2-Amino-4-arylthiazoles through One-Pot Transformation of Alkylarenes with NBS and Thioureas

Article abstract of DOI:10.1002/ejoc.201900100

Treatment of alkylarenes with N-bromosuccinimide in a mixture of ethyl acetate and water at 60 °C, a mixture of acetonitrile and water at 80 °C, or a mixture of diethyl carbonate and water under irradiation with a tungsten lamp, followed by a reaction with thioureas or arenethioamides provided the corresponding 2-amino- 4-arylthiazoles or 2,4-diarylthiazoles in good to moderate yields, respectively, in one pot. The present reaction is an efficient one-pot transformation method of alkylarenes into 2-amino-4-arylthiazoles and 2,4-diarylthiazoles directly under mild and transition-metal-free conditions.

Full text of DOI:10.1002/ejoc.201900100

DOI: 10.1002/ejoc.201900100
Full Paper
Thiazole Synthesis
2-Amino-4-arylthiazoles through One-Pot Transformation of
Alkylarenes with NBS and Thioureas
Kaho Shibasaki[a] and Hideo Togo*[a]
Abstract: Treatment of alkylarenes with N-bromosuccinimide thiazoles in good to moderate yields, respectively, in one pot.
in a mixture of ethyl acetate and water at 60 °C, a mixture of The present reaction is an efficient one-pot transformation
acetonitrile and water at 80 °C, or a mixture of diethyl carb- method of alkylarenes into 2-amino-4-arylthiazoles and 2,4-
onate and water under irradiation with a tungsten lamp, fol- diarylthiazoles directly under mild and transition-metal-free
lowed by a reaction with thioureas or arenethioamides pro- conditions.
vided the corresponding 2-amino- 4-arylthiazoles or 2,4-diaryl-
Introduction
glyoxalate in the presence of acetyl chloride and NaCN;[2e] the
reaction of α-bromoketones, thioacid potassium salts, and
AcONH4 under toluene refluxing conditions;[2f] the reaction of
α-nitroepoxides and S-alkyl dithiocarbamates;[2g] the reaction
of α-nitroepoxides and ammonium thiocyanate;[2h] the reaction
of styrenes, thioureas, and 1,3-dibromo-5,5-dimethylhydantoin
(DBH);[2i] and the reaction of aromatic aldehydes and cysteine
esters with iodine and tert-butyl hydroperoxide (TBHP).[2j] We
also enumerate recent synthetic studies of thiazoles with transi-
tion metals, as follows:[3] the reaction of terminal alkynes and
MsOH in the presence of Au catalyst, followed by the reaction
with thioamides;[3a] the reaction of terminal alkynes, sulfonyl
azides, and thionoesters in the presence of Cu and Rh cata-
lysts;[3b] the reaction of vinyl azides and KSCN in the presence
of Pd or Fe catalyst;[3c] the reaction of oximes, carboxylic an-
hydrides, and KSCN in the presence of CuI catalyst;[3d] the reac-
tion of aliphatic primary amines, aliphatic aldehydes, and ele-
mental sulfur in the presence of 1,10-phenanthroline and
CuBr2;[3e] and the reaction of enamines and elemental sulfur in
the presence of FeCl3.[3f] Among these reactions, the most use-
ful and practical one is the Hantzsch thiazole synthesis using
α-haloketones and thiourea or thioamides.[4] Previously, we
reported a one-pot preparation of aromatic nitriles from
methylarenes[5a] and primary aromatic amides from ethyl-
arenes,[5b] respectively, by using N-bromosuccinimide (NBS),
molecular iodine, and aq. ammonia. Here, as part of our contin-
uing synthetic studies of nitrogen-containing heterocycles,[6]
we would like to report a novel one-pot transformation of
alkylarenes into 2-amino-4-arylthiazoles and 2,4-diarylthiazoles
by the treatment with NBS, followed by the reaction with thio-
ureas or thioamides under mild and transition-metal-free condi-
tions.
Thiazole is one of the most important heteroaromatic units, as
there are many pharmaceuticals and natural products bearing
a thiazole unit.[1] For example, Fanetizole (an anti-inflammatory
agent), Abafungin (an antifungal agent), Famotidine (a hist-
amine H2 receptor antagonist), and Fentiazac (an anti-inflamma-
tory agent) are typical pharmaceuticals bearing a thiazole unit,
as shown in Figure 1.[1f] Vitamin B1 (thiamine) contains a thi-
azolium unit as an important reaction site.
Figure 1. Examples of pharmaceuticals bearing the thiazole unit.
Therefore, the still extensive synthetic study of thiazoles has
been carried out. Examples of recent synthetic study of thiaz-
oles without transition metals are as follows:[2] thiazoles from
the reaction of acetophenone derivatives and thiourea in the
presence of molecular iodine under microwave irradiation;[2a]
the reaction of α-bromoketones, amines, and trimethylsilyl iso-
thiocyanate;[2b] the reaction of α-boryl-α-bromoaldehydes and
thioamides;[2c] the reaction of ketones and thiourea in the pres-
ence of O2/KI/NH4NO3;[2d] the reaction of thioamides and ethyl
[a] Graduate School of Science, Chiba University,
Yayoi-cho 1-33, Inage-ku, Chiba 263-8522 Japan
E-mail: togo@faculty.chiba-u.jp
Results and Discussion
Based on our previous study,[5b] the transformation of ethyl-
http://reaction-2.chem.chiba-u.jp/index.html
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201900100.
arenes 1 (1.0 mmol), such as ethylbenzene (1a), n-propyl-
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benzene (1j), n-butylbenzene (1k), n-hexylbenzene (1l), phen- Wohl-Ziegler reaction. The key points in using solvents A, B,
ethylbenzene (1m), p-(methoxycarbonyl)ethylbenzene (1b), p- and C are the hydrolysis of α,α-(dibromo)alkylarenes that are
(methoxycarbonyl)-n-propylbenzene (1r), p-(methoxy)ethyl- formed through the dual Wohl-Ziegler reaction of alkylarenes
benzene (1c), and p-(methoxy)-n-propylbenzene (1w) into aryl 1 and the α-bromination of alkyl aryl ketones formed by the
α-bromoalkyl ketones 2 with NBS (3.5 equiv.) and AIBN (10 mol- hydrolysis of α,α-(dibromo)alkylarenes.
%) in a mixture of ethyl acetate and water (A) at 60 °C, a mixture
of acetonitrile and water (B) at 80 °C, and a mixture of diethyl
carbonate and water (C) under irradiation with a tungsten lamp
at 35 °C–40 °C was carried out under the optimized reaction
conditions, as shown in Table 1. Here, the organic solvent was
changed from ethyl acetate to acetonitrile and to diethyl carb-
onate, respectively, depending on the electron density of the
aromatic ring in alkylarenes 1. Treatment of alkylbenzenes (1a,
1j–1m) in a mixture of ethyl acetate and water at 60 °C gave
α-bromoalkyl phenyl ketones (2a, 2j–2m) in good yields, re-
spectively (entries 1–5). For p-(methoxycarbonyl)ethylbenzene
(1b) and p-(methoxycarbonyl)-n-propylbenzene (1r) bearing an
electron-withdrawing group, treatment of them in a mixture of
acetonitrile and water at 80 °C gave α-bromomethyl p-(meth-
oxycarbonyl)phenyl ketone (2b) and α-bromoethyl p-(methoxy-
carbonyl)phenyl ketone (2r) in good yields, respectively (entries
6, 7). On the other hand, treatment of p-(methoxy)ethylbenzene
(1c) and p-(methoxy)-n-propylbenzene (1w) with NBS
(5.0 equiv.) in a mixture of diethyl carbonate and water under
irradiation with a tungsten lamp at 35 °C–40 °C gave α-bromo-
methyl 3-bromo-4-methoxyphenyl ketone (2c) and α-bromo-
ethyl 3-bromo-4-methoxyphenyl ketone (2w) in good yields, re-
spectively (entries 8, 9). Here, the electron-rich p-methoxy-
phenyl group in p-(methoxy)ethylbenzene (1c) and p-(meth-
oxy)-n-propylbenzene (1w) is smoothly brominated prior to the
Based on the optimized reaction conditions for transforma-
tion of alkylarenes 1 into aryl α-bromoalkyl ketones, the succes-
sive treatment of ethylarenes 1, such as ethylbenzene (1a),
p-(methoxycarbonyl)ethylbenzene (1b), and p-(methoxy)-
ethylbenzene (1c), with NBS (3.5 equiv. for 1a and 1b, 5.0 equiv.
for 1c) and AIBN (10 mol-%) in solvents A, B, and C (1st step),
followed by the reaction with thiourea (I, 1.1 equiv.) at room
temperature for 1 h (2nd step) was carried out to generate 2-
amino-4-phenylthiazole (3a-I) in 84 % yield (entry 1), 2-amino-
4-(4′-methoxycarbonylphenyl)thiazole (3b-I) in 53 % yield
(entry 4), and 2-amino-4-(3′-bromo-4′-methoxyphenyl)thiazole
(3c-I) in 73 % yield (entry 7), respectively, as shown in Table 2.
As a gram-scale experiment, when ethylbenzene (1a, 10 mmol)
was used under the same procedure and conditions, 2-amino-
5-phenylthiazole 3a-I was obtained in 82 % yield, as shown in
Scheme 1. On the other hand, the same successive treatment of
the above three ethylarenes (1a–1c) with N-chlorosuccinimide
(NCS) or N-iodosuccinimide (NIS) in solvents A, B, and C, respec-
tively, followed by the reaction with thiourea (I) was carried out.
However, the corresponding 2-amino-5-arylthiazoles were not
obtained at all (entries 2, 3, 5, 6, 8, and 9), and mainly starting
ethylarenes were recovered. An exception was the formation of
4-ethyl-2-iodoanisole from p-(methoxy)ethylbenzene (1c) with
NIS (entry 9), as shown in Table 2. Thus, NBS plays an important
role in the formation of aryl α-bromomethyl ketones from
ethylarenes 1a–1c via the Wohl-Ziegler reaction.
Table 1. Transformation of alkylarenes 1 to aryl α-bromoalkyl ketones 2 with
optimum reaction conditions.
Table 2. Transformation of ethylarenes 1 to 2-amino-4-arylthiazoles 3-I.
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Scheme 1. Transformation of alkylarenes 1 to 2-amino-4-arylthiazoles 3.
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Based on those results, treatment of alkylarenes 1, such as (1u), and 2-ethylbenzothiophene (1v) bearing electron-rich aryl
p-(methyl)ethylbenzene (1d), p-(tert-butyl)ethylbenzene (1e), groups, with NBS (5.0 equiv.) in solvent C under irradiation with
p-(phenyl)ethylbenzene (1f), 4-bromo-1-ethylnaphthalene (1g), a tungsten lamp (300 W) at 35 °C–40 °C (1st step) for 10 h,
followed by the reaction with thiourea (I, 1.1 equiv.) at room
temperature for 1 h (2nd step), gave 2-amino-4-(3′-bromo-4′-
isopropoxyphenyl)thiazole 3s-I, 2-amino-4-(5′-bromo-2′-meth-
oxyphenyl)thiazole 3t-I, 2-amino-4-(3′-bromo-4′-methoxy-
phenyl)-5-methylthiazole 3u-I, and 2-amino-4-(3′-bromoben-
zothiophen-2′-yl)thiazole 3v-I in good to moderate yields, re-
spectively, as shown in Scheme 1. Under the present irradiation
conditions at 35 °C–40 °C, the aromatic rings of those alkyl-
arenes (1s–1v) were smoothly brominated by NBS via an ionic
pathway at the 1st reaction step.
p-(bromo)ethylbenzene (1h), p-(iodo)ethylbenzene (1i), n-
propylbenzene (1j), n-butylbenzene (1k), n-hexylbenzene (1l),
and phenethylbenzene (1m), with NBS (3.5 equiv.) and AIBN
(10 mol-%) in solvent A at 60 °C (1st step), followed by the
reaction with thiourea (I, 1.1 equiv.) at room temperature for
1 h (2nd step) provided 2-amino-4-arylthiazoles 3d-I–3m-I in
good yields, respectively, as shown in Scheme 1. In contrast,
when p-(methoxycarbonyl)ethylbenzene (1b) and p-(meth-
oxy)ethylbenzene (1c) were treated in solvent A under the
same procedure and conditions, 2-amino-4-(4′-methoxy-
carbonyl)phenylthiazole 3b-I and 2-amino-4-(3′-bromo-4′-
methoxyphenyl)thiazole 3c-I were obtained in very low yields,
respectively. For the reactions with other thioureas and thio-
amides instead of thiourea (I), treatment of ethylbenzene (1a)
with NBS (3.5 equiv.) and AIBN (10 mol-%) in solvent A at 60 °C
(1st step), followed by the reactions with thioureas or thio-
amides, such as N-methylthiourea (II), N-phenethylthiourea (III),
thioacetamide (IV), thiobenzamide (V), p-methylthiobenzamide
(VI), p-methoxythiobenzamide (VII), and p-chlorothiobenz-
amide (VIII), at room temperature for 1 h (2nd step) gave 2-(N-
methyl)amino-4-phenylthiazole (3a-II), 2-(N-phenethyl)amino-4-
phenylthiaozle (3a-III), 2-methyl-4-phenylthiazole (3a-IV), 2,4-
diphenylthiazole (3a-V), 2-(4′-methylphenyl)-4-phenylthiazole
(3a-VI), 2-(4′-methoxyphenyl)-4-phenylthiazole (3a-VII), and 2-
(4′-chlorophenyl)-4-phenylthiazole (3a-VIII) in good yields, re-
spectively, as shown in Scheme 1. Here, 2-(N-phenethylamino)-
4-phenylthiaozle 3a-III, i.e., Fanetizole in Figure 1, was obtained
from ethylbenzene in 85 % yield.
Possible reaction pathway for the transformation of alkyl-
arenes 1 into 2-amino-4-arylthiazoles 3-I is shown in Scheme 2.
Ethylarene 1 reacts with bromine atom to form α-bromoethylar-
ene I-1 through the Wohl-Ziegler reaction. α-Bromoethylarene
I-1 reacts again with bromine atom to form α,α-dibromoethyl-
arene I-2 which undergoes further hydrolysis to generate aryl
methyl ketone I-3 and HBr. Aryl methyl ketone I-3 reacts with
NBS in acidic conditions smoothly to form aryl α-bromomethyl
ketone 2. Once aryl α-bromomethyl ketone 2 is formed, it
smoothly reacts with thiourea I to form 2-amino-4-arylthiazole
3-I. Practically, treatment of α,α-dibromoethylarene I-2a with
NBS (1.5 equiv.) and AIBN (10 mol-%), and of aryl methyl ketone
I-3a with NBS (1.5 equiv.), AIBN (10 mol-%), and aq. HBr (50 %,
2.0 equiv.) in a mixture of ethyl acetate and water (7:1, solvent
A) for 4 h at 60 °C, followed by the reaction with thiourea (I,
1.1 equiv.) at room temperature for 1 h gave 2-amino-4-phenyl-
thiazole 3a-I in 77 % and 78 % yields, respectively, as shown in
Scheme 3 (Equation 1 and Equation 2). Treatment of α-phenyl-
ethanol I-1a′ with NBS (2.5 equiv.) and AIBN (10 mol-%) in the
presence of aq. HBr (50 %, 1.0 equiv.) in a mixture of ethyl acet-
ate and water (7:1, solvent A) for 4 h at 60 °C, followed by the
reaction with thiourea (I, 1.1 equiv.) at room temperature for
1 h also gave 2-amino-4-phenylthiazole 3a-I in 75 % yield
(Equation 3). Therefore, the formation of α-arylethanol I-1′ by
the hydrolysis of α-bromoethylarene I-1 and its oxidation to
Then, treatment of p-(p-methoxycarbonylphenyl)ethyl-
benzene (1b), p-(cyano)ethylbenzene (1n), p-(nitro)ethylbenz-
ene (1o), o-(methanesulfonyloxy)ethylbenzene (1p), p-(meth-
anesulfonyl)ethylbenzene (1q), and p-(methoxycarbonyl)-n-
propylbenzene (1r) bearing electron-withdrawing groups, with
NBS (3.5 equiv.) and AIBN (10 mol-%) in solvent B at 80 °C (1st
step), followed by the reaction with thiourea (I, 1.1 equiv.) at
room temperature for 1 h (2nd step), gave 2-amino-4-arylthiaz-
oles (3b-I, 3n-I, 3o-I, 3p-I, 3q-I, and 3r-I) in good to moderate
yields, respectively, as shown in Scheme 1. The yield of 3b-I
was slightly improved to 63 % by treatment of the reaction mix-
ture with TMSCl (1 mL) and MeOH (5 mL) at 70 °C for 3 h
after the 1st reaction step, which converted partly hydrolyzed
carboxylic acid into the methyl ester. For the formation of 3n-I
and 3o-I, NBS (1.1 equiv.) and aq. HBr (50 %, 1 mL) were added
to the reaction mixture to promote the formation of aryl α-
bromomethyl ketones from the formed aryl methyl ketones
after the 1st reaction step. When ethylbenzene (1a) and p-
(methoxy)ethylbenzene (1c) were treated in solvent B at 60 °C
under the same procedure and conditions, 2-amino-4-phenyl-
thiazole 3a-I and 2-amino-4-(3′-bromo-4′-methoxyphenyl)thia-
zole 3c-I were obtained in 72 % and 25 % yields, which were
lower than those obtained in solvent A and solvent C, respec-
tively.
Finally, the reactions of p-(isopropoxy)ethylbenzene (1s), o-
(methoxy)ethylbenzene (1t), p-(methoxy)-n-propylbenzene
Scheme 2. Possible reaction pathway.
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temperature, thiourea (1.1 mmol, 85.4 mg) was added to the reac-
tion mixture, and the obtained mixture was stirred for 1 h at room
temperature. The mixture was quenched by adding sat. aq. NaHCO3
(10 mL), and extracted with AcOEt (20 mL × 3). Then, the organic
layer was dried with Na2SO4. After removal of the solvent under
reduced pressure, the residue was purified by short column chro-
matography on silica gel (hexane/AcOEt = 2:1) to afford 2-amino-4-
phenylthiazole 3a-I in 84 % yield (148.0 mg).
aryl methyl ketone I-3 by bromine atom may also partly partici-
pate.
Procedure B: To a solution of p-(methoxycarbonyl)ethylbenzene 1b
(1.0 mmol, 167.6 mg) in CH3CN/water (3:1, 10.0 mL) were added
NBS (3.5 mmol, 635.6 mg) and AIBN (0.1 mmol, 16.8 mg) at room
temperature, and the mixture was stirred for 12 h at 80 °C. After
cooling to room temperature, thiourea (1.1 mmol, 85.4 mg) was
added to the reaction mixture, and the obtained mixture was stirred
for 1 h at room temperature. The mixture was quenched by adding
sat. aq. NaHCO3 (10 mL), and extracted with CHCl3 (20 mL × 3).
Then, the organic layer was dried with Na2SO4. After removal of the
solvent under reduced pressure, the residue was purified by short
column chromatography on silica gel (hexane/AcOEt = 2:1) to afford
2-amino-4-(4′-methoxycarbonylphenyl)thiazole 3b-I in 53 % yield
(124.2 mg).
Scheme 3. Control experiments.
Procedure C: To
a solution of p-(methoxy)ethylbenzene 1c
(1.0 mmol, 139.7 mg) in diethyl carbonate/water (4:1, 3.0 mL) was
added NBS (5.0 mmol, 908.0 mg) at room temperature, and the
mixture was stirred under irradiation with a tungsten lamp for 10 h
at room temperature. Thiourea (1.1 mmol, 85.4 mg) was added to
the reaction mixture, and the obtained mixture was stirred for 1 h
at room temperature. The mixture was quenched by adding sat. aq.
NaHCO3 (10 mL), and extracted with CHCl3 (20 mL × 3). Then, the
organic layer was dried with Na2SO4. After removal of the solvent
under reduced pressure, the residue was purified by short column
chromatography on silica gel (hexane/AcOEt = 2:1) to afford 2-
amino-4-(3′-bromo-4′-methoxyphenyl)thiazole 3c-I in 73 % yield
(208.2 mg).
Conclusions
A one-pot transformation of alkylarenes with NBS in a mixture
of ethyl acetate, acetonitrile, or diethyl carbonate with water,
depending on the substituent of the aromatic ring, followed by
the reaction with thioureas and arenethioamides proceeded
with ease to give 2-amino-4-arylthiazoles and 2,4-diarylthi-
azoles in good to moderate yields, respectively. The present
method would be useful for the preparation of 2-substituted 4-
arylthiazoles from alkylarenes as the reactions could be carried
out with easily available substrates and reagents under transi-
tion-metal-free conditions.
2-Amino-4-phenylthiazole (3a-I): Yield: 148.0 mg (84 %); white
solid; mp: 147–148 °C; IR(neat): 3436, 3254, 3114, 1598, 1518 cm–1
;
1H-NMR (400 MHz, CDCl3): δ = 5.17 (br, 2H), 6.72 (s, 1H), 7.29 (t, 1H,
J = 7.5 Hz), 7.38 (t, 2H, J = 7.3 Hz), 7.77 (d, 2H, J = 7.0 Hz); 13C-NMR
(100 MHz, CDCl3): δ = 102.8, 126.0, 127.7, 128.6, 134.6, 151.3, 167.5;
HRMS (APCI): Calcd for C9H9N2S [M + H]+ = 177.0481, Found =
177.0480.
Experimental Section
1
General: H NMR spectra were measured on 400 MHz spectrome-
2-Amino-4-(4′-methoxycarbonylphenyl)thiazole (3b-I): Yield:
ters. Chemical shifts were recorded as follows: chemical shift in ppm
from internal tetramethylsilane on the δ scale, multiplicity (s = sin-
glet; d = doublet; t = triplet; q = quartet; sext = sextet; m = multi-
plet; br = broad), coupling constant (Hz), integration, and assign-
ment. 13C NMR spectra were measured on 100 MHz spectrometers.
Chemical shifts were recorded in ppm from the solvent resonance
employed as the internal standard (CDCl3 at 77.0 ppm, or [D6]DMSO
at 39.5 ppm). Characteristic peaks in the infrared (IR) spectra were
recorded in wave number, cm–1. High-resolution mass spectra
(HRMS) were recorded by Thermo Fisher Scientific Exactive Orbitrap
mass spectrometers. Melting points were uncorrected. Thin-layer
chromatography (TLC) was performed using 0.25 mm silica gel
plates (60F254). The products were purified by column chromatog-
raphy on neutral silica gel 60N (63–200 mesh).
124.2 mg (53 %); white solid; mp: 196–197 °C; IR(neat): 3407, 3314,
3153, 1695, 1606, 1546, 1281, 1110 cm–1 1H-NMR (400 MHz,
;
[D6]DMSO): δ = 3.84 (s, 3H), 7.16 (br, 2H), 7.24 (s, 1H), 7.91 (d, 2H,
J = 8.8 Hz), 7.94 (d, 2H, J = 8.8 Hz); 13C-NMR (100 MHz, [D6]DMSO):
δ = 52.1, 104.5, 125.6, 127.9, 129.6, 139.1, 148.7, 166.1, 168.4; HRMS
(APCI): Calcd for C11H11O2N2S [M + H]+ = 235.0536, Found =
235.0531.
2-Amino-4-(3′-bromo-4′-methoxyphenyl)thiazole (3c-I): Yield:
208.2 mg (73 %); pale orange solid; mp: 181–182 °C; IR(neat): 3422,
1
3230, 3112, 2858, 1639, 1478 cm–1; H-NMR (400 MHz, [D6]DMSO):
δ = 3.84 (s, 3H), 6.96 (s, 1H), 7.06 (br, 2H), 7.09 (d, 1H, J = 8.8 Hz),
7.75 (dd, 1H, J = 8.6, 2.0 Hz), 7.99 (d, 1H, J = 2.0 Hz); 13C-NMR
(100 MHz, [D6]DMSO): δ = 56.2, 100.7, 110.7, 112.6, 126.0, 129.2,
130.0, 148.1, 154.5, 168.3; HRMS (APCI): Calcd for C10H10ON2BrS [M
+ H]+ = 284.9692, Found = 284.9691.
Typical Procedures for Direct Transformation of Alkylarenes 1
into 2-Amino-4-arylthiazoles 3
Procedure A: To a solution of ethylbenzene 1a (1.0 mmol,
106.2 mg) in AcOEt/water (7:1, 6.0 mL) were added NBS (3.5 mmol,
635.6 mg) and AIBN (0.1 mmol, 16.8 mg) at room temperature, and
the mixture was stirred for 4 h at 60 °C. After cooling to room
2-Amino-4-(4′-methylphenyl)thiazole (3d-I): Yield: 138.9 mg
(73 %); white solid; mp: 130–131 °C; IR(neat): 3454, 3219, 3117, 1636,
1522 cm–1; 1H-NMR (400 MHz, CDCl3): δ = 2.36 (s, 3H), 5.02 (br, 2H),
6.67 (s, 1H), 7.18 (d, 2H, J = 7.9 Hz), 7.66 (d, 2H, J = 8.1 Hz);
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13C-NMR (100 MHz, CDCl3): δ = 21.2, 101.9, 125.8, 129.2, 131.9, J = 7.5 Hz), 7.47 (d, 2H, J = 7.0 Hz); 13C-NMR (100 MHz, [D6]DMSO):
137.5, 151.2, 167.5; HRMS (ESI): Calcd for C10H11N2S [M + H]+
191.0637, Found = 191.0636.
=
δ = 13.6, 21.8, 26.2, 33.8, 121.2, 126.9, 128.1 (2C), 135.7, 144.9, 164.8;
HRMS (APCI): Calcd for C13H17N2S [M + H]+ = 233.1107, Found =
233.1102.
2-Amino-4-(4′-tert-butylphenyl)thiazole (3e-I): Yield: 178.9 mg
(77 %); pale yellow solid; mp: 134–135 °C; IR(neat):3442, 3274, 3114,
2-Amino-4,5-diphenylthiazole (3m-I): Yield: 154.3 mg (61 %);
1
1604, 1519, 1268 cm–1; H-NMR (400 MHz, CDCl3): δ = 1.33 (s, 9H),
white solid; mp: 181–182 °C; IR(neat): 3423, 3276, 3051, 1631,
5.03 (br, 2H), 6.68 (s, 1H), 7.40 (d, 2H, J = 8.6 Hz), 7.70 (d, 2H, J =
8.6 Hz); 13C-NMR (100 MHz, CDCl3): δ = 31.2, 34.5, 101.9, 125.5,
125.7, 131.9, 150.7, 151.2, 167.6; HRMS (ESI): Calcd for C13H17N2S
[M + H]+ = 233.1107, Found = 233.1105.
1527 cm–1 1H-NMR (400 MHz, [D6]DMSO): δ = 7.14 (br, 2H), 7.18–
;
7.30 (m, 8H), 7.35–7.37 (m, 2H); 13C-NMR (100 MHz, [D6]DMSO): δ =
119.1, 127.1, 127.3, 128.1, 128.5, 128.7, 129.0, 132.8, 135.4, 144.9,
166.2; HRMS (APCI): Calcd for C15H13N2S [M + H]+ = 253.0794,
Found = 253.0791.
2-Amino-4-(biphenyl-4′-yl)thiazole (3f-I): Yield: 211.9 mg (84 %);
white solid; mp: 200–201 °C; IR(neat): 3437, 3287, 3106, 1629,
2-(N-Methylamino)-4-phenylthiazole (3a-II): Yield: 98.6 mg (83 %);
1
1523 cm–1; H-NMR (400 MHz, [D6]DMSO): δ = 7.06 (s, 1H), 7.08 (br,
pale yellow solid; mp: 134–135 °C; IR (neat): ν = 3106, 3057, 1498,
˜
1
2H), 7.35 (t, 1H, J = 7.3 Hz), 7.45 (t, 2H, J = 7.3 Hz), 7.65–7.70 (m,
1170 cm–1; H-NMR (400 MHz, CDCl3): δ = 2.92 (d, 3H, J = 3.9 Hz),
4H), 7.87 (d, 2H, J = 8.4 Hz); 13C-NMR (100 MHz, [D6]DMSO): δ = 6.43 (br, 1H), 6.69 (s, 1H), 7.28 (t, 1H, J = 7.3 Hz), 7.38 (t, 2H, J =
101.8, 126.1, 126.4, 126.7, 127.4, 129.0, 134.0, 138.7, 139.7, 149.5, 7.3 Hz), 7.79 (d, 2H, J = 7.0 Hz); 13C-NMR (100 MHz, CDCl3): δ = 32.2,
168.3; HRMS (ESI): Calcd for C15H13N2S [M + H]+ = 253.0794, Found =
253.0791.
100.6, 126.1, 127.6, 128.5, 135.1, 151.7, 171.3; HRMS (ESI): Calcd for
C
10H11N2S [M + H]+ = 191.0637, Found = 191.0636.
2-Amino-4-(4′-bromonaphthalen-1′-yl)thiazole (3g-I): Yield:
2-(N-Phenethylamino)-4-phenylthiazole (3a-III): Yield: 238.3 mg
185.7 mg (61 %); gray solid; mp: 182–183 °C; IR(neat): 3460, 3275,
(85 %); white solid; mp: 111–112 °C; IR (neat): ν = 3192, 3061, 2925,
˜
1
3065, 1636, 1500 cm–1; H-NMR (400 MHz, [D6]DMSO): δ = 6.82 (s, 1584, 1482 cm–1
;
1H-NMR (400 MHz, CDCl3): δ = 2.91 (t, 2H, J =
1H), 7.16 (br, 2H), 7.53 (d, 1H, J = 7.9 Hz), 7.61 (t, 1H, J = 7.0 Hz),
7.69 (t, 1H, J = 6.8 Hz), 7.88 (d, 1H, J = 7.7 Hz), 8.18 (d, 1H, J =
8.4 Hz), 8.50 (d, 1H, J = 8.4 Hz); 13C-NMR (100 MHz, [D6]DMSO): δ =
7.0 Hz), 3.51 (q, 2H, J = 6.8 Hz), 5.76 (br, 1H), 6.68 (s, 1H), 7.16–7.39
(m, 8H), 7.79 (d, 2H, J = 7.3 Hz); 13C-NMR (100 MHz, CDCl3): δ =
35.4, 47.2, 100.7, 126.0, 126.6, 127.6, 128.5, 128.6, 128.7, 135.0, 138.4,
105.8, 121.6, 126.6, 126.9, 127.1, 127.2, 127.7, 129.7, 131.3, 132.0, 151.5, 169.5; HRMS (ESI): Calcd for C17H17N2S [M + H]+ = 281.1107,
133.9, 149.1, 168.3; HRMS (APCI): Calcd for C13H10N2BrS [M + H]+ = Found = 281.1103.
304.9743, Found = 304.9741.
2-Methyl-4-phenylthiazole (3a-IV): Yield: 150.7 mg (86 %); white
2-Amino-4-(4′-bromophenyl)thiazole (3h-I): Yield: 201.6 mg
(79 %); white solid; mp: 178–179 °C; IR(neat): 3439, 3274, 3111, 1633,
1533 cm–1; 1H-NMR (400 MHz, CDCl3): δ = 4.98 (br, 2H), 6.74 (s, 1H),
7.50 (d, 2H, J = 8.6 Hz ), 7.65 (d, 2H, J = 8.4 Hz); 13C-NMR (100 MHz,
[D6]DMSO): δ = 102.4, 120.1, 127.6, 131.4, 134.1, 148.6, 168.4; HRMS
solid; mp: 68–69 °C; IR (neat): ν = 3106, 2924, 1497, 1440, 1169,
˜
740 cm–1 1H-NMR (400 MHz, CDCl3): δ = 2.75 (s, 3H), 7.28 (s, 1H),
;
7.31 (t, 1H, J = 7.3 Hz), 7.40 (t, 2H, J = 7.3 Hz), 7.87 (d, 2H, J =
7.0 Hz); 13C-NMR (100 MHz, CDCl3): δ = 19.3, 112.2, 126.2, 127.9,
128.6, 134.5, 155.1, 165.8; HRMS (ESI): Calcd for C10H10NS [M + H]+ =
(APCI): Calcd for C9H8N2BrS [M + H]+ = 254.9586, Found = 254.9585. 176.0528, Found = 176.0528.
2-Amino-4-(4′-iodophenyl)thiazole (3i-I): Yield: 226.5 mg (75 %);
2,4-Diphenylthiazole (3a-V): Yield: 201.7 mg (85 %); pale orange
1
white solid; mp: 176–177 °C; IR(neat): 3422, 3275, 3109, 1631,
solid; mp: 70–71 °C; IR (neat): ν = 3061, 1598, 1476, 759 cm–1; H-
˜
1
1532 cm–1; H-NMR (400 MHz, [D6]DMSO): δ = 7.07 (s, 1H), 7.08 (br,
NMR (400 MHz, CDCl3): δ = 7.28 –7.41 (m, 7H), 7.94–8.01 (m, 4H);
2H), 7.58 (d, 2H, J = 8.5 Hz), 7.70 (d, 2H, J = 8.5 Hz); 13C-NMR
13C-NMR (100 MHz, CDCl3): δ = 112.5, 126.3, 126.4, 128.0, 128.6,
(100 MHz, [D6]DMSO): δ = 93.0, 102.4, 127.7, 134.4, 137.2, 148.8, 128.7, 129.9, 133.6, 134.3, 156.1, 167.6; HRMS (ESI): Calcd for
168.3; HRMS (APCI): Calcd for C9H8N2IS [M + H]+ = 302.9447,
Found = 302.9445.
C15H12NS [M + H]+ = 238.0685, Found = 238.0684.
4-Phenyl-2-(4′-methylphenyl)thiazole (3a-VI): Yield: 226.2 mg
2-Amino-5-methyl-4-phenylthiazole (3j-I): Yield: 142.7 mg (75 %);
(90 %); white solid; mp: 121–122 °C; IR (neat): ν = 3116, 1612, 1477,
˜
pale yellow solid; mp: 112–113 °C; IR(neat): 3418, 3276, 3063, 2923, 739 cm–1
;
1H-NMR (400 MHz, CDCl3): δ = 2.41 (s, 3H), 7.27 (d, 2H,
1633, 1530 cm–1 1H-NMR (400 MHz, CDCl3): δ = 2.40 (s, 3H), 4.91 J = 6.6 Hz), 7.35 (t, 1H, J = 7.3 Hz), 7.43 (s, 1H), 7.45 (d, 2H, J =
;
(br, 2H), 7.30 (t, 1H, J = 7.3 Hz), 7.40 (t, 2H, J = 7.3 Hz), 7.56 (d, 2H,
J = 7.0 Hz); 13C-NMR (100 MHz, CDCl3): δ = 12.3, 117.3, 127.1, 128.2,
128.3, 135.1, 146.0, 164.1; HRMS (ESI): Calcd for C10H11N2S [M +
H]+ = 191.0637, Found = 191.0637.
8.4 Hz), 7.94 (d, 2H, J = 8.2 Hz), 8.00 (d, 2H, J = 7.0 Hz); 13C-NMR
(100 MHz, CDCl3): δ = 21.4, 112.1, 126.4, 126.5, 128.1, 128.7, 129.6,
131.1, 134.6, 140.2, 156.1, 168.0; HRMS (ESI): Calcd for C16H14NS
[M + H]+ = 252.0841, Found = 252.0840.
2-Amino-5-ethyl-4-phenylthiazole (3k-I): Yield: 143.1 mg (70 %);
2-(4′-Methoxyphenyl)-4-phenylthiazole (3a-VII): Yield: 248.6 mg
pale yellow solid; mp: 68–69 °C; IR(neat): 3446, 3279, 3116, 2965,
(93 %); white solid; mp: 97–98 °C; IR (neat): ν = 3109, 3057, 2838,
˜
1
1602, 1528 cm–1
;
1H-NMR (400 MHz, CDCl3): δ = 1.26 (t, 3H, J =
1605, 1519, 1172 cm–1; H-NMR (400 MHz, CDCl3): δ = 3.88 (s, 3H),
7.5 Hz), 2.81 (q, 2H, J = 7.5 Hz), 4.88 (br, 2H), 7.30 (t, 1H, J = 7.3 Hz),
7.39 (t, 2H, J = 7.3 Hz), 7.52 (d, 2H, J = 7.0 Hz); 13C-NMR (100 MHz,
CDCl3): δ = 16.7, 20.5, 125.5, 127.1, 128.1, 128.3, 135.3, 145.1, 164.6;
HRMS (ESI): Calcd for C11H13N2S [M + H]+ = 205.0794, Found =
205.0791.
6.98 (d, 2H, J = 9.0 Hz), 7.35 (t, 1H, J = 7.4 Hz), 7.41 (s, 1H), 7.45 (t,
2H, J = 7.2 Hz), 7.97–8.00 (m, 4H); 13C-NMR (100 MHz, CDCl3): δ =
55.4, 111.7, 114.2, 126.4, 126.7, 128.1 (2C), 128.7, 134.6, 156.0, 161.1,
167.7; HRMS (ESI): Calcd for C16H14ONS [M + H]+ = 268.0791,
Found = 268.0787.
2-Amino-5-butyl-4-phenylthiazole (3l-I): Yield: 132.3 mg (57 %);
pale orange solid; mp: 61–62 °C; IR(neat): 3418, 3255, 3080, 2930,
1627, 1540 cm–1; 1H-NMR (400 MHz, [D6]DMSO): δ = 0.83 (t, 3H, J =
7.5 Hz), 1.30 (sext, 2H, J = 7.3 Hz), 1.51 (quin, 2H, J = 7.9 Hz), 2.69
(t, 2H, J = 7.3 Hz), 6.78 (br, 2H), 7.27 (t, 1H, J = 7.3 Hz), 7.37 (t, 2H,
2-(4′-Chlorophenyl)-4-phenylthiazole (3a-VIII): Yield: 220.1 mg
(81 %); white solid; mp: 101–102 °C; IR (neat): ν = 3117, 3066, 1593,
˜
1501, 739 cm–1
;
1H-NMR (400 MHz, CDCl3): δ = 7.36 (t, 1H, J =
7.4 Hz), 7.42–7.47 (m, 4H), 7.49 (s, 1H), 7.99 (d, 4H, J = 8.8 Hz); 13C-
NMR (100 MHz, CDCl3): δ = 112.8, 126.4, 127.8, 128.3, 128.8, 129.1,
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132.2, 134.3, 135.9, 156.5, 166.5; HRMS (ESI): Calcd for C15H11NClS
[M + H]+ = 272.0295, Found = 272.0294.
13C-NMR (100 MHz, [D6]DMSO): δ = 12.1, 56.1, 110.3, 112.2, 114.2,
128.1, 129.5, 132.2, 143.0, 154.1, 164.3; HRMS (ESI): Calcd for
C11H12ON2BrS [M + H]+ = 298.9848, Found = 298.9848.
2-Amino-4-(4′-cyanophenyl)thiazole (3n-I): Yield: 127.8 mg
2-Amino-4-(3′-bromobenzo[b]thien-2′-yl)thiazole (3v-I): Yield:
(64 %); pale orange solid; mp: 154–155 °C; IR(neat): 3379, 3299,
3126, 2228, 1645, 1540 cm–1 1H-NMR (400 MHz, [D6]DMSO): δ =
;
159.7 mg (51 %); pale yellow solid; mp: 223–224 °C; IR(neat): 3452,
3290, 3158, 3125, 1626, 1516, 1318, 1013, 752 cm–1 1H-NMR
;
7.18 (br, 2H), 7.32 (s, 1H), 7.81 (d, 2H, J = 8.6 Hz), 7.96 (d, 2H, J =
8.6 Hz); 13C-NMR (100 MHz, [D6]DMSO): δ = 105.5, 109.2, 119.1,
126.1, 132.6, 138.9, 148.0, 168.6; HRMS (ESI): Calcd for C10H8N3S [M
+ H]+ = 202.0433, Found = 202.0432.
(400 MHz, [D6]DMSO): δ = 7.33 (br, 2H), 7.43 (t, 1H, J = 7.0 Hz), 7.49
(t, 1H, J = 7.0 Hz), 7.54 (s, 1H), 7.74 (d, 1H, J = 7.5 Hz), 7.96 (d, 1H,
J = 7.7 Hz); 13C-NMR (100 MHz, [D6]DMSO): δ = 102.0, 105.7, 122.5,
122.7, 125.5, 125.7, 134.1, 136.5, 138.7, 142.0, 167.6; HRMS (ESI):
Calcd for C11H8N2BrS2 [M + H]+ = 310.9307, Found = 310.9305.
2-Amino-4-(4′-nitrophenyl)thiazole (3o-I): Yield: 145.2 mg (66 %);
white solid; mp: 127–128 °C; IR(neat): 3151, 3116, 1541, 1507,
1
1372 cm–1; H-NMR (400 MHz, [D6]DMSO): δ = 7.23 (br, 2H), 7.41 (s,
Supporting Information (see footnote on the first page of this
1
article): Copies of the H NMR and 13C NMR spectra of all thiazoles
1H), 8.03 (d, 2H, J = 9.1 Hz), 8.22 (d, 2H, J = 8.8 Hz); 13C-NMR
(100 MHz, [D6]DMSO): δ = 106.7, 124.0, 126.3, 140.9, 145.9, 147.9,
168.7; HRMS (ESI): Calcd for C9H8O2N3S [M + H]+ = 222.0332,
Found = 222.0331.
3a-I–3v-I and 3a-II–3a-VIII.
Acknowledgments
2-Amino-4-[2′-(methanesulfonyloxy)phenyl]thiazole
(3p-I):
Financial support from the Ministry of Education, Culture,
Sports, Science, and Technology in Japan in the form of a Grant-
in-Aid for Scientific Research (No. 15K05418) is acknowledged.
Yield: 195.7 mg (72 %); white solid; mp: 109–110 °C; IR(neat): 3401,
3276, 3124, 1631, 1523, 1356, 1155 cm–1; 1H-NMR (400 MHz,CDCl3):
δ = 2.91 (s, 3H), 5.16 (br, 2H), 7.05 (s, 1H), 7.35–7.39 (m, 2H), 7.47–
7.49 (m, 1H), 7.92–7.95 (m, 1H); 13C-NMR (100 MHz, [D6]DMSO): δ =
38.6, 106.5, 122.8, 127.3, 128.3, 128.5, 130.5, 144.5, 145.9, 167.5;
HRMS (APCI): Calcd for C10H11O3N2S2 [M + H]+ = 271.0206, Found =
271.0204.
Keywords: Heterocycles · Thiazoles · Cyclization · One-pot
reactions · Synthetic methods
2-Amino-4-(4′-methanesulfonylphenyl)thiazole (3q-I): Yield:
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(Eds.: A. R. Katritzky, C. W. Rees, E. F. V. Scriven), Pergamon Press: Oxford,
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G. J. Mena-Rejón, Tetrahedron Lett. 2012, 53, 3934–3936; b) V. Golubev,
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172.9 mg (68 %); white solid; mp: 246–247 °C; IR(neat): 3420, 3235,
1
3130, 1592, 1540, 1293, 1145 cm–1; H-NMR (400 MHz, [D6]DMSO):
δ = 3.21 (s, 3H), 7.19 (br, 2H), 7.30 (s, 1H), 7.89 (d, 2H, J = 8.5 Hz),
8.03 (d, 2H, J = 8.5 Hz); 13C-NMR (100 MHz, [D6]DMSO): δ = 43.6,
105.2, 126.1, 127.4, 138.8, 139.4, 148.2, 168.6; HRMS (APCI): Calcd
for C10H11O2N2S2 [M + H]+ = 255.0256, Found = 255.0251.
2-Amino-4-(4′-methoxycarbonylphenyl)-5-methylthiazole (3r-I):
Yield: 171.3 mg (69 %); pale yellow solid; mp: 175–176 °C; IR(neat):
1
3412, 3292, 3131, 1604, 1537, 1281, 1101 cm–1; H-NMR (400 MHz,
[D6]DMSO): δ = 2.36 (s, 3H), 3.84 (s, 3H), 6.87 (br, 2H), 7.71 (d, 2H,
J = 8.5 Hz), 7.96 (d, 2H, J = 8.7 Hz); 13C-NMR (100 MHz, [D6]DMSO):
δ = 12.3, 52.1, 117.4, 127.4, 127.9, 129.2, 140.0, 143.8, 164.5, 166.1;
HRMS (APCI): Calcd for C12H13O2N2S [M + H]+ = 249.0692, Found =
249.0688.
2-Amino-4-(3′-bromo-4′-isopropoxyphenyl)thiazole (3s-I): Yield:
166.0 mg (53 %); white solid; mp: 163–164 °C; IR(neat): 3417, 3307,
3163, 2924, 1636, 1535 1272 cm–1 1H-NMR (400 MHz,CDCl3): δ =
;
1.39 (d, 6H, J = 6.1 Hz), 4.58 (sep, 1H, J = 6.1 Hz), 4.96 (br, 2H), 6.61
(s, 1H), 6.91 (d, 1H, J = 8.8 Hz), 7.65 (dd, 1H, J = 8.5, 2.2 Hz), 7.97 (d,
1H, J = 2.2 Hz); 13C-NMR (100 MHz, [D6]DMSO): δ = 21.8, 71.3, 100.6,
112.4, 115.4, 125.9, 129.2, 130.1, 148.1, 152.9, 168.2; HRMS (APCI):
Calcd for C12H14ON2BrS [M + H]+ = 313.0005, Found = 313.0004.
2-Amino-4-(5′-bromo-2′-methoxyphenyl)thiazole (3t-I): Yield:
211.6 mg (74 %); white solid; mp: 146–147 °C; IR(neat): 3328, 3162,
2925, 2844, 1633, 1525, 1241 cm–1 1H-NMR (400 MHz,CDCl3): δ =
;
3.91 (s, 3H), 4.95 (s, 2H), 6.83 (d, 1H, J = 8.8 Hz), 7.24 (s, 1H), 7.33
(dd, 1H, J = 8.8, 2.7 Hz), 8.22 (sd, 1H, J = 2.7 Hz); 13C-NMR (100 MHz,
[D6]DMSO): δ = 55.8, 107.2, 111.9, 113.8, 125.0, 130.1, 131.3, 144.1,
155.7, 166.5; HRMS (APCI): Calcd for C10H10ON2BrS [M + H]+
284.9692, Found = 284.9691.
=
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Lett. 2016, 18, 784–787.
2-Amino-4-(3′-bromo-4′-methoxyphenyl)-5-methylthiazole (3u-
I): Yield: 165.0 mg (72 %); white solid; mp: 204–205 °C; IR(neat):
3396, 3289, 3100, 1638, 1530, 1261 cm–1 1H-NMR (400 MHz,
;
[D6]DMSO): δ = 2.30 (s, 3H), 3.85 (s, 3H), 6.78 (br, 2H), 7.11 (d, 1H,
J = 8.8 Hz), 7.52 (dd, 1H, J = 8.6, 2.0 Hz), 7.75 (sd, 1H, J = 2.0 Hz);
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5274; c) T. Sasaki, K. Miyagi, K. Moriyama, H. Togo, Org. Lett. 2016, 18,
944–947; d) T. Imai, R. Harigae, K. Moriyama, H. Togo, J. Org. Chem. 2016,
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Received: January 21, 2019
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Full Paper
Thiazole Synthesis
Various alkylarenes were successfully
transformed into the corresponding 2-
amino-4-arylthiazoles and 2,4-diaryl-
thiazoles in good to moderate yields
by the treatment with NBS, followed
by the reaction with thioureas or
arenethioamides.
K. Shibasaki, H. Togo* ...................... 1–9
2-Amino-4-arylthiazoles
One-Pot Transformation of Alkylar-
enes with NBS and Thioureas
through
DOI: 10.1002/ejoc.201900100
Eur. J. Org. Chem. 0000, 0–0
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