Synthesis of 2-Amino-5-Carboxamide Thiazole Derivatives via Dehydrative Cyclization of Thiourea Intermediate Resin on Solid Phase

Article abstract of DOI:10.1021/acscombsci.9b00001

In this study, we synthesized 2-amino-5-carboxamide thiazole derivatives on solid phase. The synthesis of the library starts with the reductive amination of the 4-formyl-3-methoxy phenoxy resin to prevent isomer formation. The dehydrative cyclization of thiourea intermediate resin, which is the key step in the synthetic process, was successfully synthesized using α-bromoketone in the presence of the DMF so as to afford 2-amino-5-carboxylate thiazole resin. The resulting resin is coupled with various amines. Finally, the 2-amino-5-carboxamide thiazole resin was cleaved from the polymer support using a TFA and DCM cocktail. The physicochemical properties of the proposed 2-amino-5-carboxamide thiazole derivatives were calculated and showed potential to be an reasonable oral bioavailability drug properties as determined by Lipinski's Rule.

Full text of DOI:10.1021/acscombsci.9b00001

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Article
Synthesis of 2-Amino-5-Carboxamide Thiazole derivatives via
Dehydrative Cyclization of Thiourea Intermediate Resin on Solid Phase
Ye-Ji Kim, Hye-Jin Kwon, Si-Yeon Han, and Young-Dae Gong
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.9b00001 • Publication Date (Web): 08 Mar 2019
Downloaded from http://pubs.acs.org on March 14, 2019
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Graphical Abstract
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Synthesis of 2-Amino-5-Carboxamide Thiazole derivatives via Dehydrative
Cyclization of Thiourea Intermediate Resin on Solid Phase
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Ye-Ji Kim, Hye-Jin Kwon, Si-Yeon Han and Young-Dae Gong*
Innovative Drug Library Research Center, Department of Chemistry, College of Science,
Dongguk University, 30, Pildong-ro 1-gil, Jung-gu, Seoul 04620, Korea
N
R2
R2
R4
OH
O
N
Amines
N
N
R3
Cl
S
N
P
O
S
HN
R1
O
Cleavage
R1
O
O
P = Merrifield resin
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1
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Synthesis of 2-Amino-5-Carboxamide Thiazole derivatives via Dehydrative
Cyclization of Thiourea Intermediate Resin on Solid Phase
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Ye-Ji Kim, Hye-Jin Kwon, Si-Yeon Han and Young-Dae Gong*
Innovative Drug Library Research Center, Department of Chemistry, College of Science,
Dongguk University, 30, Pildong-ro 1-gil, Jung-gu, Seoul 04620, Korea
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*Corresponding author Tel.: +82-2-2290-3206, Fax: +82-2-2260-1349; e-mail:
ydgong@dongguk.edu
Abstract: In this study, we synthesized 2-amino-5-carboxamide thiazole derivatives on solid phase.
The synthesis of the library starts with the reductive amination of the 4-formyl-3-methoxy phenoxy
resin in order to prevent isomer formation. The dehydrative cyclization of thiourea intermediate resin,
which is the key step in the synthetic process, was successfully synthesized using α-bromoketone in
the presence of the DMF so as to afford 2-amino-5-carboxylate thiazole resin. The resulting resin is
coupled with various amines. Finally, the 2-amino-5-carboxamide thiazole resin was cleaved from the
polymer support using a TFA and DCM cocktail. The physicochemical properties of the proposed 2-
amino-5-carboxamide thiazole derivatives were calculated and showed potential to be an reasonable
oral bioavailability drug properties as determined by Lipinski’s Rule.
KEYWORDS: 2-amino-5-carboxamide thiazole, isomer, dehydrative cyclization, solid-phase
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Introduction
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Solid-phase organic synthesis (SPOS) is a method widely used in drug discovery for its profound
effect on making massive numbers of small molecules in short periods of time.1 These small
molelcules usually contain heterocyclic systems, which are considered to be an important class of
organic compounds, as they play a vital role in the medicinal field.2 Among many type of heterocylic
compounds, five-membered rings have been used in a number of medicinal research projects due to
their activity against diseases.3
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Thiazole is one of the representative five-membered ring compounds which has attracted research
interest in recent years.4 Thiazole core skeleton has shown various biological activites, such as
antibacterial,5 antioxidant,6 diuretic,7 antifungal,8 antitubercular,9 anti-inflammatory,10
anticonvulsant,11 anti-HIV,12 antidiabetic,13 antihypertensive,14 anti-Alzheimer15 and anticancer16
activities. Additionally, most of the antitumor agents contain substituted 1,3-thiazole ring and
carboxamide groups (Figure 1).17 Therefore, thiazole core was a target molecule for synthesis and
biological testing with following numerous reported methods so as to afford thiazole core skeleton.18
Thus, many organic chemists and medicinal chemists have maintained interest in synthesizing thiazole,
and there have been several reported methods to afford this core skeleton in the literature.19
NH2
O
O
S
O
OH
S
O
O
N
O
N
H
N
N
N
O
N
N
S
H
N
N
H
N
S
S
H
O
O
H2N
O
O
Nitazoxanide 20a
Meloxicam 20b
Thia-netropsin 20c
O
H
N
HN
NH2
N
Cl
HN
N
H
O
N
S
HO
OH
O
N
N
NH
N
N
O
O
N
O
H
N
S
N
S
H
N
N
HO
OH
O
Thiazotropsin A 20d
Tiazofurin 20e
Dasatinib 20f
Figure 1. Examples of 2-amino-5-carboxamide thiazole derivatives with broad-spectrum antitumor
activities 20
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Herein, we were interested in developing new synthetic methodology for thiazole carboxamide
moiety. As an extension of our previous work,21 we envisioned synthesizing thiazole from the
isothiocyanate-terminated resin (Scheme 1 (a)). Unfortunately, our previous methodology was limited
to the use of ethyl carbamate, as undesired dihydrothiazole was formed. In order to improve the
synthetic methodology, we synthesized N-alkylated amine resin 3 from the reductive amination of
AMEBA resin. Next, we synthesized thiourea resin 4 in the absence of base. We then synthesized
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isothiourea resin by modifying the functional group on Merrifield resin (Scheme 1 (b)). In contrast to
the previous method, this method increases the reactivity of the intermediate and also reduces the
number of reaction steps. Herein, we report our recent progress on this project.
Scheme 1. Synthetic Strategy for the Synthesis of Ethyl (N-alkyl-benzylcarbamothioyl)carbamate
resins
(a) Our previous method
O
O
2 steps
S
H2N
R
Cl
H
NH2
N
C S
R
P
P
N
N
Base
H
H
O
P
O
NH2
=
O
P
P = Merrifield resin
5 steps
O
O
O
O
2 steps
S
O
H2N
O
N
Cl
H
NH2
N
C S
O
P
P
N
N
O
N
Base
H
H
S
O
P
R2
A
B
C
(b) Our present method
3 steps
O
R2
O
O
R4
N
S
O
S C N
O
R3
N
NH
R1
Cl
P
H
P
N
R1
N
O
H
S
N
R1
O
O
P
3
4
Results and Discussion
Preliminary studies show the reaction conditions for 2-amino-5-carboxamide thiazole derivatives on
solution phase (Scheme 2). The synthesis began with the preparation of N-acylthiourea. The reaction
between ethoxycarbonyl isothocyante with primary amine 17 affored ethoxycarbonyl thiourea 18.
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Unfortunately, the cyclization reaction between ethoxycarbonyl thiourea 18 and α-
bromoacetophenone resulted in the formation of undesired dihydrothiazole 19 (Scheme 3). A
convincing mechanism for this cyclization reaction is depicted in Scheme S1.22 In order to prevent
isomer formation, we used a secondary amine as a starting marterial instead of primary amine. The N-
benzyl-N-methyl-N'-(ethoxycarbonyl)thiourea 13 was succesfuly cyclized to form ethyl 2-
(benzyl(methyl)amino)-4-phenylthiazole-5-carboxylate 14 under conditions using TEA and α-
bromoacetophenone in DMF. A plausible mechanism for the above cyclization reaction is shown in
Scheme S2.23 Hydorylsis of the thiazole-5-carboxylate 14 with 2 M NaOH in EtOH at 70 ℃, results
in 2-(benzyl(methyl)amino)-4-phenylthiazole-5-carboxylic acid 15. Further, N-benzyl-2-
(benzyl(methyl)amino)-4-phenylthiazole-5-carboxamide 16 was obtained by the amide coupling of
benzylamine using EDC·HCl and HOBt in DMF for 6 h.
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Scheme 2. Study for solution-phase synthesis of 2-amino-5-carboxamide thiazole derivativesa
S
O
N
O
N
H
N
N
O
H
a
b
S
N
O
12
13
14
c
HN
O
OH
N
N
d
S
S
N
N
O
16
15
a Reagents and conditions: (a) Ethoxycarbonyl isothiocyanate, DCM, rt, 1.5 h. (b) α-bromoacetophenone, TEA, DMF, rt,
4 h.(c) 2 M NaOH, EtOH, 70 ℃, 12 h. (d) Benzylamine, EDC·HCl, HOBt, DMF, rt, 6 h
Scheme 3. Formation of the undesired isomers 2-aminothiazole 8a
O
O
N
S
O
NH2
S
N
N
N
O
H
H
a
b
17
18
19
a Reagents and conditions: (a) Ethoxycarbonyl isothiocyanate, DCM, rt, 4 h. (b) α-bromoacetophenone, DMAP 5% AcOH
in DMF, 90 ℃, 4 h.
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Thus, as the solution-phase reaction conditions were successfully optimized, the solid-phase
synthesis of 2-amino-5-carboxamide derivatives introduced various amines. Merrifield resin 1 was
used as a starting material, and reacted with 4-hydroxy-2-methoxybenzaldehyde, K2CO3, and KI in
DMF for 16 h in order to yield the 4-formyl-3-methoxy phenoxy resin 2.24 This process was monitored
using ATR-FTIR, the results of which showed an ester (C=O) peak at 1675 cm-1 (Figure S1(2)). After
the reductive amination of resin 2, with amines and NaBH(OAc)3 in DCM, the representative ester
(C=O) peak at 1675 cm-1 disappeared (Figure S1(3{1})). The attachment of ethoxycarbonyl
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isothiocyanate
to
N-alkylated
resin
3
in
DCM
obtained
Ethyl
(N-alkyl-
benzylcarbamothioyl)carbamate resin 4, whose FTIR spectrum showed the ester (C=O) peak at 1735
cm-1
(N-alkyl-
(Figure
S1(4{1})).
The
dehydrative
cyclization
of
Ethyl
benzylcarbamothioyl)carbamate resin 4 was successfully conducted using α-bromoacetophenone or
3-(Bromoacetyl)pyridine hydrobromide in the presence of the DMF so as to afford 2-amino-5-
carboxylate thiazole resin 7, and its FTIR spectrum showed a shift in the ester (C=O) peak from 1735
cm-1 to 1667 cm-1 (Figure S1(7{1,1})). Following the hydrolysis of 2-amino-5-carboxylate thiazole
resin 7 with 2M NaOH in DMSO at 60 ℃, we could obtain 2-amino-thiazole-5-carboxylic acid resin
8, and its FTIR spectrum showed carboxylic acid (C=O) peak at 1610 cm-1 and an OH peak at 3369
cm-1 (Figure S1(8{1,1})). In order to obtain the 2-amino-thiazole-5-carboxylic acid 9, resin 8 was
cleaved from the polymer support under TFA in DCM (1:2, v/v) at room temperature for 12 h (Table
2).
As we can see in Table 2, The yield of compound 9{1,2} was high (57%), while the yield of
compound 9{2,1} was low (6%). The plausible mechanistic pathway for cyclization of thiourea
intermediate resin 4 is shown in Scheme S3. In the reaction, cyclization using 3-(Bromoacetyl)pyridine
has better reactivity than cyclization using 2-bromoacetophenone because of the electron withdrawing
effect of the pyridine ring. Also, compounds which the R1 group is a furfuryl group show a lower yield
than compounds with a benzyl group because of the electron-withdrawing effect of the oxygen in furan
ring.
Next, Resin 8 undergoes amide coupling under conditions using EDC·HCl, HOBt, and various
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amines and the reaction was monitored using FTIR, which shows the disappearance of the OH peak
(Figure S1(10{1,1,1})). In order to afford the 2-amino-5-carboxamide thiazole derivatives 11, resin
10 was cleaved from the polymer support under TFA in DCM (1:2, v/v) at RT for 12 h (Table 3).
In the case of a cyclization reaction using a 1-bromopinacolone, the decarboxylative cyclization of
Ethyl (N-alkyl-benzylcarbamothioyl)carbamate resin 4 was carried out using DMF at 80 ℃. As a result,
we could obtain 4-tert-butyl thiazole resin 5, not in the dehydrative cyclization form. The IR spectra
of the compounds that can support this were shown in Figure S2. In order to obtain the 4-tert-butyl
thiazole 6, resin 5 was cleaved from the polymer support under TFA in DCM (1:2, v/v) at room
temperature for 12 h (Table 1).
1
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Scheme 4. Synthesis of 2-Amino-5-Carboxamide Thiazole Derivatives on Solid Phasea
O
O
S
O
O
O
O
H2N R1
R1
S
C
N
O
N
R1
N
O
Cl
H
N
H
P
H
O
a
O
b
O
c
1
2
3
4
P = Merrifield resin
a-haloketone
R2
e
d
Br
Br
O
O
R2
R2
R2
R4
R4
R3
R3
N
H
N
OH
O
O
N
O
N
O
N
O
N
S
S
S
N
R1
N
R1
N
R1
O
O
O
S
N
R1
g
f
O
O
O
O
10
8
7
5
h
h
h
R2
R2
R4
R3
N
OH
N
N
N
S
S
HN
R1
HN
R1
O
O
S
HN
R1
11
9
6
a
o
Reagents and conditions: (a) 4-hydroxy-2-methoxybenzaldehyde, K2CO3, KI, 60 C, 16 h. (b) NaBH(OAc)3, 1,2-
dichloroethane, rt, 1.5 h. (c) DCM, rt, 19 h. (d) DMF, 80 ℃, 12 h. (e) TEA, DMF, rt, 2~12 h. (f) 2 M NaOH, DMSO, 60
oC, 72 h (g) EDC·HCl, HOBt, DMF, rt, 24 h. (h) TFA/DCM (1:2, v/v), rt, 12 h.
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- Amines (R1)
NH2
1
2
3
NH2
O
NH2
NH2
4
5
1
2
3
4
6
7
- a-Bromoketones (R2)
N
8
9
Br
Br
Br
10
11
12
13
14
15
16
17
18
19
20
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22
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O
O
O
2
3
1
- Amines (NR3R4)
H2N
H2N
H2N
H2N
H2N
H2N
Cl
O
1
2
3
4
5
O
H
N
O
O
NH2
O
H2N
H2N
H2N
O
O
O
6
7
8
9
10
11
Figure 2. Building Block for 2-Amino-5-carboxamide Thiazole Derivatives
Table 1. Yields and Purities of 4-tert-butyl Thiazole 6
Yield
(%)a
Purity
R1
R2
Compound
6{1,3}
(%)b
35
17
100
O
6{2,3}
100
aFor five -step overall yields (loading capacity of resin 1 is 2.28 mmol/g). bAll of the purified products were checked by LC/MS at 254 nm.
Table 2. Yields and Purities of 2-Amino-Thiazole-5-Carboxylic Acid 9
Yield
(%)a
Purity
(%)b
R1
R2
Compound
9{1,1}
30
6
100
92.53
100
O
9{2,1}
9{3,1}
9{4,1}
19
18
97.75
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N
N
1
2
3
4
5
6
7
8
9{1,2}
9{2,2}
9{3,2}
9{4,2}
57
9
100
100
O
N
N
21
23
99.6
98.4
9
10
11
aFor six-step overall yields (loading capacity of resin 1 is 2.28 mmol/g). bAll of the purified products were checked by LC/MS at 254 nm.
12
13
14
15
16
17
18
19
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36
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
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57
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59
60
Table 3. Yields and Purities of 2-Amino-5-Carboxamide Thiazole 11
Yield Purity
Yield Purity
R1
R2
NR3R4
R1
R2
NR3R4
No.
No.
(%)a
(%)b
(%)a
(%)b
N
O
H
11
{1,1,1}
11
{1,2,10}
H
N
N
15
100
24
97
O
O
H
N
N
O
11
11
O
H
N
19
19
12
21
25
29
16
23
21
28
100
85.9
85.9
98
13
13
15
15
11
13
19
19
15
14
97.2
99
{1,1,2}
{1,2,11}
Cl
11
{1,1,3}
11
{3,1,1}
H
N
H
N
O
O
11
{1,1,10}
11
{3,1,2}
H
H
N
N
100
95
O
N
N
N
N
N
N
N
Cl
11
{1,2,1}
11
{3,1,3}
H
H
N
N
O
O
11
{1,2,2}
11
{3,1,7}
H
N
96
99
N
Cl
O
11
{1,2,3}
11
{3,1,10}
H
H
N
N
97
100
100
100
100
100
O
N
N
N
N
11
{1,2,4}
11
{3,2,1}
H
N
H
N
100
93.8
95.3
99
11
{1,2,5}
11
{4,2,1}
H
H
N
N
O
11
{1,2,6}
11
{4,2,4}
H
H
N
N
O
O
11
{1,2,7}
11
{4,2,5}
H
N
N
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1
2
3
4
5
6
H
N
N
N
N
N
O
O
11
{1,2,8}
11
{4,2,6}
H
N
12
20
100
12
18
100
O
11
{1,2,9}
11
{4,2,10}
H
H
N
N
95.6
90.6
O
7
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aFor seven-step overall yields (loading capacity of resin 1 is 2.28 mmol/g). bAll of the purified products were checked by LC/MS at 254 nm.
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The final goal of the drug discovery process is to develop orally active drugs. Lipinski’s rule and
some related parameters are used as guidelines to determine the potentials of orally available drugs.
In this context, in order to evaluate the potential orally available drug properties, we calculated the
physicochemical properties of 2-amino-5-carboxamide thiazole derivatives via Discovery Studio 2018.
According to Lipinski’s rule of five, orally absorbed drugs must obey following rules : a molecular
weight should be less than 500. It must have less than 5 hydrogen bond donor groups and less than 10
hydrogen bond acceptor groups. The calculated logP value should be less than 5.25 It is also
demonstrated that more flexible molecules are less likely to be orally active, few rotational bonds,
with polar surface area less than 140 Å2 are preferable drugs.26 As can be seen in Figure 3, most of the
physicochemical parameters of 2-amino-5-carboxamide thiazole derivatives are within the ranges of
those predicted for orally bioavailable drugs.
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Figure 3. Calculated physicochemical properties of 2-amino-5-carboxamide thiazole derivatives
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(MW : Molecular Weight, HBA : Hydrogen Bonding Acceptor, HBD : Hydrogen Bonding Donor, PSA : Polar Surface Area)
In conclusion, we have established a solid-phase synthetic method for constructing 2-amino-5-
carboxamide thiazole derivatives which avoids the formation of undesired isomers. Analogously to
our solution-phase synthesis, solid-phase synthesis was carried and contained three diversity sites that
were introduced, including amines (R1), α-haloketone (R2), and amines (NR3R4). The thiazole core
was prepared from the Ethyl (N-alkyl-benzylcarbamothioyl)carbamate resin 4 via the dehydrative
cyclization approach. Additionally, following the hydrolysis of the ester group, amide coupling was
carried out with various amines such as benzylamine, aliphatic amine, and amino acid. Following the
functionalization of 2-amino-5-carboxaminde thiazole, the supporting resin was treated with a cocktail
of TFA and DCM, affording the desired final compounds. Finally, in order to determine whether the
synthesized library has the potential to be used as an orally bioavailable drug, we calculated
physicochemical parameters such as Alog P, molecular weight, the number of hydrogen bond
acceptors and donors, the number of rotatable bonds, and polar surface area. As a result, most of the
key parameters of constructed 2-amino-5-carboxamide thazole derivatives fall within the ranges for
orally active drugs.
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Experimental section
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General procedure for synthesis: All chemicals were reagent grade and used as purchased. Reactions
were monitored by TLC analysis using Merk silica gel 60 F-254 thin layer plates (for solution-phase
synthesis) and an ATR-FTIR spectrometer (for solid-phase synthesis). Flash column chromatography
was carried out on Merk silic gel 60 (230-400 mesh). 1H NMR and 13C NMR spectra were recorded
in  units relative to deuterated solvent as an internal reference using a 500 MHz NMR instrument
(Bruker). Liquid chromatography tandem mass spectrometry (Agilent 6460 Triple Quad LC/MS)
analysis was performed using an electro spray ionization (ESI) mass spectrometer with photodiode-
array detector (PDA) detection. High-resolution mass spectrometry spectra were obtained using aTOF
LC/MS system (Agilent 6550 iFunnel Q-TOF LC/MS).
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Preparation of AMEBA resin 2
To a suspension of Merrifield resin 1 (2.28 mmol/g, 5.00 g, 11.4 mmol) in DMF (25 mL), potassium
carbonate (4.73 g, 34.2 mmol) and potassium iodide (0.02 g, 0.11 mmol) were added, followed by 3-
methoxy-4-formylphenol (5.20 g, 34.2 mmol). The resulting mixture was stirred at 60 ℃ for 16 h,
after the resin was filtered and washed successively with DMF, MeOH, H2O, MeOH, DCM, and
MeOH. The resin was then dried under high vacuum. Resin 2 was obtained as a white solid. Single-
Bead ATR-FTIR: 3023, 2920, 1675 (C=O), 1595, 1491, 1451, 1395, 1291, 1258, 1197, 1162, 1113,
1102, 1026, 1017, 815, 757, 697 cm−1.
Representative procedure for the preparation of N-substituted resin 3{1} (R1 = Bn)
To a mixture of AMEBA resin 2 (1 g, theoretically 1.80 mmol), and NaBH(OAc)3 (1.45 g, 6.84 mmol)
in 1,2-DCE (20 mL), benzylamine (0.747 mL, 6.84 mmol) was added and the resulting mixture was
shaken at room temperature for 1.5 h. The resin was then filtered and washed several times with DCM,
H2O, and MeOH, then dried under high vacuum. Resin 3{1} was obtained as a light-yellow solid.
Single-Bead ATR-FTIR: 3023, 2920, 1610 (C=O), 1586, 1503, 1492, 1450, 1419, 1374, 1284, 1258,
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1195, 1157, 1128, 1028, 821, 734, 696 cm−1
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Representative procedure for preparation of Ethoxycarbonylthiourea resin 4{1} (R1 = Bn)
To a mixture of N-substituted resin 3a (1.16 g, theoretically 1.80 mmol) in 1,2-DCE (20 mL),
ethoxycarbonylisothiocyante (0.94 mL, 7.96 mmol) was added and the resulting mixture was shaken
at room temperature for 19 h. The resin was then filtered and washed several times with DCM and
MeOH, then dried under high vacuum. Resin 4{1} was obtained as a light-yellow solid. Single-Bead
ATR-FTIR: 3023, 2923, 1735 (C=O), 1611, 1586, 1506, 1450, 1414, 1288,1228, 1187, 1160, 1112,
1027, 1012, 820, 759, 734, 697 cm−1
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Representative procedure for preparation of Ethyl thiazole-5-carboxylate resin 5{1,3} (R1 = Bn,
R2 = tert-butyl)
To a mixture of Ethoxycarbonylthiourea resin 4{1} (0.5 g, theoretically 0.644 mmol) in DMF (10
mL), 1-Bromopinacolone (0.61 g, 3.42 mmol) was added and the resulting mixture was shaken at 80
oC for 12 h. The resin was then filtered and washed several times with DMF, MeOH, H2O, and DCM,
then dried under high vacuum. Resin 5{1,3} was obtained as a pink solid. Single-Bead ATR-FTIR:
3023, 2926, 1610, 1583, 1505, 1450, 1286, 1195, 1159, 1128, 1113, 1025, 1015, 817, 697 cm−1
Representative procedure for preparation of Ethyl thiazole-5-carboxylate resin 7{1,1} (R1 = Bn,
R2 = Aryl)
To a mixture of Ethoxycarbonylthiourea resin 4{1} (1 g, theoretically 1.29 mmol) in DMF (10 mL),
2-Bromoacetophenone (1.36 g, 6.84 mmol) was added and the resulting mixture was shaken at room
temperature for 2 h. The resin was then filtered and washed several times with DMF, MeOH, H2O,
and DCM, then dried under high vacuum. Resin 7{1,1} was obtained as a light-yellow solid. Single-
Bead ATR-FTIR: 3023, 2921, 1667 (C=O), 1610, 1586, 1532, 1504, 1493, 1450, 1419, 1385, 1330,
1285, 1256, 1196, 1158, 1128, 1072, 1027, 822, 752, 697, 623 cm−1
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Representative procedure for preparation of Ethyl thiazole-5-carboxylate resin 7{1,2} (R1 = Bn,
R2 = 4-Pyridine)
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To a mixture of Ethoxycarbonylthiourea resin 4{1} (0.5 g, theoretically 0.644 mmol) and Et3N (0.35
g, 9.54 mmol) in DMF (10 mL), 3-(Bromoacetyl)pyridine Hydrobromide (0.961 g, 3.42 mmol) was
added and the resulting mixture was shaken at room temperature for 2 h. The resin was then filtered
and washed several times with DMF, MeOH, H2O, and DCM, then dried under high vacuum. Resin
7{1,2} was obtained as a dark-brown solid. Single-Bead ATR-FTIR: 3021, 2923, 1698 (C=O), 1605,
1585, 1530, 1505, 1492, 1450, 1419, 1337, 1284, 1249, 1195, 1159, 1111, 1077, 1023, 817, 756, 697
cm−1
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Representative procedure for preparation of thiazole-5-carboxylic acid resin 8{1,1} (R1 = Bn, R2
= Aryl)
To a mixture of Ethyl thiazole-5-carboxylate Resin 7{1,1} (0.358 g, theoretically 0.408 mmol) in
DMSO (40 mL), 2M NaOH (4.1 mL, 8.16mmol) was added and the resulting mixture was shaken at
o
60 C for 72 h. The resin was then filtered and washed several times with MeOH, H2O, and DCM,
then dried under high vacuum. Resin 8{1,1} was obtained as a light-yellow brown solid. Single-Bead
ATR-FTIR: 3359(br), 3024, 2924, 1610 (C=O), 1586, 1505, 1493, 1451, 1420, 1372, 1323, 1286,
1259, 1196, 1159, 1129, 1116, 1027, 822, 754, 697 cm−1
Representative procedure thiazole-5-carboxamide resin 10{1,1,1} (R1 = Bn, R2 = Aryl, NR3R4 =
Benzylamino)
A mixture of thiazole-5-carboxylic acid resin 8{1,1} (0.5 g, theoretically 0.589 mmol), EDC·HCl
(0.66 g, 3.42 mmol), and HOBt (0.52 g, 3.42 mmol) in DMSO (20 mL) was shaken at room
temperature for 24 h. The resin was then filtered and washed several times with DMF, MeOH, H2O,
and DCM, then dried under high vacuum. Resin 10{1,1,1} was obtained as a light-yellow solid.
Single-Bead ATR-FTIR: 3023, 2918, 1609 (C=O), 1586, 1505, 1492, 1450, 1419, 1380, 1328, 1286,
1260, 1195, 1159, 1028, 820, 744, 697 cm−1
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Representative Procedure for the Preparation of 6{1,3} (R1 = Bn, R2 = tert-butyl)
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A resin 5{1,3} (0.2 g, theoretically 0.2466 mmol) was treated with a mixture of TFA and DCM (1:3,
v/v, 9 mL), then shaken for 12 h at room temperature. The resin was filtered and washed several times
with DCM, EA, and MeOH, and organic filtrate was collected and evaporated. The residue was
dissolved in EA, washed with H2O, and neutralized to pH 7 with saturated aqueous NaHCO3 solution.
The organic layer was dried with anhydrous Na2SO4 and evaporated. The crude mixture was purified
by column chromatography on silica gel (hexane/ethyl acetate) and triturated with hexane and diethyl
ether (1:1, v/v), affording 6{1,3} (35%, five-step overall yield). 1H NMR (500 MHz, CDCl3) δ 7.41 –
7.31 (m, 4H), 7.29 (d, J = 6.0 Hz, 1H), 6.06 (s, 1H), 4.40 (s, 2H), 1.27 (s, 9H). 13C NMR (126 MHz,
CDCl3) δ 169.56, 162.13, 137.63, 128.78, 127.84, 127.81, 98.05, 50.20, 34.64, 29.75. LC-MS (ESI):
m/z = 247.2 [M + H]+ : HRMS (ESI) calcd for C14H14N2S [M + H]+ : 247.1263, found : 247.1266.
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Representative Procedure for the Preparation of 9{1,1} (R1 = Bn, R2 = Aryl)
A resin 8{1,1} (0.5 g, theoretically 0.589 mmol) was treated with a mixture of TFA and DCM (1:3,
v/v, 9 mL), then shaken for 12 h at room temperature. The resin was filtered and washed several times
with DCM, EA, and MeOH, and organic filtrate was collected and evaporated. The residue was
dissolved in EA, washed with H2O, and adjusted to pH 4 with saturated aqueous NH4Cl solution. The
organic layer was dried with anhydrous Na2SO4 and evaporated. The crude mixture was purified by
column chromatography on silica gel (hexane/ethyl acetate) and triturated with hexane and diethyl
ether (1:1, v/v), affording 9{1,1} (30%, six-step overall yield). 1H NMR (500 MHz, CDCl3) δ 12.51
(s, 1H), 7.64 (d, J = 6.5 Hz, 2H), 7.42 (d, J = 6.9 Hz, 2H), 7.37 (s, 4H), 7.34 (s, 2H), 6.48 (s, 1H), 4.49
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(s, 2H). C NMR (126 MHz, CDCl3) δ 171.47, 142.33, 134.18, 130.11, 129.44, 129.13, 128.78,
128.61, 128.31, 127.89, 126.01, 98.72, 50.70. LC-MS (ESI): m/z = 267.2 [M – CO2 + H]+ :27
Representative Procedure for the Preparation of 11{1,1,1} (R1 = Bn, R2 = Aryl, NR3R4 =
Benzylamino)
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A resin 10{1,1,1} (0.552 g, theoretically 0.589 mmol) was treated with a mixture of TFA and DCM
(1:3, v/v, 9 mL), then shaken for 12 h at room temperature. The resin was filtered and washed several
times with DCM, EA, and MeOH, and organic filtrate was collected and evaporated. The residue was
dissolved in ethyl acetate, washed with H2O, and neutralized to pH 7 with saturated aqueous NaHCO3
solution. The organic layer was dried with anhydrous Na2SO4 and evaporated. The crude mixture was
purified by column chromatography on silica gel (hexane/ethyl acetate) and triturated with hexane and
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diethyl ether (1:1, v/v), affording 11{1,1,1} (15%, seven-step overall yield). H NMR (500 MHz,
CDCl3) δ 8.03 (s, 1H), 7.44 (d, J = 5.7 Hz, 2H), 7.36 – 7.14 (m, 11H), 7.01 (s, 2H), 5.68 (s, 1H), 4.32
13
(d, J = 3.4 Hz, 2H), 4.09 (s, 2H). C NMR (126 MHz, CDCl3) δ 170.93, 161.53, 152.03, 137.79,
136.76, 134.61, 129.51, 129.16, 129.04, 128.73, 128.62, 127.77, 127.62, 127.49, 127.42, 117.77,
49.55, 43.85. LC-MS (ESI): m/z = 400.3 [M + H]+ : HRMS (ESI) calcd for C24H21N3OS [M + H]+ :
400.1478, found : 400.1476.
Supporting Information
Full analytical data of compounds, along with the copies of 1H NMR, 13C NMR, LC-MS, and HRMS
spectra of all the synthesized compounds, and complete descriptions of the studies for the reactions.
Acknowledgements
All authors were supported from the Basic Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of Education (No.2016R1D1A1B04932654), and
the Ministry of Trade, Industry & Energy, and the Korean Institute for Advancement of Technology
through the industrial infrastructure program for fundamental technologies (No.
2014M3A9A9073847) in Korea.
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Graphical Abstract
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Synthesis of 2-Amino-5-Carboxamide Thiazole derivatives via Dehydrative
Cyclization of Thiourea Intermediate Resin on Solid Phase
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Ye-Ji Kim, Hye-Jin Kwon, Si-Yeon Han and Young-Dae Gong*
Innovative Drug Library Research Center, Department of Chemistry, College of Science,
Dongguk University, 30, Pildong-ro 1-gil, Jung-gu, Seoul 04620, Korea
* Corresponding author Tel. : +82-2-2290-3206, Fax : +82-2-2260-1349 ; e-mail:
ydgong@dongguk.edu
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