Convenient Multicomponent One-Pot Synthesis of 2-Iminothiazolines and 2-Aminothiazoles Using Elemental Sulfur Under Aqueous Conditions

Article abstract of DOI:10.1002/ejoc.202100548

Herein, we present a novel one-pot aqueous reaction for the synthesis of 2-iminothiazolines and 2-aminothiazoles using isocyanides, amines, sulfur, and 2′-bromoacetophenones. The three-component preparation of thioureas is followed by the one-pot cyclization leading to the heterocyclic product. This efficient and mild procedure features excellent step- and atom-economy and enables the chromatography-free preparation of diversely substituted 2-iminothiazoline and 2-aminothiazole derivatives.

Full text of DOI:10.1002/ejoc.202100548

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Convenient multicomponent one-pot synthesis of 2-
iminothiazolines and 2-aminothiazoles using elemental sulfur
under aqueous conditions
Authors: András Gy. Németh, Bence Marlok, Attila Domján, Qinghe
Gao, Xinya Han, György M Keserű, and Péter Ábrányi-Balogh
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100548
Link to VoR: https://doi.org/10.1002/ejoc.202100548
01/2020

10.1002/ejoc.202100548
European Journal of Organic Chemistry
FULL PAPER
Convenient multicomponent one-pot synthesis of 2-
iminothiazolines and 2-aminothiazoles using elemental sulfur
under aqueous conditions
András Gy. Németh,[a] Bence Marlok,[a] Attila Domján,[b] Qinghe Gao,[c] Xinya Han,[d] György M.
Keserű,* [a] Péter Ábrányi-Balogh*[a]
Dedicated to professor Ferenc Fülöp on the occasion of his 70th birthday.
[a]
András Gy. Németh, Bence Marlok, Prof. György M. Keserű, Dr. Péter Ábrányi-Balogh
Medicinal Chemistry Research Group
Research Centre for Natural Sciences
Magyar tudósok krt. 2, H-1117 Budapest, Hungary
URL: http://medchem.ttk.hu
E-mail: keseru.gyorgy@ttk.hu; abranyi-balogh.peter@ttk.hu
Dr. Attila Domján
NMR Research Laboratory
Research Centre for Natural Sciences
Magyar tudósok krt. 2, H-1117 Budapest, Hungary
Dr. Qinghe Gao
School of Pharmacy
Xinxiang Medical University
Xinxiang, Henan 453003, P. R. China
Dr. Xinya Han
[b]
[c]
[d]
School of Chemistry and Chemical Engineering
Anhui University of Technology
Maanshan, Anhui 243002, P. R. China
Supporting information for this article is available on the WWW under https://doi.org/....
Abstract: Herein, we present a novel one-pot aqueous reaction for
the synthesis of 2-iminothiazolines and 2-aminothiazoles using
isocyanides, amines, sulfur and 2′-bromoacetophenones. The three-
component preparation of thioureas is followed one-pot by the
cyclization leading to the heterocycle. This efficient and mild
procedure features excellent step– and atom–economy and enables
the chromatography–free preparation of diversely substituted 2-
iminothiazoline and 2-aminothiazole derivatives.
synthesis, e.g. the application of less toxic solvents, exclusion of
chromatographic purification and simple isolation of the desired
products should be considered.[22,23] Water is an ideal non-toxic,
abundant and cheap medium that offers a simple isolation
protocol of apolar products as a main advantage.[24–27]
Introduction
2-Iminothiazolines are biologically active compounds represented
by selective cannabinoid receptor type 2 (CB2) agonists,[1–4]
carbonic anhydrase (CA), cyclooxygenase (COX) and
[10,11]
lipoxygenase (LOX) inhibitors,[5–9] anticancer
and
antithrombotic agents, [12] HIV1 reverse transcriptase inhibitors [13]
and fungicides (Figure 1).[14] Similarly, related 2-aminothiazoles
showed
anticancer,[15–18]
antibacterial,[19]
anticonvulsant,
antidiabetic, antihypertensive, anti-inflammatory, antiviral,
antimicrobial and neuroprotective activities.[20] They are
represented by the marketed antiviral and antiparasitic drug
Nitazoxanide, the β3 adrenergic receptor agonist Mirabegron, the
antileukemic Dasatinib and the antiulcer Famotidine (Figure 1).[21]
The significance of the 2-iminothiazoline and 2-aminothiazole
structures calls for new and efficient synthetic methods, which
offer simple and convenient access towards diverse
functionalization patterns. Also, the environmental aspects of the
Figure 1. Examples of biologically active 2-iminothiazolines and 2-
aminothiazoles
1
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10.1002/ejoc.202100548
European Journal of Organic Chemistry
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Scheme 1. Previous one-pot and multicomponent approaches for the synthesis of 2-iminothiazolines, 2-aminothiazoles and this work
Chromatographic purification produces large waste of organic
solvents and dischargeable solid phase, thus, the improvement of
existing synthetic methods to avoid chromatography remains an
important issue.[23,28–33]
The traditional Hantzsch thiazole synthesis starts from thioureas
and α-haloketones [34,35]. Unsubstituted and N-monosubstituted
thioureas lead to 2-aminothiazoles while N,N’-disubstituted ones
lead to 2-iminothiazolines. The regioselectivity is driven by the pKa
values of the NH protons, particularly the more basic nitrogen
participates in the formation of the heterocycle.[14,36,37] Several
methods.[39–41] Considering green chemistry principles and
synthetic efficiency, we focused on one-pot and multicomponent
approaches that have been designed by the in situ synthesis of
thioureas or α-haloketones. Raja et al., Samimi et al. and Heravi
et al. reported the preparation of 2-iminothiazolines in one-pot,
based on the in situ generation of thioureas from amines and
isothiocyanates followed by the ring annulation with 2’-
bromoacetophenones (Scheme 1, eq. 1).[42–44] Appalanaidu et al.
applied carbon disulfide in the microwave assisted preparation of
symmetrical thioureas in the one-pot synthesis of 2-
iminothiazolines (Scheme 1, eq. 2).[45] Notably, De Andrade et al.
published a tribromoisocyanuric acid (TBCA) mediated approach
variant of the original synthetic method have been developed, like
[14,38]
solid supported synthesis
base-catalyzed and aqueous
2
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10.1002/ejoc.202100548
European Journal of Organic Chemistry
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for the in situ synthesis of 2’-bromoacetophenones which they Results and Discussion
sequentially reacted with thioureas to obtain 2-aminothiazoles
(Scheme 1, eq. 3).[46] Recently, Kumar et al. developed
Starting from 2,6-dimethylphenyl isocyanide (1a), benzylamine
(2a) and the aqueous polysulfide solution made of 1.0 M PMDTA
and 0.4 M sulfur, we synthesized the thiourea 3a at 80 °C in 0.5
hour through an isothiocyanate intermediate detected by HPLC-
MS.[54–56] Next, we did not isolate 3a, but aimed to transform it
using 2’-bromoacetophenone (4a) to the corresponding
iminothiazoline 5a. Under basic conditions, however, the ring
annulation with 4a could not reach full conversion, a mixture of
the product 5a and the intermediate 6a could be observed in
HPLC-MS. Therefore, we decided to acidify the reaction mixture
to pH < 3 with cc aq. HBr to have the same anion present as the
leaving group from 4a. Then, we added 2’-bromoacetophenone
(4a) and continued the reaction at 100 °C that temperature was
necessary for the cyclization.[49,62] After 0.5 hour, we observed the
total consumption of the in situ generated thiourea by HPLC-MS.
The hydrogen bromide salt of 5a precipitated from the reaction
mixture, which we isolated by filtration and washed with 1.0 M aq.
NaOH and water providing 5a in 81% yield (Scheme 2). Thus, to
our delight, starting from simple building blocks we have obtained
the desired 2,3,4-trisubstituted iminothiazoline 5a in a one-pot
two–step synthesis without applying chromatographic purification.
Although the ring-closure may lead to the regioisomer 5a’, we did
not observed its formation in the reaction. Presumably the
significant difference between the pKa values of benzylamine and
2,6-dimethylaniline enables the regioselective preparation of
5a.[14,36,37]
multicomponent method using in situ peroxide-generated aryl
iodoalkynes for the ring annulation (Scheme 1, eq. 4).[47] Finally,
Fu et al. synthesized 5-acyl-2-aminothiazoles starting from
enaminones, sulfur and cyanamide in a multicomponent reaction
(Scheme 1, eq. 5).[48] Although these approaches provided the
desired products efficiently, they have limited substrate scope.
Furthermore, they either enable the generation of only
symmetrical thioureas or require the preparation and handling of
highly toxic isothiocyanate intermediates (Scheme 1, eq. 1, 2 and
4). Other approaches offer one or two positions of variability, thus
benefit merely from a limited chemical space (Scheme 1, eq. 3
and 5). Moreover, the application of toxic and hazardous solvents
or inert conditions and long reaction times urges for the
development of an all-purpose and convenient synthetic
procedure leading to structurally diverse 2-iminothiazolines and
2-aminothiazoles.
Elemental sulfur is a bench-stable environmentally benign,
nontoxic reagent for sulfuration offering an atom-economical and
safe alternative to incorporate the sulfur atom.[49–52] Although
plenty of sulfurating reagents are available, the application of
elemental sulfur is considered to the most atom economical
approach.[53] Certain nucleophiles, such as aliphatic amines are
able to activate sulfur, generating open-chain ionic polysulfide
anions which can be used in the atom efficient sulfuration of
isocyanides leading to isothiocyanates.[54–57] Recently, we have
published the preparation of aqueous solutions of sulfur that we
applied in the chromatography–free and continuous flow
synthesis of thioureas starting from isocyanides and both aliphatic
and aromatic amines.[54,56] These methodologies enable the
synthesis of symmetric or asymmetric thioureas from the
isothiocyanate precursor isocyanides and the isolation of the pure
products by a simple filtration. In continuation of our interest in
multicomponent reactions[58–60] and reactions involving elemental
sulfur[54–56,61] we have aimed to further elaborate the application of
aqueous polysulfide solutions. Herein we present the
multicomponent one-pot synthesis of diverse 2-iminothiazolines
and 2-aminothiazoles starting from isocyanides, sulfur, amines,
and 2′-bromoacetophenones (Scheme 1, eq. 6).
The nucleophilic character of aliphatic amines such as
phenethylamine, or benzylamine [63] are able to activate sulfur that
might provide 3a and then 5a in the absence of external bases.
The reaction of 1a, 2a and the aqueous polysulfide solution made
of 1.0 M PMDTA and 0.4 M sulfur at 80 °C provide the thiourea
[54]
3a in 89% yield in 0.5 hour in water (Table 1, entry 1, see ref.
and supplementary information for detailed experimental
description). Applying sulfur powder with no external base in the
reaction of 1a and 2a at 80 °C, we only observed traces of the
expected thiourea in water (Table 1, entry 2). Applying the mixture
Scheme 2. Multicomponent one-pot synthesis of 2-iminothiazoline 5a
3
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10.1002/ejoc.202100548
European Journal of Organic Chemistry
FULL PAPER
Table 1. Optimization of the reaction conditions for the synthesis of thioureas
Table 2. Optimization of the reaction conditions for the synthesis of 2-
starting from aliphatic amines
iminothiazolines
Molar
Temperature
excess of
1a / sulfur
atoms / 2a
Entry
Co-solvent
Yield[a,b]
Temperature
[°C]
Entry
Co-solvent
Yield[a,b]
[°C]
1
2
100
110
80
10% dioxane
10% dioxane
10% dioxane
10% MeCN
90
89
87
82
85
1
2
80
80
80
80
80
80
80
60
-
1 / 2 / 1.5
1 / 1.5 / 1.1
1 / 1.5 / 1.1
1 / 1.5 / 1.1
1 / 1.5 / 1.1
1 / 1.3 / 1.1
1 / 2 / 1.1
89c
-
Traces of 3a
3
3
10% MeCN
10% THF
10% dioxane
10% MeCN
10% MeCN
10% MeCN
>99
90
98
91
97
81
4
80
4
5c
100
10% dioxane
5
6
[a] Reaction conditions: 3a (0.5 mmol), 2’-bromoacetophenone (4a, 0.75 mmol),
water and co-solvent mixture (2.5 mL), temperature, 0.5 hour; [b] Isolated yields;
[c] 0.6 mmol of 4a was employed.
7
8d
1 / 1.5 / 1.1
reaction using the optimized conditions. Electron rich 2’-
bromoacetophenones
provided
the
corresponding
2-
[a] Reaction conditions: 2,6-dimethylphenyl isocyanide (1a, 0.5 mmol), sulfur,
benzylamine (2a), water and co-solvent mixture (2.5 mL), temperature, 0.5 hour;
[b] Isolated yields; [c] Applying aqueous polysulfide solution (1.0 M PMDTA/0.4
M S8 in water, 2.5 mL); [d] 1 hour reaction time.
iminothiazolines in moderate to good yields (5b–g, 43–85%). No
evident electronic effects influenced the reaction, 2’-
bromoacetophenones equipped with electron withdrawing groups
provided the corresponding iminothiazolines also in good yields
(5h–l, 63–77%). This reaction setup tolerated nitrile and nitro
groups and all of the halogen atoms offering functionalities for
further modifications. Next, applying the aliphatic allyl-, hexyl- and
ethanolamine, we have obtained 2-iminothiazolines 5m–o in 76%,
92% and 87% yields, respectively. 2-Aminomethylfurane and 2-
aminomethylthiophene both gave the corresponding2-
iminothiazolines 5p and 5q in 83% yield. 2-Phenetylamine and
tryptamine reacted smoothly and selectively leading to the
desired heterocycles 5r and 5s in excellent 82% and 93% yields,
respectively.
The weak nucleophilicity of anilines makes them unable to
efficiently cleave sulfur-sulfur covalent bonds and unlike to
benzylamine it does not activate sulfur. Therefore, in this case we
have applied the aqueous polysulfide solution made from 1.0 M
PMDTA and 0.4 M sulfur.[54,56] The reaction of phenethyl
isocyanide (1b), aniline (7a) and the aqueous polysulfide solution
made of PMDTA and sulfur at 80 °C was followed by HPLC-MS
and after full conversion of the isocyanide, the reaction mixture
was acidified with cc. aq. HBr. Then, we added 4a, and continued
the reaction at 100 °C for another 0.5 hour. After full consumption
of the thiourea intermediate, we filtered the reaction mixture and
washed the product with 1.0 M aq. NaOH that provided the 2-
iminothiazoline 5t in 68% yield (Scheme 4). In contrast to the
reaction setup demonstrated in Scheme 2 and 3, here the
isocyanide provide the thiourea NH group with higher pKa value.
Eventually, this leads to the regioselective incorporation of the
isocyanide in the heterocycle, with the aniline ending up at the 2nd
position. Anilines equipped with electron donating groups led to
the corresponding iminothiazolines 5u, v and x in 52%, 66% and
77% yields respectively. As the 4-OMe derivative 5w have
remained an oil both as a salt and in neutral form, this was isolated
after flash chromatography. Applying the anilines equipped with
of water:acetonitrile 9:1 in further experiments, the reduction of
the excess of sulfur to 1.3 equivalents led to the drop of the yield
to 91%, however, raising the excess to 2 equivalents, did not
result in better yields (Table 1, entries 6, 7). Performing the
reaction at 60 °C led to a longer reaction time providing 3a in a
significantly lower, 81% yield (Table 1, entry 8).
Next, we have performed a brief optimization for the ring
annulation leading to 2-iminothiazoline 5a in the presence of co-
solvent. Employing 10% dioxane at 100 °C led to the formation of
5a in 0.5 hour in 90% yield (Table 2, entry 1). Increasing the
temperature to 110 °C did not result in a better yield (Table 2,
entry 2). Applying either dioxane or acetonitrile as co-solvent at
80 °C the yield slightly decreased to 87% and 82%, respectively
(Table 2, entries 3, 4). Decreasing the excess of 2’-
bromoacetophenone to 1.2 equivalent reduced the yield to 85%
(Table 2, entry 5). Eventually, we have concluded that the
formation of thiourea from benzylamine without an external base
requires 80 °C, and 10% co-solvent for the full conversion in 0.5
h. The annulation went smoothly also at 100 °C, and this step
suggested dioxane as co-solvent. Using the optimized conditions
we have performed the reaction of the isocyanide 1a, sulfur and
benzylamine (2a) at 80 °C in a mixture of water:dioxane 9:1 for
0.5 hour, then, sequentially added 2’-bromoacetophenone (4a)
and continued the reaction at 100 °C for 0.5 hour until the total
consumption of the in situ generated thiourea followed by HPLC-
MS. The hydrogen bromide salt of 5a precipitated from the
reaction mixture, which we isolated by filtration, then washed with
1.0 M aq. NaOH and water providing 5a in an excellent 91% yield
(Scheme 3). Since the process provided the product in higher
yield with co-solvents than that in the presence of an external
base, we have chosen the former conditions for follow-up. Next,
we have evaluated the scope of this multicomponent one-pot
4
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10.1002/ejoc.202100548
European Journal of Organic Chemistry
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Scheme 3. Scope of 2’-bromoacetophenones (4) and aliphatic amines (2)
halogen atoms resulted in the formation of the iminothiazolines
5y–5za in good 68–81% yields respectively.
(Scheme 5). 4-Fluorophenyl and 4-methoxyphenyl isocyanides
lead to the desired thiazoles 8b and 8c in 95% and 67% yield
respectively. Phenethyl, cyclohexyl and tert-butyl isocyanides
gave rise to the corresponding thiazoles 8e,f and the anti-
inflammatory fanetizole 8d in moderate yields.[64] Notably, the
salts of 8b, 8e and 8f were oil and therefore these products were
Employing aqueous ammonia, 2,6-dimethylphenyl isocyanide
(1a) and the polysulfide solution made of PMDTA and sulfur and
at 80 °C led to the full conversion of 1a to the corresponding
thiourea 3 in 1 hour. Adjusting the pH of the reaction below pH 3
with cc aq. HBr followed by the addition of 2’-bromoacetophenone
(4a) resulted in the precipitation of the HBr salt of 8a after 1 hour
at room temperature. After filtration, the product was washed with
1.0 M aq. NaOH providing the 2-aminothiazole 8a in 72% yield
purified
by
flash
chromatography.
Various
2’-
bromoacetophenones underwent the reaction smoothly, providing
the thiazoles 8g–8j in moderate to excellent yields (55–93%).
Scheme 4. Scope of anilines (7)
5
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Scheme 5. Scope of isocyanides (1) and 2’-bromoacetophenones (4) for the synthesis of thiazoles (8a–j)
To demonstrate the robustness of the reaction we performed the
40-fold scale-up synthesis of 5p (20 mmol, Scheme 6). To our
delight, both the preparation of the thiourea and thiazolimine was
ready in 1 hour leading to the desired heterocycle. Filtration of the
crude product, treatment with 1.0 M aq. NaOH and washing with
water provided 5p in 90% yield (6.51 g).
on a diversely functionalized set of 37 compounds from those 31
are first synthesized here, and also enables scale-up to multiple
grams.
Acknowledgements
Krisztina Németh and Pál Szabó for the HRMS measurements. P.
Ábrányi-Balogh was supported by the Hungarian Science
Foundation OTKA (PD124598) grant.
Keywords: sulfur • multicomponent reaction • 2-iminothiazoline •
2-aminothiazole • aqueous polysulfide solution
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European Journal of Organic Chemistry
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Entry for the Table of Contents
A multicomponent one-pot process led to the formation of diversely trisubstituted 2-iminothiazolines and disubstituted 2-
aminothiazoles under aqueous conditions. Starting from isocyanides, amines, 2’-bromoacetophenones and aqueous polysulfide
solution or sulfur powder, this efficient procedure enabled the chromatography-free separation of solid products.
9
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