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]
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
13C DEPTQ NMR Spectrum (101 MHz, DMSO)
-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
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
-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
13C DEPTQ NMR Spectrum (101 MHz, DMSO)
-100102030405060708090100110120130140150160170180190200
38.8
9339
.102
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
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
-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
13C DEPTQ NMR Spectrum (101 MHz, DMSO)
-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
13C DEPTQ NMR Spectrum (101 MHz, CDCl3)
-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
13C DEPTQ NMR Spectrum (101 MHz, DMSO)
-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
13C DEPTQ NMR Spectrum (101 MHz, CDCl3)
-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
13C DEPTQ NMR Spectrum (101 MHz, DMSO)
-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
4-(3-Methoxyphenyl)thiazol-2-amine (20) 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
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
13C DEPTQ NMR Spectrum (101 MHz, DMSO)
-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
4-(4-Methoxyphenyl)thiazol-2-amine (21) 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
3.02
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
13C DEPTQ NMR Spectrum (101 MHz, DMSO)
-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-(3-(Trifluoromethyl)phenyl)thiazol-2-amine (11)
4-(4-(Trifluoromethyl)phenyl)thiazol-2-amine (12)
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)
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