Solid-phase synthesis of thiazolo[4,5-b]pyridine derivatives using friedlaender reaction

Article abstract of DOI:10.1021/cc900147y

Traceless solid-phase synthesis of 2,5,6,7-tetrasubstituted thiazolo[4,5-]pyridine derivatives is described. Thorpe-Ziegler type cyclization of solid supported cyanocarbonimidodithioate with a-hal.o ketones afforded thiazole resin, which were converted to the desired thiazolopyridine resin by the Friedlaender protocol under microwave irradiation conditions. After oxidation of sulfides to sulfones, nucleophilic desulfonative substitution with amines gave the target thiazolo[4,5- &lpyridme derivatives in good overall yields.

Full text of DOI:10.1021/cc900147y

J. Comb. Chem. 2010, 12, 95–99
95
Solid-Phase Synthesis of Thiazolo[4,5-b]pyridine Derivatives Using
Friedla¨nder Reaction
Taeho Lee,*,† Doohyun Lee,† Ill Young Lee,† and Young-Dae Gong‡
Center for High Throughput Synthesis Platform Technology, Korea Research Institute of Chemical
Technology, P.O. Box 107, Singseongno, Yuseong-gu, Daejeon 305-600, Korea, and Department of
Chemistry, Science College, Dongguk UniVersity, 26 Pildong 3-ga, Jung-gu, Seoul 100-715, Korea
ReceiVed September 24, 2009
Traceless solid-phase synthesis of 2,5,6,7-tetrasubstituted thiazolo[4,5-b]pyridine derivatives is described.
Thorpe-Ziegler type cyclization of solid supported cyanocarbonimidodithioate with R-halo ketones afforded
thiazole resin, which were converted to the desired thiazolopyridine resin by the Friedla¨nder protocol under
microwave irradiation conditions. After oxidation of sulfides to sulfones, nucleophilic desulfonative
substitution with amines gave the target thiazolo[4,5-b]pyridine derivatives in good overall yields.
Introduction
the first solid-phase synthetic protocol for the preparation
of 2,5,6,7-tetrasubstituted thiazolo[4,5-b]pyridines 1 (see
Figure 1), which is applicable to high throughput construction
of drug-like compound libraries.
The thiazole and fused-thiazole heterocycles are important
structural components of bioactive molecules, and, as a result,
they serve as attractive targets for combinatorial library
construction via solution- and solid-phase synthesis.1,2
Because of their pharmaceutical importance in the area of
drug discovery, we have been interested in developing an
efficient protocol to prepare fused-thiazole scaffolds such as
2,5,6,7-tetrasubstituted thiazolo[4,5-b]pyridines 1 and re-
cently reported a facile and rapid traceless linker based solid-
phase strategy for the preparation of a small molecule library
based on the thiazoles,3a thiazolo[4,5-c][1,2]thiazin-4(3H)one-
2,2-dioxide,3b and thiazolo[4,5-d]pyrimidine-5,7-dione3c (Fig-
ure 1).
Thiazolo[4,5-b]pyridine derivatives (1, Figure 1) exhibit
a wide range of biological properties.4 For example, thia-
zolo[4,5-b]pyridines have demonstrated activities as epider-
mal growth factor receptor (EGFR) tyrosine kinase
inhibitors,4a as metabotropic glutamate receptor 5 (mGluR5)
antagonists for various CNS disorders,4b as serine protease
factor Xa (fXa) inhibitors for thrombosis,4c as histamine H3-
receptor antagonists for epilepsy and Alzheimer’s disease,4d
and as cAMP phosphodiesterase (PDE) III inhibitors for
congestive heart failure.4e
Thus, many synthetic methods for thiazolo[4,5-b]pyridine
derivatives have been well documented.5 In addition, Kirsch
and co-workers reported a solution-phase synthesis of
7-amino-thiazolo[4,5-b]pyridine derivatives5a as well as
fused-pyridine derivatives such as the selenopheno[2,3-b]
pyridines6a and thiopheno[2,3-b]pyridines6b using the Fried-
la¨nder reaction. However, to the best of our knowledge, there
is no report which describes the synthesis of thiazolo[4,5-b]
pyridine derivatives on solid support. Herein, we wish to
represent our recent progress on this project which includes
Results and Discussion
In preliminary studies, the initial synthetic route began with
the conversion of the known thiazole 27 to thiazolo[4,5-b]
pyridine 4 via the Friedla¨nder reaction using microwave
(MW) irradiation with cyclohexanone 3 that serve as one
diversity element (Table 1).5a,6,8 Recently, microwave ir-
radiation has been shown to be a powerful tool for various
solution- or solid-phase chemical reactions.9
First, two reaction parameters (amounts of AlCl3 and MW
irradiation time) were examined for the reaction of thiazole
2a and 3 (Table 1, entries 1-4). Under these conditions,
MW irradiation (15 min) and AlCl3 (3.0 equiv.) gave the
best result with a high yield (91%) of thiazolo[4,5-b]pyridine
4a (entry 4). Under conventional heating conditions (entry
5), product 4a was obtained with an 85% yield. The
Friedla¨nder reaction was attempted with FeCl3,8a LiBr,8b or
TsOH8c instead of AlCl3 in acetonitrile using MW irradiation
(entries 6-8). The conditions with FeCl3 led to a poor yield
(36%) of thiazolo[4,5-b]pyridine 4a, whereas the cases of
LiBr and TsOH were unsuccessful. In trials for expansion
of diversity in the target thiazolo[4,5-b]pyridines 1 (entries
9-11), the desired thiazolo[4,5-b]pyridine derivatives 4b,
* To whom correspondence should be addressed. E-mail: taeholee@
krict.re.kr. Phone: 82-42-860-7693. Fax: 82-42-860-7698.
† Korea Research Institute of Chemical Technology.
‡ Dongguk University.
Figure 1. Structure of the thiazole and fused-thiazoles.
10.1021/cc900147y  2010 American Chemical Society
Published on Web 12/02/2009

96 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Lee et al.
Table 1. Synthesis of Thiazolo[4,5-b]pyridine 4 under the
Scheme 2. Solid-Phase Synthesis of Thiazolo[4,5-b]pyridine
Derivatives 1
Friedla¨nder Reactiona
entry reactant
reagent
reaction condition product yield (%)b
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
AlCl3 (1.5 equiv)
AlCl3 (0.5 equiv)
AlCl3 (3.0 equiv)
AlCl3 (3.0 equiv)
AlCl3 (3.0 equiv)
FeCl3 (3.0 equiv)
LiBr (3.0 equiv)
MW (5 min)
MW (5 min)
MW (5 min)
MW (15 min)
reflux, 12 h
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
72
23c
86
91
85
MW (15 min)
MW (15 min)
36c
N.R.d
N.R.d
N.R.d
N.R.d
N.R.d
TsOH (3.0 equiv) MW (15 min)
9
10
11
AlCl3 (3.0 equiv)
AlCl3 (3.0 equiv)
AlCl3 (3.0 equiv)
MW (15 min)
MW (15 min)
MW (15 min)
at 3469 and 3321 cm-1 (Figure 2). The thiazole resin 10
were then reacted under the Friedla¨nder reaction condition
with a ketone (AlCl3 and MW irradiation). The progress of
this process, which efficiently produced the thiazolo[4,5-
d]pyridine resin 11 (R1 ) Ph, R2 and R3 ) -(CH2)4-) and
introduced the second potential diversity element R2 and R3,
was monitored by using ATR-FTIR (specifically, the disap-
pearance of the ketone carbonyl stretching band at 1600 cm-1
and the NH2 stretching bands at 3469 and 3321 cm-1).
Treatment of resin 11 with mCPBA in CH2Cl2 provided the
resin-bound sulfone intermediate 12. Although this reaction
is not amenable to ATR-FTIR monitoring, solid- and
solution-phase thiazole synthetic studies are well-known.3,12
Finally, the sulfone group in resin 12 was displaced by a
desulfonative substitution reaction with the corresponding
amines (benzylamine for 1a), serving as a third diversity
element in THF.13 This process, which is accompanied by
a All reactions, unless otherwise noted, were performed on 2 (0.2
mmol) and 3 (0.4 mmol) using MW irradiation at 150 °C. b Isolated
yield. c Starting material 2a was recovered. d No reaction.
Scheme 1. Synthesis of Thiazolo[4,5-b]pyridine 1a
4c, and 4d were not obtained under MW irradiation with
AlCl3 from 2b, 2c, and 2d, respectively.
With optimized Friedla¨nder reaction conditions for the
formation of 4a, the stage progressed to the corresponding
thiazolo[4,5-b]pyridines 1a (Scheme 1). The resulting thia-
zolo[4,5-b]pyridine 4a was oxidized to form sulfone 5 by
treatment with mCPBA in CH2Cl2. The sulfone group in 5
without additional purification was displaced by benzylamine
in CH2Cl2 to produce the target thiazolo[4,5-b]pyridine
derivative 1a (61% yield from 4a). This product was
1
characterized by using ESI-LC-MS as well as H and 13C
NMR spectroscopy.10 Overall, this efficient and practical
solution-phase synthetic route is available for solid-phase
synthesis of 2,5,6,7-tetrasubstituted thiazolo[4,5-b]pyridine
derivatives 1.
The solid-phase synthetic route for preparation of thia-
zolo[4,5-d]pyridine derivatives utilizes appropriate R-bro-
moacetophenones, ketones, and amines as key building
blocks and diversity elements. The sequence began with the
formation of the known solid supported cyanocarbonimi-
dodithioate 63 through the reaction of Merrifield resin 7 with
dipotassium cyanodithioimidocarbonate 811 (Scheme 2).
The resin 6 were first swollen in DMF and then treated
with R-bromoacetophenone 9 (the first diversity element) and
triethylamine at 80 °C to give the corresponding thiazole
resin 10 via the Thorpe-Ziegler cyclization.3,7 The reaction
progress (R1 ) Ph) was monitored by using ATR-FTIR
(Attenuated Total Reflection Fourier Transform Infrared)
which showed the disappearance of the nitrile stretching band
at 2170 cm-1 and the appearance of the ketone carbonyl
stretching band at 1600 cm-1 and the NH2 stretching bands
Figure 2. ATR-FTIR spectra of resins 6, 10, 11, and 12 (R1 ) Ph,
R2 and R3 ) -(CH2)4-).

Solid-Phase Synthesis of Thiazolo[4,5-b]pyridines
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 97
Table 2. Thiazolo[4,5-b]pyridine Derivatives1 Using the Solid-Phase Synthetic Routea
a All reactions were performed on 150-200 mg scale of resin 12. b Five-step overall isolated yield from Merrifield resin 7 (loading capacity ) 0.94
mmol/g).
concurrent cleavage from the resin, furnished the final
thiazolo[4,5-d]pyridine derivative 1a (32% over five steps,
from Merrifield resin 7)14 which was purified by column
chromatography. The H NMR spectrum of thiazolo[4,5-
d]pyridine 1a matched that of material produced by using
When the R1 is phenyl, 4-methoxyphenyl, or 4-nitrophenyl,
the corresponding thiazolo[4,5-d]pyridines are formed in
good overall yields (Table 2: for Ph, entries 1-8, 27-35%;
for 4-MeO-Ph, entries 29-32, 32-48%; and for 4-NO2-Ph,
entries 41-45, 35-45%). In cases where the R2 and R3
substituents are cyclized moieties, the yield of target product
1 is high in accordance with the ring size of cycloalkanone
(R1 ) Ph: cyclopentanone, entries 9-13, 13-21%; cyclo-
hexanone, entries 1-8, 27-35%; and cycloheptanone, entries
14-18, 34-50%). Also, in cases where the R2 and R3
substituents are non-cyclized moiety from 3-pentanone, the
1
the solution-phase synthetic route.
By using the new solid-phase synthetic route, we were
able to prepare a number of thiazolo[4,5-d]pyridine deriva-
tives displayed in Table 2 starting from Merrifield resin 7
and appropriate R-bromoacetophenones (R1COCH2Br), ke-
tones (R2CH2COR3), and amines (R4R5NH).

98 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Lee et al.
D. J. Comb. Chem. 2009, 11, 288–293. (c) Lee., T.; Park,
J.-H.; Lee, D.-H.; Gong, Y.-D. J. Comb. Chem 2009, 11, 495–
499.
products 1 are obtained in moderate yields (entries 19-23
and entries 37-40). However, when the R2 and R3 substit-
uents are from cyclohexan-1,3-dione, the overall yields are
lower (entries 24-28, 16-24%). Among the R4R5NH series,
desulfonative nucleophilic substitution takes place smoothly
with benzyl, primary aliphatic, and secondary amines (entries
1-8). The isolated overall yields for thiazolo[4,5-d]pyridines
ranged from 13 to 50% for the five step linear pathway from
the Merrifield resin 7, indicating that the average yield for
each step is 67 to 87%). Moreover, the target compounds
are furnished in high purities following column chromatog-
raphy [>95% as judged from LC-MS traces (integration of
diode array 200-400 nm traces)] and characterized by using
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1
MS, as well as H NMR spectroscopy.
In summary, this investigation has led to the development
of the first traceless solid-phase synthetic route that efficiently
generated 2,5,6,7-tetrasubstituted thiazolo[4,5-b]pyridine de-
rivatives, which is one of the fused-thiazole scaffolds. The
sequence contains four diversity sites that are introduced in
reactions involving R-bromoacetophenones (R1), ketones (R2
and R3), and amines (R4R5N). The strategy, based on an
efficient solution-phase sequence, allows for a ready access
to a large library and is potentially applicable to the
preparation of other drug-like fused-thiazole ring systems.
Further studies in this area are underway, the results of which
will be reported in due course.
Acknowledgment. This work was supported by the Korea
Science and Engineering Foundation (KOSEF) grant funded
by the Korea government (MEST) (R01-2008-000-020205-
0), and a grant (2008-05681) from the R&D Program,
Ministry of Education, Science and Technology, Korea.
Supporting Information Available. Full experimental
procedures, analytical data of compounds, copies of 1H NMR
and LC-MS spectra of compounds 1a-1ax and 4a, and 13C
NMR spectra of compounds 1a and 4a. This material is
available free of charge via the Internet at http://pubs.acs.org.
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Solid-Phase Synthesis of Thiazolo[4,5-b]pyridines
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 99
127.8, 128.0, 128.3, 128.7, 128.8, 137.5, 138.6, 142.9, 155.1,
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CC900147Y