Solid-Phase Parallel Synthesis of N-Substituted-2-aminothiazolo[4,5-b]pyrazine Derivatives via Tandem Reaction of Isothiocyanate Terminated Resin with o-Bromo-2-Aminopyrazines

Article abstract of DOI:10.1021/acscombsci.6b00127

A novel solid-phase synthesis methodology of N-substituted-2-aminothiazolo[4,5-b]pyrazine derivatives was developed. The key step in this synthesis strategy is the tandem reaction of isothiocyanate terminated resin 2 with o-bromo-2-aminopyrazine, affording cyclized 2-aminothiazolo[4,5-b]pyrazine resin 4. To increase the diversity of our library, Suzuki coupling reaction was performed at the position C6. Further functionalization of 2-aminothiazolo[4,5-b]pyrazine core skeleton with various electrophiles such as alkyl halides, acyl chlorides, and sulfonyl chlorides and cleavage from the resin with TFA in DCM generated N-alkyl-, N-acyl-, and N-sulfonyl-2-aminothiazolo[4,5-b]pyrazine derivatives. The physicochemical properties and the polar surface areas of synthesized compounds were evaluated.

Full text of DOI:10.1021/acscombsci.6b00127

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Article
Solid-Phase Parallel Synthesis of N-Substituted-2-
aminothiazolo[4,5-b] pyrazine Derivatives via Tandem Reaction of
Isothiocyanate Terminated Resin with o-Bromo-2-Aminopyrazines
Aizhan Abdildinova, Seung-Ju Yang, and Young-Dae Gong
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.6b00127 • Publication Date (Web): 19 Oct 2016
Downloaded from http://pubs.acs.org on October 23, 2016
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SolidꢀPhase Parallel Synthesis of N-Substitutedꢀ2ꢀaminothiazolo[4,5ꢀb]
pyrazine Derivatives via Tandem Reaction of Isothiocyanate Terminated
Resin with oꢀBromoꢀ2ꢀAminopyrazines
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Aizhan Abdildinova, SeungꢀJu Yang, YoungꢀDae Gong*
Innovative Drug Library Research Center, Department of Chemistry, College of Science,
Dongguk University, 26, 3-ga, Pil-dong, Jung-gu, Seoul 04620, Korea
ABSTRACT
A novel solidꢀphase synthesis methodology of Nꢀsubstitutedꢀ2ꢀaminothiazolo[4,5ꢀb]pyrazine
derivatives was developed. The key step in this synthesis strategy is the tandem reaction of
isothiocyanate terminated resin 2 with oꢀbromoꢀ2ꢀaminopyrazine, affording cyclized 2ꢀ
aminothiazolo[4,5ꢀb]pyrazine resin 4. To increase the diversity of our library, Suzuki coupling
reaction was performed at the position C6. Further functionalization of 2ꢀaminothiazolo[4,5ꢀ
b]pyrazine core skeleton with various electrophiles such as alkyl halides, acyl chlorides, and
sulfonyl chlorides and cleavage from the resin with TFA in DCM generated Nꢀalkylꢀ, Nꢀacylꢀ,
and Nꢀsulfonylꢀ2ꢀaminothiazolo[4,5ꢀb]pyrazine derivatives. The physicochemical properties and
the polar surface areas of synthesized compounds were evaluated.
KEYWORDS: solidꢀphase, thiazolo[4,5ꢀb]pyrazine, BOMBA resin, tandem reaction
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INTRODUCTION
The solidꢀphase organic synthesis (SPOS) is one of the powerful tools in the synthesis of small
organic molecules and building of libraries of compounds for drug discovery. In SPOS, an
excess of reagents can be used to drive reaction to completion. Also products can be easily
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isolated by simple filtration and removed from solid support. Other benefits of solidꢀphase are
the ease of automation and the ability of polymer to “fish out” low concentrations of product
2
molecules from excess of starting material. Heterocyclic compounds usually serve as a
3
backbone for hundreds of marketed drugs. In this respect, we have been interested in
thiazolo[4,5ꢀb]pyrazine core skeleton. Even though thiazolo[4,5ꢀb]pyrazine has not been
4
investigated enough in the medicinal chemistry area, we have focused on it because of its
structural similarity with thiazolopyrimidine (Figure 1).
(
a)
(
b)
Figure 1. Comparison of energy minimized 3D structure (a) and polar surface area (b) of
thiazolopyrimidine and thiazolopyrazine
Thiazolopyrimidine core skeleton has shown various biological activities in the medicinal
5
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chemistry area such as kinase inhibitors, TRPV1 antagonists, E. coli and S. aureus SecA
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8
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inhibitors, stearoylꢀCoA desaturase (SCD) inhibitor, adenosine A3 receptor antagonist. Figure
1 shows similar structural features of thiazolopyrimidine and thiazolopyrazine (Figure 1a). The
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only difference is the position of nitrogen atom equipped in each core skeleton, and this
positional difference causes different polar surface area (Figure 1b). In drug discovery, polar
surface area is considered as a key factor to interact with target protein by nonꢀcovalent
interaction, and positional difference of nitrogen atom has a different possibility for hydrogen
bonding. In this respect, thiazolo[4,5ꢀb]pyrazine was expected to exhibit various biological
activities and good physicochemical properties.
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Scheme 1. Synthetic Strategy for the Synthesis of
]pyrazines
N
ꢀSubstitutedꢀ2ꢀaminothiazolo[4,5ꢀ
b
(a) Synthesis in Solution Phase
(b) Synthesis on Solid Phase
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Several solutionꢀphase synthesis routes of 2ꢀaminothiazolopyrazines have been published. We
have been interested in the synthesis of 2ꢀaminothiazolopyrazines as well. As a result, we
reported solutionꢀphase synthetic method of Nꢀsubstitutedꢀ2ꢀaminothiazolo[4,5ꢀb]pyrazines via
1
1
tandem reaction of oꢀaminohalopyrazines with isothiocyanates in 2012 (Scheme 1 (a)). Even
though various solutionꢀphase synthesis methodologies have already been reported, no solidꢀ
phase synthesis approach has been reported until now. Accordingly, we aimed to develop an
efficient synthesis route using solidꢀphase and construct a diverse library of compounds. Herein,
we report an efficient synthetic methodology of 2ꢀaminothiazolo[4,5ꢀb]pyrazine on solid phase
and its further functionalization to provide Nꢀsubstitutedꢀ2ꢀaminothiazolo[4,5ꢀb]pyrazine
derivatives based on the solutionꢀphase synthetic route (Scheme 1 (b)).
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RESULTS AND DISCUSSION
Chemistry
Scheme 2. Synthesis of NꢀSubstitutedꢀ2ꢀaminothiazolo[4,5ꢀb]pyrazine Derivatives on Solid
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a
Phase
a
2
Reaction conditions: (a) CS , p-TsCl, TEA, THF, room temperature, 18 h; (b) oꢀdihaloꢀ2ꢀaminopyrazine, NaOH,
4
DMSO/THF or acetone, room temperature, 8 h; (c) R B(OH)
2 2 3 2 3 2
, Cs CO , Pd (dba) , XPhos, 1,4ꢀdioxane, H O, 110
°C, 24 h.; (d) alkyl halide, tꢀBuOK, THF, 60 °C, 16 h.; (e) acyl chloride, TEA, DMAP, THF, room temperature, 8 h.;
(
f) sulfonyl chloride, NaH, DMAP, THF, room temperature, 8 h; (g) TFA:DCM (1:4, v/v), 60 °C, 6 h; (h)
TFA:DCM (1:9, v/v), room temperature, 6 h; (i) TFA:DCM (1:9, v/v), room temperature, 8 h.
The overall synthetic strategy for the synthesis of Nꢀsubstitutedꢀ2ꢀaminothiazolo[4,5ꢀb]pyrazine
derivatives is shown in Scheme 2. The synthesis route starts from the preparation of
1
2
isothiocyanate terminated resin 2 from the 4ꢀbenzyloxyꢀ2ꢀmethoxybenzylamine (BOMBA)
13
3 2
resin 1 by the treatment with Et N, CS , and pꢀTsCl. The formation of the desired resin 2 was
confirmed by attenuated total reflectance Fourier transform infrared spectroscopy (ATRꢀFTIR),
ꢀ1
showing typical isothiocyanate band at 2062 cm (Figure S1 (b), Supporting Information). Next,
the cyclization reaction of 2ꢀaminothiazolo[4,5ꢀb]pyrazine was performed. Before accomplishing
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cyclization reaction on solid phase, model study in solution phase was performed (Table S1,
Supporting Information). According to the results from the model study, resin 2 was reacted with
3,5ꢀdibromoꢀ2ꢀaminopyrazine 3a in the presence of NaOH in DMSO at room temperature (Table
1, entry 1).
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a
Table 1. Results of the Optimization of Cyclization Reaction Conditions on Solid Phase
b
entry
X
Br
Br
I
base
solvent
DMSO
temp. (°C)
time (h)
yield (%)
trace
56
1
2
3
NaOH
NaOH
NaOH
RT
RT
RT
8
8
DMSO, THF
acetone
12
60
a
Reaction conditions: 3,5ꢀdihaloꢀ2ꢀaminopyrazine (3.0 equiv) was treated with NaOH (5.0 equiv) in
DMSO; after stirring for 20 min, reaction mixture was poured into a suspension of isothiacyanate
terminated resin (1.0 equiv) in THF and mixture was shaken for 8 h.
b
Threeꢀstep overall yield from BOMBA resin 1 (loading capacity of resin 1 is 0.91 mmol/g).
Unfortunately, desired cyclized product 15a was obtained in trace amount because of low
swelling property of DMSO into the lipophilic resin 2. To solve this problem, we changed the
solvent to a mixture of DMSO and THF in equal ratio to increase solvent system’s swelling
properties. As a result, 15a was obtained in 56% threeꢀstep overall yield (Table 1, entry 2). Next,
for better reactivity for further modification using Suzuki coupling, we replaced bromine to
iodine at C6 position. From the result of the model study (Table S1, entry 7, Supporting
Information), resin 2 was reacted with 3ꢀbromoꢀ5ꢀiodopyrazinꢀ2ꢀamine 3b in the presence of
NaOH in acetone (Table 1, entry 3). Consequently, 15b was obtained in 60% threeꢀstep overall
yield. The cyclization reaction on solid phase was monitored by ATRꢀFTIR, and the absence of
ꢀ1
the isothiocyanate band and the presence of the imine stretching band at 1581 cm confirmed the
completion of the reaction (Figure S1 (c), Supporting Information).
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Table 2. Yields and Purities of the Nꢀalkylꢀ2ꢀaminothiazolo[4,5ꢀb]pyrazine Derivatives
Yield
Purity
Yield
Purity
1
1
No
R
No
R
a
b
a
b
(%)
(%)
(%)
(%)
9
9
a
39
100
100
9i
9j
31
100
100
b
29
35
39
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7
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0
9c
100
9k
100
9
d
33
47
27
33
34
100
100
100
100
100
9l
9m
9n
9o
25
38
50
43
20
100
100
100
100
100
9
e
9f
9
9
g
h
9p
a
Fourꢀstep overall yield from BOMBA resin 1 (loading capacity of resin 1 is 0.91 mmol/g).
All the purified products were checked by LC/MS.
b
For the diversification of the obtained 2ꢀaminothiazolo[4,5ꢀb]pyrazine core skeleton, various
electrophiles such as alkyl halides, acyl chlorides, and sulfonyl chlorides were introduced. First,
we introduced alkyl halides in the presence of tꢀBuOK in THF at 60
°C for 16 h. The cleavage
from the supporting resin 6 with TFA in DCM (1:4, v/v) at 60 C for 6 h afforded the desired
°
product. The crude product mixture was purified by flash chromatography (hexane/ethyl acetate)
and trituration with diethyl ether and ethyl acetate (9:1, v/v) to afford Nꢀalkylꢀ2ꢀ
aminothiazolo[4,5ꢀb]pyrazine derivatives 9 in good overall yields and high purities, as listed in
Table 2.
Table 3. Yields and Purities of the
N
ꢀacylꢀ2ꢀaminothiazolo[4,5ꢀb]pyrazine Derivatives
Yield
Purity
Yield
Purity
2
2
No
R
No
R
a
b
a
b
(%)
(%)
(%)
(%)
1
0a
43
100
100
10l
41
47
100
100
10b
52
10m
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10c
47
46
100
100
10n
10o
47
49
100
100
10d
10e
35
50
100
100
10p
10q
29
19
100
100
10f
10
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10g
51
100
10r
33
100
10h
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100
100
10s
10t
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39
100
100
10i
10j
48
55
100
100
10u
10v
37
26
100
100
10k
a
Fourꢀstep overall yield from BOMBA resin 1 (loading capacity of resin 1 is 0.91 mmol/g).
All the purified products were checked by LC/MS.
b
Table 4. Yields and Purities of the
N
ꢀsulfonylꢀ2ꢀaminothiazolo[4,5ꢀ
b
]pyrazine Derivatives
Yield
Purity
Yield
Purity
3
3
No
R
No
R
a
b
a
b
(%)
(%)
(%)
(%)
11a
19
14
14
24
20
100
100
100
100
100
11j
11k
11l
18
17
13
17
14
100
100
100
100
100
1
1b
1c
1d
11e
1f
11g
1h
1i
1
1
11m
11n
1
29
100
1
1o
19
100
21
21
24
100
100
100
1
11p
11q
14
9
100
100
1
a
Fourꢀstep overall yield from BOMBA resin 1 (loading capacity of resin 1 is 0.91 mmol/g).
All the purified products were checked by LC/MS.
b
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Next, 2ꢀaminothiazolo[4,5ꢀb]pyrazine resin 4a was diversified with various acyl chlorides by
3
acylation reaction in the presence of Et N, 4ꢀdimethylaminopyridine (DMAP), and THF for 8 h
at room temperature. The reaction was also monitored by ATRꢀFTIR, showing increasing
ꢀ1
intensity of the amide band at 1670 cm (Figure S1 (e), Supporting Information). The cleavage
0
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2
3
4
5
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9
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9
0
of the acylated compound from resin 7 by the treatment with TFA in DCM (1:9, v/v) for 6 h
afforded desired Nꢀacylꢀ2ꢀaminothiazolo[4,5ꢀb]pyrazine derivatives 10 in high yields and
purities. The LC/MS spectra of the crude product mixture (Figure S2, Supporting Information)
showed fair purity without further purification after the cleavage. Thus, purification of acylated
compounds was proceeded by trituration with diethyl ether and ethyl acetate (4:1, v/v) affording
acylated compounds in good yields and high purities (Table 3).
Further diversification was proceeded by the reaction of sulfonyl chlorides with 2ꢀ
aminothiazolo[4,5ꢀb]pyrazine resin 4a at room temperature for 8 h in THF in the presence of
NaH as the base and DMAP. Reaction monitoring by ATRꢀFTIR showed the increase in the
ꢀ1
intensity of the sulfonamide band at 1364 and 1166 cm (Figure S1 (f), Supporting Information).
By the cleavage of the Nꢀsulfonylꢀ2ꢀaminothiazolo[4,5ꢀb]pyrazine resin 8 with TFA in DCM
(1:9, v/v) for 8 h at room temperature, Nꢀsulfonylꢀ2ꢀaminothiazolo[4,5ꢀb]pyrazine derivatives 11
were obtained in good yields and high purities as listed in Table 4.
Table 5. Results of the Optimization of Suzuki Coupling Reaction Conditions on Solid
a
Phase
b
entry
X
base
catalyst
Pd (dba)
ligand
solvent
temp. (°C) time (h)
yield (%)
2
3
XPhos
1,4ꢀdioxane : H
9 : 1
2
2
O
O
1
Br Cs
3
CO
3
3
110
110
16
20
NR
1
0 mol% 20 mol%
Pd (dba) XPhos
10 mol% 20 mol%
2
3
1,4ꢀdioxane : H
9 : 1
2
I
Cs
3
CO
20
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Pd
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XPhos
1,4ꢀdioxane : H
9 : 1
2
O
3
I
Cs
3
CO
3
110
24
42
20 mol% 40 mol%
a
Reaction conditions: To a suspension of 2ꢀaminothiazolo[4,5ꢀb]pyrazine resin 4 (1.0 equiv) in 1,4ꢀdioxane,
were added successively Pd (dba) (20 mol%), XPhos (40 mol%), phenylboronic acid (3.0 equiv), and Cs CO
5.0 equiv) dissolved in H O. Reaction mixture was shaken at 110 °C for 24 h. NR – No Reaction.
Fourꢀstep overall yield from BOMBA resin 1 (loading capacity of resin 1 is 0.91 mmol/g).
2
3
2
3
(
2
b
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For additional diversification, Suzuki coupling was performed. First, reaction conditions were
optimized in solution phase giving high yield of the coupled product by the reaction of 6ꢀbromoꢀ
thiazolo[4,5ꢀb]pyrazinꢀ2ꢀamine with phenyl boronic acid, tris(dibenzylideneacetone)dipalladium
(0) (Pb
2
(dba)
3
) as the catalyst, XPhos as the ligand in the presence of cesium carbonate (Cs
2 3
CO )
in 1,4ꢀdioxane:H
2
O (9:1, v/v) for 20 h at 110 C (Table S2, Supporting Information). However,
°
these optimized conditions were not successful on solid phase as it shown in Table 5, entry 1.
Thus, we decided to change bromine atom to more reactive iodine atom at C6 position and run
reaction under the same conditions. Fortunately, changing halogen to iodine increased the
reactivity and Suzuki coupling was carried out on solid phase under the same reaction conditions
and the fourꢀstep overall yield was 20 % (Table 5, entry 2).
Table 6. Yields and Purities of 6ꢀarylꢀN-substitutedꢀ2ꢀaminothiazolo[4,5ꢀ
b
]pyrazine
Derivatives
Yield
Purity
Yield
Purity
1
4
2
4
No
R
R
No
13a
13b
R
R
a
b
a
b
(%)
(%)
(%)
(%)
12a
22
32
100
100
39
31
100
100
1
2b
12c
2d
2e
2f
2g
2h
29
7
100
96
13c
13d
13e
13f
15
40
32
30
100
100
100
100
1
1
13
16
100
100
1
1
9.5
100
ꢀ
13g
13h
37
100
ꢀ
1
NR
NR
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Yield
Purity
Yield
Purity
3
4
3
4
No
R
R
No
14d
14e
R
R
a
b
a
b
(%)
(%)
(%)
(%)
14a
5
9
100
100
29
85
ꢀ
14b
NR
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14c
10
100
a
Fiveꢀstep overall yield from BOMBA resin 1 (loading capacity of resin 1 is 0.91 mmol/g).
All the purified products were checked by LC/MS. NR – No Reaction.
b
However, the conversion of starting material was not completed. Thus, we increased the ratio of
catalyst and reaction time. With new conditions, we obtained Suzuki coupled product with 42 %
fourꢀstep overall yield (Table 5, entry 3). To increase the diversity of compound, Suzuki
coupling was accomplished with different boronic acids. In the case of aryl boronic acid (phenyl
boronic acids and 3ꢀthiophenyl boronic acid) the Suzuki coupling proceeded with good yields
and high purities. However, with aliphatic ethyl boronic acid there was no reaction (Table 6, 12h,
1
3h, and 14e). Next, the functionalization of 6ꢀarylꢀ2ꢀaminothiazolo[4,5ꢀb]pyrazine resin 5 with
various alkyl halides, acyl chlorides, and sulfonyl chlorides was carried out as it was explained
before (d/e/f, Scheme 2) to afford corresponding Nꢀsubstituted resins 6′, 7′, and 8′ respectively.
The subsequent treatment of each resin with TFA in DCM afforded desired Nꢀalkylꢀ6ꢀ
arylthiazolo[4,5ꢀb]pyrazinꢀ2ꢀamine 12, 6ꢀarylꢀNꢀacylꢀ2ꢀaminothiazolo[4,5ꢀb]pyrazine 13, and 6ꢀ
arylꢀNꢀsulfonylꢀ2ꢀaminothiazolo[4,5ꢀb]pyrazine 14 derivatives (Table 6).
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Displayed 3D structure and calculation for physicochemical properties
(aꢀ1)
(aꢀ2)
(bꢀ2)
(aꢀ3)
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54
55
56
57
58
59
60
(
bꢀ1)
(
bꢀ3)
(
cꢀ1)
(cꢀ2)
Figure 2. Alignment of energy minimized 3D structure of alkylated compounds 9 and 12 (aꢀ1),
acylated compounds 10 and 13 (aꢀ2), and sulfonylated compounds 11 and 14 (aꢀ3); polar surface
areas of 9a (bꢀ1), 10a (bꢀ2), 11a (bꢀ3); physicochemical properties in 3D plots: number of
rotatable bonds, clean energy, and pKa (cꢀ1); polar surface area, calculated LogP, and molecular
weight (cꢀ2)
Lastly, 3D structural difference, polar surface areas, and physicochemical properties are
displayed in Figure 2. As it shown in Figure 2a, each energy minimized 3D structure is aligned
with pyrazine ring of thiazolo[4,5ꢀb]pyrazine and the structure diverged widely by various
building blocks in 3D space. Next, the polar surface areas of representative alkylated product 9a,
acylated product 10a, and sulfonylated product 11a are shown in Figure 2b. It is clear that the
polar surface area of each functionalized thiazolo[4,5ꢀb]pyrazine is different, indicating that this
thiazolo[4,5ꢀb]pyrazine derivatives can interact with different biomarkers. In addition, the
physicochemical properties (number of rotatable bonds, clean energy, pKa, polar surface area,
calculated LogP, and molecular weight) of the constructed thiazolo[4,5ꢀb]pyrazine library are
displayed in 3D chemical plots showing that the physicochemical properties are arranged widely.
(Figure 2c).
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Molecular docking study
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8
9
0
Figure 3. Comparison of already known PTPꢀ1B inhibitor and 14d
For a biological docking evaluation, we conducted virtual screening with protein phosphatase 1B
PTPꢀ1B, PDB Code : 2F71) by discovery studio 2016 (DS 2016). PTPꢀ1B is associated with
(
type 2 diabetes mellitus (T2DM) which is metabolic disease characterized by insulin resistance
in peripheral tissues (liver, muscle, and adipose) and damaged insulin secretion by the
14
pancreas. NavarreteꢀVazquez reported that 2ꢀarylsulfonylaminobenzothiazoles showed antiꢀ
15
hyperglycemic activity by inhibition of PTPꢀ1B. As can be seen in Figure 3, most potent
inhibitor (Figure 3a) to PTPꢀ1B reported by NavarreteꢀVazquez has a similar structural features
with our 2ꢀsulfonamidoꢀthiazolo[4,5ꢀb]pyrazine 14d, promising that 2ꢀsulfonamidoꢀthiazolo[4,5ꢀ
b]pyrazine 14d might play as potent inhibitor to PTPꢀ1B. For this reason, we investigated
molecular docking study with 14d to PTPꢀ1B.
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Figure 4. A superimposed view of 14d binding to the active site of PTPꢀ1B
According to the molecular docking result, 14d interacted with the active site of PTPꢀ1B in
similar way as already known PTPꢀ1B inhibitor (Figure 4). It seems clear that nitro group in 14d
plays important role in binding PTPꢀ1B with GLY220, and ARG221 through hydrogen bonding
in hydrophilic binding pocket. The oxygen in sulfonamide group also makes hydrogen bonding
with TYR46. It is interesting to note that the hydrogen at C5 position makes carbon hydrogen
bonding with ASP48 since this hydrogen might be quite acidic because of adjacent nitrogen
atom in pyrazine ring. Furthermore, the phenyl group introduced by Suzuki coupling makes piꢀ
donor hydrogen bonding with ARG24.
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1
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6
Conclusion
In conclusion, we established an effective solidꢀphase synthetic methodology to synthesize Nꢀ
substitutedꢀ2ꢀaminothiazolo[4,5ꢀb]pyrazines. Diversification of the obtained core skeleton was
accomplished by functionalization with alkyl halides, acid chlorides, and sulfonyl chlorides, as
well as by introducing Suzuki coupling at the C6 position. After the functionalization of 2ꢀ
aminothiazolo[4,5ꢀb]pyrazines, the supporting resin was cleaved with TFA in DCM, affording
the desired final compounds in good yields and purities. To investigate the potential of the
synthesized compounds as a drug, structural diversity, polar surface area, and physicochemical
properties were evaluated. As a result, we confirmed that our library of compounds has high
structural diversity in 3D space resulted by functionalization, and difference polar surface area,
indicating different possibilities to interact with biomarkers. The physicochemical properties of
the library are widely arranged in 3D chemical plots. Finally, molecular docking study clearly
showed the possibility of the 14d to be used as a PTPꢀ1B inhibitor of type 2 diabetes mellitus
0
1
2
3
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2
3
4
5
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7
8
9
0
1
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3
4
5
6
7
8
9
0
(T2DM). We will explore biological evaluation with Nꢀsubstitutedꢀ2ꢀaminothiazolo[4,5ꢀ
b]pyrazines in hand to extract potent PTPꢀ1B inhibitor in our future work.
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EXPERIMENTAL PROCEDURES
General Procedure for Synthesis All the chemicals were of reagent grade and used as
purchased. Reactions were monitored by TLC analysis using Merck silica gel 60 Fꢀ254 thin layer
plates (for solutionꢀphase synthesis) and by ATRꢀFTIR spectrometer (for solidꢀphase synthesis).
The crude product mixtures were purified by flash chromatography system using Isolera One
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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26
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(Biotage). Flash column chromatography was carried out on Merck silica gel 60 (230−400 mesh).
1
13
H NMR and C NMR spectra were recorded in δ units relative to deuterated solvent as an
internal reference using a 500 MHz NMR spectrometer (Bruker). For liquid chromatography
tandem mass spectrometry (ESI, PDA detection), 6460 Triple Quad LC/MS (Agilent) was used.
Highꢀresolution mass spectrometry was performed using a 6550 iFunnel QꢀTOF LC/MS system
(Agilent).
Representative Procedure for the Preparation of the Isothiocyanate Terminated Resin 2 To a
mixture of BOMBA resin 1 (5 g, 4.55 mmol) in THF (25 mL), Et N (4.6 g, 46 mmol) and CS (2
g, 27.3 mmol) were added at 0 C, resulting in a suspension. After shaking the suspension for 3 h
at room temperature, pꢀTsCl (4.34 g, 22.7 mmol) was added slowly at 0 C, and the suspension
was shaken for 12 h at room temperature. Isothiocyanate terminated resin 2 was filtered and
washed successively with THF, MeOH, H O, MeOH (×2), and DCM (×2), and dried under high
vacuum. SingleꢀBead ATRꢀFTIR: 3028, 2923, 2062 (N=C=S), 1608, 1507, 1420, 1268, 1195,
3
2
°
°
2
ꢀ1
1
088, 820, 757 cm .
Representative Procedure for the Preparation of the Cyclized 2-aminothiazolo[4,5-b]pyrazine
Resin 4a 3,5ꢀdibromoꢀ2ꢀaminopyrazine (3.43 g, 13.6 mmol) was dissolved in DMSO (10 mL)
followed by adding NaOH (0.9 g, 22.6 mmol). The mixture was stirred for 20 min at room
temperature. Then, the reaction mixture was poured into a suspension of isothiocyanated resin 2
(5 g, 4.55 mmol) in THF (10 mL). The reaction mixture was shaken for 8 h at room temperature,
filtered, and washed successively with DCM, MeOH, H O, MeOH (×2) and DCM (×2), and
2
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2
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2
2
2
2
2
2
2
3
3
3
3
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4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
dried under high vacuum. SingleꢀBead ATRꢀFTIR: 3021, 2920, 1492, 1581 (N=C), 1354, 1282,
ꢀ1
1186, 1159, 815, 758 cm .
In the case of resin 4b, acetone was used instead of DMSO and THF.
Representative Procedure for the Suzuki Coupling reaction
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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0
Preparation of 6-phenylthiazolo[4,5-b]pyrazin-2-amine resin 5a Reaction was carried out under
an inert atmosphere. To a suspension of 2ꢀaminothiazolo[4,5ꢀb]pyrazine resin 4b (1.2 g, 1.09
mmol) in 1,4ꢀdioxane (5.4 mL), Pd
phenylboronic acid (0.4 g, 3.2 mmol), and Cs
were added. The reaction mixture was shaken for 24 h at 110
The resin was filtered and washed successively with DCM, MeOH, H
×2), and dried under high vacuum.
2
(dba)
3
(0.2 g, 0.22 mmol), XPhos (0.21 g, 0.44 mmol),
CO (1.78 g, 5.4 mmol) dissolved in H O (0.6 mL)
C and cooled to room temperature.
O, MeOH (×2), and DCM
2
3
2
°
2
(
Representative Procedure for the Alkylation Reaction
Preparation of N-benzyl-2-aminothiazolo[4,5-b]pyrazine Resin 6a To a mixture of cyclized
resin 4a (0.220 g, 0.2 mmol) in THF (3 ml), tꢀBuOK (0.112 g, 1.0 mmol) was added, and the
reaction mixture was shaken for 1 h at room temperature. After 1 h benzyl chloride (0.12 mL, 1.0
mmol) was added, and the temperature was increased to 60
for 16 h. The resin was filtered and washed successively with DCM, MeOH, H
and DCM (×2), and dried under high vacuum. SingleꢀBead ATRꢀFTIR: 3026, 2920, 1603, 1574,
°C. The reaction mixture was shaken
2
O, MeOH (×2),
ꢀ1
1492, 1348, 1193, 819, 758, 737 cm .
Representative Procedure for the Acylation Reaction
Preparation of N-benzoyl-2-aminothiazolo[4,5-b]pyrazine Resin 7a To a suspension of cyclized
3
resin 4a (0.220 g, 0.2 mmol) in THF (3 mL), Et N (0.14 mL, 1.0 mmol), benzoyl chloride (0.12
mL, 1.0 mmol), and DMAP (cat. amount) were added successively. The reaction mixture was
shaken for 8 h at room temperature. Nꢀbenzoylꢀ2ꢀaminothiazolopyrazine resin 7a was filtered
and washed successively with DCM, MeOH, H O, MeOH (×2), and DCM (×2), and dried under
2
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high vacuum. SingleꢀBead ATRꢀFTIR: 3021, 2923, 1670 (amide), 1654, 1600, 1507, 1449, 1375,
ꢀ1
1192, 961, 815, 759 cm .
Representative Procedure for the Sulfonylation Reaction
Preparation of N-(6-bromothiazolo[4,5-b]pyrazin-2-yl)-4-methylbenzenesulfonamide Resin 8a
To a suspension of cyclized resin 4a (0.220 g, 0.2 mmol) in THF (3 mL), NaH (0.04 g, 1.0 mmol,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
32
33
34
35
36
37
38
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6
0% suspension in oil), pꢀTsCl (0.190 g, 1.0 mmol), DMAP (cat. amount) were added
successively. The reaction mixture was shaken for 8 h at room temperature. Sulfonylated resin
a was filtered and washed successively with DCM, MeOH, H O, MeOH (×2), and DCM (×2),
and dried under high vacuum. SingleꢀBead ATRꢀFTIR: 3026, 2925, 1603, 1507, 1446, 1364
8
2
ꢀ1
(
S=O), 1186, 1166, 1109, 814, 757 cm .
Representative Procedure for the Preparation of N-benzyl-6-bromothiazolo[4,5-b]pyrazin-2-
amine 9a Resin 6a after alkylation (0.245 g, 0.22 mmol) was treated with a mixture of TFA and
DCM (1:4, v/v, 2 mL) and shaken for 6 h at 60
and MeOH (×3), and organic filtrate was collected and evaporated. The residue was dissolved in
ethyl acetate, washed with H O, and neutralized to pH 7 with saturated aqueous NaHCO
°C. The resin was filtered and washed with DCM
2
3
solution. The organic layer was dried with anhydrous MgSO and evaporated. The crude mixture
4
was purified by column chromatography on silica gel and triturated with diethyl ether and ethyl
acetate (9:1, v/v) affording Nꢀbenzylꢀ6ꢀbromothiazolo[4,5ꢀb]pyrazinꢀ2ꢀamine 9a (39%, fourꢀstep
1
overall yield). H NMR (500 MHz, CDCl3) δ 8.37 (s, 1H), 7.42–7.33 (m, 5H), 7.26 (s, 1H), 4.73
13
(
s, 2H). C NMR (126 MHz, CDCl3) δ 168.67, 157.65, 149.46, 142.91, 136.07, 130.13, 129.02,
+
+
128.35, 127.97, 48.84. LC–MS (ESI): m/z = 321.0 [M+H] . HRMS (ESI) m/z: [M+H] Calcd for
BrN S 320.9804; found 320.9813.
C
12
H
9
4
Representative Procedure for the Preparation of N-(6-bromothiazolo[4,5-b]pyrazin-2-
yl)benzamide 10a Acylated resin 7a (0.220 g, 0.2 mmol) was treated with a mixture of TFA and
DCM (1:9, v/v, 2 mL) and shaken for 6 h at room temperature. The resin was filtered and
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washed with DCM and MeOH (×3), and organic filtrate was collected and evaporated. The crude
mixture was purified by trituration with diethyl ether and ethyl acetate (4:1, v/v) solvent mixture
and dried under high vacuum. The resulting product was brown color solid (43%, fourꢀstep
1
overall yield). H NMR (500 MHz, DMSO) δ 13.53 (s, 1H), 8.82 (s, 1H), 8.17 (d, J = 8.0 Hz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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1
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4
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3
4
5
6
7
8
9
0
13
2
H), 7.72 (t, J = 7.8 Hz, 1H), 7.61 (t, J = 7.7 Hz, 2H). C NMR (126 MHz, CDCl
3 2 3 2
+ C HF O ) δ
169.82, 167.76, 150.15, 149.18, 144.36, 136.96, 136.66, 130.71, 130.09, 129.63. LCꢀMS (ESI):
+
+
m/z = 335.0 [M+H] . HRMS (ESI) m/z: [M+H] Calcd for C12
7 4
H BrN OS 334.9597; found
334.9597.
Representative Procedure for the Preparation of N-(6-bromothiazolo[4,5-b]pyrazin-2-yl)-4-
methylbenzenesulfonamide 11a Sulfonylated resin 8a (0.235 g, 0.21 mmol) was treated with a
mixture of TFA and DCM (1:9, v/v, 2 mL) and shaken for 8 h at room temperature. The resin
was filtered and washed with DCM and MeOH (×3), and organic filtrate was collected and
2
evaporated. The residue was dissolved in ethyl acetate, washed with H O, and neutralized to pH
7
with saturated aqueous NaHCO solution. The organic layer was dried with anhydrous MgSO
3
4
and evaporated. The crude mixture was purified by column chromatography on silica gel and
triturated with diethyl ether and ethyl acetate (9:1, v/v) affording desired product Nꢀ(6ꢀ
bromothiazolo[4,5ꢀb]pyrazinꢀ2ꢀyl)ꢀ4ꢀmethylbenzenesulfonamide 11a (19%, fourꢀstep overall
1
yield). H NMR (500 MHz, DMSO) δ 8.22 (s, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.2 Hz,
13
2
H), 2.32 (s, 3H). C NMR (126 MHz, CDCl
3
+ C
2
3
HF O
2
) δ 166.03, 146.96, 145.83, 143.74,
+
1
42.31, 135.21, 135.16, 130.78, 127.42, 21.82. LCꢀMS (ESI): m/z = 384.9 [M+H] . HRMS (ESI)
+
m/z: [M+H] Calcd for C H BrN O S 384.9423; found 384.9434.
12
9
4
2 2
1
1
In the case of H NMR of Nꢀsulfonylꢀ2ꢀaminothiazolo[4,5ꢀb]pyrazine derivatives, H NMR was
checked in different solvents (DMSOꢀD6, CDCl
was observed.
3
, THFꢀD8, acetoneꢀD6), but still no NH proton
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Molecular docking
The molecular docking study was performed by mean of CDOCKER and Flexible Docking
using the DS CHARMm function and 3D structure of PTPꢀ1B (PDB Code : 2F71).
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Acknowledgment This study was supported by the Bio & Medical Technology Development
Program of the National Research Foundation funded by the Ministry of Science, ICT & Future
Planning (No. 2014M3A9A9073847), the Ministry of Trade, Industry & Energy, and the Korean
Institute for Advancement of Technology through the industrial infrastructure program for
fundamental technologies (Grant Number M0000338).
Supporting Information Available: Full analytical data of compounds, along with the copies of
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H NMR, C NMR, LC/MS, and HRMS spectra of all the synthesized compounds and ATRꢀ
FTIR spectrum of the corresponding resins; this material is available free of charge via the
Internet at http://pubs.acs.org.
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Graphical Abstract
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Solid-Phase Parallel Synthesis of N-Substituted-2-aminothiazolo[4,5-b]
pyrazine Derivatives via Tandem Reaction of Isothiocyanate
Terminated Resin with o-Bromo-2-Aminopyrazines
Aizhan Abdildinova, Seung-Ju Yang, Young-Dae Gong*
Innovative Drug Library Research Center, Department of Chemistry, College of Science,
Dongguk University, 26, 3-ga, Pil-dong, Jung-gu, Seoul 04620, Korea
*
Corresponding author. Tel. : +82-2-2260-3206, Fax : +82-2-2290-1349 ; e-mail: ydgong@dongguk.edu
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Graphical Abstract
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Solid-Phase Parallel Synthesis of N-Substituted-2-aminothiazolo[4,5-
b] pyrazine Derivatives via Tandem Reaction of Isothiocyanate
Terminated Resin with o-Bromo-2-Aminopyrazines
Aizhan Abdildinova, Seung-Ju Yang, Young-Dae Gong*
Innovative Drug Library Research Center, Department of Chemistry, College of Science,
Dongguk University, 26, 3-ga, Pil-dong, Jung-gu, Seoul 04620, Korea
*
Corresponding author. Tel. : +82-2-2260-3206, Fax : +82-2-2290-1349 ; e-mail: ydgong@dongguk.edu
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