Synthesis of 2-aminothiazoles from styrene derivatives mediated by 1,3-dibromo-5,5-dimethylhydrantoin (DBH)

Article abstract of DOI:10.1016/j.tet.2018.05.021

An efficient procedure for the synthesis of 2-aminothiazoles via DBH-mediated oxidative cyclization of styrenes and thioureas is reported. Various alkenes were successfully transformed to the corresponding 2-aminothiazoles in yields of 10–81% via a two-step one-pot manner using DBH as both the bromine source and oxidant. The method can be readily carried out in gram-scale and successfully applied to the synthesis of anti-inflammatory drug fanetizole using styrene as starting material.

Full text of DOI:10.1016/j.tet.2018.05.021

Accepted Manuscript
Synthesis of 2-aminothiazoles from styrene derivatives mediated by 1,3-dibromo-5,5-
dimethylhydrantoin (DBH)
Chunhua Ma, Yuqi Miao, Minghao Zhao, Ping Wu, Jianglu Zhou, Zhi Li, Xilei Xie, Wei
Zhang
PII:
S0040-4020(18)30540-4
10.1016/j.tet.2018.05.021
TET 29528
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 February 2018
Revised Date: 30 April 2018
Accepted Date: 7 May 2018
Please cite this article as: Ma C, Miao Y, Zhao M, Wu P, Zhou J, Li Z, Xie X, Zhang W, Synthesis of
2-aminothiazoles from styrene derivatives mediated by 1,3-dibromo-5,5-dimethylhydrantoin (DBH),
Tetrahedron (2018), doi: 10.1016/j.tet.2018.05.021.
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ACCEPTED MANUSCRIPT
Synthesis of 2-aminothiazoles from styrene derivatives mediated by
1,3-dibromo-5,5-dimethylhydrantoin (DBH)
Chunhua Ma,† Yuqi Miao,† Minghao Zhao,† Ping Wu,‡ Jianglu Zhou,‡ Zhi Li,‡ Xilei Xie,§ Wei
Zhang*,‡
†School of Chemistry and Chemical Engineering, Henan Normal University, Collaborative
Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Henan Key
Laboratory of Organic Functional Molecule and Drug Innovation, Xinxiang 453007, China
‡School of Pharmacy, Fudan University, Shanghai 201203, China
§College of Chemistry, Chemical Engineering and Materials Science, Shandong Normal
University, Jinan 250014, China
*E-mail: zhang416@fudan.edu.cn
NHR3
N
1,3-dibromo-5,5-dimethylhydantoin/H2O
S
R2
S
R1
R1
EtOH, 80 oC, 2h
then
R2
H2N
NHR3
34 examples, 10-81% yields

ACCEPTED MANUSCRIPT
Synthesis of 2-aminothiazoles from styrene derivatives mediated by
1,3-dibromo-5,5-dimethylhydrantoin (DBH)
Chunhua Ma,† Yuqi Miao,† Minghao Zhao,† Ping Wu,‡ Jianglu Zhou,‡ Zhi Li,‡ Xilei Xie,§ Wei
Zhang*,‡
†School of Chemistry and Chemical Engineering, Henan Normal University, Collaborative
Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Henan Key
Laboratory of Organic Functional Molecule and Drug Innovation, Xinxiang 453007, China
‡School of Pharmacy, Fudan University, Shanghai 201203, China
§College of Chemistry, Chemical Engineering and Materials Science, Shandong Normal
University, Jinan 250014, China
*E-mail: zhang416@fudan.edu.cn
Abstract: An efficient procedure for the synthesis of 2-aminothiazoles via
DBH-mediated oxidative cyclization of styrenes and thioureas is reported. Various
alkenes were successfully transformed to the corresponding 2-aminothiazoles in
yields of 10-81% via a two-step one-pot manner using DBH as both the bromine
source and oxidant. The method can be readily carried out in gram-scale and
successfully applied to the synthesis of anti-inflammatory drug fanetizole using
styrene as starting material.
Keywords:
2-Aminothiazole,
1,3-Dibromo-5,5-dimethylhydrantoin,
Alkenes,
Heterocycles, Oxidative cyclization
2-Aminothiazole ring systems are privileged structural motifs found in a great deal
of biologically active compounds which are used to treat bacterial infections1,
inflammation2, hypertension3, allergies4, schizophrenia5, cancer6 and so on. Several
compounds bearing 2-aminothiazole core have been approved as therapeutic drugs or
under clinical trials (Fig. 1). In view of the importance of 2-aminothiazole ring in the
pharmaceutical industry7, several methods have been developed for the construction
of this scaffold from various starting materials. Traditional 2-aminothiazole formation
was achieved by the Hantzsch reaction of α-halocarbonyl compounds and thioureas8.
Recently, modified Hantzsch protocols were reported. The heterocycle-formation was
promoted by various catalytic systems such as ammonium-12-molybdophosphate9,
NaF10, β-cyclodextrin11, or catalyst-free in water12/ionic liquid13, or accelerated by
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microwave irradiation in ethanol14. To avoid direct handling of lachrymatic reagents,
starting materials other than α-halocarbonyl compounds were also developed. Yadav
reported Cu(OTf)2-catalyzed coupling of α-diazoketones with thiourea to synthesize
2-aminothiazoles15. Zhao16, Kaushik17, Telvekar18 and Yadav19 presented their studies
on the transformation of ketones to 2-aminothiazoles under various conditions.
Halogenation followed by cyclocondensation of ketone with thiourea is also attractive,
which is accessed by using iodine20, NBS21, and 1,3-dichloro-5,5-dimethylhydantoin
22
as halogen sources and catalyzed by nanoparticles. Transformation of
phenylacetylenes to corresponding 2-aminothiazoles was also achieved, as reported
by Nageswar23. Alkenes have been recognized as attractive starting materials for a
number of organic transformations because they are inexpensive and readily available
in chemical industry. Donohoe24 and Kshirsagar25 demonstrated the synthesis of
2-aminothiazoles from alkenes mediated by I2/IBX in DMSO or NBS in water.
Recently, our group reported that 1,3-dibromo-5,5-dimethylhydantoin (DBH) could
be served as a powerful reagent in the transformation of alkenes to other versatile
intermediates such as α-bromo/amino ketones, α,α-dibromoacetophenones, and
amides26. Based on these works, we hypothesized that our strategy could be further
expanded to the formation of 2-aminothiazoles. Herein, we would like to report a
practical synthesis of 2-aminothiazoles by means of DBH-mediated oxidative
cyclization of alkenes with thiourea under mild conditions.
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Fig 1. Selected drugs bearing 2-aminothiazole scaffold.
According to our previous work in the conversion of olefins into α-bromoketones26a,
we treated styrene (0.5 mmol) with DBH (1.5 equiv) and 1% (v/v) tween-80 as an
emulsifier in water at 60 °C for 1h, followed by reaction with thiourea (1.5 equiv) at
80 °C for 2h. To our glad, the reaction gave 4-phenylthiazol-2-amine (2a) in 81%
yield (Table 1). Encouraged by this result, we next engrossed in exploring the
substrate scope of the reaction with different substituted alkenes. As shown in Table 1,
most 2-aminothiazoles were obtained in moderate to good yields regardless of an
electron withdrawing or donating group on the benzene ring (2c-2z). Substrates
bearing
weak electron-donating group (alkyl group) were transformed to
corresponding 2-aminothiazoles in good yields from 65% to 79% (2c-2f). However,
this protocol did not work on styrenes bearing strong electron-donating group such as
methoxyl group. On the contrary, derivatives with electron-withdrawing substituents
gave desired products smoothly in yields from 32% to 71% (2g-2r, 2u-2z). The effect
of steric hindrance on the benzene ring was also observed. The yield of styrene
derivative with meta-substituent was considerably lower than its para-counterparts
(2i/2j vs. 2g/2h, 2m/2n vs. 2k/2l, and 2q/2r vs. 2o/2p); while for ortho-substituent,
the yield was as low as about 10% (2s/2t). As shown in Table 1, not only terminal
alkenes but also linear- and cyclic-internal styrene derivatives, provided satisfactory
results (2ac/2ad and 2ag/2ah). Furthermore, this protocol also worked well on
aliphatic olefins (2ae/2af).
Subsequently, in order to evaluate the scalability of the method, the reaction of
styrene was performed in a 1.0-g scale (Scheme 1), affording the 2-aminothiazole (2a)
in satisfactory yield (79%).
Fanetizole (N-phenethyl-4-phenylthiazol-2-amine, Fig. 1) is an anti-inflammatory
agent under clinical trials for the treatment of rheumatoid arthritis. This compound
has been previously synthesized by coupling of 2-bromoacetophenone with
N-phenethylthiourea12,13. Recently, Zhao16 reported the oxidative cyclization of
acetophenone and N-phenethylthiourea to yield fanetizole by using the combination of
KI/NH4NO3/H2SO4 in [Bmim]OTf/H2O and molecular oxygen as oxidant. According
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to our new protocol, commercial available and cheap styrene was treated with DBH,
subsequently reacted with N-phenethylthiourea to afford fanetizole in 72% yield
(Scheme 2), avoiding the using of 2-bromoacetophenone with serious lachrymatic
property.
Table 1. Transformation of alkenes to 2-aminothiazoles promoted by DBH.
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Scheme 1. Scale-up of the reaction.
Scheme 2. Synthetic utilization of the method in the preparation of fanetizole.
Scheme 3. Plausible mechanism of the reaction
Based on our previous works and the disclosed reaction pathway26, we proposed a
plausible mechanism of this reaction, as shown in Scheme 3. The reaction is initiated
by halohydroxylation with DBH or active species HBrO to obtain 2-bromo-1-phenyl
ethanol. The further bromination of this intermediate is investigated with DBH or
HBrO as bromo source, followed by cleaving one molecule of HBr to give phenacyl
bromide. Finally, the in situ generated phenacyl bromide reacts with thiourea
smoothly to form aminothiazoles 2a.
In summary, various alkenes were successfully transformed to corresponding
2-aminothiazoles in moderate to good yields via a two-step one-pot manner using
DBH as both the bromine source and oxidant. This method is attractive because of the
use of low-toxic reagents, readily available and inexpensive starting materials without
preliminary functionalization, and mild conditions. The reaction can be readily carried
out in gram-scale, providing a practical strategy for the preparation of
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2-aminothiazole derivatives. The synthesis of anti-inflammatory drug fanetizole using
styrene as starting material demonstrated a successful application of this method.
Experimental section
General information. All commercial reagents were used without further purification.
Reactions were magnetically stirred and monitored by thin layer chromatography
(TLC) with silica gel plates (60F-254). Preparative thin layer chromatography was
performed on silica gel F254 glass plates (layer thickness 400–500 mm). Yields refer
to isolated yields and spectroscopically pure compounds. Melting points were
determined on a melting point apparatus in open capillaries and are uncorrected.
Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker 400 MHz or
Bruker Avance III 600 MHz spectrometer as indicated in the data list. Chemical shifts
for proton nuclear magnetic resonance (1H NMR) spectra are reported in parts per
million relative to the signal residual (CDCl3 at 7.26 ppm, DMSO-d6 at 2.50 ppm) or
TMS. Chemical shifts for carbon nuclear magnetic resonance (13C NMR) spectra are
reported in parts per million relative to the center line of the CDCl3 triplet at 77.16
ppm or DMSO-d6 multiplet at 39.52 ppm. The abbreviations s, d, t, q, br, and m stand
for the resonance multiplicity singlet, doublet, triplet, quartet, broad and multiplet,
respectively. High resolution mass spectra (HRMS) were obtained using a Q TOF
mass spectrometer or Agilent LC-TOF mass spectrometer equipped with an APCI/ESI
multimode ion source detector.
General procedure for the synthesis of aminothiazoles2a-2ah
To a mixture of olefin (0.5 mmol) and tween-80 (30 ꢀL) in water (3 mL) was
added DBH (214.5 mg, 0.75 mmol) at room temperature, and the mixture was stirred
under the conditions as indicated in Table 1. After cooling to room temperature and
removal of solvent under reduced pressure, EtOH (3 mL), thiourea (57.1 mg, 0.75
mmol) (or 0.75 mmol of N-methylthiourea/N-phenethylthiourea) were added to the
mixture, and the obtained mixture was stirred for 2h at 80 °C. The mixture was
diluted with ethyl acetate (60 mL). The organic phase was washed with brine (10
mL×3) and dried over Na2SO4. After concentrated under reduced pressure, the residue
was purified by preparative thin layer chromatography to afford the corresponding
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2-aminothiazoles.
4-Phenylthiazol-2-amine (2a). Yield 81%; White solid, mp 149-151 °C; 1H NMR
(CDCl3, 600 MHz) δ: 7.77 (d, J = 7.2 Hz, 2H), 7.38 (t, J = 7.2 Hz, 2H), 7.29 (t, J =
7.2 Hz, 1H), 6.72 (s, 1H), 5.29 (s, 2H); 13C NMR (CDCl3, 150 MHz) δ: 167.5, 151.5,
134.8, 128.7, 127.9, 126.1, 102.9; ESI-HRMS [M + H]+ m/z = 177.0489, calcd for
C9H9N2S, 177.0481.
N-Methyl-4-phenylthiazol-2-amine (2b). Yield 78%; White solid, mp
135-137 °C; 1H NMR (CDCl3, 600 MHz) δ: 7.80 (d, J = 7.3 Hz, 2H), 7.38 (t, J = 7.2
13
Hz, 2H), 7.29 (t, J = 6.9 Hz, 1H), 6.71 (s, 1H), 5.81 (s, 1H), 2.98 (s, 3H); C NMR
(CDCl3, 150 MHz) δ: 171.1, 151.8, 135.1, 128.7, 127.8, 126.2, 100.9, 32.4;
ESI-HRMS [M + H]+ m/z = 191.0638, calcd for C10H11N2S, 191.0637.
1
4-(p-Tolyl)thiazol-2-amine (2c). Yield 67%; White solid, mp 124-126 °C; H
NMR (CDCl3, 600 MHz) δ: 7.66 (d, J = 7.2 Hz, 2H), 7.18 (d, J = 7.2 Hz, 2H), 6.65 (s,
13
1H), 5.26 (s, 2H), 2.36 (s, 3H); C NMR (CDCl3, 150 MHz) δ: 167.4, 151.4, 137.7,
132.0, 129.4, 126.1, 102.1, 21.4; ESI-HRMS [M + H]+ m/z = 191.0639, calcd for
C10H11N2S, 191.0637.
N-Methyl-4-(p-tolyl)thiazol-2-amine (2d). Yield 65%; White solid, mp
127-129 °C; 1H NMR (CDCl3, 600 MHz) δ: 7.68 (d, J = 7.2 Hz, 2H), 7.18 (d, J = 7.2
13
Hz, 2H), 6.66 (s, 1H), 5.42 (s, 1H), 3.00 (s, 3H), 2.36 (s, 3H); C NMR (150 MHz,
CDCl3) δ: 170.8, 152.0, 137.5, 132.5, 129.4, 126.1, 100.3, 32.4, 21.4; ESI-HRMS [M
+ H]+ m/z = 205.0792, calcd for C11H13N2S, 205.0794.
4-(4-(tert-Butyl)phenyl)thiazol-2-amine (2e). Yield 79%; White solid, mp
107-109 °C; 1H NMR (CDCl3, 600 MHz) δ: 7.70 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4
Hz, 2H), 6.64 (s, 1H), 5.64 (s, 2H), 1.35 (s, 9H); 13C NMR (CDCl3, 150 MHz) δ:
168.1, 151.0, 150.9, 132.0, 125.8, 125.6, 101.9, 34.7, 31.4; ESI-HRMS [M + H]+ m/z
= 233.1105, calcd for C13H17N2S, 233.1107.
4-(4-(tert-Butyl)phenyl)-N-methylthiazol-2-amine (2f). Yield 76%; White solid,
mp 124-126 °C; 1H NMR ( CDCl3, 600 MHz) δ: 7.72 (d, J = 7.7 Hz, 2H), 7.40 (d, J =
13
7.7 Hz, 2H), 6.65 (s, 1H), 6.01 (s, 1H), 2.97 (s, 3H), 1.34 (s, 9H); C NMR (CDCl3,
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150 MHz) δ: 171.1, 151.6, 150.9, 132.2, 125.9, 125.6, 100.1, 34.7, 32.4, 31.4;
ESI-HRMS [M + H]+ m/z = 247.1257, calcd for C14H19N2S, 247.1263.
4-(4-Fluorophenyl)thiazol-2-amine (2g). Yield 58%; White solid, mp 103-104 °C;
1H NMR (CDCl3, 400 MHz) δ: 7.73 (dd, J = 8.6, 5.6 Hz, 2H), 7.05 (t, J = 8.6 Hz, 2H),
6.63 (s, 1H), 5.35 (s, 2H); 13C NMR (CDCl3, 150 MHz) δ: 167.8, 162.5 (d, J = 244.5
Hz), 150.4, 131.1 (d, J = 3.0 Hz), 127.8 (d, J = 7.5 Hz), 115.6 (d, J = 22.5 Hz), 102.4;
19F NMR (CDCl3, 376 MHz) δ: -114.2; ESI-HRMS [M + H]+ m/z = 195.0932, calcd
for C9H8FN2S, 195.0387.
4-(4-Fluorophenyl)-N-methylthiazol-2-amine (2h). Yield 55%; White solid, mp
1
136-138 °C; H NMR (CDCl3, 600 MHz) δ: 7.76 (t, J = 6.4 Hz, 2H), 7.06 (t, J = 8.2
Hz, 2H), 6.63 (s, 1H), 5.74 (s, 1H), 2.97 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ:
171.1, 162.5 (d, J = 244.5 Hz), 150.9, 131.5 (d, J = 3.0 Hz), 127.9 (d, J = 7.5 Hz),
115.5 (d, J = 21.0 Hz), 100.5, 32.4; 19F NMR (CDCl3, 376 MHz) δ: -114.5;
ESI-HRMS [M + H]+ m/z = 209.0540, calcd for C10H10FN2S, 209.0543.
4-(3-Fluorophenyl)thiazol-2-amine (2i). Yield 47%; White solid, mp 108-110 °C;
1H NMR (CDCl3, 600 MHz) δ: 7.54 (d, J = 7.4 Hz, 1H), 7.48 (d, J = 10.2 Hz, 1H),
7.34–7.31 (m, 1H), 6.98 (t, J = 8.2 Hz, 1H), 6.75 (s, 1H), 5.09 (s, 2H); 13C NMR
(CDCl3, 150 MHz) δ: 167.4, 163.3 (d, J = 243.0 Hz), 150.2, 136.9 (d, J = 9.0 Hz),
130.2 (d, J = 9.0 Hz), 121.7 (d, J = 3.0 Hz), 114.7 (d, J = 21.0 Hz), 113.1 (d, J = 22.5
Hz), 104.0; 19F NMR (CDCl3, 376 MHz) δ: -113.2; ESI-HRMS [M + H]+ m/z =
195.0396, calcd for C9H8FN2S, 195.0387.
4-(3-Fluorophenyl)-N-methylthiazol-2-amine (2j). Yield 45%; White solid, mp
1
103-105 °C; H NMR (CDCl3, 400 MHz) δ: 7.57–7.49 (m, 2H), 7.36-7.30 (m, 1H),
13
7.00–6.96 (m, 1H), 6.72 (s, 1H), 6.36 (s, 1H), 2.95 (s, 3H); C NMR (CDCl3, 100
MHz) δ: 171.4, 163.2 (d, J = 243.0 Hz), 150.6 (d, J = 3.0 Hz), 137.4 (d, J = 8.0 Hz),
130.1 (d, J = 9.0 Hz), 121.7 (d, J = 3.0 Hz), 114.5 (d, J = 22.0 Hz), 113.2 (d, J = 23.0
Hz), 101.8, 32.3; 19F NMR (CDCl3, 376 MHz) δ: -113.4; ESI-HRMS [M + H]+ m/z =
209.0552, calcd for C10H10FN2S, 209.0543.
4-(4-Chlorophenyl)thiazol-2-amine (2k). Yield 56%; White solid, mp
161-163 °C; 1H NMR (CDCl3, 600 MHz) δ: 7.70 (d, J = 7.6 Hz, 2H), 7.34 (d, J = 7.6
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Hz, 2H), 6.71 (s, 1H), 5.10 (s, 2H); 13C NMR (Acetone-d6, 150 MHz) δ: 169.3, 150.3,
134.9, 133.1, 129.3, 128.2, 103.2; ESI-HRMS [M + H]+ m/z = 211.0084, calcd for
C9H8ClN2S, 211.0091.
4-(4-Chlorophenyl)-N-methylthiazol-2-amine (2l). Yield 61%; White solid, mp
138-140 °C; 1H NMR (CDCl3, 600 MHz) δ: 7.73 (d, J =8.0 Hz, 2H), 7.34 (d, J = 8.0
Hz, 2H), 6.69 (s, 1H), 5.65 (s, 1H), 2.98 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ:
171.0, 150.7, 133.6, 133.4, 128.8, 127.5, 101.3, 32.4; ESI-HRMS [M + H]+ m/z =
225.0247, calcd for C10H10ClN2S, 225.0248.
4-(3-Chlorophenyl)thiazol-2-amine (2m). Yield 43%; White solid, mp
1
126-128 °C; H NMR (CDCl3, 400 MHz) δ: 7.77 (s, 1H), 7.64 (d, J = 7.4 Hz, 1H),
7.32–7.24 (m, 2H), 6.74 (s, 1H), 5.18 (s, 2H); 13C NMR (CDCl3, 150 MHz) δ: 167.5,
150.0, 136.5, 134.7, 130.0, 127.8, 126.3, 124.2, 104.0; ESI-HRMS [M + H]+ m/z =
211.0085, calcd for C9H8ClN2S, 211.0091.
4-(3-Chlorophenyl)-N-methylthiazol-2-amine (2n). Yield 41%; White solid, mp
1
120-121 °C; H NMR (CDCl3, 600 MHz) δ: 7.81 (s, 1H), 7.66 (d, J = 7.5 Hz, 1H),
7.30 (t, J = 7.5 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H), 6.74 (s, 1H), 5.34 (s, 1H), 3.02 (s,
3H); 13C NMR (CDCl3, 150 MHz) δ: 170.8, 150.5, 136.9, 134.7, 129.9, 127.7, 126.4,
124.2, 102.1, 32.4; ESI-HRMS [M + H]+ m/z = 225.0246, calcd for C10H10ClN2S,
225.0248.
4-(4-Bromophenyl)thiazol-2-amine (2o). Yield 71%; White solid, mp
179-181 °C; 1H NMR (CDCl3, 600 MHz) δ: 7.65 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0
Hz, 2H), 6.73 (s, 1H), 4.96 (s, 2H); 13C NMR (Acetone-d6, 150 MHz) δ: 169.2, 150.4,
135.3, 132.3, 128.5, 121.3, 103.3; ESI-HRMS [M + H]+ m/z = 254.9586, calcd for
C9H8BrN2S, 254.9586.
4-(4-Bromophenyl)-N-methylthiazol-2-amine (2p). Yield 65%; White solid, mp
146-148 °C; 1H NMR (CDCl3, 600 MHz) δ: 7.66 (d, J = 7.2 Hz, 2H), 7.49 (d, J = 8.0
Hz, 2H), 6.70 (s, 1H), 5.83 (s, 1H), 2.97 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ:
171.2, 150.7, 134.1, 131.8, 127.8, 121.6, 101.4, 32.4; ESI-HRMS [M + H]+ m/z =
268.9736, calcd for C10H10BrN2S, 268.9743.
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4-(3-Bromophenyl)thiazol-2-amine (2q). Yield 38%; White solid, mp
1
130-132 °C; H NMR (CDCl3, 600 MHz) δ: 7.97 (s, 1H), 7.72 (d, J = 7.5 Hz, 1H),
7.44 (d, J = 7.7 Hz, 1H), 7.30–7.26 (m, 1H), 6.78 (s, 1H), 5.20 (s, 2H); 13C NMR (150
MHz, CDCl3) δ: 167.5, 149.9, 136.8, 130.7, 130.2, 129.2, 124.6, 122.9, 104.1;
ESI-HRMS [M + H]+ m/z = 254.9589, calcd for C9H8BrN2S, 254.9586.
4-(3-Bromophenyl)-N-methylthiazol-2-amine (2r). Yield 32%; White solid, mp
1
106-108 °C; H NMR (CDCl3, 600 MHz) δ: 7.96 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H),
7.40 (d, J = 7.8 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 6.73 (s, 1H), 5.57 (s, 1H), 3.01 (s,
13
3H); C NMR (CDCl3,150 MHz) δ: 170.8, 150.1, 137.0, 130.5, 130.1, 129.1, 124.5,
122.8, 101.9, 32.3; ESI-HRMS [M + H]+ m/z = 268.9737, calcd for C10H10BrN2S,
268.9743.
4-(2-Bromophenyl)thiazol-2-amine (2s). Yield 13%; White solid, mp 122-123 °C;
1H NMR (CDCl3, 400 MHz) δ: 7.68 (dd, J = 7.8, 1.7 Hz, 1H), 7.63 (dd, J = 8.0, 1.1
Hz, 1H), 7.34–7.30 (m, 1H), 7.17–7.13 (m, 1H), 6.91 (s, 1H), 5.30 (s, 2H); 13C NMR
(CDCl3, 150 MHz) δ: 166.6, 149.0, 135.6, 133.7, 131.5, 129.0, 127.4, 121.7, 107.7,
29.8; ESI-HRMS [M + H]+ m/z = 254.9550, calcd for C9H8BrN2S, 254.9586.
4-(2-Bromophenyl)-N-methylthiazol-2-amine (2t). Yield 10%; White solid, mp
94-95 °C; 1H NMR (CDCl3, 400 MHz) δ: 7.69 (dd, J = 7.8, 1.7 Hz, 1H), 7.64 (dd, J =
8.0, 1.1 Hz, 1H), 7.35–7.31 (m, 1H), 7.18–7.13 (m, 1H), 6.86 (s, 1H), 6.27 (s, 1H),
13
2.87 (d, J = 2.2 Hz, 3H); C NMR (CDCl3, 100 MHz) δ: 170.4, 149.7, 136.3, 133.7,
131.6 129.0, 127.4, 122.0, 105.4, 32.3; ESI-HRMS [M + H]+ m/z = 268.9699, calcd
for C10H10BrN2S, 268.9743.
4-(2-Aminothiazol-4-yl)benzonitrile (2u). Yield 42%; White solid, mp
222-224 °C; 1H NMR (DMSO-d6, 400 MHz) δ: 7.96 (d, J = 8.6 Hz, 2H), 7.81 (d, J =
8.6 Hz, 2H), 7.32 (s, 1H), 7.18 (s, 2H); 13C NMR (DMSO-d6, 150 MHz) δ: 169.0,
148.6, 139.4, 133.0, 126.6, 119.5, 109.6, 106.0; ESI-HRMS [M + H]+ m/z = 202.0413,
calcd for C10H8N3S, 202.0433.
4-(2-(Methylamino)thiazol-4-yl)benzonitrile (2v). Yield 41%; White solid, mp
86-88 °C; 1H NMR (CDCl3, 400 MHz) δ: 7.87 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz,
11

ACCEPTED MANUSCRIPT
13
2H), 6.85 (s, 1H), 6.00 (s, 1H), 2.97 (s, 3H); C NMR (CDCl3, 150 MHz) δ: 171.1,
149.8, 139.1, 132.5, 126.5, 119.2, 110.7, 104.0, 32.3; ESI-HRMS [M + H]+ m/z =
216.0565, calcd for C11H10N3S, 216.0590.
4-(4-Nitrophenyl)thiazol-2-amine (2w). Yield 35%; Yellow solid, mp
284-286 °C; 1H NMR (DMSO-d6, 600 MHz) δ: 8.22 (d, J = 8.2 Hz, 2H), 8.03 (d, J =
8.3 Hz, 2H), 7.40 (s, 1H), 7.22 (s, 2H); 13C NMR (DMSO-d6, 150 MHz) δ: 169.1,
148.3, 146.4, 141.3, 126.7, 124.5, 107.1; ESI-HRMS [M + H]+ m/z = 222.0354, calcd
for C9H8N3O2S, 222.0332.
N-Methyl-4-(4-nitrophenyl)thiazol-2-amine (2x). Yield 34%; Yellow solid, mp
189- 190 °C; 1H NMR (DMSO-d6, 400 MHz) δ: 8.24 (d, J = 9.0 Hz, 2H), 8.08 (d, J =
9.0 Hz, 2H), 7.73 (q, J = 4.7 Hz, 1H), 7.46 (s, 1H), 2.90 (d, J = 4.8 Hz, 3H); 13C NMR
(DMSO-d6, 100 MHz) δ: 169.5, 148.1, 146.0, 140.9, 126.4, 124.0, 106.0, 31.0;
ESI-HRMS [M + H]+ m/z = 236.0489, calcd for C10H10N3O2S, 236.0488.
4-(4-Iodophenyl)thiazol-2-amine (2y). Yield 63%; White solid, mp 176-177 °C;
1H NMR (CDCl3, 600 MHz) δ: 7.70 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 6.74
(s, 1H), 5.03 (s, 2H); 13C NMR (CDCl3, 150 MHz) δ: 167.3, 150.4, 137.8, 134.3,
127.9, 103.7, 93.3; ESI-HRMS [M + H]+ m/z = 302.9399, calcd for C9H8IN2S,
302.9447.
4-(4-Iodophenyl)-N-methylthiazol-2-amine (2z). Yield 61%; White solid, mp
1
130-132 °C; H NMR (DMSO-d6, 400 MHz) δ: 7.72 (d, J = 8.5 Hz, 2H), 7.65–7.58
13
(m, 3H), 7.10 (s, 1H), 2.88 (d, J = 4.8 Hz, 3H); C NMR (DMSO-d6, 100 MHz) δ:
169.5, 149.2, 137.3, 134.5, 127.8, 101.8, 93.1, 31.1; ESI-HRMS [M + H]+ m/z =
316.9550, calcd for C10H10IN2S, 316.9604.
4-(3-Bromo-4-methylphenyl)thiazol-2-amine (2aa). Yield 52%; White solid, mp
1
132- 134 °C; H NMR (CDCl3, 400 MHz) δ: 7.96 (d, J = 2.0 Hz, 1H), 7.59 (dd, J =
8.0, 2.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.68 (s, 1H), 5.16 (s, 2H), 2.40 (s, 3H); 13C
NMR (CDCl3, 150 MHz) δ: 167.3, 149.8, 137.2, 134.1, 130.9, 129.8, 125.2, 124.7,
103.1, 22.7; ESI-HRMS [M + H]+ m/z = 268.9705, calcd for C10H10BrN2S, 268.9743.
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ACCEPTED MANUSCRIPT
4-(3-Bromo-4-methylphenyl)-N-methylthiazol-2-amine (2ab). Yield 48%; White
1
solid, mp 126-127 °C; H NMR (CDCl3, 400 MHz) δ: 7.98 (d, J = 1.6 Hz, 1H), 7.60
(dd, J = 8.0, 1.6 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.67 (s, 1H), 6.03 (s, 1H), 2.97 (d,
13
J = 2.8 Hz, 3H), 2.40 (s, 3H); C NMR (CDCl3, 150 MHz) δ: 171.1, 150.2, 137.0,
134.5, 130.8, 129.9, 125.1, 124.8, 101.0, 32.3, 22.7; ESI-HRMS [M + H]+ m/z =
282.9850, calcd for C11H12BrN2S, 282.9899.
5-Methyl-4-phenylthiazol-2-amine (2ac). Yield 57%; White solid, mp
1
117-119 °C; H NMR (CDCl3, 600 MHz) δ: 7.56 (d, J = 7.2 Hz, 2H), 7.40 (t, J = 7.2
13
Hz, 2H), 7.30 (t, J = 7.2 Hz, 1H), 4.83 (s, 2H), 2.40 (s, 3H); C NMR (CDCl3, 150
MHz) δ: 163.6, 146.4, 135.2, 128.5, 128.4, 127.4, 118.1, 12.6; ESI-HRMS [M + H]+
m/z = 191.0644, calcd for C10H11N2S, 191.0637.
N,5-Dimethyl-4-phenylthiazol-2-amine (2ad). Yield 51%; White solid, mp
124-125 °C; 1H NMR (CDCl3, 600 MHz) δ: 7.57 (d, J = 7.4 Hz, 2H), 7.39 (t, J = 7.1
13
Hz, 2H), 7.29 (t, J = 7.2 Hz, 1H), 5.38 (s, 1H), 2.93 (s, 3H), 2.40 (s, 3H); C NMR
(CDCl3, 150 MHz) δ: 167.5, 134.7, 128.6, 128.4, 127.5, 115.4, 32.5, 12.6; ESI-HRMS
[M + H]+ m/z = 205.0792, calcd for C11H13N2S, 205.0794.
4-(8-Bromooctyl)thiazol-2-amine (2ae). Yield 55%; White solid, mp 98-99 °C;
1H NMR (CDCl3, 400 MHz) δ: 6.06 (s, 1H), 5.07 (s, 2H), 3.39 (t, J = 6.8 Hz, 2H),
2.51 (t, J = 7.6 Hz, 2H), 1.87–1.80 (m, 2H), 1.65-1.58 (m, 2H), 1.44–1.31 (m, 8H);13C
NMR (CDCl3, 100 MHz) δ: 167.4, 153.6, 102.2, 34.2, 32.9, 31.8, 29.32, 29.27, 28.9,
28.8, 28.3; ESI-HRMS [M + H]+ m/z = 291.0521, calcd for C11H20BrN2S, 291.0525.
4-(8-Bromooctyl)-N-methylthiazol-2-amine (2af). Yield 52%; White solid, mp
98-100 °C; 1H NMR (CDCl3, 400 MHz) δ: 6.07 (s, 1H), 5.10 (s, 1H), 3.40 (t, J = 6.8
Hz, 2H), 2.93 (d, J = 3.8 Hz, 3H), 2.53 (t, J = 7.6 Hz, 2H), 1.88–1.82 (m, 2H), 1.67–
1.60 (m, 2H), 1.43–1.33 (m, 8H); 13C NMR (CDCl3, 150 MHz) δ: 170.9, 154.2, 100.3,
34.2, 33.0, 32.4, 32.0, 29.37, 29.35, 28.9, 28.8, 28.3; ESI-HRMS [M + H]+ m/z =
305.0705, calcd for C12H22BrN2S, 305.0682.
8H-Indeno[1,2-d]thiazol-2-amine (2ag). Yield 48%; White solid, mp 193-194 °C;
1H NMR (CDCl3, 600 MHz) δ: 7.57 (d, J = 7.5 Hz, 1H), 7.45 (d, J = 7.4 Hz, 1H), 7.33
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(t, J = 7.4 Hz, 1H), 7.19 (t, J = 7.4 Hz, 1H), 5.13 (s, 2H), 3.70 (s, 2H); 13C NMR
(DMSO-d6, 150 MHz) δ: 173.0, 156.0, 145.4, 137.8, 126.6, 124.6, 124.0, 123.2, 117.4,
32.2; ESI-HRMS [M + H]+ m/z = 189.0470, calcd for C10H9N2S, 189.0481.
N-Methyl-8H-indeno[1,2-d]thiazol-2-amine (2ah). Yield 46%; White solid, mp
131-133 °C; 1H NMR (CDCl3, 400 MHz) δ: 7.58 (d, J = 7.4 Hz, 1H), 7.45 (d, J = 7.4
Hz, 1H), 7.33 (t, J = 7.4 Hz, 1H), 7.18 (t, J = 7.4 Hz, 1H), 6.22 (s, 1H), 3.70 (s, 2H),
3.05 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 175.8, 157.2, 145.6, 138.0, 126.9, 124.6,
124.5, 122.9, 118.3, 32.7, 32.1; ESI-HRMS [M+H]+ m/z = 203.0636, calcd for
C11H11N2S, 203.0637.
N-Phenethyl-4-phenylthiazol-2-amine (Fanetizole). Yield 72%; White solid, mp
116-117 °C; 1H NMR (CDCl3, 600 MHz) δ: 7.79 (d, J = 7.8 Hz, 2H), 7.36 (t, J = 7.5
Hz, 2H), 7.27-7.33 (m, 3H), 7.23 (d, J = 6.6 Hz, 1H), 7.20 (d, J = 7.8 Hz, 2H), 6.69 (s,
1H), 5.54 (s, 1H), 3.51–3.56 (m, 2H), 2.94 (t, J = 7.2 Hz, 2H); 13C NMR (CDCl3, 150
MHz) δ: 169.5, 151.6, 138.5, 135.0, 128.8, 128.7, 128.6, 127.7, 126.7, 126.1, 100.8,
47.2, 35.5; ESI-HRMS [M + H]+ m/z = 281.1122, calcd for C17H17N2S, 281.1107.
Conflicts of interest
There are no conflicts to declare.
Acknowledgments
We gratefully acknowledge financial support from the National Natural Science
Foundation of China (81573340), China Postdoctoral Science Foundation
(2017M611463), the ‘‘ZhuoXue” Talent Plan of Fudan University, He’nan Province
Natural Science Foundation (162300410182), the Foundation of He’nan Educational
Committee (17A350008), and the Doctoral Scientific Research Foundation of He’nan
Normal University. Jianglu Zhou is grateful to FDUROP (Fudan’s Undergraduate
Research Opportunities Program, Wangdao Project).
Supporting information
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1H, 13C NMR and 19F NMR spectra for compounds 2a-2ah and Fanetizole.
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