An efficient synthesis of imidodicarbonic diamides from 1,3-thiazetidin-2-ones with NH2OH·HCl via ring-opening reaction

Article abstract of DOI:10.1016/j.cclet.2014.10.015

A ring-opening process of 4-imino-1,3-thiazetidin-2-ones with NH₂OH·HCl was described for the first time. Two different scaffolds of imidodicarbonic diamide were obtained selectively in good yields in the presence of organic base. The obtained imidodicarbonic diamides were demonstrated by X-ray diffraction analysis.

Full text of DOI:10.1016/j.cclet.2014.10.015

Accepted Manuscript
Title: An efficient synthesis of imidodicarbonic diamides from
1,3-thiazetidin-2-ones with NH2OH<ce:glyph
name="rad"/>HCl via ring-opening reaction
Author: Wen-Yuan Tang Jing-Jing Guo Xing-Xing Gui
De-Man Han Jian-Jun Li
PII:
S1001-8417(14)00438-0
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.cclet.2014.10.015
CCLET 3121
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
8-7-2014
9-9-2014
9-10-2014
Please cite this article as: W.-Y. Tang, J.-J. Guo, X.-X. Gui, D.-M. Han, J.-J.
Li, An efficient synthesis of imidodicarbonic diamides from 1,3-thiazetidin-2-ones
¨
¨
with NH2OH<ce:glyph name=rad/>HCl via ring-opening reaction, Chinese Chemical
Letters (2014), http://dx.doi.org/10.1016/j.cclet.2014.10.015
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Graphical Abstract
An efficient synthesis of imidodicarbonic diamides from 1,3-thiazetidin-2-ones with NH2OH·HCl via ring-opening reaction
Wen-Yuan Tanga, Jing-Jing Guob, Xing-Xing Guib, De-Man Hana, Jian-Jun Lib,*
a College of Pharmaceutical and Chemical Engineering, Taizhou University, Zhejiang 317000, China
b Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of
Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China
O
O
R2
H2N
N
R1
N
R1 = aryl
R2 = aryl
H
O
NH2OH HCl
S
O
N
R1
imidazole/EtOH
R2
R1 = Ph
R2 = i-Pr, n-Bu
N
R1
N
NH2
R2
A ring-opening process of 4-imino-1,3-thiazetidin-2-ones with NH2OH·HCl was described for the first time. Two different scaffolds of
imidodicarbonic diamide were obtained selectively in good yields in the presence of organic base. The obtained imidodicarbonic diamides
were demonstrated by X-ray diffraction analysis.
Page 1 of 6

Original article
An efficient synthesis of imidodicarbonic diamides from 1,3-thiazetidin-2-ones with
NH2OH·HCl via ring-opening reaction
Wen-Yuan Tanga, Jing-Jing Guob, Xing-Xing Guib, De-Man Hana, Jian-Jun Lib,∗
aCollege of Pharmaceutical and Chemical Engineering, Taizhou University, Zhejiang 317000, China
bKey Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang
University of Technology, Hangzhou 310014, China
ARTICLE INFO
ABSTRACT
Article history:
Received 8 July 2014
Received in revised form 9 September 2014
Accepted 9 October 2014
Available online
A ring-opening process of 4-imino-1,3-thiazetidin-2-ones with NH2OH·HCl was described for
the first time. Two different scaffolds of imidodicarbonic diamide were obtained selectively in
good yields in the presence of organic base. The obtained imidodicarbonic diamides were
demonstrated by X-ray diffraction analysis.
Keywords:
Imidodicarbonic diamides
1,3-Thiazetidin-2-one
Hydroxylamine hydrochloride
Ring-opening
1. Introduction
Imidodicarbonic diamides (Fig. 1) exhibit a wide range of biological activities, such as anti-tumor and antioxidation [1-4].
Furthermore, they play a key role in the synthesis of macrocyclic nitrogen-containing compounds such as mononitrobiuret (MNB) and
1,5-dinitrobiuret (DNB) [5-8]. In general, they can be obtained from a certain purines by oxidation or decomposition [9-10]. However,
the synthesis of these compounds has received very little attention.
Fig. 1. Structure of imidodicarbonic diamide, MNB and DNB.
It is well known that the four-membered heterocycle 4-imino-1,3-thiazetidin-2-ones 1 are useful organic intermediates in organic
synthesis. Recently, our group [11] reported the ring-opening reaction of 1 with N2H4·H2O (Scheme 1). As an extension, herein, we
wish to study the ring-opening reaction in the presence of hydroxylamine. The experiment results showed the title products were
imidodicarbonic diamides 2 rather than 1,2,4-oxadiazol-5-ones.
Scheme 1. Ring-opening reaction of 1 with N2H4·H2O or NH2OH·HCl.
———
∗ Corresponding author.
E-mail address: lijianjun@zjut.edu.cn (Jian-Jun Li)
Page 2 of 6

2. Experimental
Analytical grade solvents and commercially available reagents were used without further purification. The flash column
chromatography was carried out over silica gel (200-400 mesh), purchased from Qingdao Haiyang Chemical Co., Ltd. Melting points
were determined on a Büchi B-540 capillary melting point apparatus and uncorrected. IR spectra was recorded on an AVATAR-370,
samples were prepared as KBr plates. 1H NMR and 13C NMR spectra were recorded at VARAIN-400 using CDCl3 as the solvent with
tetramethylsilane (TMS) as an internal standard. Chemical shifts are given in δ relative to TMS, the coupling constants J are given in
Hz. Mass spectra were measured with Thermo Finnigan LCQ-Advantage. High resolution mass spectral (HRMS) analyze were
measured on an Agilent 6210 TOF LC/MS using ESI or EI (electrospray ionization) techniques. The X-ray data was recorded on
Gemini Ultra EXXH-236/09.
Syntheses of 4-(arylimino)-1,3-thiazetidin-2-ones 1a-1j: To a mixture of ethyl acetate (25 mL), sodium bicarbonate (11.5 mmol,
0.97 g) and thioureas (5 mmol), BTC [bis(trichloromethyl)carbonate] (1.7 mmol, 0.5 g) was added carefully in portions. The reaction
mixture was stirred at room temperature for 15 min. After completion (by TLC), the mixture was filtered, the organic solvent was
condensed and the compounds 1 were obtained as crystal almost quantitative.
Syntheses of imidodicarbonic diamides 2a-2h and 3f-3h: 3-Aryl-4-(arylimino)-1,3-thiazetidin-2-ones 1 (1 mmol) were added into a
mixture of hydroxylamine hydrochloride (1.2 mmol) and imidazole (1.2 mmol) in ethanol (15 mL). The reaction would last about 25
min at room temperature and the crude product was purified by flash chromatography (ethyl acetate/petroleum ether, 1/6) to provide
the pure product.
Syntheses of 1-alkyl-1-arylureas 4i and 4j: 1 (1.0 mmol) were added into a mixture of hydroxylamine hydrochloride (1.2 mmol) and
imidazole (1.2 mmol) in ethanol (15 mL). The reaction would last about 3 h at room temperature and the crude product was purified by
flash chromatography (ethyl acetate/petroleum ether, 1/8) to provide the pure product.
Syntheses of 1-carbamothioyl-1-phenylureas 5f and 5j: 1 (1.0 mmol) were added into a mixture of hydroxylamine hydrochloride
(1.2 mmol) and pyridine (1.2 mmol) in methanol (15 mL). The reaction would last about 2 h at room temperature and the crude product
was purified by flash chromatography (ethyl acetate/petroleum ether, 1/6) to provide the pure product.
Physical and chemical data of the chosen product is demonstrated below.
o
1-Carbamoyl-1,3-bis(4-chlorophenyl)urea (2a): White solid; mp: 177.6-179.8 C. IR (KBr, cm-1): υmax 3489, 3172, 1681, 1596,
1404. 1H NMR (400 MHz, CDCl3): δ 10.73 (s, 1H), 7.49 (d, 2H, J = 8.8 Hz), 7.40 (d, 2H, J = 8.8 Hz), 7.28 (d, 2H, J = 8.8 Hz), 7.23 (d,
2H, J = 8.8 Hz), 5.18 (s, 2H). 13C NMR (100 MHz, CDCl3): δ 156.7, 151.8, 136.0, 135.6, 135.2, 130.6 (CH×2), 130.4 (CH×2), 128.9,
128.8 (CH×2), 121.2 (CH×2). MS (ESI): m/z 346 [M+Na]+. HRMS-ESI: calcd. for C14H11Cl2N3NaO2: 346.0126; found: 346.0130.
1-Carbamoyl-1-(4-chlorophenyl)-3-phenylurea (3f): White solid; mp: 144.7-147.5 oC. IR (KBr, cm-1): υmax 3482, 3221, 1677, 1602,
1446. 1H NMR(400 MHz, CDCl3): δ 10.36 (s, 1H), 7.48 (d, 2H, J = 8.4 Hz), 7.43 (d, 2H, J = 8.4 Hz), 7.31-7.26 (m, 4H), 7.07 (t, 1H, J
= 7.6 Hz), 5.31 (s, 2H). 13C NMR (100 MHz, CDCl3): δ 157.3, 152.3, 137.1, 136.5, 130.4 (CH×2), 129.7, 129.4 (CH×2), 129.0 (CH×2),
128.9, 121.4 (CH×2). MS (ESI): m/z 312 [M+Na]+. HRMS-ESI: calcd. for C14H12ClN3NaO2: 312.0516; found: 312.0527.
1
1-Isopropyl-1-phenylurea (4i): White solid; mp: 154.9-159.5 oC. IR (KBr, cm-1): υmax 3347, 3187, 1693, 1555, 1442. H NMR (400
MHz, CDCl3): δ 7.26 (d, 4H, J = 7.2 Hz), 7.02-7.05 (m, 1H), 6.70 (s, 1H), 3.97 (m, 1H), 1.15 (dd, 6H, J1 = 2.0 Hz, J2 = 6.4 Hz). 13C
NMR (100 MHz, CDCl3): δ 138.8, 129.3 (CH×2), 123.6, 120.9 (CH×2), 42.4, 23.6 (CH×2). MS (ESI): m/z 179 [M+1]+. HRMS-ESI:
calcd. for C10H15N2O: 179.1184; found: 179.1186.
o
1-(4-Chlorophenyl)-1-(phenylcarbamothioyl)urea (5f): White solid; mp: 117.6-120.1 C. IR (KBr, cm-1): υmax 3435, 3265, 1702,
1
1534, 1033. H NMR(400 MHz, CDCl3): δ 12.46 (s, 1H), 7.56 (d, 2H, J = 7.6 Hz), 7.41-7.36 (m, 4H), 7.26 (d, 1H, J = 7.2 Hz), 7.14
(dd, 2H, J1 = 2.0 Hz, J2 = 7.6 Hz), 3.75 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): δ 182.0, 156.2, 140.0, 136.9, 131.8, 130.5, 129.1
(CH×2), 128.8, 128.7, 128.2, 126.2 (CH×2), 125.0, 54.6. MS (ESI): m/z 321 [M+1]+. HRMS-ESI: calcd. for C15H14ClN2O2S: 321.0465;
found: 321.0465.
3. Results and discussion
3-(4-Chlorophenyl)-4-((4-chlorophenyl)imino)-1,3-thiazetidin-2-one 1a was selected as the starting material for the ring-opening
reaction in our initial studies, which was synthesized from thiourea with triphosgene in excellent yield (up to 95%) [12]. Then 1a was
treated with hydroxylamine hydrochloride in the presence of imidazole under reflux conditions for 35 min. It was found that 1a reacted
with hydroxylamine quickly with the release of H2S (Scheme 2). A novel compound 2a was gotten in 88% yield. The structure 2a was
confirmed via single crystal X-ray diffraction analysis (Fig. 2, details see Supporting information).
Scheme 2. Unexpected 2a was synthesized by 1a.
Page 3 of 6

Fig. 2 The X-ray structure of 2a.
Then, we focused on screening for the reaction conditions promoted by these results in mild conditions. In order to minimize the
generation of side products that could arise from the reaction between substrate 1a and organic base imidazole, the procedure was
firstly proceeded in the presence of equal equivalent of imidazole and NH2OH·HCl before the addition of 1a. Experiment results
showed that the solvents had great influence on this reaction (Table 1). Solvents such as ethanol and CH2Cl2, had little effect on the
yields of 2a (Table 1, entries 2-4). None of 2a (Table 1, entry 1) was observed by using water as solvent. Hence, ethanol was selected
as solvent and imidazole (pKa = 14.5) was chosen as the base to free NH2OH·HCl (pH 6.5) at room temperature [13-16].
With the determined structure of the product and the optimized reaction conditions in hand, we then turned to explore the scope of
this reaction. It showed that 1 reacted with hydroxylamine smoothly, and two products 2 (minor) and 3 (major) were obtained after 25
min (Scheme 3).
Table 1
Preparation of 2a from 1a in different solvents.a
Entry
Solvent
Temp. (oC)
reflux
reflux
reflux
reflux
r.t.
Time (min)
Yield (%)b
1
2
3
4
5
6
7
8
H2O
EtOH
30
35
20
30
25
30
20
50
NDc
88
80
73
87
75
70
82
CH2Cl2
Toluene
EtOH
CH2Cl2
Toluene
EtOH
r.t.
r.t.
0
a All reactions were run with the molar ratio of 1a : NH2OH·HCl : imidazole = 1 : 1.2 : 1.2.
b Isolated yield based on 1a.
c No desired product was detected.
Scheme 3. Regioselective synthesis of 3 from 1.
In order to investigated further similar reactions, various 1,3-thiazetidin-2-ones were subsequently used as the substrates to study the
scope and general applicability of the protocol, as shown in Table 2. In most cases, the desired products were gotten in good yields
(Table 2, 76%-89%). When symmetrical thiourea (R1 = R2) was used in this reaction, the only product (2 = 3) was gotten in the
presence of NH2OH. Then, we turned to study the effects of substrates by using unsymmetrical thiourea (R1 ≠ R2). It was found that
compounds 1 with electron-donating groups showed higher selectivity than these with electron-withdrawing group on benzene ring
(Compounds 1f, 1g and 1h). The regioselectivity of this ring-opening reaction may be correlated with the electron density of the
substituents on the aromatic rings. Moreover, substituents with bulky groups on the aromatic rings showed a dramatic effect on the
formation of 2 (compounds 1g). The higher steric hindrance they had, the lower yields of 2 were obtained. When alkyl groups were
investigated in this reaction, none of the expected compounds 2 and 3 were obtained (Compounds 1i and 1j). The 1,3-δ-shift reaction
occurred, and products of 1-isopropyl-1-phenylurea 4i and 1-butyl-1-phenylurea 4j were in 75% and 68% yield, respectively (Scheme
4).
Table 2
Synthesis of imidodicarbonic diamides 2 and 3 from 4-imino-1,3-thiazetidin-2-ones 1.a
Compound
Thiazetidin (R1)
4-ClC6H4
Thiazetidin (R2)
4-ClC6H4
2-MeC6H4
C6H5
Time (min)
Productb
2a
2b
2c
2d
2e
2f:3f
Yield of 2 (%)c
87
88
89
85
78
84(1:3)
25
23
20
30
27
40
1a
1b
1c
1d
1e
1f
2-MeC6H4
C6H5
4-MeOC6H4
2,5-Me2C6H3
4-ClC6H4
4-MeOC6H4
2,5-Me2C6H3
C6H5
Page 4 of 6

2,6-(i-Pr)2C6H3
4-MeC6H4
i-Pr
C6H5
C6H5
C6H5
C6H5
30
20
150
180
76(1:9)
86(1:4)
NDd
1g
1h
1i
2g:3g
2h:3h
2i:3i
n-Bu
NDd
1j
2j:3j
a All of the new compounds were characterized by 1H NMR, 13C NMR, MS, IR and HRMS.
b Two isomers were obtained and its ratio was determined by 1H NMR.
c Isolated yields based on 1.
d No desired product was detected.
Scheme 4. Synthesis of 4i and 4j.
During the synthesis of imidodicarbonic diamide, we found another experiment phenomenon. When methanol and pyridine were
used, the reaction could also proceed in 2 h. However, we could not obtain the product 4f, while another compound thiourea 5f was
gotten in 47% yield (Scheme 5). The crystal structure of compound 5f was shown in Fig. 3 (details see Supporting information).
Scheme 5. The preparation of 5f.
Fig. 3. X-ray structure of 5f.
Scheme 6. Proposed reaction mechanism.
On the basis of the above experimental results, a possible mechanism is shown in Scheme 6 [17,18]. Intermediates 1 firstly reacted
with NH2OH to form A and H2S. Then, an intramolecular ring-opening reaction took place to afford transition state B in the presence
of H+, followed by addition of proton to afford the imidodicarbonic diamides 2 (R2= Ar). When R2 is alkyl group, B further underwent
in situ 1,3-δ-shift reaction to yield 4. Besides, compound 5 can be obtained by nucleophilic addition of CH3OH to compound 1.
4. Conclusion
In summary, a novel and efficient route for the construction of imidodicarbonic diamides was described, with the advantages of
straightforward procedure, mild conditions, good yields, simple operation, and easily available materials. Furthermore, in similar
Page 5 of 6

conditions, two different scaffolds were obtained selectively in good yields. In addition, the unexpected compounds were confirmed by
X-ray analysis.
Acknowledgment
We are grateful to the Natural Science Foundation of Zhejiang Province (No. LY13B020015) and the Science and Technology Plan
Project of Taizhou (No. 131KY03) for financial support.
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