Iodine-promoted selective synthesis of substituted aminothiazole via a self-sorting reaction network

Article abstract of DOI:10.1016/j.tetlet.2014.05.101

An iodine-promoted selective synthesis has been developed for the construction of substituted aminothiazole from easily available aryl methyl ketones and thiourea under metal free conditions. This domino process involves the cleavage of CH, CO, CS bonds and the formation of CN, CO, CS bonds.

Full text of DOI:10.1016/j.tetlet.2014.05.101

Accepted Manuscript
Iodine-promoted selective synthesis of substituted aminothiazole via a self-
sorting reaction network
Wei-jian Xue, Kai-lu Zheng, Hong-zheng Li, Fang-fang Gao, An-xin Wu
PII:
S0040-4039(14)00932-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.101
TETL 44692
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 April 2014
19 May 2014
26 May 2014
Please cite this article as: Xue, W-j., Zheng, K-l., Li, H-z., Gao, F-f., Wu, A-x., Iodine-promoted selective synthesis
of substituted aminothiazole via a self-sorting reaction network, Tetrahedron Letters (2014), doi: http://dx.doi.org/
10.1016/j.tetlet.2014.05.101
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Iodine-promoted selective synthesis of
substituted aminothiazole via a self-sorting
reaction network
Leave this area blank for abstract info.
Wei-jian Xue, Kai-lu Zheng, Hong-zheng Li, Fang-fang-Gao and An-Xin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China
Normal University, Wuhan 430079, P. R. China

1
Tetrahedron Letters
jo u rn al h ome p ag e : w ww .e lse vie r .c om
Iodine-promoted selective synthesis of substituted aminothiazole via a self-sorting
reaction network
Wei-jian Xue, Kai-lu Zheng, Hong-zheng Li, Fang-fang Gao and An-xin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
An iodine-promoted selective synthesis has been developed for the construction of subsituted
aminothiazole from easily available aryl methyl ketones and thiourea under metal free
conditions. This domino process involves the cleavage of C–H, C-O, C-S bonds and the
formation of C–N, C-O, C–S bonds.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
I2-promoted
Selective synthesis
Self-sorting
Reaction network
aminothiazole
1. Introduction
In the previous literature, acetophenone could be sequentially
One of key challenges in modern organic chemistry lies in the
maximisation of synthetic efficiency with the concurrent
minimisation of waste.1 Domino reaction combine a series of
chemical processes in a single operation and are thus considered
highly economical.2 Compared with this, however, reaction
networks are able to integrate several domino reactions in a well-
stirred solution and may thus offer enhanced efficiency in the
direct construction of complex compounds from simple
molecules.3 Based on this idea, we focus our attention on the
integration of multiple domino sequences to construct reaction
network, such as, a self-sorting domino reaction,4 a focusing
domino reaction,5 and a self-labor domino reaction.6 In this
paper, a novel self-sorting reaction network has been reported for
the construction of substituted aminothiazole from simple and
readily available starting substrates.
converted to phenylglyoxal via iodination and Kornblum
oxidation in the presence of DMSO.9 In addition, the iodination
of acetophenone leads to the formation of phenacyl iodine, which
can react with thiourea to form 4-aryl-2-aminothiazoles
derivatives.10 In the current study, the previously reported
reactions were integrated for the synthesis of substituted
aminothiazole compounds from simple and readily-available
aromatic ketones and thiourea (Scheme 1). Moreover, a novel
procedure for the methylthiolation of aryl C-H bonds was applied
with DMSO as the methylthiolation reagent.
DMSO is a versatile solvent that can be used as an oxidant in
Kornblum oxidation7 or as
a reagent in some organic
transformations.8 For example, Qing reported a copper-mediated
methylthiolation of aryl C-H bonds, which employed DMSO as a
methylthiolation reagent.8a In additioin, Cheng and Chen reported
a copper-mediated methylthiolation of aryl halides with DMSO.8b
Kantam also reported a process for the methylthiolation of aryl
halides with CuI and Zn(OAc)2, which utilized DMSO as a
source of methylthiolation.8c Moreover, Yu and coworkers
reported a Lewis acid (AgI, NiII, or FeII) catalyzed, CuII-
mediated thiolation reaction with DMSO as a methylthiolation
reagent.8d Herein, the reaction utilized DMSO in three
Scheme 1. Integration of two Domino Sequences.
important roles: as solvent, oxidant and reagent.
———
* Corresponding author. Tel./fax: +86 027 6786 7773; e-mail: chwuax@mail.ccnu.edu.cn (A. X. Wu)

2
Tetrahedron
2. Results and discussion
material in the reaction. The structure of the product was further
confirmed by an X-ray crystallographic study of 3a (Fig. 1).11
Table 2. Reaction scope of methyl ketonesa
The present study was initiated with acetophenone (1a) and
thiourea (2) as model substrates for the optimization of the
reaction conditions. The reaction was screened over a variety
of different temperatures, and 80 °C was determined as the
optimum temperature (Table 1, entry 3). Various additives
were also screened in the reaction, but only TsOH led to a
discernible increase in the product yield (Table 1, entry 9).
The dosage of iodine was also investigated, but neither
increases nor decreases in the dosage were shown to lead to
an improved product yield (Table 1, entries 16-19). Based on
the results of the aforementioned screening experiments, the
optimal reaction conditions were identified as 1 equiv of
acetophenone (1a), 0.5 equiv. of thiourea (2) and 1 equiv of
iodine in DMSO at 80 °C (Table 1, entry 9).
Entry
1 (R)
3
Yieldsb (%)
1
2
3
4
5
6
7
8
9
1a (C6H5)
3a
3b
3c
3d
3e
3f
55
58
42
40
54
50
53
43
0
1b (4-MeC6H4)
1c (4-MeOC6H4)
1d (4-EtOC6H4)
1e (4-FC6H4)
1f (4-ClC6H4)
1g (4-BrC6H4)
1h (2-Naphthyl)
1i (4-NO2-C6H4)
3g
3h
3i
Table 1. Optimization of the reaction conditionsa
a Reaction conditions: 1 (1.0 mmol), 2 (0.5 mmol), TsOH (0.25 mmol)
and I2 (1.0 mmol) in DMSO (3 mL) at 80 oC for 12 h.
b Isolated yields.
Entry
1
I2 (equiv)
1.0
Addition (equiv)
Temp (oC)
40
Yield (%)b
0
2
1.0
60
12
48
40
28
38
30
22
55
21
10
11
12
10
11
0
3
1.0
80
4
1.0
100
120
80
5
1.0
6
1.0
CuI (0.25)
CuO (0.25)
80
7
1.0
80
8
1.0
AlCl3 (0.25)
TsOH (0.25)
AcOH (0.25)
HCl (0.25)
80
9
1.0
80
10
11
12
13
14
15
16
17
18
19
1.0
80
1.0
80
1.0
CsCO3 (0.25)
Na2CO3 (0.25)
K2CO3 (0.25)
DBU(0.25)
80
1.0
Fig. 1. X-ray crystal structure of compound 3a.
80
1.0
80
1.0
80
TsOH (0.25)
TsOH (0.25)
TsOH (0.25)
TsOH (0.25)
80
0.5
1.5
2.0
38
41
40
80
80
a Reaction conditions: 1a (1.0 mmol), 2 (0.5 mmol) in 3 mL DMSO for 12 h.
b Isolated yields.
With the optimal reaction conditions in hand, the scope and
generality of this procedure was subsequently examined using a
range of aryl methyl ketones (Table 2). The reaction was
successfully applied to a range of substituted aromatic ketones,
with the corresponding products being formed in moderate yields.
Aromatic ketones bearing electron-donating groups (e.g., 4-Me,
4-OMe, and 4-OEt) reacted smoothly under the optimized
conditions to provide the corresponding products 3b-d in
moderate yields (40–58%, Table 2). Slightly lower yields were
obtained when the optimized conditions were applied to aromatic
ketones bearing electron-withdrawing halogen groups (e.g., 4-F,
4-Cl, and 4-Br), with the corresponding products 3e-g obtained in
moderate yields (50–54%, Table 2). Furthermore, 2-naphthyl-
methyl ketone (1h) was also seen to react smoothly under the
optimized conditions to give the aminothiazole product (3h) in
moderate yield (43%, Table 2). However, 4-Nitroacetophenone
was found unable to react under the standard conditions (Table 2,
3i), which suggested that the strong electron-withdrawing groups
at the para position of the aromatic ketone had an adverse impact
on the reaction. No target molecule could be found when 1-
methylthiourea and 1-phenylthiourea were used as starting
Scheme 2. The controlled experiments to prove the mechanism.
To gain some insights into the mechanism of the reaction, a
series of control experiments were performed. Acetophenone
(1a) was converted into α-iodo acetophenone (1aa) in 96% yield
using the I2/CuO system (Scheme 2 (1)). When acetophenone 1a
was heated with I2 in DMSO at 100 oC in the absence of thiourea
(2), the substrate was transformed into phenylglyoxal (1ab) or
hydrated hemiacetal (1ac) in quantitative conversion (Scheme 2
(2)). The target molecule (3a) could also be obtained from the

3
reaction between α-iodo acetophenone (1aa) and thiourea (2)
(Scheme 2 (3)). Moreover, intermediate 2-aminothiozole (4a)
could be obtained from acetophenone (1a) and thiourea (2) in
Based on the aforementioned results and previous reports, a
plausible mechanism for the current reaction was proposed as
follows with acetophenone (1a) as an example (Scheme 5).
Initially, substrate 1a was converted into the intermediate α-iodo
acetophenone (1aa) in the presence of I2. Subsequently, the
oxidation of intermediate 1aa by DMSO occurred to yield
intermediate phenylglyoxal (1ab) or hydrated hemiacetal 1ac.
Meanwhile, α-iodo acetophenone (1aa) reacted with thiourea (2)
to generate intermediate 2-aminothiozole (4a). Intermediate 4a
could then be converted to 4b in the presence of I2 and DMS.4
The reaction of hydrated hemiacetal 1ac with thiourea (2)
afforded intermediate A, which subsequently underwent a
Kornblum oxidation reaction to generate the desired product 3a.
In the process, the byproduct HI was oxidized by DMSO to
regenerate at least 0.5 equiv of iodine.9
o
EtOH at 78 C (Scheme 2 (4)). Furthermore, DMSO-D6 was
subjected to the transformation and the target molecule (3a’) was
obtained (Scheme 2 (5)), which indicated that the methylthio in 3
originated from DMSO.
3. Conclusion
In conclusion, this work has proposed an iodine-promoted
self-sorting reaction network for the construction of
aminothiazole derivatives from readily-available methyl ketones
and thiourea. Notably, this metal-free transformation generated
five new bonds including two C-N bonds, one C-O bond and two
C-S bonds. Further studies towards the applications of this
reaction will be reported in due course.
Scheme 3. The controlled experiment to prove the mechanism.
Subsequently, 2-aminothiozole (4a) was used as a starting
material to react with 4’-methylacetophenone (1b) to form the
target molecule (Scheme 3). However, the product (3ab) could
not be obtained and the byproduct 5ab was separated, which
indicated that the 5-position of thiazole was more likely to react
with aryl methyl ketones than the amino of aminothiazole.
Acknowledgments
This work was supported by the National Natural Science
Foundation of China (Grant Nos. 21032001 and 21272085). We
also acknowledge the excellent doctorial dissertation cultivation
grant from Central China Normal University (2013YBYB53).
References and notes
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Appl. Chem. 2000, 72, 1233; (c) Anastas P.; Eghbali, N. Chem.
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Chem., Int. Ed. 2010, 49, 4976; (e) Zhu, Y. P.; Gao, Q. H.; Lian,
M.; Yuan, J. J.; Liu, M. C.; Zhao, Q.; Wu, A. X. Chem. Commun.
2011, 47, 12700.
Scheme 4. The step by step experiment for the addition of aryl methyl
ketones.
The proposed mechanism was further verified through a step
by step examination of the addition process of intermediate 2-
aminothiozole (4a) and aryl methyl ketones under the standard
conditions (Scheme 4). Intermediate 2-aminothiozole (4a) was
added in the vessel under the standard conditions for 4h. The
target molecules were then obtained following the addition of
various aryl methyl ketones. This confirmed that the 5-position of
thiazole was more likely to react with aryl methyl ketones than
the amino of aminothiazole.
2. For selected examples, see: (a) Tietze, L. F.; Brasche, G.; Gericke,
K. Domino Reactions in Organic Synthesis; Wiley-VCH:
Weinheim, Germany, 2006; (b) Zhu, J. P.; Bienaymé, H.
Multicomponent Reactions; Wiley-VCH: Weinheim, 2005; (c)
Tietze, L. F. Chem. Rev. 1996, 96, 115.
3. For selected examples, see: (a) Whitesides, G. M.; Ismagilov, R. F.
Science 1999, 284, 89; (b) Gerdts, C. J.; Sharoyan, D. E.;
Ismagilov, R. F. J. Am. Chem. Soc. 2004, 126, 6327; (c) Ganem, B.
Acc. Chem. Res. 2009, 42, 463.
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6. Xue, W. J.; Li, Q.; Zhu, Y. P.; Wang, J. G.; Wu, A. X. Chem.
Commun. 2012, 48, 3485.
7. For selected examples, see: (a) Kornblum, N.; Powers, J. W.;
Anderson, G. J.; Jones, W. J.; Larson, H. O.; Levand, O.; Weaver,
W. M. J. Am. Chem. Soc. 1957, 79, 6562; (b) Kornblum, N.; Jones,
W. J.; Anderson, G. J. J. Am. Chem. Soc. 1959, 81, 4113; (c)
Paquette, W. D.; Taylor, R. E. Org. Lett. 2004, 6, 103.
8. (a) Chu, L.; Yue, X.; Qing, F. L. Org. Lett. 2010, 12, 1644; (b)
Luo, F.; Pan, C.; Li, L.; Chen, F.; Cheng, J. Chem. Commun. 2011,
47, 5304; (c) Joseph, P. J. A.; Priyadarshini, S.; Kantam, M. L.;
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Huang, F.; Yu, Z.; Gao, Y. F. J. Org. Chem. 2012, 77, 4414.
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X.; Cao, L. P.; She, N. F.; Wu, A. X. Org. Lett. 2010, 12, 4026.
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Yang, Y.; Wu, A. X. Tetrahedron 2012, 68, 173.
11. The details of the crystal data have been deposited with
CambridgeCrystallographic Data Centre as Supplementary
Publication, CCDC995977.
Scheme 5. The plausible mechanism of the present reaction.

4
Tetrahedron
Supplementary Material
Evidence in support of the hypothetic mechanism, and 1H and
13C NMR spectra and X-ray crystal data for 3a. Supplementary
data related to this article can be found online at doi:
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