One-pot three-component protocol for the synthesis of substituted 2-aminothiazoles

Article abstract of DOI:10.1080/00397911.2017.1350275

Substituted 2-aminothiazoles have been synthesized from α-nitro-epoxides, cyanamide, and sodium sulfide through a facile, three-component, and ecofriendly protocol with good to excellent yields. This reaction was achieved at room temperature without any additives. A possible mechanism has also been proposed.

Full text of DOI:10.1080/00397911.2017.1350275

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
One-Pot Three-Component Protocol for the
Synthesis of Substituted 2-Aminothiazoles
Shanshan Guo, Donghong Zhao, Yue Zhu, Yongping Yu, Wenteng Chen &
Guolin Zhang
To cite this article: Shanshan Guo, Donghong Zhao, Yue Zhu, Yongping Yu, Wenteng Chen
& Guolin Zhang (2017): One-Pot Three-Component Protocol for the Synthesis of Substituted 2-
Aminothiazoles, Synthetic Communications, DOI: 10.1080/00397911.2017.1350275
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1350275
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Date: 10 July 2017, At: 22:37

One-Pot Three-Component Protocol for the Synthesis of Substituted 2-
Aminothiazoles
Shanshan Guo1, Donghong Zhao1, Yue Zhu1, Yongping Yu1, Wenteng Chen1,, Guolin
Zhang1,*
1Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of
Pharmaceutical Sciences, Zhejiang University, Hangzhou, P. R. China
Corresponding author Wenteng Chen Zhejiang Province Key Laboratory of Anti-Cancer
Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou,
310058, P. R. China E-mail: wentengchen@zju.edu.cn; Guolin Zhang
guolinzhang@zju.edu.cn
Abstract
Substituted 2-aminothiazoles have been synthesized from α-nitro-epoxides, cyanamide
and sodium sulfide via a facile, three-component, and eco-friendly protocol with good to
excellent yields. This reaction was achieved at room temperature without any additives.
A possible mechanism has also been proposed.
Graphical Abstract
KEYWORDS: Multicomponent; 2-aminothiazoles; α-nitro-epoxides; cyanamide;
sodium sulfide
INTRODUCTION
1

2-aminothiazole as one of the most important aza-heterocyles plays an important
role in many complex natural products and pharmaceutical compounds, such as
sulfathiazole (a common oral and topical antimicrobial), abafungin (a broad-
spectrum antifungal agent) and dasatinib (a multi-BCR/Abl and Src family
tyrosine kinase inhibitor for various Leukemias) (Figure 1). Moreover, 2-
aminothiazoles have drawn much attention from medicinal chemists worldwide
because of their broad biological activity, including antimicrobial [1], antiviral [2],
antiprion [3], anti-inflammatory [4], anticancer [5], and so on.
In view of the importance of the 2-aminothiazoles, a great deal of attention has
been given to its organic synthesis. Among them, the most prominent method to
synthesize 2-aminothiazoles is Hantzsch cyclocondensation and its various
improved methods [6], which involve condensation of a-haloketones with thiourea
in the presence of various catalysts. Recently, one-pot protocol directly starting
from ketones/aldehyde and thioureas has also been reported using halogenating
reagent or catalysts [7]. Also, 2-aminothiazoles are also prepared via the reaction
between isothiocyanates and oxime acetates or amine hydrochlorides [8]. Moreover,
2-aminothiazoles could be produced by treating styrenes with NBS via co-oxidant
free, in situ formation of α-bromoketone in the presence of thiourea [9]. However,
longer reaction time, harsh reaction conditions, the use of less environmentally
friendly reagents, and expensive catalysts limited its utility. Therefore, it is
desirable and challenging to develop a facile, eco-friendly approach for the
synthesis of 2-aminothiazoles.
2

Herein we present a facile, multi-component, and eco-friendly protocol for the synthesis
of 2-aminothiazoles with good to excellent yields from α-nitro-epoxides, cyanamide and
sodium sulfide.
RESULTS AND DISCUSSION
Initially, α-nitro-epoxide 1d, cyanamide 2 were selected as model reactants to optimize
the reaction conditions (Table 1). We found that the formation of 2-aminothiazole 4d
with an acceptable yield (80%) in the presence of Na2S·9H2O in n-propanol at room
temperature (Table 1, entry 1). However, when using NaHS instead of Na2S·9H2O, the
conversion of 4a was significantly decreased to 55% (Table 1, entry 2), so we selected
Na2S·9H2O as a sulfide reagent. Subsequent screening of reaction temperatures showed
that the room temperature was the best (Table 1, entries 2 and 3). Further studies found
that the solvent of the reaction had a significant impact on the efficiency for the
formation of 4d, and n-propanol was found superior to other aprotic and protic solvents
(Table 1, entries 4–9). Furthermore, optimization of the different stoichiometric amount
of Na2S·9H2O showed that the conversion of 2-aminothiazole 4d increased to 87% or
86%, respectively, when the amount of Na2S·9H2O was risen to 3 or 4 equiv (Table 1,
entries 11 and 12). However, there was no improved after reducing the amount of
Na2S·9H2O to 1 equiv (Table 1, entry 10). Besides, the screening of the stoichiometric
amount of cyanamide (Table 1, entries 13–15) showed that the best conversion was
obtained when using 3 equiv of cyanamide (Table 1, entry 14). On the basis of this initial
3

study, the optimal reactivity was obtained in n-propanol at room temperature when the
mole ratio of α-nitro-epoxide, cyanamide and Na2S·9H2O was 1:3:3 (Table 1, entry 14).
With the optimized reaction conditions in hand, we next investigated the generality
and scope of the methodology for the synthesis of 2-aminothiazoles using a set of
α-nitro-epoxides, which were readily prepared according to the literature [10] and
the results were summarized in Table 2. When the electron-rich and -deficient
benzene rings as the substituent R1 (Table 2, 4a
-4o, except 4j and 4k), α-nitro-
epoxides participated well to provide the corresponding 2-aminothiazoles in good
to excellent yields. Generally, α-nitro-epoxides with electron-deficient groups at
the R1 position gave relatively poorer results (Table 2, 4a
4n vs 4o). Additionally, the steric hindrance has a slightly effect on the reaction
yields (Table 2, 4c vs 4f 4d vs 4g 4h). However, when a heteroaryl group (Table
, 4b vs 4c–4e; 4l vs 4m;
;
,
2, 4k) or an alkyl group (Table 2, 4j) was at the R1 position, the yields of this
reaction had a slightly decrease. Moreover, when using ethyl group (Table 2, 4l
and 4m) or aryl group (Table 2, 4n and 4o) instead of methyl group at the R2
position, the reaction can also afford the desired products. However, there was
only trace or no desired product obtained when cyanamide was replaced with
cyano substituted secondary amine or amide (Table 2, 4p and 4q).
The structures of 2-aminothiazoles were characterized by IR, 1H NMR, 13C NMR, and
HRMS (ESI). On the basis of the results above, we proposed the following possible
mechanism for this reaction, as outlined in Scheme 1. In the case of sodium sulfide,
4

cyanamide 2 would undergo a nucleophilic attack to give intermediate A with a powerful
nucleophilic center [11], which makes the α-nitro-epoxides 1 undergo a ring opening to
afford intermediate B followed by the formation of intermediate C with the elimination
of the nitro [12]. Then intramolecular nucleophilic attack of intermediate C would afford
2-aminothiazoles 3 with the elimination of water.
CONCLUSION
In summary, we have developed a facile, multi-component, and eco-friendly protocol for
the one-pot synthesis of 2-aminothiazoles with good to excellent yields from α-nitro-
epoxides, cyanamide and sodium sulfide. This reaction has the advantages of available
starting materials, mild reaction conditions and no need for any additives. These features
made this reaction as a widely used approach in medicinal chemistry.
EXPERIMENTAL SECTIONS
Purifications of reaction products were carried out by chromatography using silica gel
(200 – 300 mesh). Melting points were recorded on a BÜCHI B-540 melting point
apparatus. NMR spectra were recorded for 1H NMR at 500 MHz and 13C NMR at 125
MHz. For 1H NMR, tetramethyl-silane (TMS) served as internal standard (δ = 0) and data
are reported as follows: chemical shift, integration, multiplicity (s = singlet, d = doublet, t
= triplet, Q = quartet, m = multiplet), and coupling constant (s) in Hertz. For 13C NMR,
TMS (δ = 0) or DMSO (δ = 40.45) was used as internal standard and spectra were
obtained with complete proton decoupling. HRMS data was obtained using Agilent
Technologies 6224 TOF LC/MS. Unless otherwise noted, all reagents were obtained
5

commercially and used without further purification The starting material α-nitro-epoxides
1a-1o were prepared according to literature methods [10]. The starting material cyanamide
and Na2S·9H2O were commercially available, and 2p, 2q were prepared according to
literature methods [13]
.
General Procedure For The Synthesis Of 4
A mixture of α-nitro-epoxides 1 (0.5 mmol), cyanamide 2 (1.5 mmol), Na2S·9H2O (1.5
mmol) was stirred in n-propanol 2 mL at room temperature for 8 h. After the
completeness of the reaction, the reaction was diluted with water and extracted three
times with ethyl acetate. The combined organic extracts were washed with brine, dried
over Na2SO4, concentrated, and purified by column chromatography on silica gel to
afford the desired product 4.
4-methyl-5-(p-tolyl)thiazol-2-amine (4a): Yellow solid, 76.5 mg, yield 75%; mp: 147.4 –
148.6°C; 1H NMR (500 MHz, CDCl3) δ = 7.29 – 7.26 (m, 2H), 7.22 – 7.18 (m, 2H), 5.10
(s, 2H), 2.38 (s, 3H), 2.31 (s, 3H); 13C NMR (125 MHz, CDCl3) δ = 164.9, 143.0, 136.7,
129.8, 129.3, 128.7, 121.3, 21.2, 16.0; HRMS (ESI): m/z calcd for C11H12N2S [M+H]+:
205.0799, found: 205.0797.
SUPPORTING INFORMATION
Supplemental data (full experimental procedures and characterization data) can be
accessed on the publisher’s website.
6

FUNDING
This project was supported from Zhejiang Provincial Natural Science Foundation of
China (LY16H300001) to G. Zhang, National Natural Science Foundation of China (No.
81273356 and 81473074), National Science & Technology Major Projects for "Major
New Drugs Innovation and Development" of China (2014ZX09304002-007) and
Osteoporosis & Breast Cancer Research Center, USA to Y. Yu, National Natural Science
Foundation of China (No. 81402778) to W. Chen.
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Table 1. Optimization of reaction conditions a
Entry S2- (equiv)
Solvent
Na2S·9H2O (2) n-propanol rt
NaHS (2) n-propanol rt
Na2S·9H2O (2) n-propanol 40
T/°C Conversion b/%
1
83 (80) c
2
55
3
75
4
Na2S·9H2O (2) MeOH
Na2S·9H2O (2) EtOH
Na2S·9H2O (2) Acetone
Na2S·9H2O (2) MeCN
Na2S·9H2O (2) DMF
Na2S·9H2O (2) DCE
rt
rt
rt
rt
rt
rt
72
5
52
6
37
7
58
8
20
9
59
10
11
12
13 d
14 e
15 f
Na2S·9H2O (1) n-propanol rt
Na2S·9H2O (3) n-propanol rt
Na2S·9H2O (4) n-propanol rt
Na2S·9H2O (3) n-propanol rt
Na2S·9H2O (3) n-propanol rt
Na2S·9H2O (3) n-propanol rt
77
87 (84) c
86 (84) c
82 (78) c
88 (86) c
87 (85) c
a Reaction conditions: α-nitro-epoxide (0.5 mmol, 1.0 equiv), cyanamide (2.5 mmol, 5.0
equiv), Na2S·9H2O/NaHS, 2 mL of solvent, 8 h, T/°C.
b Determined by LC-MS, based on the disappearance of the starting α-nitro-epoxide. The
most efficient entry is highlighted in bold.
c Isolated yield.
d Reaction was performed using 2.0 equiv of cyanamide.
10

e Reaction was performed using 3.0 equiv of cyanamide.
f Reaction was performed using 4.0 equiv of cyanamide.
11

Table 2. Scope of the reaction of α-nitro-epoxides, cyanamide and Na2S·9H2O
under optimal conditions a
a Reaction conditions: α-nitro-epoxides (0.5 mmol, 1.0 equiv), cyanamide (1.5
mmol, 3.0 equiv), Na2S·9H2O (1.5 mmol, 3.0 equiv), 2 mL of n-propanol, 8 h, rt.
Isolated yield.
12

Scheme 1. Proposed mechanism for the synthesis of 2-aminothiazoles.
13

Figure 1. Some drugs incorporating the 2-aminothiazole moiety
14