Synthesis of 2-aminothiazoles via rhodium-catalyzed carbenoid insertion/annulation of sulfoxonium ylides with thioureas

Article abstract of DOI:10.1016/j.cclet.2021.02.052

Sulfoxonium ylides as carbene precursors couple smoothly with thioureas in the presence of 5 mol% of rhodium(II) acetate dimmer via carbenoid insertion to afford the corresponding 2-aminothiazoles with high chemoselectivity, providing a facile and efficient approach to access a variety of 2-aminothiazole derivatives with good functional groups tolerance.

Full text of DOI:10.1016/j.cclet.2021.02.052

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CCLET-6181; No. of Pages 4
Chinese Chemical Letters xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Synthesis of 2-aminothiazoles via rhodium-catalyzed carbenoid
insertion/annulation of sulfoxonium ylides with thioureas
Yuncan Chena, Shan Lva, Ruizhi Laia, Yingying Xua, Xin Huanga, Jianglian Lia,
a,
Guanghui Lvb, , Yong Wu
*
*
a
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-
Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041,
China
b
Department of Pharmacy, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Sulfoxonium ylides as carbene precursors couple smoothly with thioureas in the presence of 5 mol% of
rhodium(II) acetate dimmer via carbenoid insertion to afford the corresponding 2-aminothiazoles with
high chemoselectivity, providing a facile and efficient approach to access a variety of 2-aminothiazole
derivatives with good functional groups tolerance.
© 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Received 21 December 2020
Received in revised form 20 February 2021
Accepted 22 February 2021
Available online xxx
Keywords:
2-Aminothiazoles
Carbene
Rhodium
Sulfoxonium ylides
Annulation
The 2-aminothiazole ring is an important structural motif found
in numerous biologically active molecules which exhibits a wide
range of activities such as antibacterial [1], anti-inflammatory [2],
anticancer [3], anti-hypertension [4] and anti HIV [5]. In addition,
2-aminothiazole ring is frequently found in a variety of market
drug such as famotidine [6], cefdinir [7], meloxicam [8] and so on.
Besides, in 2019 we reported structure-based design of N-(5-
phenylthiazol-2-yl)acrylamides as novel and potent glutathione S-
transferase omega 1 (GSTO1-1) inhibitors [9], showing that
thiazole derivatives are potential and suitable leading compounds
for cancer therapy (Fig. 1). Due to the importance and the broad
utility of 2-aminothiazole derivatives, diverse well-established
methods have been developed to construct these structural motifs.
The Hantzsch synthesis is the most commonly used typical method
using α-halocarbonyl compounds and thioureas/thioamides for the
synthesis of 2-aminothiazoles (Scheme 1a) [10]. Over the years,
many improved methods have been reported involving the use of
catalysts such as ammonium 12-molybdophosphate [11], β-
cyclodextrin [12], iodine [13] and silica chloride [14], new starting
materials from α-nitroepoxides and thiocyanate [15–18], green
solvent such as ionic liquids [19], PEG-400 [20] and water [21], and
with the aid of microwaves [22,23]. And some valuable methods
have also been developed for constructing fused polycyclic thiazole
rings [24,25]. Despite the progress, some limitations still remain.
For example, mostly using α-halocarbonyl compounds as the
starting materials is inevitable, which lead to the generation of
much chemical waste. Faced with these thorny problems,
developing more efficient and sustainable synthetic strategies
remains highly desirable.
Metal-catalyzed XꢀꢀH (X
¼N, O, S, etc.) insertion reactions into
diazo compounds have been recognized as a powerful method to
the construction of diverse carbon-heteroatom bonds [26]. In
2008, Yadav and coworkers reported Cu(II)-catalyzed coupling of
α-diazoketones with thiourea to generate a variety of 2-amino-
thiazoles (Scheme 1b) [27]. Following this pioneer work, there
were also other works to make amino-thiazoles, starting from
diazocompounds catalyzed by PEG400 or BF3 (Scheme 1b, ii and iii)
[28,29]. Nevertheless, diazo compounds suffer from instability,
synthetic inconvenience, and potential danger of rapid exothermic
reaction. So exploring alternative carbene precursors and their
applications in organic synthesis will make a great contribution to
green carbene chemistry.
In recent years, sulfoxonium ylides has been widely used as new
surrogates of carbene precursors due to their high stability and
synthetic convenience compared to diazo compounds. Many
studies on carbene insertions and CꢀꢀH functionalization have
* Corresponding authors.
E-mail addresses: 1083947919@qq.com (G. Lv), wyong@scu.edu.cn (Y. Wu).
https://doi.org/10.1016/j.cclet.2021.02.052
1001-8417/© 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article as: Y. Chen, S. Lv, R. Lai et al., Synthesis of 2-aminothiazoles via rhodium-catalyzed carbenoid insertion/annulation of
sulfoxonium ylides with thioureas, Chin. Chem. Lett., https://doi.org/10.1016/j.cclet.2021.02.052

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Table 1
Optimization of reaction conditions.a
Entry
Catalyst
Solvent
Temp. (oC)
Yield (%)b
1
2
3
4
5
6
7
8
–
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Toluene
DMF
THF
EtOH
H2O
DCE
DCE
DCE
DCE
DCE
DCE
80
80
80
80
80
80
80
80
80
80
80
80
80
80
60
100
80
80
80
80
N.R.
22
20
35
85
N.R.
N.R.
N.R.
< 5
51
< 5
25
N.R.
N.R.
55
HCl
[Cp*RhCl2]2
[Ir(cod)Cl]2
Rh2(OAc)4
Cp*Co(CO)I2
[Ru(p-cymene)Cl2]2
Mn(CO)5Br
PPhAuCl
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Fig. 1. Selected examples of bioactive molecules with 2-aminothiazole ring.
9
10
11
12
13
14
15
16
17c
18d
19e
20f
88
77
88
66
85
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (5 mol%), solvent
(1.5 mL), under air.
b
Isolated yields.
The reaction was carried out for 16 h.
The reaction was carried out for 30 h.
The reaction was carried out with 0.4 mmol of 1a and 0.2 mmol of 2a.
c
d
e
f
The reaction was carried out under Ar atmosphere.
strategies, making it a useful and attractive strategy for the
preparation of relevant 2-aminothiazole derivatives.
In order to explore the best reaction conditions, the investiga-
tion was commenced by using α-benzoyl sulfoxonium ylide 1a
(0.2 mmol) and thiourea 2a (0.4 mmol) with different catalytic
systems in DCE at 80 ꢁC for 24 h under air atmosphere. Of these
catalysts, Rh2(OAc)4 was found to be the most effective catalyst in
terms of conversion and cleanliness while others like HCl, Cp*Co
(CO)I2, [Cp*RhCl2]2, [Ir(cod)Cl]2 or [Ru(p-cymene)Cl2]2 failed to
work or gave lower yields, (Table 1, entries 2–9). With regard to
solvents, the increase in yield was not observed when solvents
were changed (Table 1, entries 10–14). Although higher tempera-
ture and longer reaction time could slightly increase the reaction
conversion, 80 ꢁC and 24 h were chosen as the final reaction
conditions in consideration of efficiency and energy conservation
(Table 1, entries 16 and 18). Subsequently, further study on the
adjustment of the two substrates’ ratio indicated that only excess
equivalents of thiourea could keep the high yield of the desired
product (Table 1, entry 19). The reaction did not proceed at all
without any catalyst (Table 1, entry 1).
Having determined the optimal conditions, the generality of
Rh-catalyzed insertion and annulations reaction was then evalu-
ated by using the diversely substituted sulfoxonium ylides with
thiourea. As shown in Scheme 2, a range of sulfoxonium ylides
bearing various electron-donating, -withdrawing and halogen
substituents at the different positions of the phenyl ring all
coupled smoothly with 2a, affording the target products in
moderate to excellent yields (3ba-3la). In general, it was indicated
that the electron-withdrawing groups attached to ylides were
more suitable than electron-donating substituents such as methyl,
methoxyl and dimethyl, probably because that inductive effect of
Scheme 1. Routes to 2-aminothiazole derivatives.
been reported to construct versatile carbon-carbon bonds and
carbon-heteroatom bonds [30–47]. It was noted that in 2006
sheppeck and co-workers first utilized sulfoxonium ylides and
thiourea to synthesize 2-aminothiazole ring with added acid [48].
Probably due to the enough acidity which protonate sulfoxonium
ylide to furnish reactive sulfoxonium. However, only three
examples were performed and the yields of the obtained products
were very low according to this method. Besides, this method
requires large amount of hydrochloride as the catalyst which led to
the inconvenience of post process and generation of chemical
waste. In 2016, a patent described the use of sulfonium salts and
thiourea to prepare the 2-amino-4-aryl-5-methylthiothiazole
compounds [49]. Still, the synthesis of α-halocarbonyl compounds
was inevitable. Our group has been long contributed to the study
on diverse reactions of sulfoxonium ylides, and we have developed
precedent water-mediated SꢀꢀH insertion reaction of sulfoxonium
ylides with mercaptan [50]. Considering we are in much need of
efficient method for preparation of 2-aminothiazoles based on our
previously study of GSTO1ꢀ1 inhibitors, we envisaged that 2-
aminothiazole ring could be obtained through carbene insertion
from sulfoxonium ylides and thiourea followed by subsequent
cyclocondensation. Herein, we report an efficient strategy for the
synthesis of 2-aminothiazoles by means of Rh2(OAc)4-catalyzed
coupling of sulfoxonium ylides with thiourea under mild condition.
This halogen-free method avoids some safety issues of previous
2

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Scheme 3. Large-scale synthesis of 3aa and 3ah.
agent Fanetizole (3 ah) directly from α-benzoyl sulfoxonium ylide
(5 mmol) and 2-phenylethylthiourea (10 mmol), affording the
expected product in 58% yield (Scheme 3b), which justifying the
synthetic applications of the current method.
According to the experimental results and relevant literatures
[27,51], we proposed a plausible mechanistic hypothesis shown in
Scheme 4. Initially, sulfoxonium ylides were activated in the
presence of Rh2(OAc)4 to generate rhodium intermediate A. The
rhodium carbene complexes B was obtained from intermediate A
by the elimination of DMSO, which underwent insertion into SꢀꢀH
bond of tautomeric thiourea to form the intermediate C, and
subsequent nucleophilic attack between the amino group and
carbonyl group afforded the product 3aa and released the rhodium
catalyst.
In summary, we presented a simple and efficient Rh-catalyzed
carbene insertion and annulation reaction to access a variety of 2-
aminothiazoles. This strategy features mild condition, high
selectivity, simple operation and employment of sulfoxonium
ylides instead of the diazo compounds or α-haloketones, making it
more attractive and practical. Moreover, this process exhibites
good functional group compatibility and chemoselectivity. We
believe that this useful strategy may have promising and
significant applications in metal carbene chemistry and prepara-
tion of biologically potent 2-aminothiazoles.
Scheme 2. The synthesis of 2-aminothiazoles derivatives. Reaction conditions: 1a
(0.2 mmol), 2a (0.4 mmol), Rh2(OAc)4 (5 mol%), DCE (1.5 mL), desired product 3 was
isolated by column chromatography on silica gel (eluent: PE/EA = 10/1).
electron-withdrawing groups make the carbonyl more susceptible
to nucleophilic attack by the amino group in the cyclocondensation
step. Notably, other factors including the positions of substitution,
size of groups and steric effect had little effect on the reaction. To
our delight, the substrates containing 1,3-benzodioxole group,
furan and thiophene rings or naphthalene could also be tolerated
well to generate the respective products in 53%–74% yields (3ma-
3qa). When the phenyl group was replaced by alkyl groups, the
yields of products were decreased to 23%–40% (3ra and 3ta). It was
worth mentioning that the reaction using alkenyl substituted ylide
also formed corresponding product 3sa in more thermodynami-
cally stable E-configuration. Among these examples, no NꢀꢀH
insertion products were observed in terms of chemoselectivity. We
then tried reaction with urea, still no desired product was
observed.
Furthermore, the scope of thiourea derivatives was studied
under the standard procedure. A series of 1-phenylthiourea
derivatives with methyl, trifluoromethyl or chloride group
substituted at different positions of phenyl ring all reacted
smoothly affording the corresponding products in high yields
(3ab-3af, 3ai). Also, 1-methylthiourea exhibited good reactivity
giving the product 3ag in 71% yield. Especially, this method could
be successfully applied for the synthesis of anti-inflammatory
agent Fanetizole 3ah from α-benzoyl sulfoxonium ylide and 2-
phenylethylthiourea in 64% yield. It was noted that using these
asymmetrical thiourea derivatives did not form any isomers
indicating that the cyclization reaction preferred the unsubstituted
side, probably due to the less steric hindrance and the stronger
nucleophilicity of primary amines.
Declaration of competing interest
The authors report no declarations of interest.
Acknowledgments
We are grateful for the support from the National Natural
Science Foundation of China (Nos. 81373259 and 81573286) and
Sichuan Science and Technology Program (Nos. 2020YJ0221 and
2018JY0537).
To show the usefulness and practical synthesis of this method,
we carried out a large-scale reaction of α-benzoyl sulfoxonium
ylide 1a (5 mmol) with thiourea 2a (10 mmol) under standard
condition. It turned out that this reaction proceeded smoothly to
afford 3aa in a yield of 67% (Scheme 3a). We have also performed a
large scale of reaction for synthesizing the anti-inflammatory
Scheme 4. Proposed mechanism for the formation of 3aa.
3

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