10.1071/ch13266 ac csiro 2013 australian journal of chemistry

10.1071/CH13266_AC

CSIRO 2013

Australian Journal of Chemistry

SUPPLEMENTARY MATERIAL

Development of inhibitors of Plasmodium falciparum apical membrane antigen 1 based on fragment screening

San Sui LimA, Cael O. DebonoA, Christopher A. MacRaildA, Indu R. ChandrashekaranA, Olan DolezalB, Robin F. AndersC, Jamie S. SimpsonA, Martin J. ScanlonA,D, Shane M. DevineA, Peter J. ScammellsA, Raymond S. NortonA,E

A Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Australia. B CSIRO Materials Science and Engineering, Parkville 3052, Australia. C Department of Biochemistry, La Trobe University, Bundoora 3086, Australia. D Centre of Excellence for Coherent X-ray Science, Monash University, Parkville 3052, Australia E Corresponding author. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Australia. Email: [email protected]

mailto:[email protected]

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2013, 66(12), 1530-1536

Synthesis of the 2-aminothiazoles. (a) For 10, 11, 12, 13, 14, 16, 17, 18: Br2, MeCN, 100 oC, 2 h; (b) For 15, 19, 20, 21: Br2, CHCl3, 50 oC, 2 h; (c) thiourea, MeCN, 100 oC, 2 h.

General methods: Melting points were determined on an Electrothermal melting point apparatus and are uncorrected. All NMR spectra were recorded on a Bruker Avance III 400-MHz Ultrashield Plus spectrometer and 1H, 19F and 13C NMR spectra were recorded at 400, 376 and 101 MHz, respectively. Thin-layer chromatography was conducted on 0.2 mm plates using Merck silica gel 60 F254. Column chromatography was achieved using Merck silica gel 60 (article size 0.063–0.200μm, 70–230 mesh). High resolution mass spectra were obtained on a Waters 2795 Alliance Separations Module. LCMS were routinely run to verify reaction outcome using an Agilent 6100 Series Single Quad couple to an Agilent 1200 Series HPLC. All compounds were of > 95% purity. 4-(2-(Trifluoromethyl)phenyl)thiazol-2-amine (10)

2’-(Trifluoromethyl)acetophenone (200 mg, 1.06 mmol, 159 µL) was added to MeCN (3 mL). Br2 (93 mg, 1.17 mmol, 30 µL) was added dropwise to the mixture at room temperature. The mixture was then heated for 2 h at 100 °C. At this time, thiourea

(89 mg, 1.17 mmol) was added to the cooled reaction mixture, which was then heated for a further 2 h at 100 °C. The reaction was cooled on ice and the precipitate that formed was filtered. This solid was dissolved in EtOAc (20 mL) and washed twice with Na2CO3 (1M) (20 mL). The organic fraction was dried over MgSO4 and the filtrate reduced in vacuo to yield a white compound. The compound was purified using column chromatography using a step gradient from Hexane: EtOAc (1:1) to EtOAc 100 % to yield a crystalline white solid (48 mg, 20 %). m.p: 116-118 oC. Analytical HPLC indicates greater than 97 % purity at 254 nm; 1H NMR (400 MHz; DMSO): δ 7.76 (d, J = 7.9 Hz, 1H, ArH), 7.70-7.64 (m, 1H, ArH), 7.63-7.58 (m, 1H, ArH), 7.55 (dd, J = 11.2, 3.9 Hz, 1H, ArH), 7.02 (br s, 2H, NH2), 6.58 (s, 1H, ArH); 19F NMR (376 MHz; DMSO) δ -56.3 (s, CF3); 13C NMR (101 MHz, DMSO): δ 167.7 (C), 147.5 (C), 135.2 (q, J = 3.0 Hz, C), 132.1 (CH), 131.8 (CH), 128.1 (CH), 126.6 (q, J = 32.0 Hz, CCF3), 126.2 (q, J = 5.5 Hz, CH), 124.2 (q, J = 273.6 Hz, CCF3), 104.9 (q, J = 3.0 Hz, CH). m/z (ESI-HRMS) Calc [M+H]+ = 245.0355; Observed [M+H]+ = 245.0353.

4-(3-(Trifluoromethyl)phenyl)thiazol-2-amine (11)

Same procedure as for 10, from 3’-(trifluoromethyl)acetophenone gave a golden yellow solid (59 mg, 23 %). m.p: 78-80 oC. Analytical HPLC indicates greater than 95 % purity at 254 nm; 1H NMR (400 MHz; MeOD): δ 8.05 (s, 1H, ArH), 7.95 (d, J = 7.1 Hz, 1H, ArH), 7.54-7.48 (m, 2H,

ArH), 6.94 (s, 1H, ArH); 19F NMR (376 MHz; MeOD) δ -64.1 (s, CF3); 13C NMR (101 MHz, MeOD): δ 171.4 (d, J = 6.8 Hz, C), 149.6 (d, J = 13.1 Hz, C), 136.8 (d, J = 2.2 Hz, C), 131.9 (q, J = 32.1 Hz, CCF3), 130.3 (CH), 130.2 (d, J = 1.0 Hz, CH), 125.8 (q, J = 271.1 Hz, CCF3), 124.9 (q, J = 3.9 Hz, CH), 123.5 (q, J = 3.9 Hz, CH), 104.5 (CH). m/z (ESI-HRMS) Calc [M+H]+ = 245.0355; Observed [M+H]+ = 245.0355. 4-(4-(Trifluoromethyl)phenyl)thiazol-2-amine (12)

Same procedure as for 10, from 4’-(trifluoromethyl)acetophenone gave a light orange solid (39 mg, 15 %). m.p: 158-160 oC. Analytical HPLC indicates greater than 97 % purity at 254 nm; 1H NMR (400 MHz; DMSO): 8.00 (d, J = 8.0 Hz, 2H, ArH), 7.72 (d, J = 8.1 Hz,

2H, ArH), 7.25 (s, 1H, ArH), 7.21 (br s, 2H, NH2); 19F NMR (376 MHz; DMSO) δ -60.8 (s, CF3); 13C NMR (101 MHz, DMSO): δ 168.5 (C), 148.1 (C), 138.4 (C), 127.2 (q, J = 31.7 Hz, CCF3), 126.0 (2 × CH), 125.5 (q, J = 3.7 Hz, 2 × CH), 124.4 (q, J = 272.0 Hz, CCF3), 104.4 (CH). m/z (ESI-HRMS) Calc [M+H]+ = 245.0355; Observed [M+H]+ = 245.0353. 4-(2-Fluorophenyl)thiazol-2-amine (13)

Same procedure as for 10, from 2’-fluoroacetophenone gave a pink solid (31 mg, 11 %). m.p: 76-80 oC. Analytical HPLC indicates greater than 97 % purity at 254 nm; Rf: 0.3 (DCM: MeOH: NH₄OH; 96: 2: 2); 1H NMR (400 MHz; CDCl3): δ 8.01

(td, J = 7.8, 1.9 Hz, 1H, ArH), 7.25 (dtd, J = 7.1, 5.4, 1.9 Hz, 1H, ArH), 7.18 (td, J = 7.5, 1.4 Hz, 1H, ArH), 7.10 (ddd, J = 11.8, 8.0, 1.3 Hz, 1H, ArH ), 7.02 (d, J = 2.2 Hz, 1H, ArH ), 5.17 (br s, 2H, NH2); 19F NMR (376 MHz; CDCl3) δ -114.2 (s, F); 13C NMR (101 MHz; CDCl3): 166.6 (C), 160.3 (d, J = 250.0 Hz, CF), 144.8 (d, J = 3.5 Hz, C), 129.8 (d, J = 3.3 Hz, CH), 128.9 (d, J = 8.6 Hz, CH), 124.4 (d, J = 3.5 Hz, CH), 122.4 (d, J = 11.3 Hz, C), 116.0 (d, J = 22.6 Hz, CH), 108.0 (d, J = 15.0 Hz, CH). m/z (ESI-HRMS) Calc [M+H]+ = 195.0387; Observed [M+H]+ = 195.0390.

4-(3-Fluorophenyl)thiazol-2-amine (14) Same procedure as for 10, from 3’-fluoroacetophenone gave a yellow powder (44 mg, 16 %) m.p: 75-78 oC. Analytical HPLC indicates greater than 97 % purity at 254 nm; Rf: 0.2, (DCM; 100); 1H NMR (400 MHz; DMSO): δ 7.66-7.61 (m, 1H, ArH), 7.57 (ddd, J = 10.9, 2.6, 1.5 Hz, 1H, ArH), 7.39 (td, J = 8.0, 6.2

Hz, 1H, ArH), 7.14 (s, 1H, ArH), 7.13-7.02 (m, 3H, ArH, NH2); 19F NMR (376 MHz; DMSO) δ -113.4 (s, F); 13C NMR (101 MHz, DMSO): δ 168.3 (C), 162.5 (d, J = 242.1 Hz, CF), 148.5 (d, J = 2.8 Hz, C), 137.3 (d, J = 8.2 Hz, C), 130.4 (d, J = 8.5 Hz, CH), 121.5 (d, J = 2.6 Hz, CH), 113.8 (d, J = 21.2 Hz, CH), 112.0 (d, J = 22.8 Hz, CH), 103.0 (CH). m/z (ESI-HRMS) Calc [M+H]+ = 195.0387; Observed [M+H]+ = 195.0389. 4-(3-Aminophenyl)thiazol-2-amine (15)

3’-Aminoacetophenone (500 mg, 3.70 mmol) was dissolved in CHCl3 (3 mL). Br2 (698 mg, 3.88 mmol, 225 µL) was added dropwise over 10 min whilst stirring at 0 oC. The mixture was then heated at 50 oC for 2 h, at which time the reaction mixture was cooled and quenched using Na2CO3 (1M). The biphasic

mixture was added to CHCl3 (20 mL) and washed twice with Na2CO3 (1M) (20 mL). The organic fraction was dried over MgSO4 and the filtrate reduced in vacuo to yield a cream-coloured powder. The crude powder was dissolved in MeCN (4 mL), thiourea (187 mg, 2.45 mmol) was added and the mixture heated at 100 oC for 2 h. The reaction was cooled on ice and the precipitate that formed was filtered. This solid was dissolved in EtOAc (20 mL) and washed twice with Na2CO3 (1M) (20 mL). The organic fraction was dried over MgSO4 and the filtrate reduced in vacuo to yield a white powder. The compound was purified using column chromatography using a step gradient from Hexane: EtOAc (1:1) to EtOAc 100 % to yield a light brown solid (36 mg, 5 %). m.p: 160-163 oC; Analytical HPLC indicates greater than 97 % purity at 254 nm; 1H NMR (400 MHz; DMSO): δ 7.03-6.90 (m, 5H, 3 × ArH, NH2), 6.77 (s, 1H, ArH), 6.45 (ddd, J = 7.7, 2.3, 1.2 Hz, 1H, ArH), 5.04 (br s, 2H, NH2); 13C NMR (101 MHz, DMSO): δ 167.8 (C), 150.7 (C), 148.6 (C), 135.5 (C), 128.8 (CH), 113.5 (CH), 113.0 (CH), 111.5 (CH), 100.5 (CH). m/z (ESI-HRMS) Calc [M+H]+ = 192.0590; Observed [M+H]+ = 192.0589. 4-(o-Tolyl)thiazol-2-amine (16)

Same procedure as for 10, from 2’-methylacetophenone gave a pink solid (84.5 mg, 30 %). m.p: 73-75 oC. Analytical HPLC indicates greater than 97 % purity at 254 nm; 1H NMR (400 MHz; CDCl3): δ 7.52 (ddd, J = 5.1, 3.7, 1.9 Hz, 1H, ArH), 7.39-

7.11 (m, 3H, 3 × ArH), 6.45 (s, 1H, ArH), 5.28 (br s, 2H, NH2), 2.44 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3): δ 166.7 (C), 151.4 (C), 136.2 (C), 135.1 (C),

130.8 (CH), 129.7 (CH), 127.9 (CH), 125.9 (CH), 105.8 (CH), 21.1 (CH3). m/z (ESI-HRMS) Calc [M+H]+ = 191.0637; Observed [M+H]+ = 191.0632. 4-(m-Tolyl)thiazol-2-amine (17)

Same procedure as for 10, from 3’-methylacetophenone gave a bright yellow solid (63.3 mg, 22 %). m.p: 56-58 oC. Analytical HPLC indicates greater than 97 % purity at 254 nm; 1H NMR (400 MHz; DMSO): δ 7.62 (s, 1H, ArH), 7.57 (d, J = 7.8 Hz, 1H, ArH), 7.23 (t, J = 7.6 Hz, 1H, ArH), 7.06 (dd, J = 8.1, 0.6

Hz, 1H, ArH), 7.02 (br s, 2H, NH2), 6.96 (s, 1H, ArH), 2.32 (s, 3H, CH3); 13C NMR (101 MHz, DMSO): δ 168.1 (C), 149.9 (C), 137.4 (C), 134.8 (C), 128.3 (CH), 127.8 (CH), 126.2 (CH), 122.7 (CH), 101.3 (CH), 21.1 (CH3). m/z (ESI-HRMS) Calc [M+H]+ = 191.0637; Observed [M+H]+ = 191.0637. 4-(p-Tolyl)thiazol-2-amine (18)

Same procedure as for 10, from 4’-methylacetophenone gave a light yellow powder (40 mg, 14 %). m.p: 100-102 oC. Analytical HPLC indicates greater than 97 % purity at 254 nm; 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.2 Hz, 2H, 2 × ArH), 7.18 (d, J = 7.9 Hz, 2H, 2 × ArH), 6.67 (s, 1H,

ArH), 5.03 (br s, 2H, NH2), 2.36 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3): 167.2 (C), 151.5 (C), 137.7 (C), 132.1 (C), 129.4 (2 × CH), 126.0 (2 × CH), 102.2 (CH), 21.4 (CH3). m/z (ESI-HRMS) Calc [M+H]+ = 191.0637; Observed [M+H]+ = 191.0639. 4-(2-Methoxyphenyl)thiazol-2-amine (19)

Same procedure as for 15, from 2’-methoxyacetophenone gave a white powder (262 mg, 38%). m.p: 83-85oC. Analytical HPLC indicates greater than 98 % purity at 254 nm; 1H NMR (400 MHz; DMSO): δ 8.02 (dd, J = 7.7, 1.8 Hz, 1H, ArH), 7.23 (ddd,

J = 8.3, 7.3, 1.8 Hz, 1H, ArH), 7.11 (s, 1H, ArH), 7.05 (dd, J = 8.3, 0.9 Hz, 1H, ArH), 7.01-6.90 (m, 3H, ArH, NH2), 3.87 (s, 3H, OCH3); 13C NMR (101 MHz, DMSO): δ 166.3 (C), 156.5 (C), 145.8 (C), 129.3 (CH), 128.0 (CH), 123.1 (C), 120.3 (CH), 111.4 (CH), 105.7 (CH), 55.3 (OCH3). m/z (ESI-HRMS) Calc [M+H]+ = 207.0587 ; Observed [M+H]+ = 207.0593. 4-(3-Methoxyphenyl)thiazol-2-amine (20)

Same procedure as for 15, from 3’-methoxyacetophenone gave a yellow solid (95 mg, 14 %). m.p: 98-100 oC. Analytical HPLC indicates greater than 97 % purity at 254 nm; 1H NMR (400 MHz; DMSO): δ 7.38-7.35 (m, 2H, ArH), 7.26 (t, J = 7.9 Hz, 1H, ArH), 7.05 (br s, 2H, NH2), 7.02 (s, 1H, ArH), 6.82 (ddd, J

= 8.1, 2.6, 1.0 Hz, 1H, ArH), 3.77 (s, 3H, OCH3); 13C NMR (101 MHz, DMSO): δ 168.0 (C), 159.4 (C), 149.7 (C), 136.3 (C), 129.5 (CH), 117.9 (CH), 113.0 (CH),

110.8 (CH), 101.9 (CH), 55.0 (OCH3). m/z (ESI-HRMS) Calc [M+H]+ = 207.0587; Observed [M+H]+ = 207.0585 4-(4-Methoxyphenyl)thiazol-2-amine (21)

Same procedure as for 15, from 4’-methoxyacetophenone gave a beige solid (96 mg, 14 %). m.p: 185-187oC. Analytical HPLC indicates greater than 98 % purity at 254 nm; 1H NMR (400 MHz; DMSO): δ 7.72 (d, J = 8.9 Hz, 2H, 2 × ArH), 6.99 (br s, 2H, NH2), 6.92 (d, J = 8.9 Hz,

2H, 2 × ArH), 6.82 (s, 1H, ArH), 3.76 (s, 3H, OCH3); 13C NMR (101 MHz, DMSO): δ 168.1 (C), 158.5 (C), 149.7 (C), 127.9 (C), 126.8 (2 × CH), 113.8 (2 × CH), 99.3 (CH), 55.1 (OCH3). m/z (ESI-HRMS) Calc [M+H]+ = 207.0587 ; Observed [M+H]+ = 207.0593.

NMR Spectra 4-(2-(Trifluoromethyl)phenyl)thiazol-2-amine (10) 1H NMR Spectrum (400 MHz, DMSO)

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.0

0.86

1.98

1.00

0.99

1.00

1.00

2.49

12.

495

2.50

02.

504

2.50

9

3.33

8

6.57

7

7.01

77.

525

7.54

37.

562

7.56

37.

589

7.60

77.

608

7.64

57.

646

7.66

47.

753

7.77

3

13C DEPTQ NMR Spectrum (101 MHz, DMSO)

-100102030405060708090100110120130140150160170180190200

38.8

9339

.103

39.3

1139

.520

39.7

2939

.938

40.1

47

104.

938

104.

970

122.

804

125.

524

126.

069

126.

124

126.

179

126.

234

128.

105

131.

827

132.

073

135.

163

147.

465

167.

671

19F NMR Spectrum (376 MHz, DMSO)

-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-10010

-56.

338

4-(3-(Trifluoromethyl)phenyl)thiazol-2-amine (11) 1H NMR Spectrum (400 MHz, MeOD)

-1.5-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.511.512.5

1.00

2.32

1.13

1.09

3.30

23.

306

3.31

03.

314

3.31

8

4.87

9

6.94

77.

483

7.50

27.

521

7.52

67.

537

7.54

17.

948

7.96

68.

050

13C DEPTQ NMR Spectrum (101 MHz, MeOD)

-100102030405060708090100110120130140150160170180190200

48.3

6148

.574

48.7

8749

.000

49.2

1349

.426

49.6

39

104.

501

124.

315

127.

014

129.

712

130.

237

130.

246

130.

333

131.

455

131.

773

132.

092

136.

790

136.

812

149.

524

149.

654

171.

366

171.

433

19F NMR Spectrum (376 MHz, MeOD)

-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-10010

-64.

123

4-(4-(Trifluoromethyl)phenyl)thiazol-2-amine (12) 1H NMR Spectrum (400 MHz, DMSO)

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.5

2.86

2.01

2.00

2.49

12.

496

2.50

02.

505

2.50

9

3.42

9

7.21

07.

258

7.70

77.

727

7.98

78.

007


-100102030405060708090100110120130140150160170180190200

39.3

1139

.520

39.7

29

104.

394

125.

413

125.

451

125.

489

125.

525

125.

757

126.

033

127.

067

127.

382

138.

441

148.

069

168.

526


-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-10010

-60.

817

4-(2-Fluorophenyl)thiazol-2-amine (13) 1H NMR Spectrum (400 MHz, CDCl3)

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.0

2.06

0.98

1.04

1.07

1.32

1.00

5.16

97.

021

7.02

67.

096

7.10

07.

126

7.12

97.

178

7.18

17.

197

7.20

07.

236

7.26

0

7.99

27.

997

8.01

18.

016

8.03

18.

036

13C DEPTQ NMR Spectrum (101 MHz, CDCl3)

-100102030405060708090100110120130140150160170180190200

76.8

4277

.160

77.4

78

107.

918

108.

067

115.

887

116.

112

122.

383

124.

386

124.

420

128.

813

128.

899

129.

791

129.

824

144.

769

159.

062

161.

547

166.

617

19F NMR Spectrum (376 MHz, CDCl3)

-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-10010

-114

.162

4-(3-Fluorophenyl)thiazol-2-amine (14) 1H NMR Spectrum (400 MHz, DMSO)

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.0

2.84

1.02

1.03

0.99

1.00

2.49

12.

495

2.50

02.

504

2.50

9

3.33

0

7.04

67.

048

7.05

27.

055

7.06

87.

073

7.07

57.

088

7.09

17.

095

7.09

87.

105

7.13

87.

367

7.38

27.

387

7.40

27.

407

7.42

27.

551

7.55

47.

557

7.56

17.

578

7.58

17.

584

7.58

87.

625

7.62

87.

631

7.64

57.

648

7.65

0


-100102030405060708090100110120130140150160170180190200

38.8

9339

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39.3

1139

.520

39.7

2939

.937

40.1

46

103.

020

111.

881

112.

108

113.

875

121.

500

121.

525

130.

381

130.

466

137.

278

137.

359

148.

507

148.

535

161.

266

163.

673

168.

266


-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-10010

-113

.411

4-(3-Aminophenyl)thiazol-2-amine (15) 1H NMR Spectrum (400 MHz, DMSO)

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.0

2.05

1.06

1.00

5.40

2.49

12.

495

2.50

02.

504

2.50

9

3.32

5

5.04

36.

437

6.44

06.

442

6.44

56.

456

6.45

96.

462

6.46

56.

768

6.91

26.

915

6.91

96.

931

6.93

46.

938

6.94

46.

962

6.98

17.

000

7.01

47.

018

7.02

3


-100102030405060708090100110120130140150160170180190200

38.8

9339

.102

39.3

1139

.520

39.7

2939

.938

40.1

46

100.

548

111.

457

113.

024

113.

457

128.

828

135.

509

148.

629

150.

725

167.

780

4-(o-Tolyl)thiazol-2-amine (16) 1H NMR Spectrum (400 MHz, CDCl3)

-1.5-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.511.512.5

3.27

2.06

0.91

3.23

1.00

2.44

1

5.27

6

6.44

87.

197

7.20

97.

213

7.21

77.

225

7.22

87.

236

7.26

07.

502

7.50

87.

511

7.51

57.

521

7.52

27.

528

7.53

1


-100102030405060708090100110120130140150160170180190200

21.1

47

76.8

4277

.160

77.4

77

105.

750

125.

853

127.

914

129.

690

130.

823

135.

053

136.

154

151.

438

166.

708

4-(m-Tolyl)thiazol-2-amine (17) 1H NMR Spectrum (400 MHz, DMSO)

-1.5-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.511.512.5

3.06

1.04

1.88

1.11

1.05

1.01

1.00

2.31

82.

495

2.50

02.

504

2.50

9

3.32

8

6.96

17.

017

7.05

17.

053

7.07

17.

073

7.21

57.

234

7.25

37.

564

7.58

47.

621


-100102030405060708090100110120130140150160170180190200

21.1

05

38.8

9139

.102

39.3

1139

.520

39.7

2839

.937

40.1

46

101.

287

122.

686

126.

198

127.

805

128.

322

134.

825

137.

419

149.

900

168.

055

4-(p-Tolyl)thiazol-2-amine (18) 1H NMR Spectrum (400 MHz, CDCl3)

-1.5-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.511.512.5

3.30

2.13

0.94

2.03

2.00

2.36

1

5.02

5

6.67

07.

174

7.19

47.

260

7.65

57.

676


-100102030405060708090100110120130140150160170180190200

21.3

79

76.8

4277

.160

77.4

77

102.

232

126.

049

129.

425

132.

072

137.

699

151.

531

167.

227

4-(2-Methoxyphenyl)thiazol-2-amine (19) 1H NMR Spectrum (400 MHz, DMSO)

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.0

3.08

3.01

1.06

0.87

1.03

1.00

2.49

02.

495

2.50

02.

504

2.50

9

3.36

2

3.87

46.

945

6.94

86.

950

6.96

46.

966

6.98

26.

985

7.04

07.

043

7.06

17.

063

7.11

47.

210

7.21

57.

228

7.23

17.

233

7.23

57.

249

8.00

58.

009

8.02

48.

029


-100102030405060708090100110120130140150160170180190200

38.8

9439

.102

39.3

1139

.520

39.7

2839

.937

40.1

46

55.3

38

105.

724

111.

405

120.

297

123.

100

128.

046

129.

252

145.

753

156.

529

166.

255


-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.0

3.08

1.00

1.05

1.91

1.03

1.97

2.49

12.

495

2.50

02.

504

2.50

9

3.32

5

3.77

1

6.80

56.

808

6.81

26.

814

6.82

66.

828

6.83

26.

835

7.02

27.

049

7.24

07.

260

7.28

07.

345

7.34

87.

351

7.35

57.

358

7.36

07.

364

7.37

77.

379

7.38

3


-100102030405060708090100110120130140150160170180190200

38.8

9439

.103

39.3

1139

.520

39.7

2939

.938

40.1

48

55.0

06

101.

872

110.

813

112.

967

117.

903

129.

456

136.

320

149.

686

159.

409

168.

049


-1.5-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.511.512.5

3.02

0.98

2.00

1.93

2.00

2.49

12.

496

2.50

02.

505

2.51

0

3.32

5

3.76

3

6.81

86.

905

6.92

76.

989

7.70

47.

726


-100102030405060708090100110120130140150160170180190200

38.8

9539

.102

39.3

1139

.520

39.7

2939

.938

40.1

47

55.0

72

99.3

10

113.

796

126.

814

127.

859

149.

679

158.

507

168.

057

High-Resolution Mass Spectra 4-(2-(Trifluoromethyl)phenyl)thiazol-2-amine (10)



4-(2-Fluorophenyl)thiazol-2-amine (13)

4-(3-Fluorophenyl)thiazol-2-amine (14)

4-(3-Aminophenyl)thiazol-2-amine (15)

4-(o-Tolyl)thiazol-2-amine (16)

4-(m-Tolyl)thiazol-2-amine (17)

4-(p-Tolyl)thiazol-2-amine (18)

4-(2-Methoxyphenyl)thiazol-2-amine (19

4-(3-Methoxyphenyl)thiazol-2-amine (20)

4-(4-Methoxyphenyl)thiazol-2-amine (21)

10.1071/ch13266 ac csiro 2013 australian journal of chemistry

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