.73 (3H, q, 6JHF = 1.2, CH3), 7.96 (1 H, s, CH)
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D. M. Volochnyuk et al.
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Table 1 Yields, Melting Points and 1H NMR Data of Compounds 3, 4, 6, 11, 13, 14, 18 and 19f (continued)
N
R
–
R
Yield (%)a Mp, (ºC)b 1H NMR, δ (ppm), J (Hz)
13d
15ad
OH
Ph
88
56
148–150g 2.46 (3 H, q, 6JHF = 0.9, CH3), 7.05 (1 H, s, CH)
–
237–238 1.39 (3 H, t, 3JHH = 7.2, CH3), 4.42 (2 H, q, 3JHH = 7.2, CH2), 7.55– 7.58 (3 H, m, CH), 7.75
(1H, q, 5JHF = 1.2, CH), 8.23–8.26 (2 H, m, CH), 8.37 (1 H, s, CH)
15bd
16d
-
-
74
172–173 1.42 (3 H, t, 3JHH = 7.2, CH3), 4.45 (2 H, q, 3JHH = 7.2, CH2), 7.26 (1 H, dd, 3JHH = 5.0,
3JHH = 3.8, CH), 7.76 (1 H, s, CH), 7.85 (1 H, d, 3JHH = 5.0, CH), 8.20 (1 H, d, 3JHH = 3.8,
CH), 8.38 (1 H, s, CH)
OH
Ph
81
73
78
63
158-160g 1.35 (3 H, t, 3JHH = 7.2, CH3), 4.36 (2 H, q, 3JHH = 7.2, OCH2), 7.11 (1 H, s, CH), 7.64 (1 H,
q, 5JHF = 1.2, CH)
17ad Me
17bd Me
17cc Et
155–156 3.95 (3 H, s, OCH3), 7.57 (3 H, m, CH), 8.01 (1 H, s, CH), 8.27 (2 H, m, CH), 8.40 (1 H, s,
CH)
159-160
72–73
210g
3.94 (3 H, s, OCH3), 7.26 (1 H, dd, 3JHH = 4.8, 3JHH = 3.9, CH), 7.85 (1 H, d, 3JHH = 4.8, CH),
7.98 (1 H, s, CH), 8.21 (1 H, d, 3JHH = 3.9, CH), 8.40 (1 H, s, CH)
CF3
1.47 (3 H, t, 3JHH = 7.2, CH3), 4.50 (2 H, q, 3JHH = 7.2, CH2), 7.96 (1 H, s, CH), 8.24 (1 H,
s, CH)
18d Me
20ad Ph
OH
–
84
98
3.88 (3 H, s, OCH3), 7.03 (1 H, s, CH), 7.80 (1 H, q, 5JHF ca. 1, CH)
173–175g 1.70 (3 H, s, CH3), 2.14 (3 H, s, CH3), 5.07 (2 H, br s, NH2), 6.57 (1 H, s, OH), 7.25 (1 H, t,
3JHH = 7.5, CH), 7.40–7.61 (4 H, m, CH)
20bc Me
–
99
43
84–86
107
1.76 (3 H, s, CH3), 2.19 (3 H, s, CH3), 3.55 (3 H, s, NCH3), 4.15 (3 H, br s, NH2 and OH)
24d
–
Ph
3.12 [6 H, s, N(CH3)2], 7.19 (1 H, d, 4JHH = 2.6, CH), 7.45 (1 H, dd, 3JHH = 9.6, 4JHH = 2.6,
CH), 7.53–7.57 (3 H, m, CH), 7.89 (1H, dq, 3JHH = 9.6, 5JHF = 1.2, CH), 8.01 (1 H, s, CH),
8.28 (2 H, m, CH)
25ac
–
63
114–115 1.17 (3 H, s, CH3), 1.22 (3 H, d, 3JHH = 6.6, CH3), 1.39 (3 H, s, CH3), 2.88 (3 H, s, NCH3),
3.25 (1 H, q, 3JHH = 6.6, CH), 6.92 (1 H, s, CH), 7.15 (1 H, dd, 3JHH = 5.1, 3JHH = 3.3, CH),
7.45 (1 H, d, 3JHH = 5.1, CH), 7.53 (1 H, q, 5JHF = 1.2, CH), 7.69 (1 H, d, 3JHH = 3.3, CH),
7.72 (1 H, s, CH)
25bc
26c
–
–
CF3
60
31
46–49
1.20 (3 H, s, CH3), 1.24 (3 H, d, 3JHH = 6.6, CH3), 1.41 (3 H, s, CH3), 2.90 (3 H, s, NCH3),
3.34 (3 H, q, 3JHH = 6.6, CH), 6.98 (1 H, s, CH), 7.62 (2 H, m, CH)
132
3.96 (3 H, s, OCH3), 3.97 (3 H, s, OCH3), 6.61 (1 H, d, 4JHH = 2.4, CH), 7.13 (1 H, d,
4JHH = 2.4, CH), 7.17 (1 H, dd, 3JHH = 5.1, 3JHH = 3.9, CH), 7.49 (1 H, dd, 3JHH = 5.1,
4JHH = 1.9, CH), 7.75 (1 H, dd, 3JHH = 3.9, 4JHH = 1.9, CH), 7.96 (1 H, s, CH)
a Yields refer to pure isolated products.
b Melting points are uncorrected.
c CDCl3.
d DMSO-d6.
e Acetone-d6.
f Satisfactory microanalysis data were obtained: C 0.33; H 0.45; N 0.25.
g Sublimation.
Table 2 Yields, Melting Points and 1H NMR Datac of Compounds 14d
N
R
R
H
R
Yield Mp
1H NMR, (ppm), J (Hz)
(%)a (°C)b
14a Bn
Ph
92
239
5.52 (2 H, s, NCH2), 7.21 (1 H, t, 3JHH = 7.5, CH), 7.28 (2 H, t, 3JHH = 7.5, CH), 7.40 (2 H,
d, 3JHH = 7.5, CH), 7.49–7.54 (3 H, m, CH), 8.04 (1 H, s, CH), 8.11 (2 H, d, 3JHH = 6.3, CH),
11.98 (1 H, s, NH)
14b Bn
14c Bn
H
H
91
95
253
5.42 (2 H, s, NCH2), 7.17–7.31 (4 H, m, CH), 7.46 (2 H, d, 3JHH = 7.5, CH), 7.82 (1 H, d,
3JHH = 4.8, CH), 8.02 (1 H, s, CH), 8.17 (1 H, d, 3JHH = 3.6, CH), 11.91 (1 H, s, NH)
CF3
156–158 5.37 (2 H, s, NCH2), 7.20–7.29 (3 H, m, CH), 7.42 (2 H, d, 3JHH = 7.5, CH), 7.84 (1 H, s,
CH), 12.19 (1 H, br s, NH)
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Electron-Rich Amino Heterocycles for Synthesis of Trifluoromethyl-Containing Fused Pyridines
1535
Table 2 Yields, Melting Points and 1H NMR Datac of Compounds 14d (continued)
N
R
R
R
Yield Mp
1H NMR, (ppm), J (Hz)
(%)a (°C)b
14d Bn
14e Me
H
Me
73
200–202 2.63 (3 H, s, CH3), 5.34 (2 H, NCH2), 7.25–7.28 (3 H, m, CH), 7.37 (2 H, d, 3JHH = 6.6, CH),
7.52 (1 H, s, CH), 11.88 (1 H, s, NH)
Me
90
180–183 3.30 (3 H, s, NCH3), 3.62 (3 H, s, NCH3), 7.26 (1 H, dd, 3JHH = 5.4, 3JHH = 3.3, CH), 7.89 (1
H, d, 3JHH = 5.4, CH), 8.01 (1 H, s, CH), 8.19 (1 H, d, 3JHH = 3.3, CH)
a Yields refer to pure isolated products.
b Melting points are uncorrected.
c DMSO-d6.
d Satisfactory microanalysis data were obtained: C 0.28; H 0.45; N 0.18.
Table 3 Yields, Melting Points and 1H NMR Data of Compounds 27–30 and 32–34g
N
NRR
–
Yield Mp (°C)b
(%)a
1H NMR, (ppm), J (Hz)
27e
87
110
2.43 (3 H, q, 6JHF = 1.5, CH3), 6.73 (1 H, s, CH), 7.02 (1 H, t, 3JHH = 8.1, CH), 7.29 (2 H, t,
3JHH = 8.1, CH), 8.38 (2 H, d, 3JHH = 8.1, CH)
28f
29d
–
–
86
84
68–70
2.65 (3 H, q, 6JHF = 1.5, CH3), 7.27–7.46 (14 H, m, CH), 8.11 (2 H, d, 3JHH = 7.2, CH)
151–153
2.44 (3 H, s, CH3), 2.61 (3 H, s, CH3), 7.35–7.51 (6 H, m, CH), 7.77 (2 H, d, 3JHH = 7.8, CH),
7.89 (2 H, d, 3JHH = 8.1, CH)
30ac
30bc
68
72
126
1.71 (6 H, m, CH2), 2.58 (3 H, q, 6JHF = 1.2, CH3), 3.72 (4 H, m, NCH2), 6.87 (1 H, s, CH),
7.25 (1 H, t, 3JHH = 7.5, CH), 7.48 (2 H, t, 3JHH = 7.5, CH), 8.19 (2 H, d, 3JHH = 7.5, CH)
137–139
2.61 (3 H, s, CH3), 3.70 (4 H, t, 3JHH = 5.1, NCH2), 3.86 (4 H, t, 3JHH = 5.1, OCH2), 6.86 (1
H, s, CH), 7.26 (1 H, t, 3JHH = 7.5, CH), 7.49 (2 H, t, 3JHH = 7.5, CH), 8.16 (2 H, d, 3JHH = 7.5,
CH)
30cc
30dc
53
62
87
2.37 (3 H, s, NCH3), 2.53–2.60 (7 H, m, NCH2 and CH3), 3.76 (4 H, t, 3JHH = 4.5, NCH2),
6.85 (1 H, s, CH), 7.27 (1 H, t, 3JHH = 7.5, CH), 7.47 (2 H, t, 3JHH = 7.5, CH), 8.18 (2 H, d,
3JHH = 7.5, CH)
112
1.27 (3 H, t, 3JHH = 6.6, CH3), 1.83 (2 H, m, CH2), 2.04 (2 H, m, CH2), 2.59 (4 H, br s, CH3
and CH), 3.19 (2 H, t, JHH = 12.3, NCH2), 4.16 (2 H, q, 3JHH = 6.6, OCH2), 4.37 (2 H, d,
2JHH = 12.3, NCH2), 6.87 (1 H, s, CH), 7.26 (1 H, t, 3JHH = 7.5, CH), 7.48 (2 H, t, 3JHH = 7.5,
CH), 8.18 (2 H, d, 3JHH = 7.5, CH)
30ec
30fd
63
43
109
1.21–1.39 (2 H, m, CH2), 1.60–1.59 (5 H, m, CH2, CH and PhCH2), 2.58 (3 H, s, CH3), 2.95
(2 H, t, JHH = 13.5, NCH2), 4.46 (2 H, d, 2JHH = 13.5, NCH2), 6.86 (1 H, s, CH), 7.15–7.36 (6
H, m, CH), 7.46 (2 H, t, 3JHH = 7.5, CH), 8.18 (2 H, d, 3JHH = 7.5, CH)
174–176
2.46 (3 H, s, CH3), 3.50 (2 H, br m, NCH2), 3.63 (2 H, br m, OCH2), 4.67 (1 H, br s, OH),
6.89 (1 H, s, CH), 7.24 (1 H, t, 3JHH = 7.2, CH), 7.46 (2 H, t, 3JHH = 7.2, CH), 7.70 (1 H, br s,
NH), 8.23 (2 H, d, 3JHH = 7.2, CH)
32e
–
–
59
73
72
52
64
107–108
98–99
3.35 (3 H, s, OCH3), 3.56 [6 H, d, 3JHP = 12.0, P(OCH3)2], 6.87 ( 1 H, s, CH), 8.01 (1 H, q,
5JHF = 1.5, CH)
33d
2.47 (3 H, s, CH3), 3.95 (3 H, s, OCH3), 7.50 (2 H, d, 3JHH = 7.8), 7.68 (1 H, s, CH), 7.94 (2
H, d, 3JHH = 7.8, CH), 8.04 (1 H, s, CH)
34ac
34b
34c
115–116
156–157
120–121
1.76 (6 H, m, CH2), 3.73 (4 H, m, NCH2), 3.93 (3 H, s, OCH3), 6.97 (1 H, s, CH), 7.93 (1 H,
q, 5JHF ca. 1, CH)
1.30 (6 H, d, 3JHH = 6.6, CH3), 2.71 (2 H, t, JHH = 11.7, NCH2), 3.72 (2 H, m, OCH), 3.94 (3
H, s, OCH3), 4.26 (2 H, d, 2JHH = 11.7), 6.95 (1 H, s, CH), 7.97 (1 H, s, CH)
2.37 (3 H, s, NCH3), 2.55 (4 H, t, 3JHH = 5.1, NCH2), 3.77 (4 H, t, 3JHH = 5.1, NCH2), 3.94 (3
H, s, OCH3), 6.96 (1 H, s, CH), 7.96 (1 H, q, 5JHF = 1.8)
Synthesis 2003, No. 10, 1531–1540 © Thieme Stuttgart · New York

1536
D. M. Volochnyuk et al.
PAPER
Table 3 Yields, Melting Points and 1H NMR Data of Compounds 27–30 and 32–34g (continued)
N
NRR
Yield Mp (°C)b
(%)a
1H NMR, (ppm), J (Hz)
34dc
34ee
75
160–161
2.07 (4 H, m, CH2), 3.59 (4 H, m, NCH2), 3.93 (3 H, s, OCH3), 6.71 (1 H, s, CH), 7.96 (1 H,
q, 5JHF = 1.5, CH)
71
116–117
1.13 (4 H, m, CH2), 1.31 (4 H, m, CH2), 3.12 (4 H, br m, NCH2), 3.40 (3 H, s, OCH3), 6.52
(1 H, s, CH), 8.26 (1 H, s, CH)
a Yields refer to pure isolated products.
b Melting points are uncorrected.
c CDCl3.
d DMSO-d6.
e C6D6.
f CD3CN.
g Satisfactory microanalysis data were obtained: C 0.40; H 0.45; N 0.34; except for: 27 and 28: H 0.80; N 0.95.
Table 4 19F and 13C NMR Data of Pyrozolopyridines (X = NPh or NMe) and Isoxazolopyridines (X=O) obtained.
N
19F NMR 13C NMR, (ppm), J (Hz)
(ppm)
Me at
C(3)
C(3)
C(3a)
C(4)
C(5)
C(6)
C(7a)
151.5
151.5
151.6
151.2
140.3
146.3
170.7
169.5
170.6
152.0
CF3
R at C(2)
R at C(6)
5ca –62.1
5db –62.1
13.3
(1.5)
140.0
140.5
143.3
139.8
150.4
109.3
(1.5)
131.3
(33.6)
109.7
(4.3)
153.3
151.8
151.8
121.6
(273.6)
120.2, 125.2,
128.0, 137.8
122.8 132.3, 133.8,
147.7, 150.0
14.5
108.6
(1.5)
130.3
(33.4)
114.8
(4.3)
123.2
(273.0)
121.4, 126.6,
129.6, 139.0
25.1
5fb
–62.5
14.3
(1.7)
107.1
111.1
104.7
97.7
130.8
(34.4)
109.4
(2.3)
123.2
(272.6)
34.0
129.1, 129.3, 131.0,
138.4
5ga –61.8,
14.1
(2.9)
133.2
(34.9)
108.6
146.7
(36.0)
122.2
(274.0)
34.1
121.1 (274.7)
–68.0
6b
7c
–60.7
13.9
14.1
12.5
12.6
12.1
14.6
132.5
(33.6)
103.9
(4.3)
163.4
125.0
(273.7)
121.1, 126.0,
129.0, 138.5
–
–77.3,
-83.6
143.3
(4.6)
70.5
(31.1)
35.2
83.2
(29.5)
126.0
(285.0)
123.2, 127.5,
129.9, 138.9
124.1 (283.3)
12ab –61.2
159.4
107.2
107.2
100.3
102.3
133.5
(39.5)
114.0
(4.4)
154.6
122.4
(274.5)
–
–
–
128.3, 129.6, 131.7,
136.3
12cb –60.8,
155.3
135.4
(36.0)
114.3
106.6
101.6
148.2
(36.0)
121.8
(274.3)
121.0 (276.1)
–67.0
13b –61.9
154.1
(11.3)
134.4
(34.8)
166.1
122.2
(273.2)
–
30ab –62.3
140.8
131.8
(31.1)
157.8
123.4
(272.8)
120.5, 125.7,
129.5, 139.6
24.6, 25.6, 46.6
a CDCl3.
b DMSO-d6.
c Acetone-d6.
Synthesis 2003, No. 10, 1531–1540 © Thieme Stuttgart · New York

PAPER
Electron-Rich Amino Heterocycles for Synthesis of Trifluoromethyl-Containing Fused Pyridines
1537
Table 5 19F and 13C NMR Data of Furopyridines and Thienopyridines Obtained
N
19F NMR, 13C NMR, (ppm), J (Hz)
(ppm)
C(2)
C(3)
C(3a)
113.6
C(4)
C(5)
C(6)
C(7a)
161.8
CF3
R at C(6)
R at C(6)
15ba –61.9
146.3
113.3
133.4
(34.9)
111.2
152.0
122.3
(274.5)
14.5, 62.4, 158.3 129.3, 129.5, 131.6,
142.7
16a
–62.5
143.6
134.6
111.7
125.3
107.1
125.1
134.9
(34.5)
106.1
113.8
158.5
153.0
161.6
163.6
122.8
(273.4)
14.6, 62.0, 164.5
–
17ba –63.8
133.5
(33.8)
121.6
(273.6)
53.6, 161.9
129.5, 129.8, 132.0,
142.7
17ca –64.0,
140.3
135.3
126.4
124.5
126.0
126.0
129.8
121.4
116.8
134.8
(35.8)
114.9
124.1
146.7
(36.0)
163.0
135.7
165.1
122.7
(273.5)
14.5, 63.2, 161.1 121.3 (275.1)
–68.2
18a
–63.3
133.8
(36.3)
163.2
(3.9)
124.9
(273.7)
53.3, 162.2
53.1, 162.6
–
34aa –64.9
a DMSO-d6.
133.9
(32.6)
104.4
(5.0)
157.5
123.5
(274.4)
24.6, 25.8, 46.3
3-Methyl-1-phenyl-4,6-bis(trifluoromethyl)-4,5,6,7-tetrahydro-
1H-pyrazolo[3,4-b]pyridine-4,6-diol (7)
1H, 31P and 19F NMR spectra were recorded on a Varian VXR-300
spectrometer and 13C NMR spectra were recorded on a Varian Mer-
cury-400 spectrometer. 1H and 13C (300 and 100 MHz, respectively)
with TMS as an internal standard; 31P (121 MHz) with 85% H3PO4
as an external standard; 19F (282.2 MHz) with CFCl3 as an internal
standard. Mass-spectra were obtained on a Hewlett–Packard HP
GC/MS 5890/5972 instrument (EI, 70 eV). Column chromatogra-
phy was performed on silica gel (63–200 mesh, Merck). Silica gel
Merck 60F254 plates were used for TLC. Analytical data are given
in Tables 1–5.
To a solution of aminopyrazole 1a (519 mg, 3.00 mmol) in EtOH (5
mL) hexafluoroacetylacetone 2d (624 mg, 3.00 mmol) and a few
crystals of iodine were added and the solution was refluxed for 30
min. After cooling the crystalline precipitate formed was filtered
off.
6-R -3-Methyl-4-trifluoromethylisoxazolo[5,4-b]pyridines (12)
Compounds 12 were prepared from aminoisoxazole 8 and diketones
2 using the above procedure for 5, with exception of 12c, which was
purified by column chromatography (silica gel; EtOAc–cyclohex-
ane, 1:1; Rf 0.89).
Commercially unavailable starting amino heterocycles (5-aminopy-
razoles 1,17 5-aminoisooxazoles 8,18 5-aminouracyles 9,19 2-amino-
furan 10,20 2-aminothiophenes 1121 and 1,2,3,3-tetramethyl-2,3-
dihydro-1H-6-indolylamine 2022) were prepared according to the
literature.
Compound 12b
MS (EI): m/z (%) = 284 (M+, 100), 256 (15), 241 (29), 215 (16), 197
(11), 146 (25), 69 (10), 45 (9).
1-R,6-R -3-Methyl-4-trifluoromethyl-1H-pyrazolo[3,4-b]py-
ridines (5); Typical Procedure
3-Methyl-4-trifluoromethyl-6,7-dihydroisoxazolo[5,4-b]pyri-
din-6-one (13)
Compound 13 was prepared from aminoisoxazole 8 and ethyl 4,4,4-
trifluoro-3-oxobutanoate 2f using the above procedure for 5.
MS (EI): m/z (%) = 218 (M+, 100), 199 (11), 190 (18), 176 (22), 149
(13), 121 (17), 106 (31), 70 (20), 63 (16), 42 (26).
A mixture of aminopyrazole 1 (3.00 mmol) and diketone 2 (3.00
mmol) in HOAc (15 mL) was refluxed for 2–4 h [the reaction mix-
ture was monitored by TLC (silica gel; EtOAc)]. HOAc was evap-
orated in vacuo and the residue was triturated with H2O and
crystallized from 2-propyl alcohol.
Exception: the substance 5g was purified by column chromatogra-
phy (silica gel; EtOAc–cyclohexane, 1:1; Rf 0.90).
1-R -3-R -7-Methyl-5-trifluoromethyl-1,2,3,4-tetrahydropyri-
do[2,3-d]pyrimidine-2,4-diones (14)
Compounds 14 were prepared from aminouracyles 9 and diketones
2 using the above procedure for 5.
Compound 5f
MS (EI): m/z (%) = 297 (M+, 100), 296 (68), 282 (12), 229 (8.6),
160 (9).
Compound 14d
13C NMR (DMSO-d6): = 24.7 (CH3), 44.5 (NCH2Ph), 104.9
[C(4a)], 116.2 [3JCF = 6.6, C(6)], 121.7 (1JCF = 273.6, CF3), 126.9
[C(p-Ph)], 127.7 [C(o-Ph)], 128.0 [C(m-Ph)], 136.9 [C(ipso-Ph)],
137.6 [2JCF = 34.3, C(5)], 149.8 [C(2)], 152.8 [C(8a)], 158.0 [C(7)],
164.9 [C(4)].
3-Methyl-1-phenyl-4-trifluoromethyl-6,7-dihydro-1H-pyrazo-
lo[3,4-b]pyridin-6-one (6)
Compound 6 was prepared from aminopyrazole 1a and ethyl 4,4,4-
trifluoro-3-oxobutanoate 2f using the above procedure for 5.
MS (EI): m/z (%) = 293 (M+, 100), 278 (13), 252 (11), 118 (11), 77
(28), 51 (12).
19F NMR (DMSO): = –60.1.
Compound 14e
MS (EI): m/z (%) = 341 (M+, 100), 313 (16), 272 (13), 229 (81), 160
(19).
Synthesis 2003, No. 10, 1531–1540 © Thieme Stuttgart · New York

1538
D. M. Volochnyuk et al.
PAPER
6-R -2-Carboethoxy-4-trifluoromethylfuro[2,3-b]pyridines(15)
Compounds 15 were prepared from aminofurane 10 and diketones
2 using the above procedure for 5.
19F NMR (DMSO): = –62.7.
MS (EI): m/z (%) = 316 (M+, 100), 315 (68).
7-R -1,2,3,3-Tetramethyl-5-trifluoromethyl-2,3-dihydro-1H-
pyrrolo[3,2-g]quinolines (25)
Compounds 25 were prepared from aniline 22 and diketones 2 using
the above procedure for 5 and were purified by column chromatog-
raphy (silica gel; EtOAc–cyclohexane; 1:1).
Compound 15b
MS (EI): m/z (%) = 341 (M+, 100), 313 (91), 296 (19), 269 (30), 240
(19), 190 (9), 176 (9).
2-Carboethoxy-4-trifluoromethylfuro[2,3-b]pyridin-6-one (16)
Compound 24 was prepared from aminofuran 10 and ethyl 4,4,4-tri-
fluoro-3-oxobutanoate 2f using the above procedure for 5.
MS (EI): m/z (%) = 275 (M+, 93), 247 (98), 230 (100), 203 (92), 147
Compound 25a
Rf (EtOAc–cyclohexane,1:1) 0.88.
13C NMR (DMSO-d6): = 12.8 [C(2)CH3], 23.5 [C(3)CH3], 26.2
[C(3)CH3], 32.1 [N(1)CH3], 42.6 [C(3)], 70.7 [C(2)], 101.4 [C(9)],
110.0 [3JCF = 4.2, C(6)], 115.3 [C(4)], 115.7 [C(4a)], 124.4
(1JCF = 273.7, CF3), 127.7 [C(3 -Thio)], 129.1 [C(4 -Thio)], 130.2
[C(5 -Thio)], 133.3 [2JCF = 30.5, C(5)], 144.8 [C(2 -Thio)], 145.3
[C(3a)], 150.6 [C(7)], 151.4 [C(8a)], 154.0 [C(9a)].
19F NMR (DMSO): = –62.5.
MS (EI): m/z (%) = 376 (M+, 49), 361 (100), 346 (49), 331 (6), 188
(45), 155 (23), 146 (33), 126 (27), 69 (19).
6-R -2-Carboalkoxy-4-trifluoromethylthieno[2,3-b]pyridines
(17)
Compounds 14 were prepared from aminothiophenes 11 and dike-
tones 2 using the above procedure for 5, with the exception of 17c,
which was purified by column chromatography (silica gel; EtOAc–
cyclohexane, 1: 1; Rf 0.87).
(5), 180 (9), 173 (18).
Compound 17b
MS (EI) m/z (%) = 343 (M+, 100), 312 (73), 284 (7), 264 (10), 240
(9), 215 (19), 156 (5).
Compound 25b
Rf (EtOAc–cyclohexane, 1:1) 0.79.
13C NMR (DMSO-d6): = 12.9 [C(2)CH3], 23.4 [C(3)CH3], 26.4
[C(3)CH3], 31.8 [N(1)CH3], 43.1 [C(3)], 70.5 [C(2)], 100.8 [C(9)],
108.9 [C(6)], 115.2 [C(4)], 118.4 [C(4a)], 121.8 (1JCF = 275.9, CF3),
123.7 (1JCF = 276.4, CF3), 134.1 [2JCF = 31.3, C(5)], 145.5
[2JCF = 31.3, C(7)] 149.2 [C(3a)], 151.3 [C(8a)], 154.4 [C(9a)].
19F NMR (DMSO): = –62.4 (3 F), –68.8 (3 F).
MS (EI): m/z (%) = 362 (M+, 31), 347 (100), 332 (57), 156 (8), 69
2-Carbomethoxy-4-trifluoromethylthieno[2,3-b]pyridin-6-one
(18)
Compound 25 was prepared from aminothiophene 11a and ethyl
4,4,4-trifluoro-3-oxobutanoate 2f using the above procedure for 5.
MS (EI): m/z (%) = 277 (M+, 58), 246 (100), 190 (15), 163 (33), 119
(8), 94 (7), 69 (11).
(7).
2-(5-Amino-1-R,3-methyl-1H-4-pyrazolyl)-1,1,1-trifluoro-2-
propanols (20); Typical Procedure
5,7-Dimethoxy-2-(2-thienyl)-4-trifluoromethylquinoline (26)
Compound 26 was prepared from aniline 23 and diketone 2b using
the above procedure for 5 and was purified by column chromatog-
raphy (silica gel; EtOAc; Rf 0.76).
13C NMR (CDCl3): = 56.4 (OCH3), 56.7 (OCH3), 101.2 [C(6)],
101.9 [C(6)], 111.0 [C(4a)], 114.2 [3JCF = 7.8, C(3)], 124.1
(1JCF = 273.5, CF3), 127.2 [C(3 -Thio)], 128.9 [C(4 -Thio)], 129.9
[C(5 -Thio)], 134.6 [2JCF = 33.1, C(4)], 144.8 [C(2 -Thio)], 152.9
[C(2)], 153.0 [C(8a)], 156.2 [C(5)], 162.2 [C(7)].
To an aminopyrazole 1 (3.00 mmol), trifluoroacetone 19 (2 mL) and
a few crystals of iodine were added and the heterogeneous reaction
mixture was refluxed 10 min. After cooling the reaction mixture
was maintained at r.t. for 1 h. The excess of trifluoroacetone was
evaporated in vacuo and the residue was crystallized from toluene
(for 20a) or a mixture toluene–cyclohexane (for 20b).
Compound 20a
13C NMR (DMSO-d6):
= 15.6 (CH3), 23.2 (CH3), 72.6
(2JCF = 27.6, CF3C), 98.8 [C(4)], 123.7 [C(o-Ph)], 126.9 [C(p-Ph)],
127.5 (1JCF = 287.4, CF3), 129.7 [C(m-Ph)], 139.3 [C(i-Ph)], 146.0
[C(3)], 146.8 [C(5)].
19F NMR (acetone): = –60.7.
MS (EI) m/z (%) = 339 (M+, 100), 310 (20), 296 (12), 281 (15), 266
19F NMR (DMSO): = –83.0.
(11), 253 (16), 108 (10).
3-Methyl-1-phenyl-4-trifluoromethyl-1H-pyrazolo[3,4-b]pyri-
din-6-yl Phosphoric Acid Dichloroanhydride (27)
Compound 20b.
13C NMR (DMSO-d6): = 15.4 (CH3), 23.2 (CH3), 34.2 (NCH3),
72.4 (2JCF = 27.9, CF3C), 97.7 [C(4)], 127.6 (1JCF = 277.8, CF3),
143.2 [C(3)], 146.7 [C(5)].
To a pyrazolopyridone 6a (2.92 g, 10 mmol) was added POCl3 (4
mL) and the reaction mixture was refluxed for 3 h. The excess of
POCl3 was evaporated in vacuo. The residue was dissolved in a
mixture of anhyd toluene (20 mL) and anhyd hexane (10 mL). The
solution was filtered under a blanket of anhyd argon to remove the
insoluble precipitate, solvents were evaporated in vacuo and the res-
idue was crystallized (anhyd hexane).
19F NMR (DMSO): = –84.2.
7-(N,N-Dimethylamino)-2-phenyl-4-trifluoromethylquinoline
(24)
Compound 24 was prepared from aniline 21 and diketone 2a using
the above procedure for 5 and was purified by column chromato-
graphy (silica gel; EtOAc, Rf 0.68).
3-Methyl-1-phenyl-4-trifluoromethyl-1H-pyrazolo[3,4-b]pyri-
din-6-yldiphenylphosphate (28)
Method via Dichloroanhydride 27
To a stirring solution of sodium phenolate (0.566 g, 4.8 mmol) in
anhyd dioxane (20 mL) dichloroanhydride 27 (1.00 g, 2.4 mmol)
was added. The reaction mixture was maintained at r.t. for 1.5 h and
13C NMR (DMSO-d6):
= 40.3 [N(CH3)2], 107.1 [C(6)], 111.3
[3JCF = 2.8, C(3)], 113.3 [C(4a)], 118.5 [C(8)], 124.1 [C(5)], 124.3
(1JCF = 274.5, CF3), 127.7 [C(m-Ph)], 129.4 [C(o-Ph)], 130.4 [C(p-
Ph)], 133.7 [2JCF = 31.5, C(4)], 138.5 [C(ipso-Ph)], 150.9 [C(8a)],
151.8 [C(2)], 156.3 [C(7)].
Synthesis 2003, No. 10, 1531–1540 © Thieme Stuttgart · New York

PAPER
Electron-Rich Amino Heterocycles for Synthesis of Trifluoromethyl-Containing Fused Pyridines
1539
then was refluxed for 15 min. Dioxane was evaporated in vacuo, the
residue was triturated with H2O and crystallized (2-propyl alcohol).
was added. The reaction mixture was refluxed 16 h, then the diox-
ane was evaporated in vacuo, the residue was triturated with H2O
and crystallized (MeOH).
Method via Phosphorylation of Pyrazolopyridone 6a
Compound 28 was prepared from pyrazolopyridone 6a and
(PhO)2POCl using the below procedure for 29.
6-(N-R,N -R -Amino)-2-carbomethoxy-4-trifluoromethylth-
ieno[2,3-b]pyridine (34); Typical Procedure
To a solution of tosylate 33 (0.43 g, 1.0 mmol) in dioxane (10 mL)
an appropriate amine (1.3 mmol) and i-Pr2NEt (0.70 mL, 4 mmol)
were added. The reaction mixture was refluxed 4–8 h (the reaction
mixture was monitored by TLC (silica gel; EtOAc). Dioxane was
evaporated in vacuo, the residue was triturated with H2O and crys-
tallized from an appropriate solvent: 34 a,d,e, i-PrOH; 34b, MeOH;
34c, mixture of i-PrOH–heptane ca. 10:3.
Yield: 71%.
3-Methyl-6-(4-methylphenylsulfonyloxy)-1-phenyl-4-trifluoro-
methyl-1H-pyrazolo[3,4-b]pyridine (29)
To a solution of pyrazolopyridone 6a (2.92 g, 10 mmol) and Et3N
(1.4 mL, 10 mmol) in dioxane (20 mL), tosyl chloride (1.91 g, 10
mmol) was added. The reaction mixture was refluxed 8 h, then di-
oxane was evaporated in vacuo, and the residue was triturated with
H2O and washed with MeOH (5 mL).
Compound 34a
MS (EI): m/z (%) = 344 (M+, 100), 329 (11), 315 (49), 301 (40), 288
(41), 276 (30), 261 (42), 245 (11), 230 (21), 182 (8), 84 (23), 41
(10).
3-Methyl-6-morpholino-1-phenyl-4-trifluoromethyl-1H-pyra-
zolo[3,4-b]pyridine (30b)
Method via Dichloroanhydride 27
To a pyrazolopyridone 6a (0.5 g, 1.71 mmol) was added POCl3 (2
mL) and reaction mixture was refluxed for 3 h. The excess of POCl3
was evaporated in vacuo. To the residue was added morpholine (3
mL) and the mixture was refluxed for 4 h, then the excess of mor-
pholine was evaporated in vacuo, the residue was triturated with
H2O and crystallized (2-propyl alcohol).
Acknowledgment
The authors acknowledge Enamine Ltd. for financial support of this
work. Also we officially thank Turov A. V. (Department of Chemi-
stry of Kyiv National Taras Shevchenko University) and Kuzmenko
Yu. V. (Central Customs Laboratory of National Customs Service
of Ukraine) for spectral measurement.
Yield: 0.245 g (39%).
6-(N-R,N -R -Amino)-3-methyl-1-phenyl-4-trifluoromethyl-
1H-pyrazolo[3,4-b]pyridines (30); Typical Procedure
To a solution of tosylate 29 (0.45 g, 1.0 mmol) in dioxane (10 mL),
the appropriate amine (2.5 mmol) was added. The reaction mixture
was refluxed 2–4 h [the reaction was monitored by TLC (silica gel;
EtOAc)]. Dioxane was evaporated in vacuo, and the residue was
triturated with H2O and crystallized from an appropriate solvent: 30
a,b, i-PrOH; 30 d,f, MeOH; 30e, mixture of i-PrOH–heptane ca. 10:
1.
References
(1) (a) Filler, R. In Flourine Containing Drugs in
Organoflourine Chemicals and Their Industrial Application,
Chap. 6; Pergamon: New York, 1979. (b) Holland, G. F.;
Pereira, J. N. J. Med. Chem. 1967, 10, 149.
(2) (a) Rempfler, H.; Duerr, D. EP 337944, 1989; Chem. Abstr.
1990, 112, 139043r. (b) Rempfler, H.; Duerr, D.; Thummel,
R. C. EP 337943, 1989; Chem. Abstr. 1990, 112, 139044s.
(c) Kawasaki, H.; Ozawa, K.; Yamamoto, K. WO 0198301,
2001; Chem. Abstr. 2001, 136, 69807. (d) Grutzmann, R.;
Muller, U.; Bischoff, H.; Zaiss, S. WO 0197787, 2001;
Chem. Abstr. 2001, 136, 64132. (e) Strobel, H.; Wohlfart,
P.; Safarova, A.; Walser, A.; Suzuki, T.; Dharanipragada, R.
M. WO 0264545, 2002; Chem. Abstr. 2002, 137, 185515.
(f) Yoshimi, K.; Kozuka, M.; Sakai, J.; Iizawa, T.; Shimizu,
Y.; Kaneko, I.; Kojima, K.; Iwata, N. Jpn. J. Pharmacol.
2002, 88, 174; Chem. Abstr. 2002, 137, 15686.
Exeption: the substunce 30c was purified by the following proce-
dure. The crude product was placed on a short silica gel column and
washed with EtOAc to wash out the by-products and then washed
with MeOH to afford the target product.
Compound 30a
MS (EI): m/z (%) = 360 (M+, 100), 345 (12), 331 (54), 317 (24), 304
(45), 292 (24), 277 (22), 251 (9), 236 (6), 180 (8), 84 (21), 77 (28).
(3) (a) Denisova, A. B.; Sosnovskikh, V. Ya.; Dehaen, W.;
Toppet, S.; Meervelt, L. V.; Bakulev, V. A. J. Flourine
Chem. 2002, 115, 183. (b) Song, L. P.; Zhu, S. Z. J.
Flourine Chem. 2001, 111, 201; and references cited
therein. (c) Ohkura, H.; Berbasov, D. O.; Soloshonok, V. A.
Tetrahedron Lett. 2003, 44, 2417.
Compound 30c
MS (EI): m/z (%) = 375 (M+, 22), 318 (11), 305 (100), 83 (19), 77
(20), 70 (51), 43 (24).
2-Carbomethoxy-4-trifluoromethylthieno[2,3-b]pyridin-6-yl
Dimethylphosphate (32)
(4) (a) Bonacorso, H. G.; Duarte, S. H. G.; Zanatta, N.; Martins,
M. A. P. Synthesis 2002, 1037. (b) Bonacorso, H. G.;
Watowski, A. D.; Muniz, M. N.; Zanatta, N.; Martins, M. A.
P. Synthesis 2002, 1079. (c) Martins, M. A. P.; Sinhorin, A.
P.; Da Rosa, A.; Flores, A. F. C.; Wastowski, A. D.; Pereira,
C. M. P.; Flores, D. S.; Beck, P.; Freitag, R. A.; Brondani,
S.; Cunico, W.; Bonacorso, H. G. Synthesis 2002, 2353.
(5) (a) Krasovsky, A. L.; Moiseev, A. M.; Nenajdenko, V. G.;
Balenkova, E. S. Synthesis 2002, 901. (b) Krasovsky, A. L.;
Hartuluari, A. S.; Nenajdenko, V. G.; Balenkova, E. S.
Synthesis 2002, 133.
To a thienopyridone 18 (2.77 g, 10 mmol) was added POCl3 (4 mL)
and reaction mixture was refluxed 3 h. The excess of POCl3 was
evaporated in vacuo. To the residue anhyd benzene (20 mL) was
added. The solution was filtered under anhyd argon to remove the
insoluble precipitate. To the stirred filtrate, Et3N (4 mL, 29 mmol)
and anhyd MeOH (1 mL, 31 mmol) were added. The reaction mix-
ture was maintained at r.t. for 1.5 h, and then was refluxed for 15
min. The precipitate of Et3N·HCl formed was filtered off. The fil-
trate was concentrated in vacuo and the residue was crystallized
(MeOH).
(6) (a) Pushechnikov, A. O.; Volochnyuk, D. M.; Tolmachev,
A. A. Synlett 2002, 1040. (b) Volochnyuk, D. M.; Kostyuk,
A. N.; Pinchuk, A. N.; Tolmachev, A. A. Tetrahedron Lett.
2003, 44, 391.
2-Carbomethoxy-6-(4-methylphenylsulfonyloxy)-4-trifluoro-
methylthieno[2,3-b]pyridine (33)
To a solution of thienopyridone 18 (2.77 g, 10 mmol) and Et3N (1.4
mL, 10 mmol) in dioxane (20 mL), tosyl chloride (1.91 g, 10 mmol)
Synthesis 2003, No. 10, 1531–1540 © Thieme Stuttgart · New York

1540
D. M. Volochnyuk et al.
PAPER
(7) (a) Volochnyuk, D. M.; Pushechnikov, A. O.; Krotko, D. G.;
Koydan, G. N.; Marchenko, A. P.; Chernega, A. N.;
Pinchuk, A. M.; Tolmachev, A. A. Synthesis 2003, 906.
(b) Tolmachev, A. A.; Dovgopoly, S. I.; Kostyuk, A. N.;
Kozlov, E. S.; Pushechnikov, A. O.; Holzer, W. Heteroat.
Chem. 1999, 10, 391. (c) Kovaleva, S. A.; Chubaruk, N. G.;
Tolmachev, A. A.; Pinchuk, A. M. Khim. Geterotsikl. Soed.
2001, 1287; Chem. Abstr. 2002, 137, 47274. (d) Oshovsky,
G. V.; Pinchuk, A. M.; Tolmachev, A. A. Mendeleev
Commun. 1999, 9, 161. (e) Kovaleva, S. A.; Ivonin, S. P.;
Pinchuk, A. M.; Tolmachev, A. A. Khim. Geterotsikl. Soed.
2001, 1285; Chem. Abstr. 2002, 137, 47273.
(8) (a) Suzuki, M.; Iwasaki, H.; Fujikawa, Y.; Sakashita, M.;
Kitahara, M.; Sakoda, R. Bioorg. Med. Chem. Lett. 2001, 11,
1285. (b) Bondavalli, F.; Botta, M.; Bruno, O.; Ciacci, A.;
Corelli, F.; Fossa, P.; Lucacchini, A.; Manetti, F.; Martini,
C.; Menozzi, G.; Mosti, L.; Ranise, A.; Schenone, S.; Tafi,
A.; Trincavelli, M. L. J. Med. Chem. 2002, 45, 4875.
(c) Straub, A.; Stasch, J.-P.; Alonso-Alija, C.; Benet-
Buchholz, J.; Ducke, B.; Feurer, A.; Fuerstner, C. Bioorg.
Med. Chem. Lett. 2001, 11, 781. (d) Shutske, G. M.; Roehr,
J. E. J. Heterocycl. Chem. 1997, 34, 789.
(13) (a) Hamann, L. G.; Kong, J.; Edwards, J. P. WO 0116133,
2001; Chem. Abstr. 2001, 134, 222698. (b) Kong, J. W.;
Hamann, L. G.; Ruppar, D. A.; Edwards, J. P.; Marschke, K.
B.; Jones, T. K. Bioorg. Med. Chem. Lett. 2000, 10, 411.
(c) Zhi, L.; Van Oeveren, C. A.; Chen, J.-H.; Higuchi, R. I.
WO 0266475, 2002; Chem. Abstr. 2002, 137, 201294.
(d) Hamann, L. G.; Mani, N. S.; Davis, R. L.; Wang, X.-N.;
Marschke, K. B.; Jones, T. K. J. Med. Chem. 1999, 42, 210.
(14) Pushechnikov, A. O.; Krotko, D. G.; Volochnyuk, D. M.;
Tolmachev, A. A. Synlett 2001, 6, 860.
(15) Chandra Sheker Reddy, A.; Narsian, B.; Venkataratman, R.
V. J. J. Flourine Chem. 1997, 86, 127; and references cited
therein.
(16) (a) Arutyunnyan, E. A.; Gunar, V. I.; Gracheva, E. P.;
Zav’yalov, S. I. Izv. Akad. Nauk USSR, Ser. Khim. 1968,
445; Chem. Abstr. 1968, 69, 86943u. (b) Rosowsky, A.;
Papathanasopoulos, N. J. Heterocycl. Chem. 1972, 9, 1235.
(17) (a) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Manna, F.; Pace, P.
Synlett 1998, 4, 446. (b) Cacchi, S.; Carangio, A.; Fabrizi,
G.; Moro, L.; Pace, P. Synlett 1997, 12, 1400. (c) Hinkle, J.
S.; Lever, O. W. Tetrahedron 1988, 44, 3391.
(18) Grandberg, I. I.; Ting, W.-P.; Kost, A. N. Zh. Obshich.
Khim. 1961, 31, 2311; Chem. Abstr. 1962, 56, 25079.
(19) Abushanab, E.; Lee, D. Y.; Goodman, L. J. Heterocycl.
Chem. 1973, 10, 181.
(9) Balicki, R. Pol. J. Chem. 1983, 57, 789.
(10) Linderman, R. J.; Kirollos, K. S. Tetrahedron Lett. 1990, 31,
2689.
(11) For distant spin-spin H–F interaction see: Ionin, B. I.;
Yershov, B. A.; Kol’tsov, A. I. NMR-Spectroscopy in
Organic Chemistry, 2nd ed.; Yershov, B. A., Ed.; Leningrad:
Khimiya, 1983.
(12) (a) Lynch, B. M.; Khan, M. A.; Teo, H. C.; Pedrotti, F. Can.
J. Chem. 1988, 66, 420. (b) Emerson, W. S.; Holly, F. W.;
Klemm, L. H. J. Am. Chem. Soc. 1941, 63, 2569.
(20) Traube, W. Chem. Ber. 1900, 33, 1381.
(21) Dann, O. Chem. Ber. 1943, 76, 419.
(22) Tolmachev, A. A.; Tolmacheva, V. S.; Shevchuk, L. I.;
Kozlov, E. S.; Babichev, F. S. Khim. Geterotsikl. Soed.
1989, 919; Chem. Abstr. 1990, 112, 35624.
Synthesis 2003, No. 10, 1531–1540 © Thieme Stuttgart · New York