5
7.78 (d, J = 8.4 Hz, 0.41H), 7.60 (t, J = 7.4 Hz, 1H), 7.51 –
7.45(m, 2.25H), 7.42 (t, J = 7.4 Hz, 0.42H), 5.68 (s, 0.2H), 4.02
(s, 2H), 3.80 (s, 0.61H), 3.76 (s, 3H). 13C NMR (150 MHz,
CDCl3) δ 192.4, 173.6, 171.5, 168.0, 135.9, 133.9, 133.3, 131.3,
128.9, 128.6, 128.6, 126.1, 87.1, 52.6, 51.5, 45.7.
DMSO-d6) δ 170.6, 161.0, 132.5, 130.0, 128.8, 127.4, 115.3,
ACCEPTED MANUSCRIPT
83.6. HRMS (ESI) calcd for C10H8N3S+ [M + H+] 202.0433,
found 202.0428.
4.3.2 2-Amino-4-(4-methoxyphenyl)thiazole-5-carbonitrile (3b).
Following the general procedure, 3b was purified by silica gel
chromatography (30% EA/PE). Yield: 92%, white solid, mp. 193
– 194 oC. 1H NMR (600 MHz, DMSO-d6) δ 8.19 (s, 2H), 7.90 (d,
J = 9.0 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 3.82 (s, 3H). 13C NMR
(150 MHz, DMSO-d6) δ 170.3, 160.8, 160.5, 129.0, 125.1, 115.7,
114.2, 81.8, 55.3. HRMS (ESI) calcd for C11H10N3OS+ [M + H+]
232.0539, found 232.0533.
4.3.3 2-Amino-4-(4-chlorophenyl)thiazole-5-carbonitrile (3c).
Following the general procedure, 3c was purified by silica gel
chromatography (30% EA/PE). Yield: 81%, white solid, mp.
>200 oC. 1H NMR (600 MHz, DMSO-d6) δ 8.27 (s, 2H), 7.93 (d,
J = 9.0 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H). 13C NMR (150 MHz,
DMSO-d6) δ 170.7, 159.5, 134.6, 131.3, 129.1, 128.9, 115.1,
84.1. HRMS (ESI) calcd for C10H7ClN3S+ [M + H+] 236.0044,
found 236.0045.
4.3.4. 2-Amino-4-(3-chlorophenyl)thiazole-5-carbonitrile (3d).
Following the general procedure, 3d was purified by silica gel
chromatography (30% EA/PE). Yield: 81%, white solid, mp.
>200 oC. 1H NMR (600 MHz, DMSO-d6) δ 8.31 (s, 2H), 7.93 (s,
1H), 7.92 – 7.85 (m, 1H), 7.56 (d, J = 4.8 Hz, 2H). 13C NMR (150
MHz, DMSO-d6) δ 170.7, 158.9, 134.3, 133.5, 130.8, 129.7,
127.1, 125.8, 114.9, 84.7. HRMS (ESI) calcd for C10H7ClN3S+
[M + H+] 236.0044, found 236.0049.
4.2.8.
Methyl
3-(4-bromophenyl)-3-oxopropanoate
(1h).
Following the general procedure B, 1h was purified by silica gel
chromatography (10% EA/PE). Yield: 86%, yellow solid, mp.
45-46oC. 1H NMR (600 MHz, CDCl3) δ 12.49 (s, 0.3H), 7.81 (d,
J = 7.1 Hz, 2H), 7.63 (d, J = 6.3 Hz, 2.6H), 7.55 (d, J = 7.9 Hz,
0.63H), 5.66 (s, 0.3H), 3.98 (s, 2H), 3.81 (s, 1H), 3.76 (s, 3H).
13C NMR (150 MHz, CDCl3) δ 191.4, 173.4, 170.2, 167.7, 134.6,
132.2, 131.8, 130.0, 129.2, 127.6, 125.8, 87.4, 52.7, 51.6, 45.6.
4.2.9. Methyl 3-(4-methoxyphenyl)-3-oxopropanoate (1i).
Following the general procedure B, 1i was purified by silica gel
1
chromatography (10% EA/PE). Yield: 77%, yellow oil. H NMR
(600 MHz, CDCl3) δ 7.92 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 7.6
Hz, 2H), 3.97 (s, 2H), 3.87 (s, 3H), 3.75 (s, 3H). 13C NMR (150
MHz, CDCl3) δ 190.9, 168.2, 164.1, 130.9, 129.0, 127.8, 114.0,
113.9, 85.6, 55.6, 52.5, 51.5, 45.6.
4.2.10.
Methyl
3-oxo-3-(thiophen-2-yl)propanoate
(1j).
Following the general procedure B, 1j was purified by silica gel
1
chromatography (10% EA/PE). Yield: 60%, yellow oil. H NMR
(600 MHz, CDCl3) δ 7.75 (d, J = 3.6 Hz, 1H), 7.72 (d, J = 4.8
Hz, 1H), 7.16 (t, J = 4.2 Hz , 1H), 3.95 (s, 2H), 3.76 (s, 3H). 13C
NMR (150 MHz, CDCl3) δ 184.9, 167.5, 143.2, 135.2, 133.4,
128.4, 52.6, 46.2.
4.2.11. Methyl 3-(naphthalen-2-yl)-3-oxopropanoate (1l).
Following the general procedure B, 1l was purified by silica gel
chromatography (10% EA/PE). Yield: 76%, yellow oil. H NMR
(600 MHz, CDCl3) δ 12.61 (s, 0.2H), 8.44 (s, 1H), 8.35 (s, 0.2H),
8.00 (d, J = 8.6 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.88 – 7.85 (m,
2.6H), 7.64 – 7.54 (m, 2.6H), 5.82 (s, 0.2H), 4.14 (s, 2H), 3.82 (s,
0.6H), 3.77 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 192.4, 173.6,
171.3, 168.1, 135.9, 134.7, 132.8, 132.4, 130.7, 130.5, 129.7,
129.0, 128.8, 128.3, 127.9, 127.7, 127.6, 127.0, 126.8, 126.7,
126.5, 123.8, 122.6, 87.8, 52.6, 51.6, 45.8.
4.3.5. 2-Amino-4-(o-tolyl)thiazole-5-carbonitrile (3e). Following
the general procedure, 3e was purified by silica gel
chromatography (30% EA/PE). Yield: 50%, white solid, mp.
1
o
>200 C. 1H NMR (600 MHz, DMSO-d6) δ 8.21 (s, 2H), 7.38
(dd, J = 15.0, 7.8 Hz, 2H), 7.33 (d, J = 7.2 Hz, 1H), 7.28 (t, J =
7.5 Hz, 1H), 2.31 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ
170.8, 163.7, 136.3, 132.6, 130.6, 129.4, 129.3, 125.7, 114.6,
86.5, 19.6. HRMS (ESI) calcd for C11H10N3S+ [M + H+]
216.0590, found 216.0580.
4.3.6
2-Amino-4-(tert-butyl)thiazole-5-carbonitrile
(3f).
4.2.12. Methyl 3-oxo-4-phenylbutanoate (1o). Following the
general procedure C, 1o was purified by silica gel
chromatography (10% EA/PE). Yield: 60%, yellow oil. H NMR
(600 MHz, CDCl3) δ 7.35 (t, J = 7.4 Hz, 2H), 7.29 (t, J = 7.4 Hz,
1H), 7.21 (d, J = 7.2 Hz, 2H), 3.83 (s, 2H), 3.71 (s, 3H), 3.47 (s,
2H). 13C NMR (150 MHz, CDCl3) δ 200.5, 167.6, 133.2, 129.6,
128.9, 127.4, 52.4, 50.1, 48.0.
Following the general procedure, 3f was purified by silica gel
chromatography (30% EA/PE). Yield: 95%, white solid, mp. 188
– 189 oC. 1H NMR (600 MHz, DMSO-d6) δ 7.99 (s, 2H), 1.32 (s,
9H). 13C NMR (150 MHz, DMSO-d6) δ 173.1, 169.8, 115.1, 82.2,
36.4, 29.6. HRMS (ESI) calcd for C8H12N3S+ [M + H+] 182.0746,
found 182.0737.
1
4.3.7 Methyl 2-amino-4-phenylthiazole-5-carboxylate (3g).
Following the general procedure, 3g was purified by silica gel
chromatography (30% EA/PE). Yield: 59%, white solid, mp. 176
4.3. General Procedure for Preparation of 2-amino-thiozoles
3.
o
1
– 177 C. H NMR (600 MHz, DMSO-d6) δ 7.87 (s, 2H), 7.63 –
7.64 (m, 2H), 7.37 – 7.38 (m, 3H), 3.62 (s, 3H). 13C NMR (150
MHz, DMSO-d6) δ 169.9, 161.5, 159.0, 134.5, 129.6, 128.7,
127.3, 107.6, 51.3. HRMS (ESI) calcd for C11H11N2O2S+ [M +
H+] 235.0536, found 235.0529.
General procedure: The substrate 1 (1.0 mmol) and thiourea 2
(2.0 mmol) were added to solvent (5 mL methanol) at room
temperature. To the reaction mixture, TBHP (3.0 mmol) and
AIBN (0.2 mmol) were added respectively. The reaction mixture
was stirred at room temperature (for substrates 1a-f) or reflux
temperature (for substrates 1g-r) until TLC indicated the total
consumption of 1 (for substrates 1p-q, the reaction time is 24 h).
The residue was treated with saturated aqueous NaHCO3 (50 mL)
and then extracted with EA (30 mL × 3). The organic phase was
washed with brine (50 mL × 1), dried over anhydrous Na2SO4.
The solvent was removed and the residue was purified by flash
column chromatography on silica gel (EA/PE) to afford the
desired compound 3.
4.3.8 Methyl 2-amino-4-(4-bromophenyl)thiazole-5-carboxylate
(3h). Following the general procedure, 3h was purified by silica
gel chromatography (30% EA/PE). Yield: 52%, white solid, mp.
o
>200 C. 1H NMR (600 MHz, DMSO-d6) δ 7.92 (s, 2H), 7.65 –
7.53 (m, 4H), 3.63 (s, 3H). 13C NMR (1510 MHz, DMSO-d6) δ
167.0, 161.4, 157.6, 133.6, 131.7, 130.4, 122.1, 108.0, 51.5.
HRMS (ESI) calcd for C11H10Br79N2O2S+ [M + H+] 312.9641,
found 312.9645.
4.3.9 Methyl 2-amino-4-(4-methoxyphenyl)thiazole-5-carboxylate
(3i). Following the general procedure, 3i was purified by silica
gel chromatography (30% EA/PE). Yield: 66%, white solid, mp.
160 – 161 oC. 1H NMR (600 MHz, CDCl3) δ 7.68 (d, J = 9.0 Hz,
2H), 6.93 (d, J = 9.0 Hz, 2H), 5.91 (s, 2H), 3.84 (s, 3H), 3.74 (s,
3H). 13C NMR (151 MHz, CDCl3) δ 169.0, 162.2, 160.4, 158.8,
4.3.1 2-Amino-4-phenylthiazole-5-carbonitrile (3a). Following
the general procedure, 3a was purified by silica gel
chromatography (30% EA/PE). Yield: 87%, white solid, mp.
>200 oC. 1H NMR (600 MHz, DMSO-d6) δ 8.25 (s, 2H), 7.93 (d,
J = 7.2 Hz, 2H), 7.56 – 7.39 (m, 3H). 13C NMR (150 MHz,