Solvent-controlled Synthesis of Thiocyanated Enaminones

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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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The Journal of Organic Chemistry

Solvent-controlled Synthesis of Thiocyanated Enaminones and 2Aminothiazoles from Enaminones, KSCN and NBS 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: [email protected]

O

NH2

R1

R2

NBS (1.0 equiv), KSCN (2.0 equiv), O DMF, 0 °C, 5 min R1

NH2 R2

NBS (1.5 equiv), O KSCN (2.0 equiv), EtOH, rt, 2 h R1

R2 N

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.

INTRODUCTION 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 sulfonyl cyanides,2e thioethers,2f disulfides,2g and 2h phosphonothioates. 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 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. 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

blocks toward potent medicinal scaffolds that exhibit a broad spectrum of biological activities, such as antiviral,4a 4b anticancer, anti-oxidant,4b antidiabetic,4c antiinflammatory,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 Figure 1. Drug Molecules Containing the Thiocyanates or 2-Aminothiazole Moiety i-Pr

PhO

NCS SCN

O

4-phenoxyphenoxyethyl thiocyanate T. cruzi proliferation inhibitor O O

O

N N H

S

nitazoxanide potent antiprotozoal agent

NO2

N

NCS 9-thiocyanatopupukeanane antimicrobial activity

N H 2N S

C6H13 fasicularin cytotoxic activity OH

•2HCl•H2O N H

pramipexole dihydrochloride hydrate treatment of Parkinsonism

S O

O

N

N N H

S

O

meloxicam non-steroidal antiinflammatory drug

anti-inflammatory drug (NSAID) that selectively inhibit COX2 enzyme (Figure 1).6 The most well-known synthetic methods of 2-aminothiazoles have utilized the direct condensation of αhalocarbonyl compounds with thiourea (Hantzsch reaction, Scheme 1b).7 Recently, Yu and co-workers reported the

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straightforward synthesis of 4‑substituted 2‑aminothiazoles 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). Scheme 1. Synthesis of Thiocyanated Enaminones and 2Aminothiazoles O

O N

R

NH2

NH4SCN, hv

O

(a)

R

R2

R1

SCN

X

S +

H 2N

NH2

(b)

X= LG, EWG O

NH2

R1

R2 SCN

NBS (1.0 equiv), KSCN (2.0 equiv), DMF, 0 °C , 5 min

O R1

NH2

NBS (1.5 equiv), KSCN (2.0 equiv), EtOH, rt, 2 h

R2

O

R2

R1

N S

(e) this work

Ph

N3

NH2 N

2-aminothiazoles moiety R1

+

KSCN

(c)

OAc R

2

+

RNCS

(d)

RESULTS AND DISCUSSION 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-4phenylthiazole-5-carboxylate (2a) in 40% yield in 1,2dichloroethane at room temperature (Table 1, entry 1). Then, various oxidants were screened for the reaction in 1,2dichloroethane 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

Page 2 of 12

mixture, 3a and 2a were obtained in moderate yields (Table 1, entry 17). Table 1. Optimization of Reaction Conditionsa O

oxidant, KSCN (2 equiv), solvent, rt, 2 h

NH2

MeO

O

O

MeO S

1a

NH2

N + MeO SCN NH2

3a

2a

entry

oxidant (equiv)

solvent

Yield of 2a (%)

Yield of 3a (%)

1

NBS (1.5)

DCE

40

trace

2

K2S2O8 (1.5)

DCE

nd

36

3

Na2S2O8 (1.5)

DCE

nd

32

4

Oxone (1.5)

DCE

nd

20

5

PIDA (1.5)

DCE

nd

trace

6

NBS (1.5)

CH2Cl2

trace

nd

7

NBS (1.5)

EtOH

93

trace

8

NBS (1.5)

EtOAc

65

trace

9

NBS (1.5)

CH3CN

33

43

10

NBS (1.5)

THF

75

trace

11

NBS (1.5)

1,4-dioxane

nd

31

12b

NBS (1.5)

DMF

15

70

13 b, c

NBS (1.0)

DMF

trace

90

14

-

EtOH

nd

nd

15

-

DMF

nd

nd

16d

NBS (1.0)

EtOH

trace

78

17e

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. c 0 ℃ d 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. e 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. 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 tertbutyl 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 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. Scheme 2. Synthesis of 2-Aminothiazoles from Enaminones, KSCN and NBSa O

NBS (1.5 equiv), KSCN (2 equiv), EtOH, rt, 2 h

NH2

R1

R2

O

R2

O

R

R1

Cl O

O

O

NH2

SCN

O

O N

S

S

NH2

2f, 50%

2e, 70%

NH2

O

O

NH2 S

MeO

O

N NH2

Cl O

O

O S

MeO

O

N NH2

2h, 89%

N

S

S

O

MeO

NH2

O

2j, 72%

O N

S

O S

N

S NH2

NH2

2l, 80%

2k, 76%

NH2

O

O

MeO

S 2n, 86%

S 2o, 68%

N NH2

S

N NH2

2p,81%

aReaction

conditions: NBS (1.5 equiv), KSCN (2 equiv), enamine 1 (1.0 equiv), EtOH (2 mL), rt, open flask, 2 h. 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

NH2 SCN

NH2

O

NH2 N SCN

3n, 88% O

Me

O

MeO

Cl

3l, 70%

SCN

MeO

F

3p, 87%

O

NH2

O

MeO

NH2

N

N

SCN 3i, 90%

NH2

O

NH2

SCN

2m, 70%

O

SCN

NH2

3o, 85% O

NH2

NH2

MeO

Me

MeO

O

SCN

3m, 80%

N

NH2

3k, trace

SCN

O

3f, 95%

3h, 85% O

3j, trace

NH2

NH2 2i, 78%

NH2

SCN

N

NH2 SCN

3e, 96%

3g, 89%

2g, 65%

O

SCN

SCN

Br

NH2

MeO

SCN

S

Br

Cl

3c, 87%

N

O N

SCN

Br

3b, 93%

3d, 68%

MeO

NH2

MeO

SCN

2d, 75%

2c, 75%

O

NH2

MeO 3a, 90%

NH2

NH2

2b,81%

S

S

N

S

O

NH2

MeO

MeO

MeO

N

R2 SCN 3

1

O

S

NH2

2

Br

MeO

R

O R1

2

R1 = aryl, OMe; R2 = aryl, alkyl

NH2

R1 = aryl, alkyl, OMe R2 = aryl, alkyl

NBS (1 equiv), KSCN (2 equiv), DMF, 0 °C, 5 min

NH2

1

N

S

1

smoothly to afford the corresponding thiocyanated 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). Scheme 3. Synthesis of Thiocyanated Enaminones from Enaminones, KSCN and NBSa

3s, 82%

aReaction

O

NH2 SCN

MeO

SCN

Me

3q, 82%

Cl Cl

SCN 3r, 82%

NH2 SCN

3t, 75%

Cl

conditions: NBS (1.0 equiv), KSCN (2.0 equiv), enamine 1a (1.0 equiv), DMF (2 mL), 0 ℃, open flask, 5 min. 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 2aminothiazole 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%). Scheme 4. Synthetic application


The Journal of Organic Chemistry O

1 2 3 4 5 6 7 8 9 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

NH2

MeO

O

iodosobenzene

Ph SCN 3a

CH2Cl2, rt , 2 h

Ph SCN

LiOH, EtOH/H2O N

S

O HO

rt

(b)

N

S

NH2

2a

(a)

4a, 85%

O MeO

scavengers (TEMPO or BHT) did not hamper the reaction, which suggested that the reaction may not involve a radical pathway (Scheme 5a). However, when N-methylated or Narylated enaminones, such as (Z)-3-(methylamino)-1,3diphenylprop-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.

N

MeO

NH2 5a, 65%

Scheme 5. Control Experiments O

NBS (1 equiv), KSCN (2 equiv), DMF, 0 °C, 5 min

NH2

MeO

Ph

O

(a)

Ph SCN

radical scavenger (Tempo or BHT)

1a

NH2

MeO 3a

TEMPO: 76% of 3a BHT: 81% of 3a O

O EtOH, rt

N Br

N OH

O NBS

(b)

O 6a 1-hydroxy-pyrrolidine-2,5-dione 82%

O

O KSCN

N Br

N SCN

(c)

CH3CN, rt

O NBS

O 7a 85%

Table 2. The formation of 2a from 3a via intramolecular cyclization.a

O N SCN (1 equiv) O MeO

O

O 7a

NH2 Ph

MeO

DMF

(1) NBS (1 equiv), DMF, rt, 1 h

KSCN (2 equiv)

(2)

O

NH2

O

NH2 Ph

O

NH2 Ph

O

Ph Br 8a

(f)

8a, 91% NH2

MeO

Ph Br

1a O

NH2

MeO

KSCN(1 equiv), DMF, rt, 15 min

O

NH2

MeO

Ph

(g)

SCN 3a, 98%

To probe the reaction mechanism of the selective formation of thiocyanated enaminones and 2-aminothiazoles, a series of control experiments were conducted. First, 2,2,6,6tetramethyl-1-piperidinyloxy (TEMPO) and 2,6-di-tert-butyl4-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

MeO

N S NH2 2a

entry

promotor (equiv)

temperature (℃)

time (h)

Yield of 2a (%)

conversion of 3a

1

NBS (1.0)

rt

2

98

100

2

-

rt

2

nd

0

3

-

40

2

nd

0

4

-

60

2

16

21

5

-

120

2

17

21

6

-

120

12

22

26

7

-

120

24

25

28

8

NIS (1.0)

rt

2

90

100

9

K2CO3 (1.0)

rt

2

98

100

10

TBAF (1.0)

rt

2

56

70

11

NCS

rt

2

nd

0

SCN

1a

NBS (1 equiv), DMF, rt, 15 min

temperature, time

3a

(e)

3a, trace

MeO

O

promotor, EtOH

Ph SCN

(d)

3a No reaction

MeO

NH2

MeO

Ph SCN

1a

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The Journal of Organic Chemistry (1.0) 12

Oxone (1.0)

rt

2

nd

0

13b

HCl (6.0)

40

2

26

100

14

Acetic acid (0.02)

rt

2

nd

0

15

TsOH (0.02)

rt

2

nd

0

16

FeCl3 (0.02)

rt

2

trace

15

Cu(OTf)2 (0.02)

rt

KSCN (1.0)

rt

17 18

thiocyano enamine 3 tautomerizes into its isomer C in protic solvent (EtOH). Then, an excess of NBS could react with a trace amount of water to generate 1-hydroxy-pyrrolidine-2,5dione 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. Scheme 6. Proposed Reaction Mechanism. O O O

12 2

41 nd

56

R2 Br A

NH2

R1

R2

Br

1

NH

R1

N

O

O

O

NH2

R1

0

NH

R1

KSCN

R2 SCN

DMF

B

R2 Br 8 O

aReaction

conditions: oxidant or base, enamine 3a, solvent, open flask, 2 h. b 1M HCl.

NBS HO N O O

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 1415). 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). 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, which tautomerizes into enaminone isomer 3. From the 1H 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 cisarrangement of carbonyl and amino groups in aprotic solvents (DMF). However, this hydrogen bond will break and the α-

H

N

R1

H

R

2

EtOH

NH2 S

HBr

N

SCN

N

C

D

3

O

R2

R1 S

NH2

O

P. T.

R2

R1

NH S

NH E

R2

R1

S

R2

O

H 2O

O

NH2

R1

F

O

-H

H

R2

R1

N S

NH2 2

NH2

In summary, we have disclosed a novel and efficient protocol to access the thiocyanated enaminones and 2aminothiazoles 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 2aminothiazoles 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 CDCl or DMSO3 d6 solution on a Bruker AV 400 MHz spectrometer. Chemical shifts are reported in parts per million (δ) relative to CDCl3 (7.27 ppm) for 1H NMR data and CDCl3 (77.0 ppm) for 13C 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,



and the eluent was a mixture of ethyl acetate (EA) and petroleum ether (PE). 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. 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. 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. 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. 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. (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 °C. 1H 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,

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21.3, 13.6, 13.5. HRMS (ESI): m/z [M + H]+ calcd for C12H15FNO: 208.1138; found: 208.1132. (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. (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, 125.6, 91.3. HRMS (ESI): m/z [M + H]+ calcd for C15H13BrNO: 302.0181; found: 302.0177. (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 °C. 1H 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 (petroleum ether/EtOAc = 8:1). Yield: 2 g, 73 %; 1H 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-(3,4-dimethoxyphenyl)-3-phenylprop-2-en-1one (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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0.2 ( petroleum ether/EtOAc = 3:1). Yield: 1.8 g, 63 %;. 1H 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. (Z)-3-amino-3-(4-chlorophenyl)-1-(4-methoxyphenyl)prop-2en-1-one (1s). 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, CDCl ) δ = 189.2, 162.1, 160.9, 3 136.5, 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. General procedure for the synthesis of the 2aminothiazoles 2a-2p from enaminones and KSCN and NBS in EtOH 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. 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). Methyl 2-amino-4-(4-bromophenyl)thiazole-5-carboxylate (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: 210213 °C. 1H NMR (400 MHz, DMSO-d6): δ = 7.91 (s, 2H), 7.63-7.56 (m, 4H), 3.64 (s, 3H). 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:176179 °C. 1H NMR (400 MHz, DMSO-d6): δ = 7.93 (s, 2H),

7.67 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 3.62 (s, 3H). 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. 13C{1H}

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:145147 °C. 1H 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). 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:189191°C. 1H 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. (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:160161 °C. 1H 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:191192°C. 1H 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. (2-amino-4-phenylthiazol-5-yl)(4-methoxyphenyl)methanone (2h). 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:198200 °C. 1H 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. (2-amino-4-(4-chlorophenyl)thiazol-5-yl)(phenyl)methanone (2i) .



The general procedure C was followed and purification by flash column chromatography (petroleum ether: EtOAc = 2:1) afforded 2i as a yellow solid. Yield: 245 mg, 78%; mp:218220 °C. 1H NMR (400 MHz, DMSO-d6): δ = 8.06 (s, 2H), 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. 1-(2-amino-4-phenylthiazol-5-yl)butan-1-one (2j) . 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:203204 °C. 1H NMR (400 MHz, DMSO-d6): δ = 7.97 (s, 2H), 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. 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: 251253 °C. 1H 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. (2-amino-4-propylthiazol-5-yl)(phenyl)methanone (2l). 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 °C. 1H NMR (400 MHz, DMSO-d6): δ = 7.99 (s, 2H), 7.647.58 (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. (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:186188 °C. 1H 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), 7.517.40 (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.

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(2-amino-4-phenylthiazol-5-yl)(3,4dimethoxyphenyl)methanone (2n). 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:212213 °C. 1H 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. (2-amino-4-(pyridin-2-yl)thiazol-5-yl)(phenyl)methanone (2o). 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:174176 °C. 1H 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.

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: 192193 °C. 1H NMR (400 MHz, DMSO-d6): δ = 7.85 (s, 2H), 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.

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. 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:180181 °C. 1H 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. 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 = 8:1) afforded 3b as a yellow solid. Yield: 313 mg, 94%; mp:183185 °C. 1H 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. 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) afforded 3c as a yellow solid. Yield: 233 mg, 87%; mp:179180 °C. 1H NMR (400 MHz, CDCl3): δ = 9.36 (s, 1H), 7.517.45 (m, 2H), 7.42-7.36 (m, 2H), 5.55 (s, 1H), 3.86 (s, 3H). 13C{1H} NMR (100 MHz, CDCl ) δ = 168.9, 168.5, 136.7, 3 134.9, 129.2, 128.8, 127.7, 113.7, 52.4. HRMS (ESI): m/z [M + H]+ calcd for C11H10ClN2O2S: 269.0152; found: 269.0146. 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 = 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.

Methyl (E)-3-amino-3-(naphthalen-2-yl)-2thiocyanatoacrylate (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:138139 °C. 1H NMR (400 MHz, CDCl3): δ = 9.40 (s, 1H), 7.957.89 (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-1,3-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) afforded 3f as a yellow oil. Yield: 266 mg, 95%. 1H NMR (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,

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. (E)-3-amino-1-(4-bromophenyl)-3-phenyl-2-thiocyanatoprop2-en-1-one (3g). 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:135137 °C. 1H NMR (400 MHz, CDCl3): δ = 11.16 (s, 1H), 7.607.47 (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. (E)-3-amino-1-(4-methoxyphenyl)-3-phenyl-2thiocyanatoprop-2-en-1-one (3h). The general procedure D was followed and purification by flash column chromatography (petroleum ether: EtOAc = 5:1) afforded 3h as a brown oil. Yield: 263 mg, 85%. 1H 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. (E)-3-amino-3-(4-chlorophenyl)-1-phenyl-2-thiocyanatoprop2-en-1-one (3i). The general procedure D was followed and purification by flash column chromatography (petroleum ether: EtOAc = 8:1) afforded 3i as a yellow oil. Yield: 283 mg, 90%;. 1H 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. (E)-3-amino-1-(naphthalen-2-yl)-3-phenyl-2-thiocyanatoprop2-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: 129130 °C. 1H NMR (400 MHz, CDCl3): δ = 11.22 (s, 1H), 8.14 (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,



128.9, 128.8, 127.8, 127.7, 127.3, 127.2, 127.1, 126.5, 124.2, 114.4, 87.1. HRMS (ESI): m/z [M + H]+ calcd for C20H15N2OS: 331.0905; found: 331.0904.

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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.

(E)-3-amino-1-(3,4-dimethoxyphenyl)-3-phenyl-2thiocyanatoprop-2-en-1-one (3n). 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%;. 1H 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.

(E)-3-amino-3-(4-chlorophenyl)-1-(4-methoxyphenyl)-2thiocyanatoprop-2-en-1-one (3s). 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:165166 °C. 1H 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-2en-1-one (3o). 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%; 1H 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.

(E)-3-amino-1,3-bis(4-chlorophenyl)-2-thiocyanatoprop-2-en1-one (3t). 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 °C. 1H 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). 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: 159161 °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. (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. (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 °C. 1H 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).

Synthetic application 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. 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.


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1-hydroxy-pyrrolidine-2,5-dione (6a)15: 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-hydroxypyrrolidine-2,5-dione as a yellow solid (127 mg, 82%). mp: 97-98°C. 1H 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: 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. 1H NMR (400 MHz, DMSO-d6): δ = 2.57 (s, 4H).

of Henan Province (182102310106). Students research training program of Henan University of Science and Technology.

REFERENCES 1.

2.

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 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 8a as a white solid. Yield: 231 mg, 91%. 1H 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, 134.4, 134.4, 133.2, 129.3, 129.2, 128.9, 128.4, 128.4, 127.9, 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. 3.

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 * [email protected]

ORCID Xiyan Duan: 0000-0003-4882-0430

Notes The authors declare no competing financial interest. 4.

ACKNOWLEDGMENTS X. Duan acknowledges the Science and Technology Foundation

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Solvent-controlled Synthesis of Thiocyanated Enaminones

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