Solvent-Controlled Synthesis of Thiocyanated Enaminones and 2-Aminothiazoles from Enaminones, KSCN, and NBS

Article abstract of DOI:10.1021/acs.joc.9b01722

An effective and simple solvent-controlled synthesis of thiocyanated enaminones and 2-aminothiazoles has been demonstrated from enaminones, potassium thiocyanate, and N-bromosuccinimide. This process features mild reaction conditions, simple and easy oper

Full text of DOI:10.1021/acs.joc.9b01722

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Article
Solvent-controlled Synthesis of Thiocyanated Enaminones
and 2-Aminothiazoles from Enaminones, KSCN and NBS
Xiyan Duan, Xiaojing Liu, Xiaodan Cuan, Lin Wang, Kun
Liu, Huiyun Zhou, Xue Chen, Huimin Li, and Junqi Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01722 • Publication Date (Web): 06 Sep 2019
Downloaded from pubs.acs.org on September 6, 2019
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Page 1 of 12
The Journal of Organic Chemistry
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Solvent-controlled Synthesis of Thiocyanated Enaminones and 2-
Aminothiazoles from Enaminones, KSCN and NBS
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Xiyan Duan,* Xiaojing Liu, Xiaodan Cuan, Lin Wang, Kun Liu, Huiyun Zhou, Xue Chen, Huimin Li,
Junqin Wang
School of Chemical Engineering & Pharmaceutics, Henan University of Science and Technology, Luoyang 471003, Henan,
China;
E-mail: duanxiyan@tju.edu.cn
NBS (1.0 equiv),
KSCN (2.0 equiv),
DMF, 0 °C, 5 min
NBS (1.5 equiv),
KSCN (2.0 equiv),
EtOH, rt, 2 h
R2
O
O
NH2
R2
O
NH2
R2
R1
N
R1
R1
S
SCN
NH2
R1 = aryl, OMe;
R2 = aryl, alkyl
R1 = aryl, alkyl, OMe;
R2 = aryl, alkyl
ABSTRACT: An effective and simple solvent-controlled synthesis of thiocyanated enaminones and 2-aminothiazoles has been
demonstrated from enaminones, KSCN and NBS. This process features mild reaction conditions, simple and easy operation, short
reaction time, high yield and chemoselectivity and thereby provides an efficient protocol for the divergent synthesis of thiocyanated
enaminones and substituted 2-aminothiazoles controlled by simply varying the solvent. All reaction components are commercially
available or easily accessible at low cost. The potential utility of these methods in organic chemistry and medicinal chemistry
application is highlighted.
blocks toward potent medicinal scaffolds that exhibit a broad
INTRODUCTION
spectrum of biological activities, such as antiviral,4a
Organic thiocyanates have gained considerable attention
because of their biological and pharmaceutical activities, such
as antifungal, antibacterial, and antiparasitic (Figure 1).1
Moreover, organic thiocyanates represent a highly valuable
class of building blocks in organic synthesis. These species
have been employed in the synthesis of functionalized
heterocycles and many sulfur-containing compounds, such as
sulfonic acids,2a sulfonyl chlorides,2b thiols,2c thiocarbamates,2d
4b
anticancer,
anti-oxidant,4b
antidiabetic,4c
anti-
inflammatory,4d antimicrobial,4e and many others. Figure 1
shows examples of molecules that contain the 2-aminothiazole
moiety in their chemical structure have proven to be effective
for treating multiple diseases. For instance, Pramipexole
dihydrochloride hydrate has been studied as a potential drug
for the treatment of Parkinsonism.5 Meloxicam is a kind of
non-steroidal
sulfonyl
cyanides,2e
thioethers,2f
disulfides,2g
and
phosphonothioates.2h As a result, the development of efficient
approaches to construct C–SCN bonds has been studied
intensively, and great progress had been made to synthesize
organic thiocyanates.3 Quite recently, Wan group reported
visible light-induced thiocyanation of enaminones for the
synthesis of thiocyanated alkene derivatives and chromones
using NH4SCN as the thiocyano source under an aerobic
atmosphere (Scheme 1a).1c Mikhailovskii and co-workers
presented thiocyanation of cyclic enaminones with KSCN/Br2
system.3g Slabko group provided a new, simple, and efficient
protocol for the synthesis of thiocyanates of heterocyclic
quinone imines using dithiocyanogen.3h However, the reports
Figure 1. Drug Molecules Containing the Thiocyanates or
2-Aminothiazole Moiety
i-Pr
PhO
NCS
SCN
O
N
NCS
4-phenoxyphenoxyethyl thiocyanate
9-thiocyanatopupukeanane
antimicrobial activity
C6H13
fasicularin
cytotoxic activity
T. cruzi proliferation inhibitor
O
O
O
N
OH
S
O
N
N
NO2
•2HCl•H2
O
H2
N
S
N
S
N
S
H
N
H
H
N
pramipexole dihydrochloride hydrate
treatment of Parkinsonism
O
O
nitazoxanide
potent antiprotozoal agent
meloxicam
non-steroidal anti-
inflammatory drug
on the thiocyanation of enaminones
are still limited.
Therefore, new synthetic options for the direct and efficient
construction of structurally diverse thiocyanated enaminones
are still in great demand.
anti-inflammatory drug (NSAID) that selectively inhibit COX-
2 enzyme (Figure 1).6 The most well-known synthetic methods
of 2-aminothiazoles have utilized the direct condensation of α-
halocarbonyl compounds with thiourea (Hantzsch reaction,
Scheme 1b).7 Recently, Yu and co-workers reported the
2-Aminothiazole scaffolds are prevalent in natural products
and bioactive compounds and occupy a privileged position in
drug discovery.4a-4e 2-aminothiazole moieties are building
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Page 2 of 12
straightforward synthesis of 4‑substituted 2‑aminothiazoles mixture, 3a and 2a were obtained in moderate yields (Table 1,
1
2
3
4
5
6
7
8
and 4‑substituted 5-thiocyano-2-aminothiazoles from vinyl
azides and potassium thiocyanate, catalyzed and promoted by
palladium and iron catalysts, respectively (Scheme 1c). 8 Jiang
and co-workers reported synthesis of 2‑aminothiazoles via
copper-catalyzed coupling of oxime acetates with
isothiocyanates (Scheme 1d).9a Cocco and co-workers reported
a general method for the formation of 2-aminothiazoles moiety
by electrophilic thiocyanation of substituted enaminones.9b-c
Tokumitsu also developed a novel 2-aminothiazoles synthesis
from β-nitroenamine and electrophilic reagents.9d However,
some procedures suffer from drawbacks including drastic
reaction conditions, low yields, poor functional group
tolerance, potentially explosive precursors (vinyl azides) and
expensive metal catalysts. More significantly, direct synthesis
of 2‑aminothiazoles from enaminones and KSCN has not been
reported to date. Herein, we developed an efficient divergent
synthesis of thiocyanated enaminones and 2-aminothiazoles
from enaminones mediated by NBS depending on the reaction
solvent (Scheme 1e).
entry 17).
Table 1. Optimization of Reaction Conditionsa
oxidant,
KSCN (2 equiv),
solvent, rt, 2 h
O
NH2
O
O
NH2
MeO
MeO
+
MeO
N
S
1a
SCN
3a
NH2
2a
9
10
11
12
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entry
oxidant
(equiv)
solvent
Yield of Yield of
2a
(%)
40
3a
(%)
trace
36
1
2
NBS (1.5)
DCE
DCE
K2S2O8 (1.5)
Na2S2O8 (1.5)
Oxone (1.5)
PIDA (1.5)
NBS (1.5)
NBS (1.5)
NBS (1.5)
NBS (1.5)
NBS (1.5)
NBS (1.5)
NBS (1.5)
NBS (1.0)
-
nd
3
DCE
nd
32
4
DCE
nd
20
5
DCE
nd
trace
nd
Scheme 1. Synthesis of Thiocyanated Enaminones and 2-
Aminothiazoles
6
CH2Cl2
EtOH
EtOAc
CH3CN
THF
trace
93
O
O
NH2
7
trace
trace
43
NH4SCN, hv
R
O
(a)
S
N
R
R2
R1
+
SCN
(b)
NH2
8
65
H2
N
X
X= LG, EWG
9
33
NBS (1.0 equiv),
KSCN (2.0 equiv),
DMF, 0 °C , 5 min
NBS (1.5 equiv),
KSCN (2.0 equiv),
EtOH, rt, 2 h
R2
O
O
NH2
R2
(e) this work
O
NH2
R2
R1
+
10
11
12b
13 b, c
14
15
16d
17e
75
trace
31
KSCN
(c)
N
Ph
R1
N3
R1
R1
S
SCN
1,4-dioxane
DMF
nd
NH2
OAc
N
(d)
RNCS
+
2-aminothiazoles moiety
R2
15
70
DMF
trace
nd
90
RESULTS AND DISCUSSION
EtOH
nd
Methyl (Z)-3-amino-3-phenylacrylate 1a, readily prepared via
condensation of methyl 3-oxo-3-phenylpropanoate with
ammonium formate, was chosen as the model substrate in
further screening tests in search of the optimal conditions. To
our delight, when N-Bromosuccinimide (NBS) was chosen as
the oxidant, the reaction provided methyl 2-amino-4-
phenylthiazole-5-carboxylate (2a) in 40% yield in 1,2-
dichloroethane at room temperature (Table 1, entry 1). Then,
various oxidants were screened for the reaction in 1,2-
dichloroethane at room temperature in the presence of
potassium thiocyanate (KSCN). Interestingly, with the use of
oxidants such as K2S2O8, Na2S2O8, Oxone or
(Diacetoxyiodo)benzene (PIDA), thiocyanated enamine 3a
was obtained in lower yields (Table 1, entries 2−5). Screening
of a series of other solvents, including dichloromethane, EtOH,
EtOAc, acetonitrile, THF, and 1,4-dioxane (Table 1, entries
6−11), showed that the reaction in EtOH at room temperature
afforded 2a in the best yield (Table 1, entry 7). We obtained
3a in 70% yield accompanied by 2a in 15% yield when DMF
was used as the solvent at room temperature in 5 min (Table 1,
entry 12). Temperature is a key factor for sp2 C−H bond
thiocyanation of enaminones because when the temperature
was reduced to 0 °C a better yield of 3a could be achieved in
the presence of 1 equivalent of NBS (Table 1, entry 13).
However, without NBS or other oxidants, no reaction occurred
(Table 1, entries 14-15). When the reaction solvent is EtOH
and the quantity of NBS and KSCN was reduced to 1
equivalent, 3a could be obtained in 78% yield (Table 1, entry
16). When water (1 equivalent) was added in the reaction
-
DMF
nd
nd
NBS (1.0)
EtOH
trace
78
NBS (1.0)
EtOH
42
40
aReaction conditions: oxidant (1.5 mmol, 1.5 equiv), KSCN
(2 mmol, 2 equiv), enamine 1a (1 mmol, 1.0 equiv), solvent (2
mL), rt, open flask, 2 h. b 5 min. 0 ℃ NBS (1.0 mmol, 1.0
equiv), KSCN (1.0 mmol, 1 equiv), enaminone 1a (1.0 mmol,
1 equiv), EtOH (2 mL), rt, open flask, 30 min. NBS (1.0
mmol, 1.0 equiv), KSCN (1.0 mmol, 1 equiv), enaminone 1a
(1.0 mmol, 1.0 equiv), H2O (1.0 mmol, 1 equiv), EtOH (2
mL), rt, open flask, 30 min.
c
d
e
With the optimal reaction conditions in hand, the scope of the
NBS-mediated cascade cyclization was then explored (Scheme
2). When the R1 position of enamine is attached to an OMe
group, R2 in 1 can be aromatic electron-withdrawing group,
such as p-Cl, p-Br benzene rings, aromatic electron-donating
group, thiophene rings and naphthalene ring. The
corresponding products 2b-2e, 2p were isolated in moderate to
good yields (75-81%). For the enaminone substrates with both
R1 and R2 being aryl groups, the reaction proceeded smoothly
and both electron-donating groups and electron-withdrawing
groups such as p-MeO, p-Br, and p-Cl were well tolerated to
afford the corresponding 2-aminothiazole products 2f-2i, 2n.
For substrates where the OMe group at R1 position was
replaced by an alkyl group or a more sterically hindered tert-
butyl group, 2-aminothiazole products 2j and 2k were
produced in 72% and 76% yield, respectively. Further
experiments showed that this method worked equally well for
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The Journal of Organic Chemistry
smoothly to afford the corresponding thiocyanated
the enaminone containing alkyl group at R2 position (2l).
Replacing the OMe group at R1 position with a naphthyl group
or benzene ring at R2 position with pyridine ring in the
substrate does not hamper the reaction, and the corresponding
product 2m or 2o could be obtained in moderate yield.
enaminones 3l, 3q-3r in good yields. To our delight, the
reaction worked well when there were two substituted aryl
groups in enaminones (3j and 3k).
1
2
3
4
Scheme 3. Synthesis of Thiocyanated Enaminones from
Enaminones, KSCN and NBSa
Scheme 2. Synthesis of 2-Aminothiazoles from
Enaminones, KSCN and NBSa
5
6
NBS (1 equiv),
KSCN (2 equiv),
DMF, 0 °C, 5 min
O
NH2
R2
7
8
9
O
NH2
R2
NBS (1.5 equiv),
KSCN (2 equiv),
EtOH, rt, 2 h
R2
O
R1
O
NH2
R2
R1
R1
SCN
3
1
N
R1
S
R1 = aryl, OMe; R2 = aryl, alkyl
1
10
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NH2
R1 = aryl, alkyl, OMe
R2 = aryl, alkyl
2
O
NH2
O
NH2
O
NH2
Br
Cl
MeO
MeO
MeO
MeO
S
S
SCN
3b
SCN
SCN
Br
Cl
O
3a
3c
, 87%
, 90%
, 93%
O
O
MeO
N
MeO
MeO
N
N
O
NH2
O
NH2
O
NH2
S
S
NH2
S
NH2
NH2
MeO
2d
, 75%
SCN
SCN
2b
2c
, 75%
,81%
SCN
3d
3e
3f
, 95%
, 68%
, 96%
O
O
O
O
NH2
O
NH2
O
NH2
MeO
N
N
N
S
S
S
SCN
89%
SCN
3h,
85%
SCN
3i,
Br
Br
MeO
Cl
NH2
, 70%
NH2
NH2
3g,
90%
2f
, 50%
2g
, 65%
2e
Cl
O
NH2
O
NH2
O
NH2
O
O
O
SCN
SCN
SCN
N
N
3j
3k
3l
, 70%
, trace
O
, trace
O
N
S
S
MeO
S
NH2
NH2
, 72%
NH2
NH2
O
NH2
NH2
, 78%
2h
, 89%
2j
MeO
MeO
2i
N
SCN
, 88%
NH2
SCN
SCN
O
O
O
3m
3n
3o
, 80%
, 85%
O
N
N
N
O
NH2
O
NH2
S
, 80%
S
S
NH2
NH2
NH2
MeO
2l
2k
, 76%
SCN
SCN
SCN
3r
, 82%
2m
, 70%
Me
F
Me
Me
3p
3q
, 87%
O
, 82%
O
O
NH2
NH2
N
O
O
MeO
MeO
N
N
MeO
SCN
SCN
82%
S
N
S
Cl
Cl
MeO
Cl
S
NH2
3t,
75%
NH2
3s,
2n
, 86%
NH2
2o
, 68%
aReaction conditions: NBS (1.0 equiv), KSCN (2.0 equiv),
enamine 1a (1.0 equiv), DMF (2 mL), 0 ℃, open flask, 5 min.
2p
,81%
aReaction conditions: NBS (1.5 equiv), KSCN (2 equiv),
enamine 1 (1.0 equiv), EtOH (2 mL), rt, open flask, 2 h.
To demonstrate the synthetic utility of this protocol, this
method has been applied to the synthesis of thiocyanated
azirines 4a from thiocyanated enamine 3a and 2-
aminothiazole acid 5a from the 2-aminothiazole 2a. As shown
in the Scheme 4, the treatment of 3a with iodosobenzene at the
room temperature produced the azirine 4a in 85% yield.
Hydrolysis of 2a under basic conditions gave acid 5a in
moderate yield (65%).
Then the scope of the NBS-promoted thiocyanation of
enaminones was examined (Scheme 3). The aryl enamino
ester bearing electron-withdrawing or electron-donating
substituent on the benzene ring were converted to the
corresponding product 3b-c, 3p in satisfactory yield
correspondingly. Replacing the phenyl ring with a thiophene
rings or naphthalene ring in the enamino esters does not
hamper the reaction, and the desired product 3d-e could be
obtained in excellent yield. The method was shown to be also
well applicable to the enaminone substrates with both R1 and
R2 being either electron-deficient or electron-rich aryl rings
(3f-3i, 3n, 3s-3t). Unfortunately, thiocyanated enaminones 3j
or 3k were not formed. For substrates with R1 being an aryl
group and R2 being an alkyl group, the reaction proceeded
Scheme 4. Synthetic application
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O
NH2
Ph
O
scavengers (TEMPO or BHT) did not hamper the reaction,
N
iodosobenzene
CH2Cl2, rt , 2 h
1
MeO
MeO
Ph
which suggested that the reaction may not involve a radical
pathway (Scheme 5a). However, when N-methylated or N-
arylated enaminones, such as (Z)-3-(methylamino)-1,3-
(a)
SCN
3a
SCN
2
4a
, 85%
3
4
diphenylprop-2-en-1-one
and
(Z)-1,3-diphenyl-3-
(phenylamino)prop-2-en-1-one were used, no corresponding
products were obtained. These results suggest that the protic
hydrogen of amino group plays an important role in the
tautomerization and cyclization. When NBS (1 mmol) was
subjected to EtOH (1 mL), 1-hydroxy-pyrrolidine-2,5-dione
was obtained in 82% yield (Scheme 5b). This result indicated
that NBS could react with a trace amount of water in EtOH to
generate 1-hydroxy-pyrrolidine-2,5-dione and HBr. In order to
investigate whether N-thiocyanatosuccinimide 7a is a key
intermediate, we prepared 7a through the reaction of NBS
with KSCN in a satisfactory 85% yield (Scheme 5c).
However, the reaction of 1a with N-thiocyanatosuccinimide
(7a) in DMF did not give the expected 3a (Scheme 5d). When
the mixture of KSCN and NBS in EtOH was stirred in
advance at room temperature for 1h and then enaminone 1a
was added, only a trace amount of 3a was observed (Scheme
5e). These results indicated N-thiocyanatosuccinimide (A) was
not the key intermediate in the thiocyanation processes. We
conducted the reactions of 1a with NBS in DMF at room
temperature. The reaction proceeded smoothly as indicated by
TLC results and furnished bromo enaminone 8a, which is
characterized a mixture of cis and trans isomers on the basis of
their spectral and analytical data (Scheme 5f). Further, the
reaction of 8a with KSCN was carried out in DMF at room
temperature and the product 3a was obtained in 98% yield
(Scheme 5g). Notably, compound 8a is very unstable and
easily decomposed at room temperature.
5
6
7
8
LiOH,
EtOH/H2O
O
O
MeO
HO
(b)
N
N
rt
S
S
NH2
NH2
9
2a
5a
, 65%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
31
32
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42
43
44
45
46
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48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Control Experiments
NBS (1 equiv),
KSCN (2 equiv),
DMF, 0 °C, 5 min
O
NH2
Ph
O
NH2
Ph
(a)
MeO
MeO
SCN
3a
TEMPO: 76% of
3a
radical scavenger
(Tempo or BHT)
1a
3a
BHT: 81% of
O
O
EtOH, rt
N
Br
N
OH
(b)
O
O
NBS
6a
1-hydroxy-pyrrolidine-2,5-dione
82%
O
O
N
KSCN
CH3CN, rt
Br
N
SCN
(c)
O
O
NBS
7a
85%
Table 2. The formation of 2a from 3a via intramolecular
cyclization.a
O
N
SCN (1 equiv)
O
NH2
O
promotor,
EtOH
O
NH2
Ph
O
7a
O
NH2
Ph
MeO
Ph
MeO
N
MeO
temperature, time
SCN
3a
S
MeO
(d)
SCN
3a
No reaction
NH2
DMF
1a
2a
entry promotor temperature time Yield conversion
O
NH2
(1) NBS (1 equiv),
DMF, rt, 1 h
of 2a
(%)
98
of 3a
KSCN
(2 equiv)
(e)
(equiv)
(h)
(℃)
MeO
Ph
SCN
trace
(2)
1a
3a,
1
NBS
(1.0)
rt
2
100
O
NH2
O
NH2
Ph
NBS (1 equiv),
DMF, rt, 15 min
2
3
4
5
6
7
8
9
-
rt
40
60
120
120
120
rt
2
2
nd
nd
16
17
22
25
90
98
0
0
(f)
MeO
Ph
MeO
MeO
Br
-
1a
8a,
91%
NH2
Ph
-
2
21
21
26
28
100
100
O
NH2
Ph
O
KSCN(1 equiv),
DMF, rt, 15 min
-
2
(g)
MeO
Br
SCN
3a,
-
12
24
2
8a
98%
-
To probe the reaction mechanism of the selective formation of
thiocyanated enaminones and 2-aminothiazoles, a series of
control experiments were conducted. First, 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) and 2,6-di-tert-butyl-
4-methylphenol (BHT) were added separately as radical
scavengers in the reaction of 1a, NBS and KSCN in EtOH
under standard reaction conditions. The addition of radical
NIS (1.0)
K2CO3
(1.0)
rt
2
10
11
TBAF
(1.0)
rt
rt
2
2
56
nd
70
0
NCS
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The Journal of Organic Chemistry
thiocyano enamine 3 tautomerizes into its isomer C in protic
(1.0)
1
2
3
4
5
6
7
8
9
solvent (EtOH). Then, an excess of NBS could react with a
trace amount of water to generate 1-hydroxy-pyrrolidine-2,5-
dione and HBr. The reaction of intermediate C with HBr
provides intermediate D, followed by intramolecular
cyclization gave intermediate E. Finally, the intermediate E
was converted into the title compound 2 via hydrogen transfer
process.
12
Oxone
(1.0)
rt
2
nd
0
13b
14
HCl (6.0)
40
rt
2
2
26
nd
100
0
Acetic
acid
(0.02)
15
16
17
18
TsOH
(0.02)
rt
rt
rt
rt
2
2
nd
trace
41
0
15
56
0
Scheme 6. Proposed Reaction Mechanism.
O
NH
FeCl3
(0.02)
R1
R2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
Br
O
NH
O
NH2
R2
A
N
Br
R1
R2
KSCN
DMF
R1
Cu(OTf)2
(0.02)
12
2
SCN
1
O
O
NH2
R2
B
R1
Br
KSCN
(1.0)
nd
8
O
N
aReaction conditions: oxidant or base, enamine 3a, solvent,
NBS
HO
open flask, 2 h. b 1M HCl.
R2
O
R2
O
H2
O
O
R1
H
H
NH2
N
R1
O
N
NH2
N
EtOH
S
S
HBr
R1
R2
As shown in the table 2, When compound 3a was subjected to
EtOH in the presence of NBS for 2 h at room temperature, we
obtained 2a in 98% yield (Table 2, entry 1). By treatment of
3a in EtOH for 2 h at room temperature or 40 ℃ in the
absence of NBS, the corresponding product 2a was not
obtained (Table 2, entries 2-3). Increasing reaction
temperature can afford product 2a in lower yields in EtOH
(Table 2, entries 4-5). These results indicated higher reaction
temperature can lead to the formation of 2a from 3a in the
absence of promotor, albeit in a low yield of 17% (Table 2,
entry 5). When the reaction was carried out at 120 ℃ in the
absence of NBS in EtOH for 12 h, 2a was isolated in 22%
yield (Table 2, entry 6). The effect of time was also examined,
and it was found that longer time did not lead to significant
differences in the yield of 2a (Table 2, entry 7). Treatment of
3a with promotors such as NIS, K2CO3 and TBAF in EtOH at
room temperature successfully delivered the desired product
2a in moderate to high yields. (Table 2, entries 8-10). Other
promotors including NCS, and Oxone were also tested, but
none of them was effective for the reaction (Table 2, entries
11-12). To our surprise, when we used 1M HCl as the
promotor, 2a was obtained in 26% yield. This result indicated
that 3a could be converted into 2a under acidic conditions
reaction (Table 2, entry 13). We have examined other acids
(0.1 equivalent), including acetic acid, TsOH, FeCl3, and
Cu(OTf)2. The results showed that no reaction occurred when
either acetic acid or TsOH was applied (Table 2, entries 14-
15). Lewis acids such as FeCl3 and Cu(OTf)2 gave 2a in lower
or moderate yield (Table 2, entries 16-17). KSCN was also
studied, but no desired product was observed (Table 2, entry
18).
SCN
H
C
D
3
R2
NH2
NH
O
R2
NH
NH2
O
R2
O
P. T.
-H
R1
R1
R1
N
S
S
S
NH2
E
F
2
In summary, we have disclosed a novel and efficient
protocol to access the thiocyanated enaminones and 2-
aminothiazoles switched by solvent from enaminones,
potassium thiocyanate, and NBS. The method features readily
available starting materials, mild reaction conditions, high
selectivity, and metal-free characteristics. Further studies on
the reaction mechanism, the scope expansion, and the utility of
this metal-free protocol are still in progress in our laboratory.
The reaction should gain much attention in medical chemistry
fields for access to potentially biologically active 2-
aminothiazoles derivatives.
EXPERIMENTAL SECTION
General Information
All reagents and solvent were commercial available with
analytical grade and used as received. Yields refer to
chromatographically and spectroscopically (1H NMR)
homogeneous materials, unless otherwise stated. The used
solvents were purified and dried according to common
procedures. High-resolution mass spectra (HRMS) were
obtained with a FTICR-MS (Ionspec 7.0T) spectrometer. The
1H and 13C NMR spectra were recorded in CDCl3 or DMSO-
d6 solution on a Bruker AV 400 MHz spectrometer. Chemical
shifts are reported in parts per million (δ) relative to CDCl3
On the basis of the above results and previous references,1a, 10,
11, 12 a possible mechanism is proposed in Scheme 6. Initially,
NBS reacts with enaminone 1 to give intermediate 8.11 The
nucleophilic substitution reaction of between intermediate 8
and KSCN occurred and resulted in the formation of imine B,
1
(7.27 ppm) for H NMR data and CDCl3 (77.0 ppm) for 13C
1
which tautomerizes into enaminone isomer 3. From the H
NMR data or the peak of DMSO-d6, defined at δ = 2.50 (1H
NMR) or δ = 39.5 (13C NMR). The following abbreviations
were used to explain multiplicities: s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, br = broad). Flash column
chromatography was performed over silica gel 200−300 mesh,
NMR spectra of 3, the formation of hydrogen bond in products
3 could be clearly observed. These data indicate the
intramolecular hydrogen may stabilize the isomer with cis-
arrangement of carbonyl and amino groups in aprotic solvents
(DMF). However, this hydrogen bond will break and the α-
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and the eluent was a mixture of ethyl acetate (EA) and
petroleum ether (PE).
21.3, 13.6, 13.5. HRMS (ESI): m/z [M + H]+ calcd for
C12H15FNO: 208.1138; found: 208.1132.
1
2
3
4
5
6
7
8
9
General Procedure for the Synthesis of Enaminones 1.
All the known enaminones 1a,13a 1b,13a 1c,13a 1d,13b 1e,13a 1f,13c
1h,13d 1i,13d 1j,13d 1l,13c 1o,13d 1p,13b and 1t13a prepared in
accordance with the indicated literature procedures.
(Z)-3-amino-1-(p-tolyl)hex-2-en-1-one (1r).
Prepared from 1-(p-tolyl)ethan-1-one (2.7 g, 20 mmol) and
methyl butyrate (6.1 g, 60 mmol) via general procedure A.
Compound 1r was obtained as a white solid. Rf = 0.2
(petroleum ether/EtOAc = 8:1). Yield: 2.5 g, 62 %; mp: 93-95
°C. 1H NMR (400 MHz, CDCl3): δ = 10.23 (s, 1H), 7.78 (d, J
= 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 5.72 (s, 1H), 5.41 (s,
1H), 2.37 (s, 3H), 2.26-2.16 (m, 2H), 1.70-1.58 (m, 2H), 0.98
(t, J = 7.4 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ =
189.4, 166.7, 141.0, 137.6, 128.8, 127.1, 91.4, 38.8, 21.4, 21.4,
13.6. HRMS (ESI): m/z [M + H]+ calcd for C13H18NO:
204.1388; found: 204.1389.
Enaminones 1q, 1r were prepared by the following known
procedure A. Enaminones 1g,13e 1k, 1m,13e 1n, and 1s were
prepared by the following known procedure B.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure A : To a solution of NaH (60 mmol, 60%)
in THF (80 mL) was added ketone (20 mmol) at 0 ℃. After
the reaction mixture was stirred at 0 ℃ for about 5 h, the ester
(60 mmol) or methyl dicarbonate (60 mmol) was added
dropwise at the same temperature. The reaction mixture was
stirred at room temperature until TLC indicated the total
consumption of the ketone. After cooling, the reaction mixture
was poured into ice water (100 mL), acidified with aqueous
HCl (1 M) to pH 2−3, and extracted with EtOAc (100 mL × 3).
The combined organic layer was dried over Na2SO4 and
evaporated under reduced pressure. The β-keto esters obtained
was used for the next step without further purification.
(Z)-3-amino-1-(4-bromophenyl)-3-phenylprop-2-en-1-one
(1g). 13e
Prepared from 1-(4-bromophenyl)ethan-1-one (2.3 g, 12 mmol)
and benzonitrile (1.0 g, 10 mmol) via general procedure B.
Compound 1g was obtained as a white solid. Rf = 0.2
( petroleum ether/EtOAc = 8:1). Yield: 2.2 g, 75%; mp: 81-82
°C. 1H NMR (400 MHz, CDCl3): δ = 10.42 (s, 1H), 7.80 (d, J
= 8.2 Hz, 2H), 7.61 (d, J = 7.3 Hz, 2H), 7.57-7.37 (m, 5H),
6.07 (s, 1H), 5.70 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ
= 188.5, 163.4, 139.0, 137.2, 131.4, 130.8, 129.0, 128.7, 126.3,
The obtained β-keto compound (15 mmol) was dissolved in
absolute methanol (60 mL), followed by the addition of
ammonium formate (75 mmol) and 4Å molecular sieves. The
reaction mixture was stirred under reflux for about 5 h and
then was filtered through a short pad of Celite. The filtrate was
concentrated in vacuo. To the residue was added water (100
mL) and EtOAc (100 mL). The mixture was extracted with
EtOAc (100 mL × 3), and the organic layer was combined,
dried over Na2SO4, and evaporated to dryness. The residue
was purified by flash column chromatography on silica gel to
give the desired product.
125.6, 91.3. HRMS (ESI): m/z [M
C15H13BrNO: 302.0181; found: 302.0177.
+
H]+ calcd for
(Z)-1-amino-4,4-dimethyl-1-phenylpent-1-en-3-one (1k).
Prepared from 3,3-dimethylbutan-2-one (1.2 g, 12 mmol) and
benzonitrile (1.0 g, 10 mmol) via general procedure B.
Compound 1k was obtained as a white solid Rf = 0.2
(petroleum ether/EtOAc = 12:1). Yield: 1.2 g, 61%; mp: 67-68
General procedure B : To a solution of copper iodine (CuI,
190 mg, 10 mol%), 2,2’-bipyridine (172 mg, 11 mol%) and
tert-butoxide (NaOtBu, 2.8 g, 30 mmol) in DMF (20 mL) was
stirred at room temperature under nitrogen atmosphere for 15
min. And then, aromatic nitrile (10 mmol) and ketone (12
mmol) were successively added. After the reaction mixture
was stirred at 80 ℃ for 12 h and quenched with saturated
aqueous ammonium chloride solution (40 mL). The reaction
mixture was extracted with EtOAc (40 mL × 3). The
combined organic layers were washed with brine (40 mL × 3),
dried over Na2SO4 and evaporated under reduced pressure.
The residue was purified by column chromatography on silica
gel using ethyl acetate-petroleum ether as the eluent to give
the desired product.
1
°C. H NMR (400 MHz, CDCl3): δ = 9.97 (s, 1H), 7.59-7.50
(m, 2H), 7.48-7.38 (m, 3H), 5.62 (s, 1H), 5.30 (s, 1H), 1.20 (s,
9H). 13C{1H} NMR (100 MHz, CDCl3) δ = 206.0, 161.7,
137.9, 130.3, 128.8, 126.2, 90.6, 42.2, 27.7. HRMS (ESI): m/z
[M + H]+ calcd for C13H18NO: 204.1388; found: 204.1386.
(Z)-3-amino-1-(naphthalen-2-yl)-3-phenylprop-2-en-1-one
(1m). 13e
Prepared from 1-(naphthalen-2-yl)ethan-1-one (2.0 g, 12
mmol) and benzonitrile (1.0 g, 10 mmol) via general
procedure B. Compound 1m was obtained as a oil. Rf = 0.2
1
(petroleum ether/EtOAc = 8:1). Yield: 2 g, 73 %; H NMR
(400 MHz, CDCl3): δ = 10.52 (s, 1H), 8.48 (s, 1H), 8.08 (dd,
J = 8.6, 1.4 Hz, 1H), 7.99-7.93 (m, 1H), 7.93-7.84 (m, 2H),
7.69-7.66 (m, 2H), 7.58-7.42 (m, 5H), 6.32 (s, 1H), 5.71 (s,
1H). 13C{1H} NMR (100 MHz, CDCl3) δ = 189.8, 163.0,
137.5, 137.4, 134.6, 132.7, 130.6, 129.1, 128.9, 127.9, 127.6,
127.5, 127.2, 126.3, 126.2, 124.1, 91.9. HRMS (ESI): m/z [M
+ H]+ calcd for C19H16NO: 274.1232; found: 274.1230.
(Z)-3-amino-1-(4-fluorophenyl)hex-2-en-1-one (1q).
Prepared from 1-(4-fluorophenyl)ethan-1-one (2.8 g, 20 mmol)
and methyl butyrate (6.1 g, 60 mmol) via general procedure A.
Compound 1q was obtained as a white solid. Rf = 0.2
(petroleum ether/EtOAc = 8:1). Yield: 2.3 g, 55 %; mp: 94-95
1
°C. H NMR (400 MHz, CDCl3): δ = 10.23 (s, 1H), 7.92-7.83
(m, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H),
7.11-7.01 (m, 1H), 5.69 (d, J = 19.9 Hz, 1H), 5.48 (d, J = 44.7
Hz, 1H), 2.25-2.16 (m, 2H), 1.71-1.57 (m, 2H), 0.97 (t, J = 7.4
Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ = 189.3, 187.9,
167.4, 166.9, 165.6, 163.1, 141.0, 137.6, 136.5, 136.5, 129.3,
129.2, 128.8, 127.0, 115.1, 114.9, 91.3, 91.1, 38.8, 38.7, 21.4,
(Z)-3-amino-1-(3,4-dimethoxyphenyl)-3-phenylprop-2-en-1-
one (1n).
Prepared from 1-(3,4-dimethoxyphenyl)ethan-1-one (2.2 g, 12
mmol) and benzonitrile (1.0 g, 10 mmol) via general
procedure B. Compound 1n was obtained as a yellow oil. Rf =
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1
0.2 ( petroleum ether/EtOAc = 3:1). Yield: 1.8 g, 63 %;. H
7.67 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 3.62 (s, 3H).
13C{1H} NMR (100 MHz, DMSO-d6) δ = 170.0, 161.5, 157.6,
133.4, 133.3, 131.5, 127.5, 108.1, 51.5. HRMS (ESI): m/z [M
+ H]+ calcd for C11H10ClN2O2S: 269.0152; found: 269.0144.
1
2
3
4
5
6
7
NMR (400 MHz, CDCl3): δ = 10.32 (s, 1H), 7.62-7.59 (m, 2H),
7.55-7.52 (m, 2H), 7.48-7.39 (m, 3H), 6.85 (d, J = 8.2 Hz, 1H),
6.09 (s, 1H), 5.59 (s, 1H), 3.91 (s, 3H), 3.89 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ = 188.8, 162.4, 151.4, 148.6, 137.6,
133.1, 130.4, 128.8, 126.2, 120.6, 110.0, 109.9, 91.2, 55.8,
55.7. HRMS (ESI): m/z [M + H]+ calcd for C17H18NO3:
284.1287; found: 284.1282.
Methyl 2-amino-4-(thiophen-2-yl)thiazole-5-carboxylate (2d) .
14
The general procedure C was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 5:1)
afforded 2d as a yellow solid. Yield: 180 mg, 75%; mp:145-
147 °C. H NMR (400 MHz, DMSO-d6): δ = 8.39-8.38 (m,
1H), 7.96 (s, 2H), 7.67-7.65 (m, 1H), 7.15-7.13 (m, 1H), 3.73
(s, 3H).
8
9
1
(Z)-3-amino-3-(4-chlorophenyl)-1-(4-methoxyphenyl)prop-2-
en-1-one (1s).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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60
Prepared from 1-(4-methoxyphenyl)ethan-1-one (1.8 g, 12
mmol) and 4-chlorobenzonitrile (1.4 g, 10 mmol) via general
procedure B. Compound 1s was obtained as a white solid. Rf
= 0.2 ( petroleum ether/EtOAc = 5:1). Yield: 1.4 mg, 50 %;
mp: 126-127 °C. 1H NMR (400 MHz, CDCl3): δ = 10.27 (s,
1H), 7.95-7.86 (m, 2H), 7.59-7.50 (m, 2H), 7.44-7.36 (m, 2H),
6.96-6.88 (m, 2H), 6.05 (s, 1H), 5.45 (s, 1H), 3.84 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ = 189.2, 162.1, 160.9,
136.5, 136.1, 132.7, 129.1, 129.1, 127.7, 113.5, 91.5, 55.30.
HRMS (ESI): m/z [M + H]+ calcd for C16H15ClNO2: 288.0791;
found:288.0791.
Methyl
2-amino-4-(naphthalen-1-yl)thiazole-5-carboxylate
(2e).
The general procedure C was followed and purification by
flash column chromatography (petroleum ether : EtOAc = 3:1)
afforded 2e as a yellow solid. Yield: 199 mg, 70%; mp:189-
1
191°C. H NMR (400 MHz, DMSO-d6): δ = 8.22 (s, 1H),
7.97-7.84 (m, 5H), 7.76 (d, J = 8.6 Hz, 1H), 7.58-7.49 (m, 2H),
3.64 (s, 3H). 13C{1H} NMR (100 MHz, DMSO-d6) δ = 170.0,
161.6, 158.9, 132.9, 132.2, 132.0, 129.1, 128.4, 127.5, 126.7,
126.5, 126.2, 107.9, 51.5. HRMS (ESI): m/z [M + H]+ calcd
for C15H13N2O2S: 285.0698; found: 285.0695.
General procedure for the synthesis of the 2-
aminothiazoles 2a-2p from enaminones and KSCN and
NBS in EtOH
(2-amino-4-phenylthiazol-5-yl)(phenyl)methanone (2f). 14
The general procedure C was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 3:1)
afforded 2f as a yellow solid. Yield: 140 mg, 50%; mp:160-
General Procedure C: To a solution of NBS (267 mg, 1.5
mmol) and enaminone (1 mol) in EtOH (2 mL) was added
KSCN (194 mg, 2.0 mmol) at room temperature. The reaction
proceeded under an air atmosphere for 2-3 h until TLC
indicated the complete consumption of starting material. The
reation mixture was poured into saturated aqueous Na2S2O3
(10 mL). The product was extracted with ethyl acetate (10
mL). The organic layers were washed with brine (10 mL×2),
and dried over Na2SO4. The solvent was removed under
reduced pressure, and the residue was purified by flash column
chromatography on silica gel to give the desired product 2a-2p.
1
161 °C. H NMR (400 MHz, DMSO-d6): δ = 8.08 (s, 2H),
7.39-7.33 (m, 2H), 7.32-7.26 (m, 1H), 7.25-7.20 (m, 2H),
7.15-7.12 (m, 3H), 7.08-7.05 (m, 2H).
(2-amino-4-phenylthiazol-5-yl)(4-bromophenyl)methanone
(2g).
The general procedure C was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 2:1)
afforded 2g as a yellow solid. Yield: 232 mg, 65%; mp:191-
1
192°C. H NMR (400 MHz, DMSO-d6): δ = 8.17 (s, 2H),
7.30-7.26 (m, 4H), 7.23-7.19 (m, 3H), 7.11-7.09 (m, 2H).
13C{1H} NMR (100 MHz, DMSO-d6) δ = 186.4, 171.3, 159.5,
137.6, 134.7, 130.6, 130.5, 129.7, 128.4, 127.5, 124.7, 120.5.
HRMS (ESI): m/z [M + H]+ calcd for C16H12BrN2OS:
358.9854; found: 358.9846.
Methyl 2-amino-4-phenylthiazole-5-carboxylate (2a).14
The general procedure C was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 4:1)
afforded 2a as a yellow solid. Yield: 217 mg, 93%; mp:
164~167°C. 1H NMR (400 MHz, DMSO-d6): δ = 7.89 (s, 2H),
7.65-7.63 (m, 2H), 7.39-7.37 (m, 3H), 3.62 (s, 3H).
(2-amino-4-phenylthiazol-5-yl)(4-methoxyphenyl)methanone
(2h).
Methyl
2-amino-4-(4-bromophenyl)thiazole-5-carboxylate
The general procedure C was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 2:1)
afforded 2h as a yellow solid. Yield: 276 mg, 89%; mp:198-
(2b).14
The general procedure C was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 4:1)
afforded 2b as a yellow solid. Yield: 253 mg, 81%; mp: 210-
213 °C. 1H NMR (400 MHz, DMSO-d6): δ = 7.91 (s, 2H),
7.63-7.56 (m, 4H), 3.64 (s, 3H).
1
200 °C. H NMR (400 MHz, DMSO-d6): δ = 7.89 (s, 2H),
7.34 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 6.9 Hz, 2H), 7.11-7.05
(m, 3H), 6.62 (d, J = 8.8 Hz, 2H), 3.62 (s, 3H). 13C{1H} NMR
(100 MHz, DMSO-d6) δ = 186.4, 179.5, 170.3, 161.8, 135.0,
131.1, 130.8, 129.5, 128.3, 127.5, 120.2, 113.1, 55.3. HRMS
(ESI): m/z [M + H]+ calcd for C17H15N2O2S: 311.0854; found:
311.0851.
Methyl
2-amino-4-(4-chlorophenyl)thiazole-5-carboxylate
(2c) .
The general procedure C was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 2:1)
afforded 2c as a yellow solid. Yield: 201 mg, 75%; mp:176-
(2-amino-4-(4-chlorophenyl)thiazol-5-yl)(phenyl)methanone
(2i) .
1
179 °C. H NMR (400 MHz, DMSO-d6): δ = 7.93 (s, 2H),
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The general procedure C was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 2:1)
(2-amino-4-phenylthiazol-5-yl)(3,4-
dimethoxyphenyl)methanone (2n).
1
2
3
4
5
6
7
8
9
afforded 2i as a yellow solid. Yield: 245 mg, 78%; mp:218-
220 °C. H NMR (400 MHz, DMSO-d6): δ = 8.06 (s, 2H),
The general procedure C was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 2:1)
afforded 2n as a yellow solid. Yield: 292 mg, 86 %; mp:212-
1
7.35-7.25 (m, 3H), 7.21-7.19 (m, 2H), 7.14-7.03 (m, 4H).
13C{1H} NMR (100 MHz, DMSO-d6) δ = 187.4, 171.1, 157.6,
138.6, 133.7, 133.1, 131.3, 131.2, 128.6, 127.8, 127.4, 120.8.
HRMS (ESI): m/z [M + H]+ calcd for C16H12ClN2OS:
315.0359; found: 315.0353.
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213 °C. H NMR (400 MHz, DMSO-d6): δ = 7.88 (s, 2H),
7.26-7.18 (m, 2H), 7.16-7.01 (m, 4H), 6.86 (d, J = 2.0 Hz, 1H),
6.73-6.70 (m, 1H), 3.64 (s, 3H), 3.45 (s, 3H). 13C{1H} NMR
(100 MHz, DMSO-d6) δ = 186.4, 179.5, 170.4, 157.3, 151.7,
147.6, 135.1, 130.7, 129.6, 128.4, 127.5, 123.0, 120.4, 112.1,
110.6, 56.0, 55.1. HRMS (ESI): m/z [M + H]+ calcd for
C18H17N2O3S: 341.0960; found:341.0958.
1-(2-amino-4-phenylthiazol-5-yl)butan-1-one (2j) .
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The general procedure C was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 2:1)
afforded 2j as a yellow solid. Yield: 177 mg, 72%; mp:203-
(2-amino-4-(pyridin-2-yl)thiazol-5-yl)(phenyl)methanone (2o).
1
204 °C. H NMR (400 MHz, DMSO-d6): δ = 7.97 (s, 2H),
The general procedure C was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 1:2)
afforded 2o as a brown solid. Yield: 191 mg, 68%; mp:174-
7.56-7.39 (m, 5H), 2.19 (t, J = 7.3 Hz, 2H), 1.38 (dd, J = 14.7,
7.4 Hz, 2H), 0.64 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (100
MHz, DMSO-d6) δ = 191.6, 170.5, 157.8, 135.9, 129.2, 128.9,
128.0, 123.3, 41.5, 18.1, 13.5. HRMS (ESI): m/z [M + H]+
calcd for C13H15N2OS: 247.0905; found: 247.0901.
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176 °C. H NMR (400 MHz, DMSO-d6): δ = 7.96 (s, 3H),
7.69-7.65 (m, 1H), 7.62-7.60 (m, 1H), 7.39-7.37 (m, 2H),
7.31-7.27 (m, 1H), 7.15-7.11 (m, 2H), 7.09-7.02 (m, 1H).
13C{1H} NMR (100 MHz, DMSO-d6) δ = 188.5, 170.2, 155.6,
152.5, 148.1, 138.9, 136.2, 131.1, 128.2, 127.7, 123.6, 122.9,
121.7, 40.1, 39.9, 39.7, 39.5, 39.3, 39.1, 38.9. HRMS (ESI):
m/z [M + H]+ calcd for C15H12N3OS: 282.0701; found:
282.0699.
1-(2-amino-4-phenylthiazol-5-yl)-2,2-dimethylpropan-1-one
(2k).
The general procedure C was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 4:1)
afforded 2k as a yellow solid. Yield: 198 mg, 76%; mp: 251-
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253 °C. H NMR (400 MHz, DMSO-d6): δ = 7.73 (s, 2H),
7.41-7.35 (m, 2H), 7.35-7.31 (m, 3H), 1.21 (s, 9H). 13C{1H}
(100 MHz, DMSO-d6) δ = 198.8, 179.6, 168.5, 136.3, 128.9,
128.1, 127.7, 113.9, 43.8, 27.2. HRMS (ESI): m/z [M + H]+
calcd for C14H17N2OS: 261.1062; found: 261.1058.
methyl 2-amino-4-(p-tolyl)thiazole-5-carboxylate (2p).
The general procedure C was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 3:1)
afforded 2p as a yellow solid. Yield: 201 mg, 81%; mp: 192-
1
193 °C. H NMR (400 MHz, DMSO-d6): δ = 7.85 (s, 2H),
(2-amino-4-propylthiazol-5-yl)(phenyl)methanone (2l).
7.55 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H), 3.62 (s, 3H),
2.33 (s, 3H). 13C{1H} NMR (100 MHz, DMSO-d6) δ = 169.8,
161.7, 159.1, 138.3, 131.7, 129.6, 127.9, 107.2, 51.4, 20.9.
HRMS (ESI): m/z [M + H]+ calcd for C12H13N2O2S: 249.0698;
found: 249.0697.
The general procedure C was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 2:1)
afforded 2l as a yellow solid. Yield: 197 mg, 80%; mp: 94-96
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°C. H NMR (400 MHz, DMSO-d6): δ = 7.99 (s, 2H), 7.64-
7.58 (m, 2H), 7.57-7.53 (m, 1H), 7.51-7.44 (m, 2H), 2.53 (dd,
J = 8.3, 6.8 Hz, 2H), 1.56 (dd, J = 15.0, 7.5 Hz, 2H), 0.77 (t, J
= 7.4 Hz,. 13C{1H} NMR (100 MHz, DMSO-d6) δ = 186.6,
171.8, 164.3, 141.2, 131.1, 128.3, 127.4, 118.8, 33.1, 21.9,
13.8. HRMS (ESI): m/z [M + H]+ calcd for C13H15N2OS:
247.0905; found: 247.0903.
General procedure for the synthesis of the thiocyanated
enaminones 3a-3t from enaminones and KSCN and NBS in
DMF
General Procedure D:
To a solution of NBS (178 mg, 1.0 mmol) and enaminone (1.0
mol) in DMF (2 mL) was added KSCN (194 mg, 2.0 mmol) at
0 ℃. The reaction proceeded under an air atmosphere for 5
min until TLC indicated the complete consumption of starting
material. The reation mixture was poured into saturated
aqueous Na2S2O3 (10 mL). The product was extracted with
ethyl acetate (10 mL). The organic layers were washed with
brine (10 mL× 2), and dried over Na2SO4. The solvent was
removed under reduced pressure, and the residue was purified
by flash column chromatography on silica gel to give the
desired product 3a-3t.
(2-amino-4-phenylthiazol-5-yl)(naphthalen-2-yl)methanone
(2m).
The general procedure C was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 2:1)
afforded 2m as a yellow solid. Yield: 231 mg, 70%; mp:186-
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188 °C. H NMR (400 MHz, DMSO-d6): δ = 8.07 (s, 2H),
7.92 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.69-7.63 (m, 2H), 7.51-
7.40 (m, 2H), 7.39-7.32 (m, 1H), 7.26-7.19 (m, 2H), 6.92-6.83
(m, 3H). 13C{1H} NMR (100 MHz, DMSO-d6) δ = 187.4,
171.0, 159.0, 135.6, 135.0, 133.9, 131.6, 130.2, 129.6, 128.8,
128.2, 127.8, 127.4, 127.4, 127.3, 126.4, 124.9, 120.7. HRMS
(ESI): m/z [M + H]+ calcd for C20H15N2OS: 331.0905; found:
331.0900.
Methyl (E)-3-amino-3-phenyl-2-thiocyanatoacrylate (3a).
The general procedure D was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 5:1)
afforded 3a as a yellow solid. Yield: 218 mg, 93%; mp:180-
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181 °C. H NMR (400 MHz, CDCl3): δ = 7.89 (s, 2H), 7.67-
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7.59 (m, 2H), 7.38-7.37 (m, 3H), 3.62 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ = 169.9, 161.6, 159.1, 134.5, 129.6,
128.7, 127.4, 107.6, 51.5. HRMS (ESI): m/z [M + H]+ calcd
for C11H11N2O2S: 235.0541; found: 235.0537.
172.8, 140.8, 136.3, 130.5, 129.9, 128.7, 127.9, 127.1, 126.7,
114.3, 86.5. HRMS (ESI): m/z [M + H]+ calcd for C16H13N2OS:
281.0749; found: 281.0743.
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(E)-3-amino-1-(4-bromophenyl)-3-phenyl-2-thiocyanatoprop-
2-en-1-one (3g).
methyl (E)-3-amino-3-(4-bromophenyl)-2-thiocyanatoacrylate
(3b).
The general procedure D was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 5:1)
afforded 3g as a yellow solid. Yield: 319 mg, 89%; mp:135-
137 °C. 1H NMR (400 MHz, CDCl3): δ = 11.16 (s, 1H), 7.60-
7.47 (m, 9H), 6.31 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3)
δ = 196.1, 173.0, 139.6, 136.3, 131.2, 130.7, 128.9, 128.6,
127.1, 124.4, 114.1, 86.7. HRMS (ESI): m/z [M + H]+ calcd
for C16H12BrN2OS: 358.9854; found: 358.9846.
The general procedure D was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 8:1)
afforded 3b as a yellow solid. Yield: 313 mg, 94%; mp:183-
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185 °C. H NMR (400 MHz, DMSO-d6): δ = 9.14 (s, 1H),
8.73 (s, 1H), 7.74 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H),
3.75 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ = 169.5,
168.1, 135.6, 131.4, 129.8, 123.4, 114.2, 73.6, 51.9, 40.1, 39.9,
39.7, 39.5, 39.3, 39.1, 38.9. HRMS (ESI): m/z [M + H]+ calcd
for C11H10BrN2O2S: 312.9646; found: 312.9643.
(E)-3-amino-1-(4-methoxyphenyl)-3-phenyl-2-
thiocyanatoprop-2-en-1-one (3h).
Methyl (E)-3-amino-3-(4-chlorophenyl)-2-thiocyanatoacrylate
(3c).
The general procedure D was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 5:1)
1
The general procedure D was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 5:1)
afforded 3c as a yellow solid. Yield: 233 mg, 87%; mp:179-
afforded 3h as a brown oil. Yield: 263 mg, 85%. H NMR
(400 MHz, CDCl3): δ = 11.12 (s, 1H), 7.68-7.62 (m, 2H),
7.56-7.50 (m, 5H), 6.98-6.93 (m, 2H), 6.15 (s, 1H), 3.86 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ = 196.3, 172.5,
161.2, 136.8, 133.1, 130.5, 129.5, 128.8, 127.2, 114.5, 113.2,
86.5, 55.3. HRMS (ESI): m/z [M + H]+ calcd for C17H15N2O2S:
311.0854; found: 311.0852.
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180 °C. H NMR (400 MHz, CDCl3): δ = 9.36 (s, 1H), 7.51-
7.45 (m, 2H), 7.42-7.36 (m, 2H), 5.55 (s, 1H), 3.86 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ = 168.9, 168.5, 136.7,
134.9, 129.2, 128.8, 127.7, 113.7, 52.4. HRMS (ESI): m/z [M
+ H]+ calcd for C11H10ClN2O2S: 269.0152; found: 269.0146.
(E)-3-amino-3-(4-chlorophenyl)-1-phenyl-2-thiocyanatoprop-
2-en-1-one (3i).
methyl (E)-3-amino-2-thiocyanato-3-(thiophen-2-yl)acrylate
(3d).
The general procedure D was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 8:1)
The general procedure D was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 5:1)
afforded 3d as a brown soild. mp: 92-94 °C. Yield: 163 mg, 68
%. 1H NMR (400 MHz, CDCl3): δ = 9.43 (s, 1H), 7.55 (dd, J =
5.1, 1.1 Hz, 1H), 7.48 (dd, J = 3.7, 1.1 Hz, 1H), 7.14 (dd, J =
5.0, 3.7 Hz, 1H), 5.78 (s, 1H), 3.84 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ = 169.0, 162.1, 135.9, 130.5, 129.3,
127.4, 113.8, 52.3. HRMS (ESI): m/z [M + H]+ calcd for
C9H9N2O2S2: 241.0105; found: 241.0105.
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afforded 3i as a yellow oil. Yield: 283 mg, 90%;. H NMR
(400 MHz, CDCl3): δ = 11.05 (s, 1H), 7.61-7.51 (m, 2H),
7.51-7.35 (m, 7H), 6.54 (s, 1H). 13C{1H} NMR (100 MHz,
CDCl3) δ = 197.3, 171.6, 140.6, 136.8, 134.6, 130.2, 129.1,
128.7, 128.0, 126.8, 114.2, 86.7. HRMS (ESI): m/z [M + H]+
calcd for C16H12ClN2OS: 315.0359; found: 315.0358.
(E)-3-amino-1-phenyl-2-thiocyanatohex-2-en-1-one (3l). The
general procedure D was followed and purification by flash
column chromatography (petroleum ether: EtOAc = 5:1)
afforded 3l as a yellow oil. Yield: 172 mg, 70%. 1H NMR (400
MHz, CDCl3): δ = 11.30 (s, 1H), 7.55-7.36 (m, 5H), 6.56 (s,
1H), 2.74 (dd, J = 8.4, 7.3 Hz, 2H), 1.83-1.68 (m, 2H), 1.08
(dd, J = 7.7, 7.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
= 196.7, 175.2, 141.2, 129.6, 127.9, 126.5, 113.9, 86.0, 38.5,
20.8, 13.7. HRMS (ESI): m/z [M + H]+ calcd for C13H15N2OS:
247.0905; found: 247.0902.
Methyl
(E)-3-amino-3-(naphthalen-2-yl)-2-
thiocyanatoacrylate (3e).
The general procedure D was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 5:1)
afforded 3e as a yellow solid. Yield: 273 mg, 96%; mp:138-
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139 °C. H NMR (400 MHz, CDCl3): δ = 9.40 (s, 1H), 7.95-
7.89 (m, 4H), 7.62-7.54 (m, 2H), 7.51-7.49 (m, 1H), 5.74 (s,
1H), 3.87 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ =
169.7, 169.0, 133.9, 133.7, 132.5, 128.6, 128.4, 127.8, 127.6,
127.1, 126.9, 124.4, 113.9, 77.2, 52.2. HRMS (ESI): m/z [M +
H]+ calcd for C15H13N2O2S: 285.0698; found: 285.0692.
(E)-3-amino-1-(naphthalen-2-yl)-3-phenyl-2-thiocyanatoprop-
2-en-1-one (3m).
The general procedure D was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 10:1)
afforded 3m as a brown solid. Yield: 264 mg, 80%; mp: 129-
(E)-3-amino-1,3-diphenyl-2-thiocyanatoprop-2-en-1-one (3f).
The general procedure D was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 5:1)
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130 °C. H NMR (400 MHz, CDCl3): δ = 11.22 (s, 1H), 8.14
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afforded 3f as a yellow oil. Yield: 266 mg, 95%. H NMR
(s, 1H), 7.99–7.84 (m, 3H), 7.70 (dd, J = 8.4, 1.7 Hz, 1H),
7.62–7.48 (m, 7H), 6.29 (s, 1H). 13C{1H} NMR (100 MHz,
CDCl3) δ = 197.3, 172.9, 138.2, 136.6, 133.9, 132.4, 130.6,
(400 MHz, CDCl3): δ = 11.07 (s, 1H), 7.61-7.44 (m, 10H),
6.59 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ = 197.2,
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128.9, 128.8, 127.8, 127.7, 127.3, 127.2, 127.1, 126.5, 124.2,
13C{1H} NMR (100 MHz, CDCl3) δ = 196.7, 174.9, 139.9,
138.4, 128.6, 126.8, 114.0, 86.0, 38.5, 21.4, 20.8, 13.7. HRMS
(ESI): m/z [M + H]+ calcd for C14H17N2OS: 261.1062; found:
261.1057.
114.4, 87.1. HRMS (ESI): m/z [M + H]+ calcd for C20H15N2OS:
331.0905; found: 331.0904.
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(E)-3-amino-1-(3,4-dimethoxyphenyl)-3-phenyl-2-
thiocyanatoprop-2-en-1-one (3n).
(E)-3-amino-3-(4-chlorophenyl)-1-(4-methoxyphenyl)-2-
thiocyanatoprop-2-en-1-one (3s).
The general procedure D was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 3:1)
afforded 3n as a yellow oil. Yield: 299 mg, 88%;. H NMR
(400 MHz, CDCl3): δ = 11.17 (s, 1H), 7.61-7.51 (m, 5H),
7.33-7.29 (m, 1H), 7.26 (d, J = 1.9 Hz, 1H), 6.95 (d, J = 8.3
Hz, 1H), 6.20 (s, 1H), 3.98 (s, 3H), 3.95 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ = 196.3, 172.8, 150.8, 148.3, 136.8,
133.3, 130.6, 128.9, 127.2, 120.9, 114.9, 110.7, 110.1, 86.7,
56.0, 55.9. HRMS (ESI): m/z [M + H]+ calcd for C18H17N2O3S:
341.0960; found: 341.0958.
The general procedure D was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 5:1)
afforded 3s as a yellow solid. Yield: 282 mg, 82%; mp:165-
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166 °C. H NMR (400 MHz, CDCl3): δ = 7.55-7.50 (m, 2H),
7.29-7.26 (m, 2H), 7.13-7.09 (m, 2H), 6.68-6.63 (m, 2H), 5.51
(s, 2H), 3.78 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ =
187.2, 177.5, 169.7, 162.8, 134.5, 132.9, 131.6, 130.9, 130.09,
128.0, 113.1, 55.4, 29.5. HRMS (ESI): m/z [M + H]+ calcd for
C17H14ClN2O2S: 345.0465; found: 345.0458.
(E)-3-amino-1-phenyl-3-(pyridin-2-yl)-2-thiocyanatoprop-2-
en-1-one (3o).
(E)-3-amino-1,3-bis(4-chlorophenyl)-2-thiocyanatoprop-2-en-
1-one (3t).
The general procedure D was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 2:1)
afforded 3o as a yellow oil. Yield: 239 mg, 85%; H NMR
(400 MHz, CDCl3): δ = 8.71 (d, J = 4.7 Hz, 1H), 7.95-7.84 (m,
2H), 7.63-7.56 (m, 2H), 7.52-7.39 (m, 4H). 13C{1H} NMR
(100 MHz, CDCl3) δ = 197.9, 168.9, 153.0, 149.8, 140.8,
137.0, 130.1, 128.0, 126.9, 125.5, 124.4, 114.2, 85.8. HRMS
(ESI): m/z [M + H]+ calcd for C15H12N3OS: 282.0701; found:
282.0700.
The general procedure D was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 5:1)
afforded 3t as a white solid. Yield: 261 mg, 75%; mp: 270-272
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°C. H NMR (400 MHz, CDCl3): δ = 11.15 (s, 1H), 7.57-7.51
(m, 4H), 7.49-7.41 (m, 4H), 6.20 (s, 1H). 13C{1H} NMR (100
MHz, CDCl3) δ = 196.1, 171.7, 138.9, 137.1, 136.3, 134.6,
129.3, 128.6, 128.5, 128.3, 113.9, 87.0. HRMS (ESI): m/z [M
+ H]+ calcd for C16H11Cl2N2OS: 348.9969; found: 348.9956.
methyl (E)-3-amino-2-thiocyanato-3-(p-tolyl)acrylate (3p).
Synthetic application
The general procedure D was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 7:1)
afforded 3p as a white soild. Yield: 216 mg, 87%; mp: 159-
161 °C. 1H NMR (400 MHz, CDCl3): 9.33 (s, 1H), 7.30 (q, J =
8.2 Hz, 4H), 5.69 (s, 1H), 3.84 (s, 3H), 2.41 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ = 170.0, 169.1, 140.7, 133.7, 129.3,
127.2, 114.1, 77.3, 77.0, 76.7, 52.1, 21.4. HRMS (ESI): m/z
[M + H]+ calcd for C12H13N2O2S: 249.0698; found: 249.0696.
Synthesis of 4a: To the solution of 3a (1 mmol) in CH2Cl2(3
mL) was added iodosobenzene (1.1 mmol) at room
temperature. The mixture was stirred in open air and
monitored by TLC. After completion of the reaction, the
reaction mixture was quenched with H2O (10 mL), and
extracted with ethyl acetate (10 mL) for three times. The
combined organic layer was dried over Na2SO4, and the
solvent removed in vacuo. The crude residue was purified by
flash column chromatography to afford the product 4a as a
yellow solid. Yield: 197 mg, 85%; mp: 118-119 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.00-7.95 (m, 2H), 7.78-7.72 (m, 1H),
7.68-7.62 (m, 2H), 3.82 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ = 167.8, 161.2, 135.6, 131.2, 129.8, 119.2, 109.1,
54.3, 46.3. HRMS (ESI): m/z [M + NH4]+ calcd for
C11H12N3O2S: 250.0650; found: 250.0643.
(E)-3-amino-1-(4-fluorophenyl)-2-thiocyanatohex-2-en-1-one
(3q). The general procedure D was followed and purification
by flash column chromatography (petroleum ether: EtOAc =
5:1) afforded 3q as a brown solid. Yield: 216 mg, 82%;
mp:65-66 °C. 1H NMR (400 MHz, CDCl3): δ = 11.31 (s, 1H),
7.53 (dd, J = 8.7, 5.4 Hz, 2H), 7.11 (t, J = 8.7 Hz, 2H), 6.42 (s,
1H), 2.82-2.71 (m, 2H), 1.76 (dt, J = 14.9, 7.5 Hz, 2H), 1.09 (t,
J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ = 195.4,
175.3, 164.6, 162.1, 137.2 (JC-F = 16), 129.0 (JC-F = 32), 115.1,
114.9, 113.8, 85.9, 38.5, 20.8, 13.7. HRMS (ESI): m/z [M +
H]+ calcd for C13H14FN2OS: 265.0811; found: 265.0802.
Synthesis of 5a: To a solution of compound 2a (234mg, 1
mmol) in 4 mL of MeOH/H2O (3:1 v/v) was added LiOH (1.5
mmol), and then the solution was warmed to the room
temperature. After 8 h, the reaction mixture was acidified to
pH 2 using 1M HCl and extracted with EtOAc (10 mL) for
three times. The combined organic extracts were washed with
10 mL of brine, dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo to afford the compound 5a as a
colorless oil (143 mg, 65%). 1H NMR (400 MHz, DMSO-d6):
δ = 12.32 (s, 1H), 7.70 (s, 2H), 7.66-7.61 (m, 2H), 7.38-7.33
(m, 3H). 13C{1H} NMR (100 MHz, DMSO-d6) δ = 169.5,
162.6, 157.9, 134.8, 129.7, 128.4, 127.2, 109.8. HRMS (ESI):
m/z [M + H]+ calcd for C10H9N2O2S: 221.0385; found:
221.0379.
(E)-3-amino-2-thiocyanato-1-(p-tolyl)hex-2-en-1-one
(3r).
The general procedure D was followed and purification by
flash column chromatography (petroleum ether: EtOAc = 5:1)
afforded 3r as a yellow solid. Yield: 213 mg, 82%; mp:99-100
1
°C. H NMR (400 MHz, CDCl3): δ = 11.31 (s, 1H), 7.43-7.41
(m, 2H), 7.24-7.22 (m, 2H), 6.42 (s, 1H), 2.78-2.74 (m, 2H),
2.40 (s, 3H), 1.81-1.72 (m, 2H), 1.09 (t, J = 7.3 Hz, 3H).
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The Journal of Organic Chemistry
1-hydroxy-pyrrolidine-2,5-dione (6a)15:
of Henan Province (182102310106). Students research training
program of Henan University of Science and Technology.
1
2
3
4
5
6
7
8
To the solution of NBS (177 mg, 1 mmol) in EtOH (1 mL)
was strried at room temperature for 2 h. The reaction mixture
was filtered and concentrated in vacuo to afforded 1-hydroxy-
pyrrolidine-2,5-dione as a yellow solid (127 mg, 82%). mp:
REFERENCES
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1
97-98°C. H NMR (400 MHz, CDCl3): δ = 8.72 (s, br, 1H),
2.76 (s, 4H). 13C{1H} NMR (100 MHz, CDCl3): δ = 177.8,
29.6.
1-thiocyanatopyrrolidine-2,5-dione (7a)10:
9
To the solution of NBS (177 mg, 1 mmol) in EtOH (1 mL)
was added KSCN (116 mg, 1.2 mmol) at room temperature for
2 h. The reaction mixture was filtered and concentrated in
vacuo to afforded 1-thiocyanatopyrrolidine-2,5-dione as a
yellow solid (132 mg, 85%). mp: 135-136 °C. H NMR (400
MHz, DMSO-d6): δ = 2.57 (s, 4H).
10
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13
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methyl 3-amino-2-bromo-3-phenylacrylate (8a):
To the solution of 1a (177 mg, 1 mmol) in DMF (1 mL) was
added NBS (212 mg, 1.2 mmol) at room temperature for 15
min. The reation mixture was poured into saturated aqueous
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1
product 8a as a white solid. Yield: 231 mg, 91%. H NMR
(400 MHz, CDCl3): δ = 8.03-7.96 (m, 2H), 7.67-7.60 (m, 1H),
7.55-7.48 (m, 2H), 7.45-7.43 (m, 1H), 5.68 (s, 1H), 3.83 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ = 188.1, 165.7,
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127.8, 57.6, 53.9, 53.8, 52.1, 51.9, 45.8. HRMS (ESI): m/z [M
+ H]+ calcd for C10H11BrNO2: 255.9973; found: 255.9970.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge via the
Internet at http://pubs.acs.org. Information on substrate
preparation and NMR spectra for all new compounds.
AUTHOR INFORMATION
Corresponding Author
* duanxiyan@tju.edu.cn
ORCID
Xiyan Duan: 0000-0003-4882-0430
Notes
The authors declare no competing financial interest.
4.
(a) antiviral: Liu, R.; Huang, Z.; Murray, M. G.; Guo, X.; Liu, G.
Quinoxalin-2(1H)-One Derivatives As Inhibitors Against
Hepatitis C Virus. J. Med. Chem. 2011, 54, 5747-5768. (b)
ACKNOWLEDGMENTS
X. Duan acknowledges the Science and Technology Foundation
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Page 12 of 12
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