One-pot synthesis of 4-aryl-2-aminothiazoles from styrenes and thioureas promoted by tribromoisocyanuric acid

Article abstract of DOI:10.1016/j.tetlet.2020.152164

A simple and efficient one-pot protocol has been developed for the conversion of styrenes into 4-aryl-2-aminothiazoles using readily available starting materials. Tribromoisocyanuric acid was successfully used for the co-bromination and oxidation of styrenes to give phenacyl bromides, which in the presence of thioureas produced the corresponding 4-aryl-2-aminothiazoles in 48–70% yield. The protocol involves three reactions in one process: a tandem (formation of phenacyl bromides from styrenes) followed by a telescoped (conversion to thiazole) reaction.

Full text of DOI:10.1016/j.tetlet.2020.152164

Journal Pre-proofs
One-pot synthesis of 4-aryl-2-aminothiazoles from styrenes and thioureas pro‐
moted by tribromoisocyanuric acid
Vitor S.C. de Andrade, Marcio C.S. de Mattos
PII:
S0040-4039(20)30624-9
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152164
TETL 152164
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
18 April 2020
13 June 2020
17 June 2020
Please cite this article as: de Andrade, V.S.C., de Mattos, M.C.S., One-pot synthesis of 4-aryl-2-aminothiazoles
from styrenes and thioureas promoted by tribromoisocyanuric acid, Tetrahedron Letters (2020), doi: https://
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Graphical Abstract
One-pot synthesis of 4-aryl-2-aminothiazoles from
Leave this area blank for abstract info.
styrenes
tribromoisocyanuric acid
Vitor S. C. de Andrade and Marcio C. S. de Mattos
and
thioureas
promoted
by

1
Tetrahedron Letters
One-pot synthesis of 4-aryl-2-aminothiazoles from styrenes and thioureas promoted
by tribromoisocyanuric acid
Vitor S. C. de Andrade and Marcio C. S. de Mattos
Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio de Janeiro, CEP 21941-590, Rio de Janeiro, Brazil
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple and efficient one-pot protocol has been developed for the conversion of styrenes into
4-aryl-2-aminothiazoles using readily available starting materials. Tribromoisocyanuric acid
was successfully used for the co-bromination and oxidation of styrenes to give phenacyl
bromides, which in the presence of thioureas produced the corresponding 4-aryl-2-
aminothiazoles in 48-70% yield. The protocol involves three reactions in one process: a
tandem (formation of phenacyl bromides from styrenes) followed by a telescoped (conversion
to thiazole) reaction.
Available online
Keywords:
Thiazole
Tribromoisocyanuric acid
Pot-economy
2009 Elsevier Ltd. All rights reserved.
Phenacyl bromide
Thiourea
Tandem reaction
Heterocyclic scaffolds are present in diverse molecules of
significant interest in several branches of chemistry (e.g.
medicinal chemistry, industry, agriculture and textile dyes).
Among the vast number of N-heterocycles, the thiazole group
(1,3-thiazole) is a privileged structural motif associated with
bioactive compounds, as well as an important building block for
materials science.1 In particular, the 2-aminothiazole subclass is
present in several drugs and natural products with broad
biological and pharmacological activities (e.g. anticancer,
antiviral, antimicrobial, antiprion, anti-inflammatory and
psychotropic activities).2 It also plays an important role as
corrosion inhibitors3 and fluorophores.4 Figure 1 shows the
diversity of structures that are found in important clinical drugs
bearing the pharmacophoric 2-aminothiazole scaffold.
Due to the importance and utility of 2-aminothiazoles, diverse
synthetic methods have been described for their preparation and
the chosen strategy is highly dependent on the substitution
pattern of the target molecule. In the particular case of 4-aryl-2-
aminothiazoles, the classical Hantzsch condensation5 of -
haloacetophenones (phenacyl halides) with thioureas is still a
subject of study.6 Useful methodologies include the metal-
catalyzed decomposition of styryl azides in the presence of
thiocyanates,7 a multicomponent reaction of phenacyl bromides,
amines and trimethylsilyl isothiocyanate,8 or the condensation of
thioureas with in situ formed phenacyl halides from
acetophenones,9 styrenes10 and alkylarenes11 (Scheme 1), among
many others.12 Although these are valuable approaches, many of
them suffer from drawbacks, especially from the standpoint of
the availability of starting materials, use of harsh reaction
Figure 1. Selected examples of clinical drugs containing the 2-
aminothiazole scaffold.
conditions and toxic chemicals.
———
 Corresponding author; e-mail: mmattos@iq.ufrj.br

2
Tetrahedron Letters
O
S
+
H3N NR1R2
Ar
(I2 or KI / O2 / NH4NO3 or I2 / WCl6 / K-10)
S
S
O
+
+
Br
H2N NR1R2
H2N NHR1
Ar
Ar
Ar
(NBS / AIBN)
Hantzsch synthesis
(R2 = H)
(R2 = H)
Ar
N
R1
N
(R1= R2 = H)
S
R2
S
N3
Ar
+
+ metal catalyst
+
SCN
H2N NHR1
(I2 / IBX / DMSO or DBDMH or NBS)
O
H
+
N
+
Br
Me3SiNCS
R1 R2
Ar
Scheme 1. Methodologies for the preparation of 4-aryl-2-aminothiazoles.
In light of growing environmental concerns, research efforts
are especially focused on heterocyclic construction processes that
are step- and atom-economic. In this regard, besides classical
methodologies to access 2-aminothiazoles, new approaches have
been reported in the literature by telescoping multi-step reactions
(i.e. execution of multiple transformations, quenches and workup
procedures without the isolation of intermediates), which avoids
handling and exposure to hazardous or toxic compounds and
minimizes the number of synthetic steps, purification processes
and, consequently, chemical waste.13 In this context, pot-
economy approaches involving N-halo reagents are widespread in
the literature for the synthesis of heterocycles.14 Among the N-
halo reagents, trihaloisocyanuric acids (Fig. 2) are effective and
stable electrophilic halogenating reagents that are commercially
available or prepared from readily accessible materials.15 From a
green chemistry point of view, they present a higher atom
economy and are able to transfer up to three halogen atoms to a
substrate.16 In addition, in reactions involving trihaloisocyanuric
can be seen in Table 1, the best results were obtained in water at
70 C for 2 h or in aqueous acetonitrile at room temperature for
o
20 h. Both conditions converted styrene into phenacyl bromide
quantitatively, but we chose the first one as being optimal.
Interestingly, although trichloroisocyanuric acid is known to
oxidize alcohols to ketones,22 the oxidation of the chlorohydrin to
the phenacyl chloride was not effective and the utilization of a
large excess of TCCA led to several products.
Table 1. Screening for the conversion of styrene into phenacyl
halides.
X+
(equiv)
Br (3.0)
Time
(h)
15
Alcohol/
ketone (%)a
48/52
Solvent
Temp.
r.t.
MeCN/H2O (4:1)
MeCN/H2O (4:1)
MeCN/H2O (4:1)
Acetone/H2O (30:1)
H2O
acids, the cyanuric acid by-product can be reused to produce
additional trihaloisocyanuric acid.17 Recently, we published an
efficient telescoped preparation of 2-aminothiazoles 5-
carboxylates from thioureas and -keto esters mediated by
tribromoisocyanuric acid.18
r.t.
Br (3.5)
Br (3.5)
Br (3.5)
Br (3.0)
Br (3.0)
Br (2.1)
Cl (3.0)
Cl (2.0)
15
20
24
2
25/75
0/100
25/75
64/36
0/100
68/32
59/41b
93/7
r.t.
r.t.
50 oC
70 oC
70 oC
r.t.
H2O
2
H2O
2
MeCN/H2O (4:1)
MeCN/H2O (4:1)
aDetermined by GC-MS.
24
24
Figure 2. Trihaloisocyanuric acids.
r.t.
Continuing our interest on the chemistry of trihaloisocyanuric
acids,19 we report herein the TBCA-promoted conversion of
styrenes into 4-aryl-2-aminothiazoles through a pot-economic
approach of three consecutive reactions in a single vessel.
bFormed along with a mixture of several products.
With these optimized conditions in hand, we studied the
reaction of the in situ formed phenacyl bromide with thiourea,
adjusting the solvent to a mixture of acetonitrile/water (1:1) and
obtained 4-phenylthiazol-2-amine (1a) in 70% yield after an
additional 15 min reaction at room temperature. The product was
easily isolated by precipitation of the reaction media and was
purified by recrystallization from aqueous ethanol. Extension of
these optimized conditions to substituted styrenes and thioureas
led to a series of 4-aryl-2-aminothiazoles (1) with different
patterns of substitution on the aryl and amino groups (Scheme 2).
There are several methodologies for the synthesis of
phenacyl bromide from styrene using different oxidants.20
Previously, we reported a convenient co-halogenation of alkenes
with oxygenated nucleophiles promoted by trihaloisocyanuric
acids.21 Hence, the reaction of styrene with TBCA in aqueous
acetone produced 2-bromo-1-phenylethanol with high
regioselectivity. Therefore, we studied the possibility of the
direct conversion of styrene into phenacyl bromide through a
one-pot tandem reaction, with excess TBCA having a double
action, i.e. as an electrophilic halogen source to form the
bromohydrin and an oxidant to convert it into the haloketone. As

3
Scheme 2. 4-Aryl-2-aminothiazoles prepared from styrenes and TBCA.
It was observed that the nature of the thiourea does not affect
the reaction. On the other hand, the group attached to the styrene
ring plays an important role on the scope/yield of the reaction.
Therefore, substrates bearing weakly electron-donating or
withdrawing groups led to the corresponding 4-aryl-2-
aminothiazoles in 48-70% yield. However, 4-methoxystyrene,
which has a strong electron-donating group attached to the
aromatic ring, led to a mixture of several products, none of which
was the thiazole, as determined by GC-MS. In fact, when 4-
methoxystyrene was subjected to the tandem co-bromination and
oxidation reactions, a mixture of several SEAr brominated
products was obtained, including ipso-substitution, in only one
hour at room temperature, even when using a stoichiometric
amount of TBCA (Scheme 3). No carbonyl products were
detected in the crude reaction mixtures by GC-MS.
stepwise was lower than in the one-pot reaction (61% versus
70%). In addition, comparison of TBCA with similar N-bromo
compounds, such as 1,3-dibromo-dimethylhydantoin (DBDMH)
and N,N-dibromo-p-toluenesulfonamide (TsNBr2), for the
conversion of styrene into phenacyl bromide is presented in
Table 2. Our results show that although TBCA gave a lower
yield, it has the advantage of possessing a higher atom efficiency
(i.e. atom economy vs. chemical yield),25 which is consistent with
green chemistry principles.26
Table 2. Comparison of N-bromo compounds for the
conversion of styrene into phenacyl bromide.
It is well-known that 4-methoxybenzyl alcohols give ipso-
substitution products when reacting with electrophilic
halogenating reagents.23 In general, the ipso-substitution process
competes with the oxidation and an investigation on the reaction
pathway detected bromoacetaldehyde to support the process.22b
Therefore, it is reasonable that 4-methoxystyrene undergoes co-
bromination followed by ipso electrophilic aromatic substitution
on the resulting bromohydrin, followed by arene bromination by
the remaining TBCA.24
N-bromo
compound
Yield (%)
Atom efficiency (%)
Ref.
DBDMH
TsNBr2
TBCA
85
87
80
39
42
63
20d
20c
This
work
A
possible rationalization for the TBCA-promoted
conversion of styrenes into 4-aryl-2-aminothiazoles involving co-
halogenation, oxidation and oxidative cyclization steps is
presented in Scheme 4. Initially, there is a regioselective co-
halogenation of styrene promoted by TBCA, followed by
oxidation of the bromohydrin by another equivalent of TBCA.
Finally, nucleophilic attack of the thiourea on the phenacyl
bromide, followed by condensation of the free amino, elimination
and oxidation give the desired 4-aryl-2-aminothiazoles.
In summary, we have developed an efficient one-pot protocol
for the synthesis of 4-aryl-2-aminothiazoles from styrenes and
thioureas, which involves three reactions in only one process, i.e.
a tandem (formation of phenacyl bromides) followed by a
telescoped (convertion to thiazole) reaction. The experimental
procedure is simple, the reagents are readily available, and there
is no need for the manipulation of lacrymmatory phenacyl
bromides, which makes our methodology attractive for a wide
Scheme 3. Reaction of 4-methoxystyrene with TBCA.
Additionally, in a comparative study, the synthesis of
phenacyl bromide and 4-phenylthiazol-2-amine (1a) was
conducted stepwise and they were obtained in 80% and 76%
yield, respectively. Thus, the overall yield of 1a produced
range
of
applications
in
organic
synthesis.

4
Tetrahedron
O
O
N
H
Br
OH
O
Br
Br
O
Br
Br
O
N
N
Br
N
N
Br
Br
Ar
Ar
Ar
Ar
Ar
H2O
2 steps
H
O
N
Br
O
B
Br
2 steps
O
Ar
H
Ar
Br
H2N NR
O
HO
+- H
-H2O
+- H
Ar
S
S
S
N
N
S
S
HN
2 steps
Ar
RHN NH2
NR
NHR
NH
Scheme 4. Possible rationalization for the TBCA-promoted conversion of styrenes into 4-aryl-2-aminothiazoles.
9. (a) Cáceres-Castillo, D.; Carballo, R. M.; Tzec-Interian, J. A.; Mena-
Acknowledgment
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M. Res. Chem. Interm. 2016, 42, 8175.
We thank CNPq and CAPES for financial support. We also thank
Prof. Rafael Garrett da Costa and LBCD-LADETEC/IQ-UFRJ
for the HRMS analyses.
10. (a) Ma, C.; Miao, Y.; Zhao, M.; Wu, P.; Zhou, J.; Li, Z.; Xie, X.; Zhang,
W. Tetrahedron 2018, 74, 3602. (b) Donohoe, T. J.; Kabeshov, M. A.;
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Z.; Izadkhah, V. Appl. Organometal. Chem. 2018, 32, e4127. (b) Zhang,
B.; Shi, L. Phosphorus Sulfur Silicon Relat. Elem. 2019, 194, 1134.
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Supporting Information
Supporting information is available which includes detailed
experimental procedures, analytical data and copies of IR, MS,
1H and 13C spectrum of all synthesized compounds.
14. (a) de Andrade, V. S. C.; de Mattos, M. C. S. Synthesis 2019, 51, 1841.
(b) Lyubchuk, T. V.; Hordiyenko, O. V. Chem. Heterocycl. Compd.
2020, 56, 1.
Declaration of Competing Interest
15. (a) Mendonça, G. F.; de Mattos, M. C. S. Curr. Org. Synth. 2013, 10,
820. (b) de Almeida, L. S.; Esteves, P. M.; de Mattos, M. C. S. Curr.
Green Chem. 2014, 1, 94.
16. Mendonça, G. F.; de Almeida, L. S.; de Mattos, M. C. S.; Esteves, P. M.;
Ribeiro, R. S. Curr. Org. Synth. 2015, 12, 603.
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to
influence the work reported in this paper.
17. Tozetti, S. D. F.; de Almeida, L. S.; Esteves, P. M.; de Mattos, M. C. S.
J. Braz. Chem. Soc. 2007, 18, 675.
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5
A pot-economy synthesis of 4-aryl-2-aminothiazoles from styrenes promoted by
tribromoisocyanuric acid
Vitor S. C. de Andrade and Marcio C. S. de Mattos
Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio de Janeiro, CEP
21941-590, Rio de Janeiro, Brazil
HIGHLIGHTS
efficient conversion of styrenes into 4-aryl-2-aminothiazoles
mild and safe reaction conditions
simple experimental using readily avaiable materials
a pot-economic approach in a single vessel
tandem and a telescoped reactions
Declaration of interests
 ☐The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered as potential
competing interests:
———
 Corresponding author; e-mail: mmattos@iq.ufrj.br