Synthesis of 2-Amino-5-acylthiazoles by a Tertiary Amine-Promoted One-Pot Three-Component Cascade Cyclization Using Elemental Sulfur as a Sulfur Source

Article abstract of DOI:10.1021/acs.joc.9b02032

A novel one-pot three-component cascade cyclization strategy for the synthesis of 2-amino-5-acylthiazoles using enaminones, cyanamide, and elemental sulfur has been developed. The reported methods have demonstrated good tolerance of various functional gro

Full text of DOI:10.1021/acs.joc.9b02032

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Note
Synthesis of 2-Amino-5-acylthiazoles by a Tertiary
Amine-Promoted One-Pot Three-component Cascade
Cyclization Using Elemental Sulfur as Sulfur Source
Rong-Geng Fu, Yong Wang, Fei Xia, Hao-Lin Zhang,
Yuan Sun, Duo-Wen Yang, Ye-Wei Wang, and Peng Yin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02032 • Publication Date (Web): 04 Sep 2019
Downloaded from pubs.acs.org on September 4, 2019
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Synthesis of 2-Amino-5-acylthiazoles by a Tertiary Amine-Promoted
One-Pot Three-component Cascade Cyclization Using Elemental
Sulfur as Sulfur Source
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Rong-Geng Fu,a, †* Yong Wang,a, † Fei Xia,a, † Hao-Lin Zhang,a Yuan Sun,b Duo-Wen
Yang,a Ye-Wei Wang,a Peng Yinc
a
Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan Key
Laboratory of Druggability and Preparation Modification for Traditional Chinese Medicine and
TCM and Ethnomedicine Innovation & Development International Laboratory, School of
Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, P. R. China
b Department of Chemistry and Biochemistry, The Ohio State University, 43210, Columbus, Ohio,
USA
c
Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research (Ministry of
Education), College of Chemistry and Chemical Engineering, Hunan Normal University,
Changsha, Hunan, 410081, P. R. China
O
O
4-Methylmorpholine
R
NH2CN
S
N
R
N
NMP, 100°C, N2, 16 h
S
NH2
R = aryl, aliphatic
2 C(sp2)-S bonds, 1 C(sp2)-N bond and 1 heterocyle formation
Broad substrate scope & good functional group compatibility
One-pot, three-component
Gram-scale synthesis
Operational simplicity
28 Examples, up to 95% yield
ABSTRACT: A novel one-pot three-component cascade cyclization strategy for the
synthesis of 2-amino-5-acylthiazoles using enaminones, cyanamide and elemental
sulfur has been developed. The reported methods have demonstrated good tolerance
of various functional groups. Up to 28 2-amino-5-acylthiazole compounds bearing
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diverse structural differences were successfully synthesized from easily obtained
starting materials with moderate to excellent yields. Our method provides an effective
way for the access of valuable and potentially bioactive 2-amino-5-acylthiazole
derivatives.
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Among the large family of thiazoles, 2-amino-5-acylthiazole compounds are
remarkably intriguing owing to their diversified biological and pharmaceutical
activities such as anticancer,1 anti-adhesive,2 antifungal,3 anti-obesity4 and
antimitotic5 activities (Fig. 1). Therefore a variety of synthetic efforts have been
devoted for the construction of the 2-amino-5-acylthiazole skeleton as well as their
derivatives.6 As illustrated in Scheme 1, current existing methods mainly tackle this
problem from two distinct approaches. One way is to use the classic Hantzsch
reaction and its related modified methodologies, where condensation of α-haloketones
with thioureas, thiocarbamoylamidine or ammonium thiocyanate is used for skeleton
synthesis. These strategies have focused on the sulfuration of C(sp3)-X bond and
activated C(sp3)-H bonds adjacent to the sp2 carbon atom. The other method relies on
the introduction of acyl and amino group onto a preexisting thiazole derivative using
Friedel-Crafts acylation and the direct amination of halogen-substituted thiazoles.
Recently, Roslan and co-workers developed a leaving group-free protocol for the
radical coupling of 1,3-dicarbonyls and thioureas to access a wide array of
2-amino-5-acylthiazoles.7
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H
H
O
O
N
N
S
S
Cl
N
O
N
F
7
8
9
I
II
p38 MAP kinase inhibitor
antifungal compound
OH
OH
O
H3CCH
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HO
H
3 H
N
HO
O
N
O
N
S
S
CH3
O
HN
S
H3C
O
N
CH3
N
IV
NPY5 receptor antagonist
III
FimH inhibitor
Fig. 1 Examples of biologically active 2-amino-5-acylthiazoles.
Although many elegant synthetic methods for 2-amino-5-acylthiazoles have been
developed,6,7 they are all using organosulfur as starting materials, which usually
requires additional steps to prefunctionalize the starting building blocks. From the
perspective of synthetic medicinal chemistry, it is highly desirable to develop an
efficient method for synthesis of 2-amino-5-acylthiazole derivatives using readily
available starting materials under simple and general reaction conditions. With the
increasing environmental concerns, many environment-friendly approaches for the
C–S bond formation using elemental sulfur have been reported.8 To the best of our
knowledge, employing elemental sulfur as the S source for the synthesis of
2-amino-5-acylthiazole moieties has not been revealed. Herein, we report a novel
synthetic strategy of 2-amino-5-acylthiazoles, featuring a one-pot three-component
cascade cyclization in a tertiary amine-promoted transformation of a readily available
enaminone and cyanamide using elemental sulfur as sulfur source.
Scheme 1. Existing Strategies for 2-Amino-5-acylthiazoles Synthesis
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A) Traditional routes
O
S
O
R1
Hantzsch reaction
R2
Halo
N
R1
N
N
N
S
H
R2
HN
B) Previous work
O
O
Friedel-Crafts
R1
R1
amination
acylation
N
N
N
S
S
S
R2
R2
HN
Halo
S
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Halo
O
O
O
R3
radical addition
R1X
N
R2
XR1
N
NH2
H
S
R3
HN
C) This work
O
O
Multicomponent
Cyclization
R1
R1
N
NH2CN
S
N
S
NH2
Initially, enaminone (1a), cyanamide, and elemental sulfur were chosen to set up
the model system for further optimization of reaction conditions, including selection
of base, choice of solvent, temperature, and inert atmosphere (Table 1). No desired
product was observed when N-methyl pyrrolidone (NMP) was used as solvent at
100 °C for 16 h in the absence of any additive (Table 1, entry 1). Interestingly, the
employment of dimethylaminopyridine (DMAP) as additive led to the formation of
product 3a with good yield (Table 1, entry 2). Subsequently, different bases were
screened (Table 1, entries 2-9). While K2CO3 cannot enable the desired cyclization
(Table 1, entry 3), pyridine gave a moderate yield of 3a (Table 1, entry 4). Among all
tested bases, N-methylmorpholine (NMM) was shown to be the best sulfur activator,
leading to the formation of product 3a with good yield (Table 1, entry 5). In parallel
entries, other aliphatic amines such as pyrrolidine, Et3N, N-methylpiperidine and
diisopropylethylamine (DIPEA) were less capable in promoting the reaction (Table 1,
entries 6-9). Therefore, NMM was identified as base additive for this reaction and
used for further optimization. The nature of solvents was found to have large impact
on the reaction. The yield would dramatically decrease if other solvents than NMP
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were used, including DMF, DMSO, pyridine, H2O and toluene (Table 1, entries
10-13). In terms of the effect of reaction temperature, 100 °C was proved to be most
favorable (Table 1, entries 14 and 15). No enhancement in yield was observed when
the reaction was carried out with less amount of sulfur or cyanamide (Table 1, entries
16 and 17). Removing the inert nitrogen atmosphere lead to notably loss of yield,
indicating that the nitrogen atmosphere was indispensable for this reaction (Table 1,
entry 18). Finally, the parallel reaction using Na2S as the alternative sulfur source
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gave no production of 3a as observed with the optimal parameters shown in entry 19.
Table 1. Condition Optimizationa
O
O
additive
NH2CN
2
S
N
N
solvent, N2
100°C
S
NH2
1a
3a
Entry
Additive
Solvent
Temp Yield
(°C)
100
(%)
0
1
2
3
4
5
6
7
8
9
-
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
DMAP
K2CO3
pyridine
NMM
100
100
100
100
100
100
100
100
60
0
40
70
50
61
63
68
pyrrolidine
NEt3
DIPEA
N-Methylpi
peridine
NMM
10
11
DMF
DMSO
pyridine
H2O
100
100
100
100
90
63
41
46
0
NMM
12
NMM
13
NMM
14
NMM
NMP
NMP
NMP
NMP
NMP
NMP
55
65
32
36
35
0
15
NMM
110
100
100
100
100
16 b
17 c
18 d
19 e
NMM
NMM
NMM
NMM
a
Reaction conditions: 1a (1 mmol), S (4 mmol), cyanamide solution (4 mmol) and
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additive (0.2 mmol) in solvent (1 mL) for 16 h under N2 atmosphere. b The amount of
6
7
c
d
S is 2.0 equiv. The amount of cyanamide solution is 2.0 equiv. Reaction under air
8
9
atmosphere. e Na2S (4 mmol) used as sulfur source.
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With the optimal conditions in hand, we then explored the scope of this cascade
cyclization reaction first with respect to enaminones (1) as shown in Scheme 2.
Pleasingly, both electron-donating (Me, OMe) and electron-withdrawing (F, Cl, Br, I,
CF3, NO2) groups are well tolerated on the aryl ring, giving the corresponding
products in moderate to good yields (3a-3o). These results revealed that the electronic
effect and position of the substituent on the aryl-enaminone had little impact on the
yield of the desired product. Additionally, more sterically hindered naphthyl group
was also found to be compatible with the reaction condition, and the respective
products 3s and 3t could be obtained in good yield. Notably, for the dimethyl-,
dimethoxyl- and difluoro-substituted benzene ring, the desired products could be
isolated in excellent yields over 90% (3p-3r). The diversity of the functional groups
(methyl, methoxyl, halogen, nitro, ester and trifluoromethyl) on substituted phenyl
moiety further demonstrated the broad substrate scope of this method. Furthermore,
enaminones bearing heterocycles, including furanyl (3v), pyrrolyl (3w) and thienyl
(3x) moieties, were also able to give the desired products in good yields.
Unfortunately, the reaction employing nitriles (such as acetonitrile or benzonitrile) or
substituted cyanamides (such as dimethylcyanamide or N-phenylcyanamide) instead
of cyanamide did not produce the target products (3aa, 3ab, 3ac and 3ad). Expanding
the scope from elemental sulfur to elemental selenium, no desired product (3ae) was
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obtained.
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7
Scheme 2. Substrate Scope, with Respect to the Aryl-enaminones a
8
9
O
O
NMM
Ar
NH2CN
2
S
N
Ar
N
S
NMP, N2, 100°C, 16h
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11
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13
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NH2
1
3
O
O
R
O
O
N
N
N
N
S
S
S
S
R
R
NH2
NH2
NH2
NH2
R
3m, R = 2-Cl, 73%
3n, R = 2-Me, 76%
3o, R = 2-OH, 65%
3p, R = 3,4-difluoro, 95%
3q, R = 3,4-dimethyl, 95%
3r, R = 3,4-dimethoxyl, 90%
3k, R = 3-Me, 67%
3l, R = 3-NO2, 68%
3a, R = H, 70%
3b, R = 4-F, 70%
3c, R = 4-Cl, 71%
3d, R = 4-Br, 65%
3e, R = 4-I, 68%
3f, R = 4-Me, 70%
3g, R = 4-OMe, 71%
3h, R = 4-CF3
3i, R = 4-NO2
3j, R = 4-COOCH3, 50%
O
O
O
O
N
S
N
N
S
S
,
,
70%
60%
NH2
NH2
O
NH2
3s, 65%
3t, 71%
3u, 80%
O
O
O
N
S
N
N
N
N
N
O
S
S
N
S
S
S
NH
S
NH2
NH2
NH2
NH2
NH2
3z, 50%
3y, 71%
3w, 50%
O
3v, 50%
O
3x, 77%
O
O
O
N
N
N
S
N
N
S
S
S
Se
N
Me
HN
NH2
3aa, 0%
3ab, 0%
3ac, 0%
3ae, 0%
3ad, 0%
a
Reaction conditions: 1 (1 mmol), S (4 mmol), cyanamide solution (4 mmol) and
NMM (0.2 mmol) in NMP (1 mL) for 16 h under N2 atmosphere.
We further inspected the scope of the reaction by using alkenyl- and
alkyl-enaminones (1) instead of aryl-enaminones under the optimal conditions
(Scheme 3). Although enaminones bearing styryl (4a) and terpenoid (4b) structures
were found to have good reactivities and produce the corresponding products, their
yields were comparably lower than that of aryl-enaminones, indicating the importance
of aromatic structure in this method. When the phenethyl-enaminone and
n-propyl-enaminone were used as substrates, the reaction did not proceed to produce
the desired products (4c and 4d).
Scheme 3. Substrate Scope, with Respect to the Alkenyl- and Alkyl-enaminonesa
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5
O
O
NMM
R
NH2CN
2
S
N
R
N
S
NMP, N2, 100°C, 16h
NH2
1
4
6
7
8
9
O
O
O
O
N
N
N
N
S
S
S
S
NH2
NH2
NH2
NH2
4c, 0%
4b, 50%
4a, 41%
4d, 0%
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60
a
Reaction conditions: 1 (1 mmol), S (4 mmol), cyanamide solution (4 mmol) and
NMM (0.2 mmol) in NMP (1 mL) for 16 h under N2 atmosphere.
To demonstrate the synthetic utility of this cyclization approach for
2-amino-5-acylthiazoles, a gram-scale synthesis was performed. As shown in Scheme
4, the cyclization could be easily scaled up to gram scale and afford 1.08 g of 3t in 71%
yield on a 6 mmol scale. Further, we were interested in employing the developed
method to synthesize a 2-amino-5-acylthiazole-based antifungal compound II. Upon a
further N-acylation of 3t with cyclohexanecarboxylic acid, product antifungal
compound II was obtained in 80% yield. As shown in Scheme 4, the synthesis of
2-amino-5-naphthoylthiazole (3t) was simplified from three steps to one single
operation with a satisfactory yield (71%). Such a synthesis is far superior to the
reported protocol (3 steps with 23% overall yield),3 since less steps (2 steps) and
less-environmentally benign reagents are employed to afford much higher overall
product yield (62.5% overall yield).
Scheme 4. Applications
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5
O
O
NMM (0.2 equiv)
NH2CN
4 equiv
S
N
NH2
N
S
NMP, N2, 100°C, 16h
4 equiv
6
1t (1.35g, 6 mmol)
3t (1.08 g, 71%)
7
8
O
O
S
H2
N
H
O
EDC, DMAP
N
S
OH
N
DCM, r.t., 16 h
O
N
9
II, 80%
antifungal compound
3t
10
11
12
13
14
15
16
17
18
19
20
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22
23
24
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Reported prcedure
1-Naphthaldehyde, n-BuLi,
THF, -78oC, 2 h
OH
S
BocHN
Dess-Martin periodinane,
DCM, r.t., 16 h
BocHN
S
N
N
step-1
step-2
O
BocHN
O
H2
N
S
S
TFA, DCM, r.t., 16 h
step-3
N
N
3t
23 % overall yield
Our streamline synthesis
O
O
O
N
H2
N
S
DMF-DMA
our protocol
step-2
N
step-1
3t
62.5% overall yield
1t
In order to elucidate the reaction mechanism, several control experiments were
carried out (Scheme 5). To determine whether the cyclization reaction was initiated
by free radicals, the radical initiator 2,2,6,6-tetramethylpiperidinooxy (TEMPO, 0.01
equiv)
or
di-tert-butyl
peroxide
(DTBP,
0.01
equiv)
or
2,2'-azobis(2-methylpropionitrile) (AIBN, 0.01 equiv) were used in the reactions. As
a result, it is found that none of the selected radical initiators could promote this
cyclization reaction, therefore suggesting that the radical process might not be
involved in this reaction mechanism. When the reactions were carried out in the
absence of S under the standard reaction conditions, compound 5 and 6 were obtained.
Subsequently, 5 and 6 were used as the substrate to react with S, respectively. As a
result, the desired product 3a was not isolated. These observations indicated that 5
and 6 are the off-cycle by-products instead of an intermediate. Next, we blended the
1a and S under the standard conditions, and the product 3a was not afforded as well.
Similarly, the reaction of 1a and thiourea in the presence of S as an oxidant under the
standard conditions did not afforded the target product 3a, suggesting that thiourea
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might not be involved in this transformation
6
7
8
Scheme 5. Control Experiments
O
O
standard conditions
NH2CN
S
N
N
S
9
NH2
1a
3a
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11
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14
15
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45
46
47
48
49
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54
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60
TEMPO 0.01 equiv.
67%
63%
61%
DTBP
AIBN
0.01 equiv.
0.01 equiv.
N
N
standard conditions
NH2CN
N
NH2
1a
N
N
6, 15%
5, 10%
standard conditions
standard conditions
standard conditions
5
6
S
S
S
3a, 0%
3a, 0%
3a, 0%
1a
S
standard conditions
3a, 0%
S
1a
H2N
NH2
According to the above-mentioned experimental observations and previous
reports,9 we suggest a possible reaction pathway (Scheme 6). Firstly, the elemental
sulfur incorporates the nucleophilic NMM to form the active 4-methylmorpholine N-S
species, which mediates the transfer of the sulfur atom to enaminone and provides
intermediate V via the enaminone’s isomeric version 1'. Next, intermediate V is
attacked by cyanamide and leads to the formation of VI, which undergoes an
intramolecular nucleophilic addition to afford intermediate VII. Subsequently,
tautomerization of intermediate VII afforded the intermediate VIII. Finally, the
intermediate VIII can be converted to the desired product 3a via the release of
dimethylamine.
Scheme 6. Possible Reaction Mechanism
S8
N
N
S
Sn-1
O
O
O
V
N
O
O
1'
N
H2
N
N
S
N
1a
N
O
N
O
N
H
O
N
O
NH2
N
NH
NH
N
N
S
S
S
S
NH2
NH2
3a
VIII
VII
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In conclusion, a novel one-pot three-component strategy to construct
2-amino-5-acylthiazoles from easily available enaminones, cyanamide, and elemental
sulfur was developed, giving products in moderate to excellent yields. The easiness of
the availability of the starting materials, excellent functional group tolerance, mild
reaction conditions, and the capacity of gram-scale synthesis, all make this reaction a
practical synthetic method in medicinal chemistry. Further development and
applications of this cascade of direct construction of two C-S bonds and a C(sp2)-N
bond, and elemental sulfur are ongoing in our laboratory and the related results will
be reported in due course.
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EXPERIMENTAL SECTION
General Information.
Enaminones 1 used in the experiments were synthesized in the lab following literature
process.10 Other chemicals and solvents used in the experiments were acquired from
commercial sources and used directly without further treatment. Column
1
chromatography was performed using silica gel, SiO2 (200-300 mesh). H NMR and
13C{1H} NMR spectra were recorded on Bruker-AV (600 or 500 and 151 or 126 MHz,
respectively) instrument internally referenced to tetramethylsilane (TMS) or
chloroform signals. High-resolution mass spectra (HRMS) were recorded using
Agilent 6545 LC/Q-TOF. The melting points of solid samples were tested in an X-4
apparatus without correcting the temperature.
General procedure for 2-amino-5-acylthiazoles synthesis
Enaminones (1 mmol), 50 wt% aqueous cyanamide solution (340 mg, 4 mmol), sulfur
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powder (128 mg, 4 mmol), NMM (20 mg, 0.2 mmol) and NMP (1 mL) were added to
an oven-dried reaction vessel (20 mL). The reaction vessel was evacuated and back
filled with nitrogen gas three times. The reaction vessel was placed in an oil bath. The
mixture was stirred at 100℃ for 16 h under N2 atmosphere. After the reaction was
completed (TLC), the mixture was cooled to room temperature and then water was
added and the aqueous phase was extracted with ethyl acetate (3 × 20 mL). The
combined organic phase was dried over anhydrous Na2SO4, filtered, dried under
reduced pressure and finally purified by silica gel column chromatography on silica
gel with petroleum ether/ethyl acetate (PE/EA = 1:1-4:1, v/v) as the eluent to afford
the desired product.
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2-Amino-5-benzoylthiazole (3a) Yellow solid, yield 142.8 mg (70%); mp 181-182 ℃;
1H NMR (600 MHz, CDCl3) 7.79 (d, J = 7.0 Hz, 2H), 7.64 (s, 1H), 7.58 (t, J = 7.4 Hz,
1H), 7.49 (t, J = 7.6 Hz, 2H), 5.71 (s, 2H). 13C{1H} NMR (151 MHz, CDCl3) δ 187.0,
173.4, 149.2, 138.1, 132.1, 130.7, 128.7, 128.6. HRMS (ESI) m/z [M+H]+: Calcd for
C10H9N2OS: 205.0429. Found: 205.0432.
2-Amino-5-(4-fluorobenzoyl)thiazole (3b) Yellow solid, yield 155.4 mg (70%); mp
1
212-214 ℃; H NMR (600 MHz, DMSO-d6) 8.24 (s, 2H), 7.82 (dd, J = 8.7, 5.6 Hz,
13
2H), 7.66 (s, 1H), 7.34 (t, J = 8.8 Hz, 2H). C{1H} NMR (151 MHz, DMSO-d6) δ
184.4, 175.2, 164.5 (C6H5F) (d, Jc-F = 249.4 Hz), 151.6, 135.2 (d, Jc-F = 3.0 Hz), 131.4
(d, Jc-F = 9.0 Hz), 127.1, 116.1 (d, Jc-F = 21.7 Hz). HRMS (ESI) m/z [M+H]+: Calcd
for C10H8FN2OS: 223.0335. Found: 223.0337.
2-Amino-5-(4-chlorobenzoyl)thiazole (3c)11 Yellow solid, yield 169 mg (71%); mp
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228-230 ℃; H NMR (600 MHz, DMSO-d6): 8.27 (s, 2H), 7.75 (d, J = 8.5 Hz, 2H),
7.67 (s, 1H), 7.58 (d, J = 8.5 Hz, 2H). 13C{1H} NMR (151 MHz, DMSO-d6) δ 184.5,
175.4, 151.9, 137.3, 136.9, 130.6, 129.1, 127.1. HRMS (ESI) m/z [M+H]+: Calcd for
C10H8ClN2OS: 239.0040. Found: 239.0043.
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2-Amino-5-(4-bromobenzoyl)thiazole (3d)11 Yellow solid, yield 183 mg (65%); mp
1
254-256 ℃; H NMR (600 MHz, DMSO-d6): 8.27 (s, 2H), 7.72 (d, J = 8.6 Hz, 2H),
7.68 (d, J = 7.5 Hz, 2H), 7.67 (s, 1H). 13C{1H} NMR (151 MHz, DMSO-d6) δ 184.6,
175.4, 151.9, 137.7, 132.1, 130.8, 127.0, 125.8. HRMS (ESI) m/z [M+H]+: Calcd for
C10H8BrN2OS: 282.9534. Found: 282.9533.
2-Amino-5-(4-iodobenzoyl)thiazole (3e) Yellow solid, yield 224.4 mg (68%); mp
1
253-255 ℃; H NMR (600 MHz, DMSO-d6) 8.25 (s, 2H), 7.89 (d, J = 8.4 Hz, 2H),
7.66 (s, 1H), 7.51 (d, J = 8.4 Hz, 2H). 13C{1H} NMR (151 MHz, DMSO-d6) δ 184.9,
175.4, 151.8, 138.0, 137.9, 130.6, 127.0, 99.9. HRMS (ESI) m/z [M+H]+: Calcd for
C10H8IN2OS: 330.9396. Found: 330.9399.
2-Amino-5-(4-methylbenzoyl)thiazole (3f)11 Yellow solid, yield 152.6 mg (70%); mp
1
215-217 ℃; H NMR (600 MHz, DMSO-d6) 8.16 (s, 2H), 7.64 (d, J = 8.1 Hz, 2H),
7.63 (s, 1H), 7.33 (d, J = 8.1 Hz, 2H), 2.39 (s, 3H). 13C{1H} NMR (151 MHz,
DMSO-d6) δ 185.6, 175.0, 151.0, 142.3, 136.0, 129.6, 128.8, 127.5, 21.5. HRMS (ESI)
m/z [M+H]+: Calcd for C11H11N2OS: 219.0586. Found: 219.0582.
2-Amino-5-(4-methoxybenzoyl)thiazole (3g) Yellow solid, yield 166 mg (71%); mp
1
214-216 ℃; H NMR (600 MHz, DMSO-d6) 8.11 (s, 2H), 7.74 (d, J = 8.8 Hz, 2H),
7.64 (s, 1H), 7.05 (d, J = 8.7 Hz, 2H), 3.84 (s, 3H). 13C{1H} NMR (151 MHz,
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DMSO-d6) δ 184.6, 174.7, 162.6, 150.3, 131.1, 130.9, 127.6, 114.3, 55.9. HRMS (ESI)
m/z [M+H]+: Calcd for C11H11N2O2S: 235.0535. Found: 235.0538.
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2-Amino-5-(4-trifluoromethylbenzoyl)thiazole (3h) Yellow solid, yield 190.4 mg
(70%); mp 232-234℃; 1H NMR (600 MHz, DMSO-d6): 8.35 (s, 2H), 7.93 (d, J = 8.0
Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H), 7.69 (s, 1H). 13C{1H} NMR (151 MHz, DMSO-d6)
δ 184.6, 175.7, 152.7, 142.3, 131.7 (C6H5CF3) (q, Jc-F = 31.8 Hz) , 129.5, 126.9, 126.0
(q, Jc-F = 3.0 Hz), 124.4 (CF3) (q, Jc-F = 271.8 Hz). HRMS (ESI) m/z [M+H]+: Calcd
for C11H8F3N2OS: 273.0303. Found: 273.0305.
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2-Amino-5-(4-nitrobenzoyl)thiazole (3i) Yellow solid, yield 149 mg (60%); mp
1
254-256℃; H NMR (600 MHz, DMSO-d6): 8.40 (s, 2H), 8.33 (d, J = 8.0 Hz, 2H),
7.96 (d, J = 8.2 Hz, 2H), 7.69 (s, 1H). 13C{1H} NMR (151 MHz, DMSO-d6) δ 184.0,
175.9, 153.1, 149.4, 144.1, 130.0, 126.8, 124.2. HRMS (ESI) m/z [M+H]+: Calcd for
C10H8N3O3S: 250.0280. Found: 250.0283.
Methyl 4-(2-aminothiazole-5-carbonyl)benzoate (3j) Yellow solid, yield 131 mg
1
(50%); mp 234-235℃; H NMR (600 MHz, DMSO-d6) 8.33 (s, 2H), 8.08 (d, J = 8.4
Hz, 2H), 7.85 (d, J = 8.5 Hz, 2H), 7.67 (s, 1H), 3.90 (s, 3H). 13C{1H} NMR (151 MHz,
DMSO-d6) δ 185.0, 175.6, 166.2, 152.4, 142.6, 132.4, 129.9, 129.0, 127.0, 52.9.
HRMS (ESI) m/z [M+H]+: Calcd for C12H11N2O3S: 263.0484. Found: 263.0486.
2-Amino-5-(3-methylbenzoyl)thiazole (3k) Yellow solid, yield 146.06 mg (67%); mp
1
223-225℃; H NMR (600 MHz, DMSO-d6) 8.19 (s, 2H), 7.61 (s, 1H), 7.51-7.53 (m,
2H), 7.38-7.42 (m, 2 H), 2.39 (s, 3H). 13C{1H} NMR (151 MHz, DMSO-d6) δ 186.0,
175.1, 151.4, 138.8, 138.5, 132.8, 129.1, 128.9, 127.4, 125.9, 21.4. HRMS (ESI) m/z
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[M+H]+: Calcd for C11H11N2OS: 219.0586. Found: 219.0582.
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2-Amino-5-(3-nitrobenzoyl)thiazole (3l) Yellow solid, yield 169 mg (68%); mp
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9
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220-222℃; H NMR (600 MHz, DMSO-d6) 8.41-8.44 (m, 2H), 8.38 (s, 2H),
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8.16-8.17 (m, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.77 (s, 1H). C{1H} NMR (151 MHz,
DMSO-d6) δ 183.4, 175.9, 153.1, 148.2, 139.8, 134.9, 130.9, 126.6, 126.4, 123.3.
HRMS (ESI) m/z [M+H]+: Calcd for C10H8N3O3S: 250.0280. Found: 250.0278.
2-Amino-5-(2-chlorobenzoyl)thiazole (3m) Yellow solid, yield 173.7 mg (73%);
mp184-186 ℃; 1H NMR (600 MHz, DMSO-d6) 8.37 (s, 2H), 7.56 (d, J = 8.0 Hz, 1H),
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7.49-7.53 (m, 2H), 7.45 (t, J = 7.4 Hz, 1H), 7.28 (s, 1H). C{1H} NMR (151 MHz,
DMSO-d6) δ 184.3, 176.1, 153.3, 138.6, 131.8, 130.4, 130.2, 129.4, 127.6, 127.0.
HRMS (ESI) m/z [M+H]+: Calcd for C10H8ClN2OS: 239.0040. Found: 239.0043.
2-Amino-5-(2-methylbenzoyl)thiazole (3n) Yellow solid, yield 165.7 mg (76%); mp
1
207-209℃; H NMR (600 MHz, DMSO-d6) 8.25 (s, 2H), 7.37-7.41 (m, 2H),
7.25-7.32 (m, 3H), 2.26 (s, 3H). 13C{1H} NMR (151 MHz, DMSO-d6) δ 188.1, 175.7,
152.2, 139.1, 135.6, 131.2, 130.2, 128.2, 127.9, 125.9, 19.5. HRMS (ESI) m/z
[M+H]+: Calcd for C11H11N2OS: 219.0586. Found: 219.0582.
2-Amino-5-(2-hydroxybenzoyl)thiazole (3o) Yellow solid, yield 143 mg (65%); mp
208-210℃; 1H NMR (600 MHz, DMSO-d6) 10.31 (s, 1H), 8.20 (s, 2H), 7.53 (s, 1H),
7.45 (d, J = 7.5 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.90 (t, J =
7.5 Hz, 1H). 13C{1H} NMR (151 MHz, DMSO-d6) δ 186.6, 175.3, 156.8, 151.8, 132.9,
129.9, 127.5, 125.1, 119.4, 117.2. HRMS (ESI) m/z [M+H]+: Calcd for C10H9N2O2S:
221.0379. Found: 221.0381.
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2-Amino-5-(3,4-difluorobenzoyl)thiazole (3p) Yellow solid, yield 228 mg (95%); mp
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232-235℃; H NMR (600 MHz, DMSO-d6) 8.30 (s, 2H), 7.77-7.80 (m, 1H), 7.72 (s,
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1H), 7.62-7.64 (m, 1H), 7.55-7.60 (m, 1H). C{1H} NMR (151 MHz, DMSO-d6) δ
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183.2, 175.5, 152.1 (C6H5F) (dd, J c-F= 252.2, 13.59 Hz), 149.7 (C6H5F) (dd, Jc-F
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247.8, 12.8 Hz), 136.0, 126.2 (dd, Jc-F = 7.3, 3.2 Hz), 118.2 (dd, Jc-F = 25.9, 17.9 Hz).
HRMS (ESI) m/z [M+H]+: Calcd for C10H7F2N2OS: 241.0241. Found: 241.0244.
2-Amino-5-(3,4-dimethylbenzoyl)thiazole (3q) Yellow solid, yield 220.4 mg (95%);
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mp 239-241℃; H NMR (600 MHz, DMSO-d6) 8.14 (s, 2H), 7.63 (s, 1H), 7.51 (s,
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1H), 7.47 (dd, J = 7.7, 1.8 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 2.29 (s, 6H). C{1H}
NMR (151 MHz, DMSO-d6) δ 185.7, 174.9, 150.9, 141.1, 137.1, 136.4, 130.0, 129.7,
127.6, 126.4, 19.9, 19.8. HRMS (ESI) m/z [M+H]+: Calcd for C12H13N2OS: 233.0743.
Found: 233.0742.
2-Amino-5-(3,4-dimethoxybenzoyl)thiazole (3r) Yellow solid, yield 237.6 mg (90%);
mp 194-196℃; 1H NMR (600 MHz, DMSO-d6) 8.10 (s, 2H), 7.69 (s, 1H), 7.41 (dd, J
= 8.3, 2.0 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 3.85 (s, 3H),
3.82 (s, 3H). 13C{1H} NMR (151 MHz, DMSO-d6) δ 184.6, 174.7, 152.4, 150.4,
149.0, 131.1, 127.6, 122.7, 111.7, 111.4, 56.1, 56.0. HRMS (ESI) m/z [M+H]+: Calcd
for C12H13N2O3S: 265.0641. Found: 265.0638.
2-Amino-5-(2-naphthoyl)thiazole (3s) Yellow solid, yield 165 mg (65%); mp
230-233℃; 1H NMR (600 MHz, DMSO-d6) 8.41 (s, 1H), 8.24 (s, 2H), 8.14 (d, J = 8.0
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Hz, 1H), 8.00-8.05 (m, 2H), 7.77-7.80 (m, 2H), 7.61-7.66 (m, 2H). C{1H} NMR
(151 MHz, DMSO-d6) δ 185.7, 175.2, 151.7, 135.9, 134.8, 132.6, 129.8, 129.4, 128.8,
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128.4, 128.1, 127.5, 127.3, 125.3. HRMS (ESI) m/z [M+H]+: Calcd for C14H11N2OS:
255.0586. Found: 255.0584.
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2-Amino-5-naphthoylthiazole (3t)3 Yellow solid, yield 180.3 mg (71%); mp
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188-190℃; H NMR (600 MHz, DMSO-d6) 8.31 (s, 2H), 8.09 (d, J = 8.3 Hz, 1H),
8.00 (dd, J = 21.1, 7.9 Hz, 2H), 7.71 (dd, J = 7.0, 1.1 Hz, 1H), 7.55-7.61 (m, 3H),
7.36 (s, 1H). 13C{1H} NMR (151 MHz, DMSO-d6) δ 187.2, 175.8, 152.6, 136.6,
133.8, 130.9, 130.3, 128.9, 128.8, 127.5, 126.9, 126.8, 125.5, 125.4. HRMS (ESI) m/z
[M+H]+: Calcd for C14H11N2OS: 255.0586. Found: 255.0584.
([1,1’-Biphenyl]-4-yl)-[2-aminothiazol-5-yl]methanone (3u) Yellow solid, yield 224
mg (80%); mp 250-252℃; 1H NMR (600 MHz, DMSO-d6) 8.23 (s, 2H), 7.81-7.85 (m,
4H), 7.75 (d, J = 7.2 Hz, 2H), 7.72 (s, 1H), 7.52 (t, J = 7.7 Hz, 2H), 7.43 (t, J = 7.4 Hz,
1H). 13C{1H} NMR (151 MHz, DMSO-d6) δ 185.3, 175.2, 151.4, 143.7, 139.6, 137.5,
129.6, 129.5, 128.7, 127.4, 127.4, 127.3. HRMS (ESI) m/z [M+H]+: Calcd for
C16H13N2OS: 281.0743. Found: 281.0740.
(2-Amino-5-thiazolyl)-2-furanyl-methanone (3v) Yellow solid, yield 97 mg (50%);
mp 259-261 ℃; 1H NMR (600 MHz, DMSO-d6) 8.20 (s, 3H), 7.99 (s, 1H), 7.34-7.35
(m, 1H), 6.72-6.73 (m, 1H). C{1H} NMR (151 MHz, DMSO-d6) δ 174.9, 171.4,
13
152.1, 150.0, 147.3, 126.3, 117.4, 112.8. HRMS (ESI) m/z [M+H]+: Calcd for
C8H7N2O2S: 195.0222. Found: 195.0223.
(2-Amino-5-thiazolyl)-1H-pyrrol-2-yl-methanone (3w) Yellow solid, yield 96.5 mg
1
(50%); mp 277-279℃; H NMR (600 MHz, DMSO-d6) 11.77 (s, 1H), 7.94 (s, 1H),
7.91 (s, 2H), 7.03-7.04 (m, 1H), 7.07-7.08 (m, 1H), 6.21-6.22 (m, 1H). 13C{1H} NMR
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(151 MHz, DMSO-d6) δ 174.06, 173.6, 147.1, 130.5, 127.0, 125.0, 115.5, 110.4.
HRMS (ESI) m/z [M+H]+: Calcd for C8H8N3OS: 194.0382. Found: 194.0375.
(2-Amino-5-thiazolyl)-2-thienyl-methanone (3x) Yellow solid, yield 161 mg (77%);
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mp 183-185℃; H NMR (600 MHz, CDCl3) 7.94 (s, 1H), 7.80 (dd, J = 3.8, 1.1 Hz,
1H), 7.66 (dd, J = 4.9, 1.1 Hz, 1H), 7.17 (dd, J = 4.9, 3.8 Hz, 1H), 5.61 (s, 2H).
13C{1H} NMR (151 MHz, CDCl3) δ 177.4, 172.9, 147.3, 142.5, 132.6, 131.8, 130.2,
127.9. HRMS (ESI) m/z [M+H]+: Calcd for C8H7N2OS2: 210.9994. Found: 210.9996.
(2-Amino-5-thiazolyl)-2-thiazolyl-methanone (3y) Yellow solid, yield 150 mg (71%);
mp 264-266℃; 1H NMR (600 MHz, DMSO-d6) 8.68 (s, 1H), 8.43 (s, 2H), 8.16 (d, J =
2.5 Hz, 1H), 8.15 (s, 1H). 13C{1H} NMR (151 MHz, DMSO-d6) δ 176.6, 173.4, 167.7,
154.0, 145.3, 127.2. HRMS (ESI) m/z [M+H]+: Calcd for C7H6N3OS2: 211.9948.
Found: 211.9951.
(2-Amino-5-thiazolyl)-4-pyridinyl-methanone (3z) Yellow solid, yield 102.5 mg
(50%); mp 254-256℃; 1H NMR (600 MHz, DMSO-d6) 8.75 (dd, J = 4.4, 1.6 Hz, 2H),
8.40 (s, 2H), 7.70 (s, 1H), 7.63 (dd, J = 4.3, 1.6 Hz, 2H). C{1H} NMR (151 MHz,
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DMSO-d6) δ 184.3, 176.0, 153.2, 150.8, 145.3, 126.5, 122.4. HRMS (ESI) m/z
[M+H]+: Calcd for C9H8N3OS: 206.0382. Found: 206.0386.
1-(2-Amino-5-thiazolyl)-3-(phenyl)-(2E)-propen-1-one (4a) Yellow solid, yield 94.3
mg (41%); mp 217-219℃; 1H NMR (600 MHz, DMSO-d6) 8.38 (s, 1H), 8.18 (s, 2H),
7.82-7.84 (m, 2H), 7.70 (d, J = 15.6 Hz, 1H), 7.55 (d, J = 15.6 Hz, 1H), 7.42-7.44 (m,
3H). 13C{1H} NMR (151 MHz, DMSO-d6) δ 180.0, 175.3, 150.4, 140.7, 135.29,
130.6, 130.0, 129.3, 129.1, 122.6. HRMS (ESI) m/z [M+H]+: Calcd for C12H10N2OS:
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231.0586. Found: 231.0594.
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1-(2-Amino-5-thiazolyl)-3-(2,6,6-trimethyl-2-cyclohexen-1-yl)-(2E)-propen-1-one
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(4b) Yellow solid, yield 138 mg (50%); mp 190-192℃; H NMR (600 MHz, CDCl3)
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7.77 (s, 1H), 7.51 (d, J = 15.7 Hz, 1H), 6.66 (d, J = 15.7 Hz, 1H), 5.65 (s, 2H), 2.10 (t,
J = 6.3 Hz, 2H), 1.82 (s, 3H), 1.62-1.66 (m, 2H), 1.49-1.51 (m, 2H), 1.10 (s, 6H).
13C{1H} NMR (151 MHz, CDCl3) δ 181.3, 173.1, 145.5, 142.6, 136.6, 136.5, 132.9,
125.1, 39.8, 34.2, 33.7, 28.9, 21.9, 18.9. HRMS (ESI) m/z [M+H]+: Calcd for
C15H21N2OS: 277.1369. Found: 277.1367.
Scale-up synthesis of 2-amino-5-naphthoylthiazole (3t)
1t (1.35 g, 6 mmol), 50 wt% aqueous cyanamide solution (2.0 g, 24 mmol), sulfur
powder (0.77 g, 24 mmol), NMM (0.12 g, 1.2 mmol) and NMP (6 mL) were added to
an oven-dried reaction vessel (20 mL). The reaction vessel was evacuated and back
filled with nitrogen gas three times. The reaction vessel was placed in an oil bath. The
mixture was stirred at 100℃ for 16 h under N2 atmosphere. After the reaction was
completed (TLC), the mixture was cooled to room temperature and then water was
added and the aqueous phase was extracted with ethyl acetate (3 × 50 mL). The
combined organic phase was dried over anhydrous Na2SO4, filtered, dried under
reduced pressure. The resulting mixture was purified by silica gel column
chromatography on silica gel with petroleum ether/ethyl acetate (PE/EA = 1:1- 4:1,
v/v) as the eluent to afford 3t in the yield of 71% (1.08 g).
Synthesis of compound 5 and 6
Enaminone 1a (175 mg, 1 mmol), 50 wt% aqueous cyanamide solution (340 mg, 4
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mmol), NMM (20 mg, 0.2 mmol) and NMP (1 mL) were added to an oven-dried
reaction vessel (20 mL). The reaction vessel was evacuated and back filled with
nitrogen gas three times. The reaction vessel was placed in an oil bath. The mixture
was stirred at 100℃ for 16 h under N2 atmosphere. After the reaction was completed
(TLC), the mixture was cooled to room temperature and then water was added and the
aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic
phase was dried over anhydrous Na2SO4, filtered, dried under reduced pressure and
finally purified by silica gel column chromatography on silica gel with petroleum
ether/ethyl acetate (PE/EA = 1:1- 4:1, v/v) as the eluent to afford the desired product.
2-Dimethylamino-4-phenylpyrimidine (5)12 Yellow oil, yield 20 mg (10%); 1H NMR
(500 MHz, CDCl3) 8.37 (d, J = 5.1 Hz, 1H), 8.06-8.08 (m, 2H). 7.46-7.47 (m, 3H),
6.91 (d, J = 5.1 Hz, 1H), 3.27 (s, 6H). 13C{1H} NMR (126 MHz, CDCl3) δ 164.1,
162.5, 158.2, 137.9, 130.4, 128.6, 127.0, 104.7, 37.1. HRMS (ESI) m/z [M+H]+:
Calcd for C12H13N3: 200.1181. Found: 200.1182.
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4-Phenylpyrimidin-2-amine (6)13 White solid, yield 26 mg (15%); mp 159-161℃; 1H
NMR (500 MHz, CDCl3) 8.35 (d, J = 5.2 Hz, 1H), 7.98-8.00 (m, 2H). 7.47-7.48 (m,
3H), 7.04 (d, J = 5.2 Hz, 1H), 5.25 (s, 2H). 13C{1H} NMR (126 MHz, CDCl3) δ 165.5,
163.3, 158.8, 137.3, 130.6, 128.8, 127.1, 107.8. HRMS (ESI) m/z [M+H]+: Calcd for
C10H9N3: 172.0868. Found: 172.0870.
Synthesis of N-[5-(1-naphthoyl)thiazol-2-yl]cyclohexanecarboxamide (II)3
To a solution of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (714
mg, 3.7 mmol), 4-dimethylaminopyridine (20 mg, 0.16 mmol) and
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cyclohexanecarboxylic acid (512 mg, 4 mmol) in dry dichloromethane (20 mL) were
added 3t (254 mg, 1 mmol) at 0 °C. The reaction mixture was stirred at room
temperature for 14 h. The mixture was diluted with water, Na2SO4, filtered, and
concentrated. The resulting mixture was purified by silica gel column
chromatography on silica gel with petroleum ether/ethyl acetate (PE/EA = 1:1- 4:1,
v/v) as the eluent to afford II.
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White solid, yield 291 mg (80%); mp 231-232℃; H NMR (600 MHz, DMSO-d6)
12.638 (s, 1H), 8.15-8.17 (m, 1H), 8.03-8.06 (m, 2H), 7.84 (s, 1H), 7.82 (d, J = 7.0 Hz,
2H), 7.57-7.65 (m, 3H), 2.53-2.58 (m, 1H), 1.85 (d, J = 12.2 Hz, 2H), 1.74-1.76 (m,
13
2H), 1.63-1.65 (m, 1H), 1.40-1.46 (m, 2H), 1.19-1.29 (m, 2H). C{1H} NMR (151
MHz, DMSO-d6) δ 189.3, 175.7, 164.7, 148.4, 136.0, 133.8, 133.3, 131.7, 130.1,
129.0, 127.8, 127.6, 127.1, 125.4, 125.3, 43.9, 29.1, 25.7, 25.5. HRMS (ESI) m/z
[M+H]+: Calcd for C21H20N2O2S: 365.1317. Found: 365.1317.
ASSOCIATED CONTENT
Supporting Information
NMR spectra of the products. The Supporting Information is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
* Fax: (+86) 731 88458227; E-mail: furonggeng@hnucm.edu.cn
Author Contributions
† R-G.F., Y.W., and F.X. contributed equally.
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Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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This work was supported by the Pharmaceutical Open Fund of Domestic First-class
Disciplines (cultivation) of Hunan Province (Grant No.2018YX04) and the College
Students' Research Learning and Innovative Experiment Plan Project of Hunan
Province (Grant No. S201910541039). Part of work was financially supported by
Natural Science Foundation of Hunan Province (Grant No. 2015JJ6085), Scientific
Research Fund of Hunan Provincial Education Department (Grant No. 13B080).
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