Synthesis of thiazolo[4,5-d]pyridines

Article abstract of DOI:10.1055/s-2008-1067152

The reaction of 2-aminothiazol-4(5H)-iminium salts with various 1,3-CCC-dielectrophiles was investigated. As a result, a set of diverse thiazolo[4,5-d]pyridines were obtained. The scope and limitation of the approach is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067152

PAPER
2337
Synthesis of Thiazolo[4,5-d]pyridines
S
ynthesis of Thiaz
i
olo[4,5
k
-
d
]pyridinestor O. Iaroshenko,a,c Dmitriy M. Volochnyuk,*b,f Nadiya V. Kryvokhyzha,d Aleksander Martyloga,c,f
Dmitri V. Sevenard,e Ulrich Groth,a Jörg Brand,a Alexander N. Chernega,b Alexander N. Shivanyuk,c,f
Andrei A. Tolmachevc
a
Fachbereich Chemie, Universität Konstanz, Fach M-720, Universitätsstraße 10, 78457 Konstanz, Germany
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska 5, 02094 Kyiv-94, Ukraine
b
Fax +380(44)5373253; E-mail: D.Volochnyuk@enamine.net
National Taras Shevchenko University, 62 Volodymyrska St., 01033 Kyiv-33, Ukraine
Department of Chemistry, University of Glasgow, University Avenue, Glasgow G12 8QQ, UK
Hansa Fine Chemicals GmbH, BITZ, Fahrenheitstraße 1, 28359 Bremen, Germany
c
d
e
f
‘Enamine Ltd.’, 23 A. Matrosova St., 01103 Kyiv, Ukraine
Received 24 February 2008; revised 2 April 2008
S
N
Cl–
S
N
Abstract: The reaction of 2-aminothiazol-4(5H)-iminium salts
with various 1,3-CCC-dielectrophiles was investigated. As a re-
sult, a set of diverse thiazolo[4,5-d]pyridines were obtained. The
scope and limitation of the approach is described.
R12N
N
R1
NH2
NH2
3 R1 = Alk, Ar
1 HCl R12N = Alk2N
2 HCl R12N = H2N
Key words: thiazoles, pyridines, annulation, fluorine, diketones,
regioselectivity
O
O
O
O
R3
R2
RF
R2
Compounds containing the thiazolo[4,5-d]pyridine struc-
tural unit have been shown to possess antibacterial,1a,b and
antisecretory1c activity. They also can be used as a non-
imidazole histamine H3-antagonists.1d
4a RF = CF3, R2 = Me
4b RF = CF3, R2 = CF3
4c RF = CF3, R2 = Ph
4d RF = CF3, R2 = 2-thienyl
9a R2 = CO2Et, R3 = Ph
9b R2 = CO2Et, R3 = 2-thienyl
9c R2 = CO2Me, R3 = Me
10 R2 = H, R3 = Ph
The thiazolo[4,5-d]pyridine system can be assembled
through the annulation of a thiazole cycle to pyridine2 or
vice versa.3,4 It has been shown that reaction of aminothi-
azoles with 1,3-dielectrophiles leads to thiazolo[4,5-d]py-
ridines in preparative yields; however, the scope and
limitation of this method has not been investigated in de-
tail.
Current studies5 were undertaken in order to develop a
facile methodology for the synthesis of thiazolo[4,5-d]py-
ridines, starting from 5-unsubstituted 4-aminothiazole de-
rivatives 1–3 and 1,3-CCC-dielectrophiles 4–18
(Figure 1).
5
R
F = CF3, R2 = OEt
6a RF = CF2Cl, R2 = 2-thienyl
R2
O
6b RF = CF2Cl, R2 = Ph
7
8
R
R
F = CF2H, R2 = Me
F = C2F5, R2 = Me
RF
EtO
11 R2 = H, RF = CF3
12 R2 = Me, RF = CF3
13 R2 = Ph, RF = CF3
14 R2 = OEt, RF = CF3
15 R2 = H, RF = C3F7
16 R2 = H, RF = CF2Cl
18
17
CF3
O
CF3
O
O
O
O
Figure 1 The aminothiazoles and 1,3-CCC-dielectrophiles used for
constructing thiazolo[4,5-d]pyridines
and 24 emerge in 19F NMR spectra at d = –65, –68, –115.7,
and –113.3, respectively. Cyclic diketone 18, reacted sim-
ilarly to 4a to give regioisomers 27 and 28 in a 3:1 molar
ratio (GC-MS).
Amines 1 and 2, generated in situ from their stable hydro-
chlorides (NaOAc, AcOH),6 reacted with fluorine-con-
taining 1,3-diones 4–6 to give thiazolo[4,5-d]pyridines as
individual isomers 19 and 20 in 77–85% yield. The struc-
ture and purity of compounds 19 and 20 was unambigu-
ously shown by GC-MS and NMR. Similarly
bis(trifluoromethyl) derivative 19c was synthesized start-
ing from 4c as a model compound for spectral investiga-
tion (Scheme 1, Table 1).
The formation of the g-isomers suggests that the initial at-
tack of the trifluoromethyl-containing diketone occurs at
the carbon atom of the thiazole cycle and the reaction pro-
ceeds via intermediates 31, 32, and 33 (Figure 2). A 19F
NMR study revealed that the reaction of in situ generated
amines 1 and 2 with trifluoromethyl-substituted 1,3-di-
ones proceeds through the formation of pyridine hydrates
32 (d = –81), which, however, were too unstable to be iso-
lated. Intermediate 33 was isolated; however it appeared
to be unstable upon storage.
Diaminothiazoles 1 reacted with diones 4a, 7, and 8 to
give mixtures of the corresponding regioisomers 21–26,
which were characterized by GC-MS and 19F NMR spec-
trometry. The fluorine atoms of compounds 21, 22, 23,
SYNTHESIS 2008, No. 15, pp 2337–2346
x
x.
x
x
.
2
0
0
8
Advanced online publication: 18.06.2008
DOI: 10.1055/s-2008-1067152; Art ID: P02108SS
© Georg Thieme Verlag Stuttgart · New York

2338
V. O. Iaroshenko et al.
PAPER
Table 1 Thiazolo[4,5-d]pyridines 19–30a
RF
i
S
Substrate Product R1 N
RF
R2
Yield (%)
19 RF = CF3, 77–84%
20 RF = CF2Cl, 79–85%
R12N
2
4b,c for 19
6 for 20
N
R2
N
2 + 4b
2 + 4c
1 + 4b
1 + 4c
3 + 4b
3 + 4c
2 + 6a
1 + 6b
1 + 4a
1 + 4a
1 + 4a
1 + 4a
1 + 7
19a
19b
19c
19d
19e
19f
20a
20b
21a
21b
21c
22
NH2
NH2
CF3
CF3
CF3
Ph
80
84
75
84
79
77
RF
Me
S
S
N(CH2CH2)2O CF3
CF3
Ph
i
R12N
R12N
+
N(CH2)4
NHCy
NHPh
NH2
CF3
CF3
CF3
N
RF
N
N
N
Me
4a for 21 and 22
7 for 23 and 24
8 for 25 and 26
22 RF = CF3 15%
24 RF = CF2H 19%
26 RF = C2F5 18%
21 RF =CF3 58%
23 RF = CF2H 49%
25 RF = C2F5 55%
CF3
Ph
CF2Cl 2-thienyl 79
CF3
N(CH2CH2)2O CF2Cl Ph
85
58
47
33
15
49
19
55
18
74
72
S
S
N
i
1,2·HCl
18
R12N
R12N
or 3
+
N(CH2)5
CF3
Me
Me
Me
CF3
N
N
N
CF3
27 55%
28 18%
N(CH2CH2)2O CF3
CF3
NHPh
CF3
Me
S
Alk2N, R2 and RF
(see Table 1)
i
5
N(CH2)5
N(CH2)5
N(CH2)5
N(CH2)5
N(CH2)5
N(CH2)5
NEt2
R12N
N
N
H
O
23
CF2H Me
29 72–74%
1 + 7
24
Me
CF2H
CF3
S
1 + 8
25
C2F5
Me
Me
17
i
OH
R12N
1 + 8
26
C2F5
OH
OH
N
N
H
O
1 + 5
29a
29b
CF3
CF3
30 84%
1 + 5
Scheme 1 Reagents and conditions: (i) (a) 1·HCl, 2·HCl, or 3, dike-
tone (1 equiv), NaOAc (1.5 equiv), AcOH, reflux, 1 h.
a Yields refer to pure isolated product.
O
OH
CF3
CF3
OH
RF
N
S
N
S
R2
R2
R12N
R12N
S
S
N
i, ii
N
R12N
R12N
N
CF3
OH
OH
NH2
H
one pot
R2
NH2
S
N
32
31
R12N
35 RF = CF3, CF2Cl, 33–41%m
34
N
O
H
Scheme
2
Reagents and conditions: (i) thiourea (1 equiv),
ClCH2CN (1.1 equiv), abs MeOH, reflux, 4 h; (ii) diketone (1 equiv),
33
Figure 2 Intermediates detected during the 19F NMR study of the
formation of thiazolo[4,5-d]pyridines
NaOAc (1.5 equiv), AcOH, reflux, 2 h.
Table 2 Thiazolo[4,5-d]pyridines 35a
N-(Monoaryl- and N-(monoalkylamino)thiazoles 3,7 react
with ketones 4 in acetic acid to give compounds 19e,f in
good yields.
Substrate Product R1 N
RF
R2
Yield (%)
2
4c
4b
4d
6a
4d
35a
35b
35c
35d
35e
NHCy
NHPh
NHPh
NHCy
CF3
CF3
CF3
CF2Cl
Ph
41
33
Subsequent treatment of N,N-dialkylthioureas 34 with
chloroacetonitrile and fluorinated diketones resulted in
thiazolopyridines 35. In spite of the rather low yield (33–
41%) this procedure allows the synthesis of compounds
such as 35e bearing the highly basic 4-methylpiperazin-1-
yl group at position 2 of the thiazolopyridine ring
(Scheme 2, Table 2).
CF3
2-thienyl 38
2-thienyl 39
2-thienyl 33
N(CH2)4NMe CF3
a Yields refer to pure isolated product.
Acylpyruvates 9 reacted with in situ generated amines 1
(NaOAc, AcOH) to give the corresponding esters 36,
which were readily transformed into acids 37, the iso-
steres of biologically active cinchoninic acids (Scheme 3,
Table 3).8 The reaction of compound 9c led to the mixture
of 38 and 39 in a 3:1 molar ratio(GC-MS). The structure
of compound 37b was unambiguously confirmed by sin-
gle crystal X-ray analysis (Figure 3) of its hydrogen-
bonded equimolar complex with N,N-dimethylformamide.
Synthesis 2008, No. 15, 2337–2346 © Thieme Stuttgart · New York

PAPER
Synthesis of Thiazolo[4,5-d]pyridines
2339
sulted in thiazolopyrimidines 41 in nearly quantitative
yields.
Compounds 11 and 12 reacted with in situ generated
amines 1 (CH2Cl2, Et3N) to give a mixture of isomers 46
and 47 respectively in a 3:1 and 4:1 molar ratio (GC-MS),
whereas the reaction of compound 13 led to individual
isomers 46. It seems likely intermediates 42 and 43 are
formed in the first step of the reaction and cyclize into hy-
drates 44 (d19F = –79) and 45 (d19F = –81). The latter
slowly dehydrate in dichloromethane solution to give a
mixture of compounds 46 and 47. In contrast to enones
11–13, compound 14 reacted with amine 1 to give com-
1
pound 48, whose structure was proved by H and 13C
NMR spectroscopy. Enones bearing CF2Cl 16 and C3F7
15 groups reacted with amines 1 to give the mixtures of
the regioisomers which were successfully separated by
preparative column chromatography (Scheme 4, Table 4).
Figure 3 Molecular structure of 37b·DMF; the hydrogen bond is
shown as a broken line
CO2H
CO2Et
S
S
N
1. ii, 2. iii
R3
i
R12N
R12N
O
O
N
R3
N
N
RF
R2
RF
R2
37
i
36
1
+
S
S
NH
NH2
CO2Me
R12N
N
Me
R12N
N
S
S
N
i
43
R12N
42
R12N
+
N
N
O
Me
N
CO2Me
R2
RF
38
39
HO
S
S
Ph
R12N
+
R12N
OH
RF
N
R2
N
N
N
S
vi
v
H
H
S
R12N
1,2
45
NH2
44
N
N
Ph
R12N
N
40
41
RF
N
R2
Scheme 3 Reagents and conditions: (i) diketone (1 equiv), NaOAc
(1.5 equiv), reflux, 1 h; (ii) NaOH (5 equiv), MeOH, reflux, 2 h; (iii)
H2O, AcOH; (vi) diketone sodium salt (1 equiv), abs EtOH, r.t., 24 h;
(v) TFA, r.t., 5–8 h.
S
S
R12N
R12N
+
R2
N
N
RF
N
47
46
F = CF3, CF2Cl, C3F7
R
Table 3 Thiazolo[4,5-d]pyridines 36–41a
Substrate Product R1 N
R2
R3
Ph
Yield (%)
70
2
CF3
N
1 + 9a
1 + 9b
36a
36a
36b
37a
37b
38
N(CH2)4 CO2Et
N(CH2)5 CO2Et
N(CH2)4 CO2H
N(CH2)5 CO2H
N(CH2)5 CO2Me
N(CH2)5 Me
S
i
R12N
1
2-thienyl 73
Ph 69
2-thienyl 72
N
OEt
48 73 %
Scheme 4 Reagents and conditions: (i) dielectrophile (1 equiv),
Et3N (2 equiv), CH2Cl2, reflux, 10–14 h.
36b
1 + 9c
1 + 9c
40
Me
41
15
97
The structure of the fluorine containing condensed py-
ridines was shown by 1H, 13C, and 19F NMR spectroscopy.
In order to establish the position of the CF3 group 19F and
13C NMR studies of ‘symmetrical’ model compounds
19a,c,e. were synthesized. The most convincing evidence
for the g-CF3 isomeric structure is the chemical shifts of
CF3 group (d19F = –64) and C7 (d13C = 129–133,
2JCF = 35 Hz). The characteristic feature of 13C NMR of a-
CF3 regioisomers 46 is the signal of C5 (quartet at d =
39
CO2Me
Ph
41
N(CH2)4
H
a Yields refer to pure isolated product.
Unexpectedly sodium enolates of acetoaldehydes 10 re-
acted with 1 in absolute ethanol to give compounds 40.
The cyclization of compound 40 in trifluoroacetic acid re-
Synthesis 2008, No. 15, 2337–2346 © Thieme Stuttgart · New York

2340
V. O. Iaroshenko et al.
PAPER
Table 4 Thiazolo[4,5-d]pyridines 46–48a
Substrate Product R1 N
RF
R2
Yield (%)
2
11
11
16
16
15
15
14
46a
47a
46b
47b
46c
47c
48
N(CH2)4
N(CH2)4
N(CH2)5
N(CH2)5
N(CH2)5
N(CH2)5
N(CH2)5
H
CF3
H
17
50
18
CF3
H
CF2Cl
H
CF2Cl
H
C3F7
H
17
45
73
C3F7
CF3
Figure 5 Molecular structure of compound 35d
OEt
a Yields refer to pure isolated product.
(300, 400 and 100 MHz, respectively) were recorded with TMS as
an internal standard; 19F (282.2 and 376.2 MHz) with CFCl3 as in-
ternal standard. IR spectra were recorded on a Perkin Elmer FT IR
1600 spectrophotometer for samples in KBr discs. Mass spectra
were obtained on a Hewlett-Packard HP GC/MS 5890/5972 instru-
ment (EI, 70 eV) by GC inlet or on a MX-1321 instrument (EI, 70
eV) by direct inlet. Elemental analyses were carried out at the Mi-
croanalytical laboratory of the Kiev Sate University of T. G.
Shevchenko (Ukraine) and in the University of Konstanz (Germa-
ny). Column chromatography was performed on silica gel (63–200
mesh, Merck). Silica gel Merck 60F254 plates were used for TLC.
All compounds satisfactory microanalysis obtained C 0.33; H
0.45; N 0.25.
2
143–147, JCF = 35 Hz). Carbon atom C7 appears as a
quartet (d = 128–133, 2JCF = 35 Hz) in compounds 19, 47
and a singlet in the corresponding a-CF3 regioisomers
(d = ~145).
Compounds 46a and 47a (R1 = H) were studied by H–H,
C–H (HMQC and HMBC), correlation spectroscopy
(Figure 4). The coupling constant JHH between H5 and
H6 in compounds 47 is about 1.5 times smaller than that
between H7 and H6 in compounds 46. This fact is in keep-
ing with the substitution pattern of the pyridine rings in
compounds 46 and 47.
3
X-ray Crystallography of 37b and 35d
Crystallographic measurements were performed at r.t. on a Enraf-
Nonius CAD4 diffractometer operating in the w-2q scan mode (the
scanning rate ratio w/2q = 1.2). The structure was solved by direct
methods and refined by full-matrix least-squares technique in aniso-
tropic approximation using SHELXS97 and SHELXL979 program
packages. Hydrogen atoms were placed at calculated position and
refined as ‘riding’ model.10
3JHH = 7.8 Hz
H
HMQC
3JCF = 3.4 Hz
H
S
N
HMQC
CF3
N
N
2JCF = 35 Hz
Crystal data of 37b·DMF: monoclinic, P21/n, a = 7.816(1),
b = 22.996(4), c = 11.510(2) Å, b = 98.334(10)°, V = 2047.1(6) Å3,
Z = 4, m(Cu-Ka) = 2.592 mm–1; 3851 reflections, 3566 unique re-
flections, (Rint = 0.0232), Cu-Ka radiation (l = 1.54184 Å), 287 pa-
rameters R1 = 0.0362 and wR2 = 0.0932, S = 1.026 [3132
reflections with I > 2s(I)].
46a
1JCF = 275 Hz
1JCF = 275 Hz
3JCF = 3.2 Hz
3JHH = 4.2 Hz
HMQC
H
2JCF = 35 Hz
CF3
N
Crystal data of 35d: monoclinic, P21/c, a = 11.584(1), b = 8.388(6),
c = 21.046(2) Å, b = 119.510(8)°, V = 1779(1)Å3, Z = 4, m(Mo-
Ka) = 0.474 mm–1. 3632 reflections collected, 3519 unique reflec-
tions, (Rint = 0.0215), Mo-Ka radiation (l = 0.71073 Å), 274 pa-
rameters, R1 = 0.0317, wR2 = 0.0839, S = 1.026 [3023 reflections
with I > 2s(I)].
S
N
N
H
47a
HMQC
Figure 4 Significant NMR data of compounds 46a and 47a
Thiazolo[4,5-d]pyridines 19–30; General Procedure
2-Aminothiazol-4(5H)-iminium salt 1·HCl, 2·HCl (0.1 mmol),
NaOAc (0.15 mmol), and diketone (0.1 mmol) were dissolved in
AcOH (15 mL) and heated under reflux for 1 h. Then this soln was
evaporated under reduced pressure, treated with H2O, filtered, and
dried in air. It was then recrystallized from an appropriate solvent or
was subjected to a column chromatography over silica gel. For com-
pounds 19e and 19f, 3 was used as the substrate and NaOAc was not
added.
The structure of compound 35d was determined by X-ray
studies (Figure 5), confirming the results of the NMR
studies in solution.
In conclusion, a facile method for the annulation of the
pyridine ring to 2-(dialkylamino)thiazolo-4-amine was
elaborated, which delivers novel and diverse thiazolo[4,5-
d]pyridines, which are interesting substrates for medicinal
chemistry and drug discovery.
5,7-Bis(trifluoromethyl)thiazolo[4,5-b]pyridin-2-amine (19a)
Recrystallized (EtOH–H2O); colorless solid; yield: 230 mg (80%);
mp 199–220 °C (subl.).
1H NMR (DMSO-d6): d = 7.73 (s, 1 H, CH), 8.79 (s, 2 H, NH2).
All solvents were purified and dried by standard methods. NMR
spectra were recorded on a Jeol JNM-LA 400, Varian VXR-300 or
Varian Mercury-400, Bruker 600 spectrometer: 1H and 13C signals
Synthesis 2008, No. 15, 2337–2346 © Thieme Stuttgart · New York

PAPER
Synthesis of Thiazolo[4,5-d]pyridines
2341
1
13C NMR (DMSO-d6): d = 108.3, 121.4 (q, JCF = 275 Hz), 122.4
(q, 1JCF = 275 Hz), 130.3 (q, 2JCF = 35 Hz), 143.8 (q, 2JCF = 35 Hz),
166.5, 171.0.
19F NMR (DMSO-d6): d = –63.
N,5-Diphenyl-7-(trifluoromethyl)thiazolo[4,5-b]pyridin-2-
amine (19f)
Recrystallized (MeOH); colorless solid; yield: 285 mg (77%); mp
224–226 °C.
1H NMR (DMSO-d6): d = 7.14 (t, 3JHH = 7.8 Hz, 1 H, CH), 7.51 (br
m, 6 H, CH), 7.82 (d, 3JHH = 7.8 Hz, 2 H), 8.02 (s, 1 H, CH), 8.21
(s, 3JHH = 7.8 Hz, 1 H, CH), 11.14 (s, 1 H, NH).
MS: m/z (%) = 288 [M+ + 1] (10), 287 [M+] (100), 268 (16), 267
(13).
5-Phenyl-7-(trifluoromethyl)thiazolo[4,5-b]pyridin-2-amine
(19b)
13C NMR (DMSO-d6): d = 108.9, 119.2, 120.3, 123.3 (q, 1JCF = 275
2
Hz), 124.2, 125.5, 126.7, 129.1, 129.2, 129.3, 130.9 (q, JCF = 35
Recrystallized (i-PrOH); colorless solid; yield: 248 mg (84%); mp
Hz), 139.0, 165.7, 165.9.
213–215 °C.
19F NMR (DMSO-d6): d = –63.
MS: m/z (%) = 372 [M+ + 1] (26), 371 [M+] (100), 370 (45), 186
1H NMR (DMSO-d6): d = 7.46 (m, 3 H, CH), 7.73 (s, 1 H), 8.11 (d,
3JHH = 7.8 Hz, 2 H, CH), 8.32 (br s, 2 H, NH2).
(14), 153 (14), 136 (10), 89 (14), 77 (37), 52 (13).
13C NMR (DMSO-d6): d = 107.4 (q, 3JCF = 3.3 Hz), 119.3, 123.4 (q,
1JCF = 275 Hz), 126.8, 129.1, 129.3, 130.9 (q, 2JCF = 35 Hz), 144.2,
150.5, 166.5, 170.4.
7-(Chlorodifluoromethyl)-5-(2-thienyl)thiazolo[4,5-b]pyridin-
2-amine (20a)
Recrystallized (i-PrOH); colorless solid; yield: 251 mg (79%); mp
193–194 °C.
19F NMR (DMSO-d6): d = –63.
MS: m/z (%) = 296 [M+ + 1] (16), 295 [M+] (100).
1H NMR (DMSO-d6): d = 7.19 (dd, 3JHH = 5.1 Hz, 3JHH = 3.9 Hz, 1
H, CH), 7.66 (dd, 3JHH = 5.1 Hz, 3JHH = 1.2 Hz, 1 H, CH), 7.81 (s, 1
H, CH), 7.97 (dd, 3JHH = 3.9 Hz, 3JHH = 1.2 Hz, 1 H, CH), 8.41 (br
s, 2 H, NH2).
13C NMR (DMSO-d6): d = 107.4 (t, 3JCF = 3.1 Hz), 118.3, 125.0 (t,
1JCF = 281 Hz), 126.7, 129.0, 129.2, 137.2 (t, 2JCF = 30 Hz), 144.3,
150.4, 166.7, 170.5.
2-Morpholino-5,7-bis(trifluoromethyl)thiazolo[4,5-b]pyridine
(19c)
Recrystallized (i-PrOH); colorless solid; yield: 268 mg (75%); mp
132–134 °C.
1H NMR (CDCl3): d = 3.84 (br s, 4 H, CH2), 3.88 (br s, 4 H, CH2),
7.56 (s, 1 H, CH).
19F NMR (DMSO-d6): d = –52.
MS: m/z (%) = 319 [M+ + 2] (45), 318 [M+ + 1] (23), 317 [M+]
13C NMR (CDCl3): d = 48.7, 66.2, 108.9, 121.8 (q, 1JCF = 275 Hz),
122.3 (q, 1JCF = 275 Hz), 125.0, 132.0 (q, JCF = 35 Hz), 145.2 (q,
2
2JCF = 35 Hz), 167.8, 171.7.
(100), 282 (49), 240 (16).
19F NMR (CDCl3): d = –68, –65.
MS: m/z (%) = 357 [M+] (44), 338 (18), 326 (14), 312 (11), 301 (19),
300 (100), 299 (19), 280 (16), 272 (40), 252 (25), 245 (18), 226
(11).
7-(Chlorodifluoromethyl)-2-morpholino-5-phenylthiazolo[4,5-
b]pyridine (20b)
Recrystallized (MeOH); colorless solid; yield: 325 mg (85%); mp
186–187 °C.
1H NMR (DMSO-d6): d = 3.73 (br s, 4 H, CH2), 3.77 (br s, 4 H,
CH2), 7.47 (m, 3 H, CH), 7.78 (s, 1 H, CH), 8.02 (d, 3JHH = 7.8 Hz,
2 H).
5-Phenyl-2-(pyrrolidin-1-yl)-7-(trifluoromethyl)thiazolo[4,5-
b]pyridine (19d)
Recrystallized (EtOH); colorless solid; yield: 294 mg (84%); mp
3
169–170 °C.
13C NMR (DMSO-d6): d = 48.3, 65.0, 109.0 (t, JCF = 3.1 Hz),
1
118.3, 125.8, (t, JCF = 281 Hz), 127.4, 129.5, 131.0, 136.9 (t,
1H NMR (DMSO-d6): d = 2.13 (br s, 4 H, NCH2), 3.61 (br s, 4 H,
CH), 7.48 (m, 3 H, CH), 7.72 (s, 1 H, CH), 8.11 (d, 3JHH = 7.8 Hz,
2 H).
2JCF = 30 Hz), 138.2, 155.4, 166.7, 170.3.
19F NMR (DMSO-d6): d = –52.
3
13C NMR (DMSO-d6): d = 25.0, 50.1, 108.6 (q, JCF = 3.3 Hz),
MS: m/z (%) = 383 [M+ + 2] (35), 382 [M+ + 1] (20), 381 [M+] (95),
380 (12), 350 (10), 346 (16), 326 (42), 325 (31), 324 (100), 323
(26), 289 (15), 288 (19), 260 (13), 234 (35), 214 (22), 164 (16), 77
(25), 69 (12).
1
118.4, 124.1 (q, JCF = 275 Hz), 128.0, 129.4, 130.0, 137.6 (q,
2JCF = 35 Hz), 138.3, 155.2, 166.8, 170.2.
19F NMR (DMSO-d6): d = –63.
MS: m/z (%) = 350 [M+ + 1] (24), 349 [M+] (100), 322 (14), 321
(64), 320 (28), 307 (15), 295 (17), 294 (81).
5-Methyl-2-piperidino-7-(trifluoromethyl)thiazolo[4,5-b]pyri-
dine (21a)
Colorless solid; yield: 174 mg (58%); mp 139–140 °C; Rf = 0.4
(EtOAc–hexane, 1:2).
1H NMR (DMSO-d6): d = 1.72 (br s, 6 H, CH), 2.60 (s, 3 H, CH3),
3.71 (br s, 4 H, NCH2), 7.07 (s, 1 H, CH).
N-Cyclohexyl-5,7-bis(trifluoromethyl)thiazolo[4,5-b]pyridin-2-
amine (19e)
Recrystallized (EtOH); colorless solid; yield: 292 mg (79%) mp
179–181 °C.
1H NMR (CDCl3): d = 1.33–1.39 (m, 3 H, CH), 1.61–1.89 (m, 5 H,
CH), 2.08–2.11 (m, 2 H, CH), 3.42 (s, 1 H, CH), 7.49 (s, 1 H, CH).
3
13C NMR (CDCl3): d = 23.2, 24.1, 25.7, 49.4, 108.1 (q, JCF = 3.3
Hz), 122.5 (q, 1JCF = 275 Hz), 125.0, 131.3 (q, 2JCF = 35 Hz), 167.8,
171.7.
13C NMR (DMSO-d6): d = 24.7, 25.3, 32.6, 54.3, 108.3, 122.0 (q,
19F NMR (DMSO-d6): d = –65.
MS: m/z (%) = 302 [M+ + 1] (15), 301 [M+] (100),
1
2
1JCF = 275 Hz), 122.6 (q, JCF = 275 Hz), 131.3 (q, JCF = 35 Hz),
145.8 (q, 2JCF = 35 Hz), 166.0, 171.0.
19F NMR (CDCl3): d = –68, –65.
MS: m/z (%) = 369 [M+] (24), 340 (10), 326 (11), 312 (18), 288 (44),
5-Methyl-2-morpholino-7-(trifluoromethyl)thiazolo[4,5-b]pyri-
dine (21b)
Recrystallized (large amount of cyclohexane); colorless solid;
287 (100).
yield: 143 mg (47%); mp 161–162 °C.
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V. O. Iaroshenko et al.
PAPER
1H NMR (CDCl3): d = 2.53 (s, 3 H, CH), 3.65 (br s, 4 H, CH), 3.74
(s, 4 H, CH), 7.31 (s, 1 H, CH).
13C NMR (CDCl3): d = 23.7, 24.5, 25.9, 49.5, 104.7, 112.7, 116.1 (t,
1JCF = 245 Hz), 139.4, 142.0 (t, 2JCF = 27 Hz), 164.0, 169.9.
3
13C NMR (CDCl3): d = 24.5, 48.4, 66.2, 112.1 (q, JCF = 3.3 Hz),
19F NMR (CDCl3): d = –113.3, (d, 2JFH = 53 Hz, 2 F).
MS: m/z (%) = 284 [M+ + 1] (21), 283 [M+] (100), 282 (17), 268
(11), 255 (15), 254 (70), 241 (33), 241 (31), 227 (50), 215 (43), 202
(18), 200 (44), 180 (28), 84 (15), 41 (11).
1
2
117.3, 122.0 (q, JCF = 275 Hz), 131.8 (q, JCF = 35 Hz), 157.3,
165.6, 171.0.
19F NMR (CDCl3): d = –65.
MS: m/z (%) = 304 [M+ + 1] (21), 303 [M+] (91), 302 (17), 272 (14),
258 (14), 247 (26), 245 (36), 232 (12), 219 (12), 218 (32), 198 (23),
191 (16), 190 (12).
5-Methyl-7-(pentafluoroethyl)-2-piperidinothiazolo[4,5-b]pyri-
dine (25)
Yellow oil; yield: 193 mg (55%); Rf = 0.30 (EtOAc–hexane, 1:2).
5-Methyl-N-phenyl-7-(trifluoromethyl)thiazolo[4,5-b]pyridin-
2-amine (21c)
1H NMR (CDCl3): d = 1.67 (br s, 6 H, CH), 2.59 (s, 3 H, CH3), 3.66
(br s, 4 H, NCH2), 6.91 (s, 1 H, CH).
Recrystallized (EtOH); colorless solid; yield: 102 mg (33%); mp
175–177 °C.
3
13C NMR (CDCl3): d = 24.2, 24.3, 25.5, 49.7, 112.6 (t, JCF = 4.8
Hz), 121.2, 130.0 (t, 2JCF = 25 Hz), 156.5, 165.9, 170.7, 172.8.
19F NMR (CDCl3): d = –83.5, –116.7.
MS: m/z (%) = 352 [M+ + 1] (23), 351 [M+] (100), 350 (20), 336
(14), 332 (10), 323 (20), 322 (82), 310 (13), 309 (23), 297 (22), 296
(64), 295 (61), 283 (20), 282 (22), 269 (26), 268 (34), 241 (14), 172
(16), 84 (18), 41 (15).
1H NMR (CDCl3): d = 2.59 (s, 3 H, CH3), 7.09 (t, 3JHH = 7.8 Hz, 1
H, CH), 7.43 (t, 3JHH = 7.8 Hz, 1 H, CH), 7.47 (s, 1 H, CH), 7.81 (d,
3JHH = 7.8 Hz, 2 H, CH), 7.92 (s, 1 H, CH), 10.95 (s, 1 H, NH).
13C NMR (DMSO-d6): d = 24.2, 113.1, 117.1, 119.2 (q, 1JCF = 275
Hz), 123.8 (q, 1JCF = 275 Hz), 124.8, 129.6, 130.8 (q, 2JCF = 35 Hz),
140.1, 157.3, 165.9, 165.9.
19F NMR (CDCl3): d = –65.
MS: m/z (%) = 310 [M+ + 1] (14), 309 [M+] (100), 308 (77).
7-Methyl-5-(pentafluoroethyl)-2-piperidinothiazolo[4,5-b]pyri-
dine (26)
Colorless solid; yield: 63 mg (18%); mp 117 °C; Rf = 0.55 (EtOAc–
hexane, 1:2).
7-Methyl-2-piperidino-5-(trifluoromethyl)thiazolo[4,5-b]pyri-
dine (22)
Colorless solid; yield: 60 mg (15%); mp 120–121 °C; Rf = 0.85
(EtOAc–hexane, 1:2).
1H NMR (CDCl3): d = 1.70 (br s, 6 H, CH), 2.49 (s, 3 H, CH3), 3.68
(br s, 4 H, NCH2), 7.19 (s, 1 H, CH).
1H NMR (CDCl3): d = 1.65 (br s, 6 H, CH), 2.41 (s, 3 H, CH3), 3.62
(br s, 4 H, NCH2), 7.06 (s, 1 H, CH).
13C NMR (CDCl3): d = 20.9, 23.9, 25.2, 49.5, 114,7 (t, 3JCF = 4 Hz),
128.3, 140.5, 144.2 (t, 2JCF = 25 Hz), 164.6, 169.6.
19F NMR (CDCl3): d = –84.4, –116.8.
MS: m/z (%) = 351 [M+] (4), 320 (28), 319 (100), 159 (14).
13C NMR (DMSO-d6): d = 23.7, 24.5, 25.6, 49.1, 107.3 (q,
1
3JCF = 3.5 Hz), 123.2 (q, JCF = 275 Hz), 125.0, 130.0 141.1 (q,
2JCF = 35 Hz), 167.2, 170.9.
19F NMR (CDCl3): d = –68.
2-Piperidino-9-(trifluoromethyl)-5,6,7,8-tetrahydrothiazo-
lo[4,5-b]quinoline (27)
Colorless solid; yield: 400 mg (55%); mp 144–145 °C; Rf = 0.30
(EtOAc–hexane, 1:4).
1H NMR (CDCl3): d = 1.58 (br s, 6 H, CH2), 1.75 (m, 4 H, CH2),
2.79 (br s, 2 H, CH2), 2.92 (br s, 2 H, CH2), 3.58 (br s, 4 H, NCH2).
13C NMR (CDCl3): d = 22.3, 22.5, 23.9, 24.0, 25.1, 33.0, 49.2,
118.9, 121.9, 123.5 (q, JCF = 275 Hz), 129.4 (q, JCF = 35 Hz),
155.9, 163.4, 169.7.
19F NMR (CDCl3): d = –61.0.
MS: m/z (%) = 342 [M+ + 1] (21), 341 [M+] (100), 340 (16), 313
(14), 312 (60), 298 (17), 287 (15), 286 (43), 285 (45), 272 (21), 259
(20), 258 (21), 84 (15), 69 (12), 55 (10), 42 (24).
MS: m/z (%) = 302 [M+ + 1] (37), 301 [M+] (100), 308 (84), 154
(11).
7-(Difluoromethyl)-5-methyl-2-piperidinothiazolo[4,5-b]pyri-
dine (23)
Colorless solid; yield: 132 mg (49%); mp 136–138 °C; Rf = 0.60
(EtOAc–hexane, 1:1).
1H NMR (CDCl3): d = 1.61 (br s, 6 H, CH2), 2.64 (s, 3 H, CH3), 3.75
(br s, 4 H, NCH2), 6.71 (t, 2JHF = 53 Hz, 1 H, CF2H), 6.91 (s, 1 H,
CH).
1
2
13C NMR (CDCl3): d = 23.9, 24.4, 25.7, 49.9, 103.2, 111.9, 114.4 (t,
1JCF = 245 Hz), 135.1 (t, 2JCF = 27 Hz), 156.7, 166.0, 167.7.
19F NMR (CDCl3): d = –115.7, (d, 2JFH = 53 Hz, 2 F).
2-Piperidino-5-(trifluoromethyl)-6,7,8,9-tetrahydrothiazo-
lo[4,5-c]isoquinoline (28)
Colorless solid; yield: 200 mg (18%); mp 123–125 °C; Rf = 0.70
(EtOAc–hexane 1:4).
1H NMR (CDCl3): d = 1.61 (br s, 6 H, CH2), 1.78 (m, 3 H, CH2),
2.36 (br s, 1 H, CH2), 2.66 (m, 2 H, CH2), 2.83 (br s, 2 H, CH2), 3.59
(br s, 4 H, NCH2).
MS: m/z (%) = 284 [M+ + 1] (24), 283 [M+] (100), 282 (22), 268
(14), 255 (20), 254 (91), 242 (14), 241 (17), 240 (25), 229 (24), 228
(75), 227 (68), 215 (26), 214 (25), 202 (32), 200 (36), 180 (16), 84
(13), 55 (11), 41 (17).
5-(Difluoromethyl)-7-methyl-2-piperidinothiazolo[4,5-b]pyri-
dine (24)
Colorless solid; yield: 51 mg (19%); mp 111–112 °C; Rf = 0.80
13C NMR (CDCl3): d = 21.5, 22.4, 24.1, 25.2, 29.5, 31.1, 49.5,
1
2
117.6, 122.7 (q, JCF = 275 Hz), 124.1, 140.9, 142.5 (q, JCF = 35
(EtOAc–hexane, 1:1).
Hz), 160.9, 169.2.
19F NMR (CDCl3): d = –64.4.
MS: m/z (%) = 342 [M+ + 1] (20), 341 (100), 340 (14), 326 (10), 313
(12), 312 (55), 298 (13), 287 (12), 286 (36), 285 (40), 273 (15), 272
(20), 259 (11), 258 (17), 257 (11), 84 (16), 69 (13), 55 (13), 41 (18).
1H NMR (CDCl3): d = 1.63 (br s, 6 H, CH2), 2.41 (s, 3 H, CH3), 3.69
(br s, 4 H, NCH2), 6.53 (t, 2JHF = 53 Hz, 1 H, CF2H), 6.90 (s, 1 H,
CH).
Synthesis 2008, No. 15, 2337–2346 © Thieme Stuttgart · New York

PAPER
Synthesis of Thiazolo[4,5-d]pyridines
2343
2-Piperidino-7-(trifluoromethyl)thiazolo[4,5-b]pyridin-5(4H)-
one (29a)
Recrystallized (MeOH); colorless solid; yield: 224 mg (74%); mp
255–257 °C.
AcOH (10 mL) and heated under reflux for 2 h. The soln was then
evaporated under reduced pressure, treated with H2O, filtered, dried
in air, and recrystallized from an appropriate solvent.
N-Cyclohexyl-5-phenyl-7-(trifluoromethyl)thiazolo[4,5-b]pyri-
din-2-amine (35a)
Recrystallized (EtOH); colorless solid; yield: 155 mg (41%); mp
229–230 °C.
1H NMR (DMSO-d6): d = 1.31–1.40 (m, 5 H, CH), 1.61–1.83 (m, 3
H, CH), 2.07–2.11 (m, 2 H, CH), 3.87 (br s, 1 H, CH), 7.45 (m, 3 H,
CH), 7.69 (s, 1 H, CH), 8.13 (d, 3JHH = 7.8 Hz, 2 H), 11.67 (br s, 1
H, NH).
1H NMR (DMSO-d6): d = 1.62 (br s, 6 H, CH), 3.59 (br s, 4 H,
NCH2), 6.41 (s, 1 H, CH), 12.07 (s, 1 H, CH).
13C NMR (DMSO-d6): d = 24.0, 25.5, 49.8, 103.8 (q, 3JCF = 3.1 Hz),
1
2
122.6 (q, JCF = 275 Hz), 133.4 (q, JCF = 35 Hz), 158.1, 162.4,
168.8, 206.3.
19F NMR (DMSO-d6): d = –64.
MS: m/z (%) = 304 [M+ + 1] (13), 303 [M+] (100), 302 (13), 275
(11), 274 (63), 260 (11), 248 (39), 247 (40), 235 (12), 234 (14), 221
(17), 220 (16), 56 (11).
3
13C NMR (CDCl3): d = 24.3, 25.0, 32.1, 55.2, 108.3 (q, JCF = 3.3
1
Hz), 123.0 (q, JCF = 275 Hz), 126.7, 128.7, 129.4, 131.5 (q,
2JCF = 35 Hz), 137.7, 154.1, 167.0, 170.0.
19F NMR (DMSO-d6): d = –63.
2-(Diethylamino)-7-(trifluoromethyl)thiazolo[4,5-b]pyridin-
5(4H)-one (29b)
Recrystallized (i-PrOH); colorless solid; yield: 210 mg (72%); mp
MS: m/z (%) = 377 [M+] (27), 296 (17), 295 (100), 291 (10).
182–183 °C.
N-Phenyl-5,7-bis(trifluoromethyl)thiazolo[4,5-b]pyridin-2-
amine (35b)
Recrystallized (EtOH); colorless solid; yield: 119 mg (33%); mp
224–225 °C.
1H NMR (DMSO-d6): d = 1.22 (t, 3JHH = 7.2 Hz, 6 H, CH3), 3.58 (q,
3JHH = 7.2 Hz, 4 H, NCH2), 6.41 (s, 1 H, CH), 12.08 (s, 1 H, NH).
3
13C NMR (DMSO-d6): d = 12.0, 45.1, 102.8 (q, JCF = 3.1 Hz),
1
2
122.1 (q, JCF = 275 Hz), 133.3 (q, JCF = 35 Hz), 159.7, 161.8,
3
1H NMR (DMSO-d6): d = 7.16 (t, JHH = 7.2 Hz, 1 H), 7.43 (t,
169.8, 207.0.
19F NMR (DMSO-d6): d = –64.
3JHH = 7.8 Hz, 2 H, CH), 7.81 (d, 3JHH = 7.8 Hz, 2 H, CH), 7.92 (s,
1 H, CH), 11.39 (br s, 1 H, NH).
MS: m/z (%) = 292 [M+ + 1] (12), 291 [M+] (84), 276 (29), 263 (15),
262 (68), 249 (11), 248 (100), 153 (15), 136 (12), 108 (15), 89 (22),
78 (12), 77 (37), 69 (22), 52 (13).
1
13C NMR (DMSO-d6): d = 108.9, 119.2, 120.0 (q, JCF = 275 Hz),
1
2
123.3 (q, JCF = 275 Hz), 124.2, 125.5, 129.3, 130.9 (q, JCF = 35
Hz), 139.0, 144.3 (q, 2JCF = 35 Hz), 165.7, 165.9.
19F NMR (DMSO-d6): d = –66, –64.
MS: m/z (%) = 364 [M+ + 1] (21), 363 [M+] (99), 362 (100), 344
2-(Pyrrolidin-1-yl)-7-(trifluoromethyl)thiazolo[4,5-b]pyridin-
5(4H)-one (29c)
Recrystallized (MeOH); colorless solid; yield: 223 mg (77%).
(11), 342 (13), 171 (10).
1H NMR (DMSO-d6): d = 2.13 (br s, 4 H, CH2), 3.60 (br s, 4 H,
N-Phenyl-5-(2-thienyl)-7-(trifluoromethyl)thiazolo[4,5-b]pyri-
din-2-amine (35c)
Recrystallized (MeOH); colorless solid; yield: 143 mg (38%); mp
209–210 °C.
NCH2), 6.44 (s, 1 H, CH), 12.01 (s, 1 H, CH).
3
13C NMR (DMSO-d6): d = 25.6, 50.1, 103.2 (q, JCF = 3.1 Hz),
1
2
122.4 (q, JCF = 275 Hz), 133.6 (q, JCF = 35 Hz), 159.7, 162.6,
168.0, 207.4
19F NMR (DMSO-d6): d = –64.
MS: m/z (%) = 291 [M+ + 1] (19), 289 [M+] (100), 288 (12), 261
(52), 260 (34), 247 (12), 234 (62), 70 (10), 69 (11), 55 (13).
1H NMR (DMSO-d6): d = 7.12–7.23, (m, 4 H, CH), 7.46 (dd,
3
3
3JHH = 5.1 Hz, JHH = 1.2 Hz, 1 H, CH), 7.72 (dd, JHH = 3.9 Hz,
3JHH = 1.2 Hz, 1 H, CH), 7.83 (d, 3JHH = 7.8 Hz, 2 H, CH), 8.05 (s,
1 H, CH), 10.89 (s, 1 H, NH).
13C NMR (DMSO-d6): d = 109.0, 118.5, 119.4, 122.3 (q, 1JCF = 275
2
6-(3-Hydroxypropyl)-2-piperidino-7-(trifluoromethyl)thiazo-
lo[4,5-b]pyridin-5(4H)-one (30)
Colorless solid; yield: 303 mg (84%); mp 195–197 °C; Rf = 0.7
(EtOAc).
1H NMR (DMSO-d6): d = 1.60 (br m, 6 H, CH2), 1.99 (br s, 2 H,
CH2), 2.87 (br s, 2 H, CH2), 3.55 (br s, 4 H, NCH2), 4.14 (br s, 2 H,
OCH2), 12.51 (br s, 1 H, NH).
13C NMR (DMSO-d6): d = 21.5, 23.7, 24.0, 26.1, 48.8, 61.6, 115.8
(q, 3JCF = 3.6 Hz), 123.0 (q, 1JCF = 275 Hz), 131.4 (q, 2JCF = 35 Hz),
155.5, 161.7, 170.1, 170.4.
19F NMR (DMSO-d6): d = –58.0.
MS: m/z (%) = 361 [M+] (3), 346 (21), 331 (17), 330 (54), 329 (100),
328 (27), 317 (21), 316 (86), 300 (14), 274 (12), 260 (17), 248 (11),
43 (15), 42 (19).
Hz), 124.1, 127.3, 129.1, 129.7, 131.4 (q, JCF = 35 Hz), 139.9,
143.9, 151.0, 165.4, 165.7.
19F NMR (DMSO-d6): d = –63.
MS: m/z (%) = 379 [M+ + 2] (11), 378 [M+ + 1] (29), 377 [M+]
(100), 376 (50), 189 (13), 107 (10), 89 (11), 77 (31), 52 (10).
7-[Chloro(difluoro)methyl]-N-cyclohexyl-5-thien-2-yl[1,3]thi-
azolo[4,5-b]pyridin-2-amine (35d)
Recrystallized (EtOH); colorless solid; yield: 150 mg (39%); mp
187–188 °C.
1H NMR (DMSO-d6): d = 1.30–1.40 (br m, 5 H, CH), 1.61–1.83 (m,
3 H, CH), 2.05–2.15 (br m, 2 H, CH), 3.88 (s, 1 H, CH), 7.19 (dd,
3
3
3JHH = 5.1 Hz, JHH = 3.9 Hz, 1 H, CH), 7.66 (dd, JHH = 5.1 Hz,
3JHH = 1.2 Hz, 1 H, CH), 7.81 (s, 1 H, CH), 7.97 (dd, 3JHH = 3.9 Hz,
3JHH = 1.2 Hz, 1 H, CH).
13C NMR (DMSO-d6): d = 25.0, 25.1, 32.9, 55.2, 107.4 (t,
3JCF = 3.1 Hz), 118.3, 125.0 (t, 1JCF = 281 Hz), 126.7, 129.0, 129.2,
137.2 (t, 2JCF = 30 Hz), 144.3, 150.4, 166.7, 170.5.
19F NMR (DMSO-d6): d = –52.
Thiazolo[4,5-d]pyridines 35; General Procedure
1-Aryl- or 1-alkylthiourea 34 (0.1 mmol) and chloroacetonitrile
(0.11 mmol) were dissolved in abs MeOH (15 mL) and heated under
reflux under N2 for 4 h. Then this soln was evaporated under re-
duced pressure. The formed brown oil, fluorine-containing 1,3-
diketone (0.1 mmol), and NaOAc (0.15 mmol) were dissolved in
Synthesis 2008, No. 15, 2337–2346 © Thieme Stuttgart · New York

2344
V. O. Iaroshenko et al.
PAPER
MS: m/z (%) = 402 [M+ + 2] (16), 401 [M+ + 1] (11), 399 [M+] (40),
5-Phenyl-2-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridine-7-carboxy-
313 (41), 312 (25), 311 (100), 276 (27), 56 (21).
lic Acid (37a)
Recrystallized (MeOH); colorless solid; yield: 2.24 g (69%); mp
>320 °C.
1H NMR (DMSO-d6): d = 2.05 (br s, 4 H, CH2), 3.59 (br s, 4 H,
NCH2), 7.43 (br m, 3 H, CH), 7.95 (s, 1 H, CH), 8.12 (d, 3JCH = 7.8
Hz, 2 H, CH).
13C NMR (DMSO-d6): d = 25.7, 49.7, 111.6, 124.2, 127.1, 129.3,
129.7, 134.1, 139.2, 154.2, 166.7, 166.9, 169.0.
MS: m/z (%) = 326 [M+ + 1] (23), 325 [M+] (100), 307 (10), 298
(15), 297 (53), 296 (26), 283 (13), 281 (16), 271 (13), 270 (70), 226
(11), 70 (12), 44 (19).
2-(4-Methylpiperazin-1-yl)-5-(2-thienyl)-7-(trifluorometh-
yl)thiazolo[4,5-b]pyridine (35e)
Recrystallized (i-PrOH); colorless solid; yield: 127 mg (33%); mp
153–155 °C.
1H NMR (DMSO-d6): d = 2.37 (br s, 3 H, NCH3), 2.55 (br s, 4 H,
3
NCH2), 3.83 (br s, 4 H, NCH2), 7.14 (t, JHH = 7.8 Hz, 3 H, CH),
7.56 (d, 3JHH = 7.8 Hz, 1 H, CH), 7.89 (d, 3JHH = 7.8 Hz, 1 H, CH).
13C NMR (DMSO-d6): d = 46.2, 48.4, 54.3, 107.8, 120.1 (q,
2
1JCF = 275 Hz), 125.6, 128.1, 132 (q, JCF = 35 Hz), 143.9, 151.2,
166.1, 170.8.
19F NMR (DMSO-d6): d = –66.
MS: m/z (%) = 385 [M+ + 1] (20), 384 [M+] (100), 372 (41), 315
2-Piperidino-5-(2-thienyl)thiazolo[4,5-b]pyridine-7-carboxylic
Acid (37b)
Recrystallized (MeOH); colorless solid; yield: 2.48 g (72%); mp
>320 °C
(57), 301 (35), 241 (11), 199 (18).
Thiazolo[4,5-d]pyridines 36, 38, 39; General Procedure
2-Aminothiazol-4(5H)-iminium salt (10 mmol) and the sodium salt
of ethyl 2,4-dioxo-4-aryl(methyl)butanoate 9 (10 mmol) were dis-
solved in AcOH (30 mL) and heated under reflux for 2 h. Then the
soln was evaporated under reduced pressure, treated with H2O, fil-
tered, dried in air, and then the residue was recrystallized from an
appropriate solvent or was subjected to column chromatography
(silica gel).
1H NMR (DMSO-d6): d = 1.67 (s, 6 H, CH), 3.67 (br s, 4 H, NCH2),
7.17 (dd, JHH = 5.1 Hz, JHH = 3.9 Hz, 1 H, CH), 7.61 (dd,
3JHH = 5.1 Hz, 3JHH = 1.2 Hz, 1 H, CH), 7.85 (s, 1 H, CH), 7.89 (dd,
3JHH = 3.9 Hz, 3JHH = 1.2 Hz, 1 H, CH).
13C NMR (DMSO-d6): d = 23.7, 25.3, 49.4, 111.9, 122.7, 125.3,
127.1, 127.9, 129.7, 144.4, 149.7, 163.0, 167.0, 169.9.
3
3
MS: m/z (%) = 346 [M+ + 1] (23), 345 [M+] (100), 328 (44), 261
(19), 83 (20).
Ethyl 5-Phenyl-2-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridine-7-
carboxylate (36a)
Recrystallized (MeOH); colorless solid; yield: 2.47 g (70%); mp
Methyl 5-Methyl-2-piperidinothiazolo[4,5-b]pyridine-7-car-
boxylate (38)
Colorless solid; yield: 1.16 g (41%); mp 108–109 °C; Rf = 0.5
(EtOAc–hexane, 1:1).
1H NMR (CDCl3): d = 1.61 (s, 6 H, CH), 2.59 (s, 3 H, CH3), 3.60
(br s, 4 H, NCH2), 4.05 (s, 3 H, CH3), 7.97 (s, 1 H, CH).
13C NMR (DMSO-d6): d = 23.3, 24.1, 25,3, 49.7, 55.4, 109.3,
124.7, 133.8, 141.1, 163.8, 165.4, 167.5.
MS: m/z (%) = 292 [M+ + 1] (17), 291 [M+] (100), 232 (21), 260
(50), 276 (52), 200 (17), 158 (14).
169–170 °C.
1H NMR (DMSO-d6): d = 1.40 (t, 3JHH = 7.2 Hz, 3 H, CH3), 2.04 (br
3
s, 4 H, CH2), 3.56 (br s, 4 H, NCH2), 4.44 (q, JHH = 7.2 Hz, 2 H,
OCH2), 7.43 (br m, 3 H, CH), 7.95 (s, 1 H, CH), 8.10 (d, 3JHH = 7.8
Hz, 2 H, CH).
13C NMR (DMSO-d6): d = 14.2, 25.3, 49.2, 61.2, 109.1, 124.5,
127.1, 129.5, 129.2, 134.1, 139.0, 154.7, 165.7, 166.9, 167.9.
MS: m/z (%) = 354 [M+ + 1] (22), 353 [M+] (100), 326 (11), 325
(46), 324 (13), 298 (41), 297 (10), 270 (22).
Methyl 7-Methyl-2-piperidinothiazolo[4,5-b]pyridine-5-car-
boxylate (39)
Colorless solid; yield: 437 mg (15%); mp 117–118 °C; Rf = 0.35
(EtOAc–hexane, 1:1).
1H NMR (CDCl3): d = 1.63 (s, 6 H, CH), 2.37 (s, 3 H, CH3), 3.65
(br s, 4 H, NCH2), 4.09 (s, 3 H, CH3), 7.89 (s, 1 H, CH).
13C NMR (DMSO-d6): d = 21.2, 25.2, 26.0, 48.9, 57.1, 112.0,
124.7, 133.0, 145.9, 164.2, 166.7, 168.0.
MS: m/z (%) = 292 [M+ + 1] (14), 291 [M+] (100), 232 (14), 260
(53), 276 (83).
Ethyl 2-Piperidino-5-(2-thienyl)thiazolo[4,5-b]pyridine-7-car-
boxylate (36b)
Recrystallized (MeOH); colorless solid; yield: 2.73 g (73%); mp
151 °C.
1H NMR (DMSO-d6): d = 1.40 (t, 3JHH = 7.2 Hz, 3 H, CH3), 1.67 (s,
3
6 H, CH), 3.69 (br s, 4 H, NCH2), 4.44 (q, JHH = 7.2 Hz, 2 H,
OCH2), 7.15 (dd, 3JHH = 5.1 Hz, 3JHH = 3.9 Hz, 1 H, CH), 7.63 (dd,
3JHH = 5.1 Hz, 3JHH = 1.2 Hz, 1 H, CH), 7.81 (s, 1 H, CH), 7.87 (dd,
3JHH = 3.9 Hz, 3JHH = 1.2 Hz, 1 H, CH).
13C NMR (DMSO-d6): d = 13.6, 23.4, 24.5, 48.9, 61.5, 108.9,
122.7, 124.7, 127.6, 127.8, 130.2, 144.0, 149.3, 163.8, 165.4, 167.5.
MS: m/z (%) = 374 [M+ + 1] (19), 373 [M+] (100), 300 (21), 290
(33), 200 (10).
(E)-3-[4-Amino-2-(pyrrolidin-1-yl)thiazol-5-yl]-1-phenylprop-
2-en-1-one (40)
2-Aminothiazol-4(5H)-iminium salt 1 (NR1 = pyrrolidin-1-yl) (1
2
mmol) and the sodium salt of 3-oxo-3-phenylpropanal 10 (R2 = Ph,
R3 = H) (1 mmol) were dissolved in abs EtOH (40 mL) and stirred
for 24 h under N2. The red precipitate that formed was filtered,
washed with cold H2O (2 ×) and i-PrOH (2 ×), dried in air, and re-
crystallized (MeOH) to give a red-colored solid; yield: 990 mg
(33%); mp 214 °C.
2-(Dialkylamino)thiazolo[4,5-b]pyridine-7-carboxylic Acids37;
General Procedure
Ethyl carboxylate 36 (10 mmol) and NaOH (50 mmol) were dis-
solved in MeOH (20 mL) and heated under reflux for 2 h. Then soln
was left overnight at 0 °C, the thus formed precipitate was filtered
and dried in air. Then it was dissolved in H2O and AcOH (2 mL)
was added, after 2–4 h the precipitate was filtered and dried in air.
1H NMR (DMSO-d6): d = 1.99 (br s, 4 H, NCH2), 3.50 (br s, 4 H,
CH2), 6.13 (d, 3JHH = 14 Hz, 1 H, CH), 7.29 (s, 2 H, NH2), 7.48 (br
m, 3 H, CH), 7.87 (d, 3JHH = 7.2 Hz, 2 H), 8.15 (d, 3JHH = 14 Hz, 1
H, CH).
Synthesis 2008, No. 15, 2337–2346 © Thieme Stuttgart · New York

PAPER
Synthesis of Thiazolo[4,5-d]pyridines
2345
13C NMR (DMSO-d6): d = 25.2, 49.7, 94.5, 104.3, 127.4, 128.0,
130.7, 134.5, 140.0, 164.3, 169.1, 184.8.
1H NMR (CDCl3): d = 1.69 (br s, 6 H, CH), 3.91 (br s, 4 H, CH),
7.24 (d, 3JHH = 7.8 Hz, 1 H, CH), 7.95 (d, 3JHH = 7.8 Hz, 1 H, CH).
13C NMR (CDCl3): d = 24.3, 25.1, 48.7, 114.8 (t, JCF = 4.2 Hz),
3
5-Phenyl-2-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridine (41)
119.7, 130.3, 132.0, 146.1 (t, 2JCF = 27 Hz), 164.1, 170.0.
(E)-3-(4-Dialkylamino)-1-phenylprop-2-en-1-one (40, 0.1 mmol)
was dissolved in TFA (15 mL) and stirred for 5–8 h (until the red
color vanished). The soln was evaporated under reduced pressure
and the residual oil was treated with 0.1 M NaHCO3 soln. The pre-
cipitate was filtered and washed with H2O (2 ×) and dried in air to
give a colorless solid; yield: 273 mg (97%); mp 158–159 °C.
1H NMR (CF3CO2D): d = 2.33 (br s, 4 H, CH2), 3.69 (br s, 2 H,
NCH2), 3.95 (br s, 2 H, NCH2), 7.68–7.85 (m, 6 H, CH), 8.56 (d,
3JHH = 7.8 Hz, 1 H, CH).
13C NMR (DMSO-d6, 120 °C): d = 25.0, 50.2, 105.2 117.1, 128.9,
129.9, 130.9, 135.7, 140.0, 155.7, 166.1, 170.9.
MS: m/z (%) = 282 [M+ + 1] (32), 281 [M+] (100), 280 (11), 263
(12), 254 (15), 253 (71), 252 (32), 239 (18), 227 (19), 226 (80), 212
(11), 141 (12), 140 (14), 115 (22), 105 (20), 97 (17), 70 (53), 55
(34).
19F NMR (CDCl3): d = –125.0 (s, 2 F), –115.3 (qv, 4JFF = 9.4 Hz, 2
F), –81.7 (qv, 4JFF = 9.4 Hz, 3 F).
MS: m/z (%) = 338 [M+ + 1] (18), 387 [M+] (100), 386 (13), 372
(11), 368 (14), 359 (10), 358 (69), 344 (12), 333 (17), 332 (32), 331
(33), 318 (20), 305 (23), 304 (25), 200 (18), 213 (13), 185 (12), 158
(30), 84 (10), 77 (17), 55 (22), 43 (11), 41 (36).
2-(Pyrrolidin-1-yl)-7-(trifluoromethyl)thiazolo[4,5-b]pyridine
(47a)
Colorless solid; yield: 273 mg (50%); mp 151–153 °C; Rf = 0.3
(EtOAc–hexane, 1: 2).
1H NMR (CDCl3): d = 2.07 (br s, 4 H, CH), 3.67 (br s, 4 H, NCH2),
7.05 (d, 3JHH = 4.2 Hz, 1 H, CH), 8.47 (d, 3JHH = 4.2 Hz, 1 H, CH).
13C NMR (CDCl3): d = 25.5, 49.5, 111.2 (q, 3JCF = 3.4 Hz), 120.9,
1
2
123.5 (q, JCF = 275 Hz), 131.2 (q, JCF = 35 Hz), 147.1, 166.3,
166.9.
Thiazolo[4,5-d]pyridines 46–48; General Procedure
19F NMR (CDCl3): d = –64.
MS: m/z (%) = 274 [M+ + 1] (13), 273 [M+] (90), 254 (12), 245 (74),
244 (50), 231 (14), 219 (13), 218 (100), 204 (13), 198 (15), 177
(21), 158 (12).
2-Aminothiazol-4(5H)-iminium salt 1 (0.1 mmol) and 2-alkoxyvi-
nyl trihalomethyl ketone 11–16 (0.1 mmol) were dissolved in anhyd
CH2Cl2 (15 mL) and dropped with chilling of Et3N (0.2 mmol) in
CH2Cl2 (10 mL). The soln was left for 36 h and then was heated un-
der reflux for 10–14 h until the cyclic product had formed. Then
soln was treated with distilled H2O (×), dried (MgSO4), and purified
by flash column chromatography.
7-(Chlorodifluoromethyl)-2-piperidinothiazolo[4,5-b]pyridine
(47b)
Colorless solid; yield: 284 mg (47%); mp 80–81 °C; Rf = 0.35
(EtOAc–hexane, 1:2).
2-(Pyrrolidin-1-yl)-5-(trifluoromethyl)thiazolo[4,5-b]pyridine
(46a)
Colorless solid; yield: 93 mg (17%); mp 192–194 °C; Rf = 0.6
(EtOAc–hexane, 1:2).
1H NMR (CDCl3): d = 1.61 (br s, 6 H, CH), 3.79 (br s, 4 H, CH),
7.01 (d, 3JHH = 4.2 Hz, 1 H, CH), 8.37 (d, 3JHH = 4.2 Hz, 1 H, CH).
3
13C NMR (CDCl3): d = 23.9, 25.5, 49.5, 111.2 (q, JCF = 4.1 Hz),
1H NMR (CDCl3): d = 2.03 (br s, 4 H, CH2), 3.53 (br s, 4 H, NCH2),
1
2
7.22 (d, 3JHH = 7.8 Hz, 1 H, CH), 7.90 (s, 3JHH = 7.8 Hz, 1 H, CH).
120.9, 123.5 (q, JCF = 275 Hz), 131.2 (q, JCF = 35 Hz), 147.1,
166.3, 166.9.
19F NMR (CDCl3): d = –52.
13C NMR (CDCl3): d = 25.6, 49.8, 112.0 (q, 3JCF = 3.2 Hz), 120.9,
1
2
121.9 (q, JCF = 275 Hz), 128.7, 129.4, 145.2 (q, JCF = 35 Hz),
164.5, 167.3.
19F NMR (CDCl3): d = –67.
MS m/z (%): 274 [M+ + 1] (13), 273 [M+] (79), 255 (14), 254 (11),
245 (70), 244 (48), 231 (14), 219 (12), 218 (100), 177 (11).
MS: m/z (%) = 305 [M+ + 2] (40), 304 [M+ + 1] (24), 303 [M+]
(100), 302 (16), 288 (13), 276 (31), 275 (16), 274 (73), 268 (24),
262 (19), 261 (14), 260 (17), 250 (24), 249 (32), 248 (54), 247 (40),
234 (17), 222 (15), 221 (21), 220 (30), 213 (17), 212 (15), 200 (22),
185 (17), 158 (38), 84 (20), 69 (31), 56 (13), 55 (19), 42 (14), 41
(54).
5-(Chlorodifluoromethyl)-2-piperidinothiazolo[4,5-b]pyridine
(46b)
7-(Heptafluoropropyl)-2-piperidinothiazolo[4,5-b]pyridine
(47c)
Colorless solid; yield: 348 mg (45%); mp 132–134 °C; Rf = 0.4
(EtOAc–hexane, 1:2).
Colorless solid; yield: 109 mg (18%); mp 168–170 °C; Rf = 0.6
(EtOAc–hexane, 1:2).
1H NMR (CDCl3): d = 1.63 (br s, 6 H, CH), 3.80 (br s, 4 H, CH),
7.18 (d, 3JHH = 7.8 Hz, 1 H, CH), 7.93 (d, 3JHH = 7.8 Hz, 1 H, CH).
1H NMR (CDCl3): d = 1.67 (br s, 6 H, CH), 3.88 (br s, 4 H, CH),
13C NMR (CDCl3): d = 24.2, 26.1, 49.2, 115.0 (t, JCF = 3.4 Hz),
120.1, 122.7 (t, JCF = 255 Hz), 129.4, 131.1, 145.0 (t, JCF = 27
Hz), 164.1, 167.9.
19F NMR (CDCl3): d = 54.
MS: m/z (%) = 305 [M+ + 2] (40), 304 [M+ + 1] (23), 303 [M+]
(100), 302 (16), 288 (13), 276 (23), 275 (13), 274 (57), 268 (39),
262 (14), 261 (13), 260 (13), 250 (16), 249 (22), 248 (38), 247 (31),
235 (18), 220 (22), 212 (36), 200 (44), 185 (19), 158 (35), 84 (13),
69 (21), 55 (12), 42 (30).
3
6.99 (d, 3JHH = 4.2 Hz, 1 H, CH), 8.43 (d, 3JHH = 4.2 Hz, 1 H, CH).
1
2
3
13C NMR (CDCl3): d = 23.8, 25.1, 48.1, 113.5 (t, JCF = 5.6 Hz),
122.9, 129.0 (t, 2JCF = 27 Hz), 145.3, 168.0, 171.6.
19F NMR (CDCl3): d = –124.6 (s, 2 F), –113.9 (qv, 4JFF = 9.4 Hz, 2
F), –80.5 (qv, 4JFF = 9.4 Hz, 3 F).
MS: m/z (%) = 338 [M+ + 1] (17), 387 [M+] (100), 386 (14), 372
(14), 368 (13), 359 (15), 358 (74), 345 (14), 344 (15), 333 (16), 332
(50), 331 (42), 318 (14), 305 (19), 304 (28), 239 (11), 213 (19), 185
(16), 158 (25), 84 (15), 77 (19), 69 (20), 55 (22), 43 (11), 41 (36).
5-(Heptafluoropropyl)-2-piperidinothiazolo[4,5-b]pyridine
(46c)
Colorless solid; yield: 132 mg (17%); mp 123–125 °C; Rf = 0.7
(EtOAc–hexane, 1:2).
5-Ethoxy-2-piperidino-7-(trifluoromethyl)thiazolo[4,5-b]pyri-
dine (48)
Colorless solid; yield: 483 mg (73%); mp 108–110 °C; Rf = 0.70
(EtOAc–hexane, 1:4).
Synthesis 2008, No. 15, 2337–2346 © Thieme Stuttgart · New York

2346
V. O. Iaroshenko et al.
PAPER
(4) (a) Flaig, R.; Hartmann, H. Monatsh. Chem. 1997, 128,
1H NMR (CDCl3): d = 1.35 (t, 3JHH = 7.2 Hz, 3 H, CH), 1.66 (br s,
6 H, CH), 3.64 (br s, 4 H, CH), 4.42 (q, JHH = 7.2 Hz, 2 H, CH),
6.61 (s, 1 H, CH).
3
1051. (b) El-Desoky, E. I.; Aboul-Fetouh, S.; Metwally, M.
A. J. Chem. Technol. Biotechnol. 1996, 67, 153.
(c) Komaritsa, I. D. Khim. Geterotsikl. Soedin. 1989, 11,
1547.
13C NMR (CDCl3): d = 14.5, 24.0, 25.3, 49.5, 62.4, 100.0 (q,
1
2
3JCF = 4 Hz), 110.5, 122.3 (q, JCF = 275 Hz), 133.5 (q, JCF = 35
(5) For our previous work with aminoheterocycles see:
(a) Volochnyuk, D. M.; Pushecnikov, A. O.; Krotko, D. G.;
Sibgatulin, D. A.; Kovaleva, S. A.; Tolmachev, A. A.
Synthesis 2003, 1531. (b) Volochnyuk, D. M.; Kostyuk, A.
N.; Pinchuk, A. M.; Tolmachev, A. A. Tetahedron Lett.
2003, 44, 391. (c) Pushechnikov, A. O.; Volochnyuk, D. M.;
Tolmachev, A. A. Synlett 2002, 1040. (d) Vovk, M. V.;
Bol’but, A. V.; Volochnyuk, D. M.; Pinchuk, A. M. Russ. J.
Org. Chem. 2004, 40, 63. (e) Ryabukhin, S. V.; Plaskon, A.
S.; Volochnyuk, D. M.; Tolmachev, A. A. Synthesis 2007,
1861. (f) Iaroshenko, V. O.; Volochnyuk, D. M.; Wang, Y.;
Vovk, M. V.; Boiko, V. J.; Rusanov, E. B.; Groth, U. M.;
Tolmachev, A. O. Synthesis 2007, 3309.
(6) Flaig, R.; Hartmann, H. J. Heterocycl. Chem. 1997, 34,
1291.
(7) (a) Yokoyama, M.; Kurauchi, M.; Imamoto, T. Tetrahedron
Lett. 1981, 22, 2285. (b) Kikelj, D.; Urleb, U. Science of
Synthesis, Vol. 11; Schaumann, E., Ed.; Georg Thieme
Verlag: Stuttgart, 2002, 627.
Hz), 163.3, 164.1, 170.0.
19F NMR (CDCl3): d = –65.
MS: m/z (%) = 333 [M+ + 2] (12), 332 [M+ + 1] (35), 331 [M+]
(100), 317 (13), 316 (70), 303 (35), 302 (47), 288 (20), 276 (28),
275 (48), 275 (46), 248 (38), 247 (25), 221 (13), 220 (12), 69 (12),
55 (11), 41 (17).
Acknowledgment
To the Enamine Ltd (Ukraine) for generous gifts of reagents. We
thank also Prof. Dr. Sosnovskikh V. Ya (Department of Chemistry,
Ural State University) for the discussion of the obtained results and
for help during the preparation of the manuscript. Also a special
acknowledgment to Prof. Dr. Andreas Marx for financial support.
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Synthesis 2008, No. 15, 2337–2346 © Thieme Stuttgart · New York