Formation of 1,4,2-Dithiazolidines or 1,3-Thiazetidines from 1,1-Dichloro-2-nitroethene and Phenylthiourea Derivatives

Article abstract of DOI:10.1021/acs.joc.6b01307

A method for preparation of 1,4,2-dithiazolidine or 1,3-thiazetidine heterocycles was developed by reactions of phenylthioureas with 1,1-dichloro-2-nitroethene. The solvent has a significant influence on the type of product formation. 1,4,2-Dithiazolidines were formed in the aprotic solvent chloroform, while in the protic solvent ethanol, 1,3-thiazetidines were the main products.

Full text of DOI:10.1021/acs.joc.6b01307

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Article
Formation of 1,4,2-Dithiazolidines or 1,3-Thiazetidines from
1,1-Dichloro-2-nitroethene and Phenylthiourea Derivatives
Yian Feng, Minming Zou, Runjiang Song, Xusheng Shao, Zhong Li, and Xuhong Qian
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01307 • Publication Date (Web): 25 Aug 2016
Downloaded from http://pubs.acs.org on August 26, 2016
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Formation of 1,4,2-Dithiazolidines or 1,3-Thiazetidines from
1,1-Dichloro-2-nitroethene and Phenylthiourea Derivatives
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Yian Feng‡a , Minming Zou‡a, Runjiang Songa, Xusheng Shaoa, ∗, Zhong Lia,b and
Xuhong Qiana
a Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and
Technology, Shanghai, 200237, China.
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b Shanghai Collaborative Innovation Center for Biomanufacturing Technology, 130 Meilong Road, Shanghai
200237, China.
ABSTRACT: A method for preparation of 1,4,2ꢀdithiazolidine or 1,3ꢀthiazetidine heterocycles
was developed by reactions of phenylthioureas with 1,1ꢀdichloroꢀ2ꢀnitroethene. Solvent has
significant influence on the formation of product type. 1,4,2ꢀdithiazolidines were formed in
aprotic solvent chloroform, while in protic solvent ethanol, the 1,3ꢀthiazetidines were the main
products.
INTRODUCTION
The main N, Sꢀcontaining heterocycles (NSHs) include thiazoles,1 isothiazoles,2 thiadiazoles,3
dithiazoles,4
thioꢀmorpholines,5
1,4ꢀthiazepines6
and
thiazetidines7
and
their
dihydro/tetrahydroꢀderivatives. The ascendancy and impacts of NSHs are well understood by
scientists across various areas due to their broad applications.8 Thus, discovering novel synthetic
methods or unexploited NSHs is important for fundamental science studies and practical
applications.
The NSHs addressed in this article are 1,3ꢀthiazetidines (TADs) and 1,4,2ꢀdithiazolidines
(DTAs). The fourꢀmembered 1,3ꢀthiazetidines find uses as important intermediates and pesticidal,
antibacterial or antiviral compounds9. Their preparations involved cyclization of thiourea
derivatives with dihaloalkanes or triphosgene10, cyclothiomethylation of anilines by formaldehyde
and hydrogen sulfide,11 highꢀpressure reactions of carbon disulfide, dialkylcyanamides and
benzylideneaniline,12 addition of isothiocyanates with imines13 and threeꢀcomponent reaction of
phosphorodithioate, aldehydes and aldimines.14
The utilizations regarding with 1,4,2ꢀdithiazolidines were scarcely reported probably due to
their limited synthetic choices.15 The rarely reported synthetic methods of DTAs included
cyclization of (methylsulfinyl)methyl carbamimiꢀdothioate,14 reaction of 1,3ꢀdithietane with
anilines16 and condensation of thione Sꢀimide with diphenylmethanethione.17 However, these
synthetic methods have some drawꢀbacks of using uncommon intermediates and limited patterns
∗ Corresponding author. eꢀmail: shaoxusheng@ecust.edu.cn
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Scheme 1. Reactions of DCNE with aryl hydrazides, anthranilic acids and phenylthiourea
Despite the chemical or pharmaceutical importance of TADs and DTAs, limited efforts have
been made for their synthetic methodologies, in particular the synthetic availabilities for DTAs.
We discovered herein a straightforward synthesis of TADs and DTAs from thioureas and
1,1ꢀdichloroꢀ2ꢀnitroethene (DCNE) through solventꢀdependent product selectivity. TADs were
formed in protic solvent ethanol, while in the aprotic solvent chloroform, the DTAs were the main
products.
RESULTS AND DISCUSSION
DCNE can be readily prepared by the chloronitration/dehydrochlorination sequence of
the easily available 1,1ꢀdicloroethylene which is massively used in polymers science.19 The
highlyꢀpolarized ethylene system makes DCNE has the similar reactivity with that of
phosgene, making it can be attacked by nucleophiles such as amines, aryl alcohols and
mercaptans.18 Our recent studies on DCNE chemistry revealed its ability in oxadiazoles
construction and nitroacetylation in reacting with aryl hydrazides and anilines, respectively.
(Scheme 1)19 The above observations stimulated us to explore its reaction behaviors towards
thioureas. To probe the feasibility, diphenylthiourea (DPTU) 2a was treated with DCNE at
0 °C in acetonitrile, affording two new products through direct purification using flash
chromatography. However, NMR and HRMS analysis could not unequivocally confirm the
structure. The exact chemical structures of the two products were afterwards assigned with the
aid of Xꢀray crystallography studies of their analogues 3g and 4e, confirming the products
were fiveꢀmembered 3a and fourꢀmembered 4a rings, respectively.
Having identified the interesting heterocyclic scaffolds, we started the reactionꢀcondition
optimization to raise the yields and improve the selectivity. Initially, the product dependency
on solvents was investigated. A model reaction of DCNE with DPTU 2a was evaluated in
molecular ratio of 1.1:2 at 0 °C (Table 1). Screening of the solvents indicated that the reaction
was sensitive to the solvents. Acetonitrile and ethyl acetate provided almost a 1:1 formation of
3a and 4a (Table 1, entry 1 and 2). The maximum formation of 3a was achieved in
chloroform with a ratio of 5:1 of 3a:4a (Table 1, entry 5). In contrast, the reaction progressed
well in ethanol with excellent selectivity for TAD 4a (66:2) and good yields (Table 1, entry
7).
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Table 1. Solvent dependency of the formation of DTA 3a and TAD 4a
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Entry
Solvent
CH3CN
EtOAc
CH2Cl2
C2H4Cl2
CHCl3
Acetone
C2H5OH
DMF
3a (yields, %) a 4a (yields, %) a
25
23
10
8
1
10
2
23
3
26
8
4
35
7
5
8
31
66
10
trace
trace
n.r.
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2
7
0
8
THF
trace
trace
n.r.b
9
Toluene
H2O
10
11
a The yields were determined by the HPLC analysis. b n.r., no reaction.
With the elucidation of the solvent effects on the reaction, the formation of DTA 3a was
then screened in chloroform. Reducing the reaction temperature to ꢀ10 °C (Table 2, entry 2)
led to the increase of the yield to 49%, while further lowering the temperature caused the
yields decrease. Increase the ratio of DCNE would not have the positive effects to the yields
(Table 2, entry 5ꢀ8). Acid captures Na2CO3 and Cs2CO3 had the detrimental effects to the
reaction accompanying with the great loss of the formation of 3a (Table 2, entry 10 and 11).
Since the conversion proceeded with the formation of side products due to the high reactive
feature of the reactants, therefore, catalysts that can stabilize the DCNE or thioureas were
investigated. Ureas are usually used as organic catalysts operating through formation of
hydrogenꢀbonding interactions with the substrates.20 Etter et al. observed that a urea and a
nitro compound can form ureaꢀnitro group recognition which could catalyze a variety of nitro
compounds including nitroalkenes.21 Thus, diphenylurea (DPU) was evaluated to see its
influence on the reaction. To our delight, the reaction proceeded with more efficiency with a
16% yield increase reaching up to 65% (Table 2, entry 12. In this observation, the diminished
activity of DCNE by hydrogen bonding with urea would favor the formation of 3a. With the
above success, we then turned our attention to stabilize the thiourea. For the fact that thiourea
derivatives are good receptor for anion recognition in particular fluorine anion, by forming
strong hostꢀguest complex,22 therefore, tetrabutylammonium fluoride (TBAF) was subjected
to the reaction. It is interesting to observe a significant yield increase (67%) and a lower
reaction rate (Table 2, entry 13), suggesting the attenuated reactivity of the thiourea by
Hꢀbonding with TBAF. However, coapplication of the DPU and TBAF led to a dramatic
decrease in the yields (Table 2, entry 14).
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A similar optimization process was then performed for the generation of TAD 4a using
DCNE and DPTU 2a in a ratio of 1.1:1 (Table S1). The highest yielding of 4a was achieved
using ethanol at ꢀ25 °C. Notably, the catalysts DPU or TBAF did not have any beneficial
effects to this transformation.
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Table 2. Optimization of the formation of DTA 3a
Entry
1
T (°C)
0
2a:1
Additive
Yields (%)
2:1.1
2:1.1
2:1.1
2:1.1
2:1.5
2:1.7
1:1
ꢀꢀ
35
49
40
35
46
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41
40
49
<5
<5
65
67
ꢀ10
ꢀ15
ꢀ20
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀꢀ
2
ꢀꢀ
3
ꢀꢀ
4
ꢀꢀ
5
ꢀꢀ
6
ꢀꢀ
7
1:2
ꢀꢀ
8
3:1.2
2:1.1
2:1.1
2:1.1
2:1.1
ꢀꢀ
9
Na2CO3
Cs2CO3
DPUa, 0.2eq
TBAFb, 2eq
DPU, 0.2eq
TBAF, 2eq
10
11
12
13
ꢀ10
2:1.2
23
14
a DPU, diphenylurea. b TBAF, tetrabutylammonium fluoride.
By applying the conditions to favor the DTA 3 formation, the reaction scopes were
investigated with varying thioureas (Scheme 2). DPTUs with electronꢀdonating substituents
were well tolerated, despite the moderate yields. Using DPTUs with electronꢀwithdrawing
groups (cyano, nitro, and trifluoromethyl) met with no success with the recovery of the
staring materials, probably due to the low nucleophilicity of the thiourea. A selection of
phenylthioureas were also accommodated in this process. In these observations the exocyclic
double bond isomerized to an endoꢀcyclic one. The substrate 2m with strongꢀwithdrawing
nitro group generated the DTA 3m in 31% yield.
Nꢀcarbamothioylbenzamide 2n and benzothioamide 2o were also competent substrates,
affording 3n and 3o in 37% and 46% yields, respectively. No reactions occurred on
Nꢀ(phenylcarbamothioyl)benzamide 2r or cyclic thiourea 2s. Reaction of 1,3ꢀdimethylthioure
2t gave an intractable mixture without any separable products.
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NO2
or
N
S
R1
NO2
S
CHCl3
NO2
N
R
+
N
2a-t
S
TBAF/-10 o
C
Cl
Cl
S
R
R
DCNE
Substrate investigated
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H
H
H
O
S
S
N
N
N
NH2
R
Ph
N
NH2
Ph
NH2
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S
S
H
R
R
2o
2a-f
2g-m
2n
Unsuccessful substrates
H
N
H
H
O
S
S
N
N
Ph
S
N
N
N
H
N
Ph
S
N
H
H
H
H
R
R
2p-q R = CF3, CN, NO2
O2N
2r
2t
2s
O2N
O2N
O2N
O
S
S
S
S
N
S
N
S
N
S
N
S
N
O
N
N
N
O
O
3d 40%
3a 51%
3c 56%
3b 55%
O2N
O2N
O2N
O2N
S
S
N
S
S
Br
S
S
S
N
Cl
N
S
N
N
N
N
N
H
H
Br
Cl
3f 36%
3h 43%
3g 54%
3e 43%
S
O2N
O2N
O2N
O2N
O
Cl
Br
O
S
S
S
S
S
S
S
N
N
N
N
N
H
N
N
N
H
H
H
3j 45%
3k 44%
O2N
3l 41%
3i 58%
O2N
O2N
NO2
S
S
S
O
S
S
N
S
N
N
N
N
H
H
3m 31%
3n 37%
3o 46%
Scheme 2. Substrate investigation on synthesizing DTA 3
A strong substrate specificity on the formation of TADs 4 was observed (Scheme 3). The
substrates applicable to this conversion are limited to DPTUs and no corresponding TADs
were detected on other thioureas. Fourꢀmembered rings are less stable because of ring strain.
Slight changes in the substituents of electron density may cause their ringꢀopening reaction,
providing a possible explanation for the specific substrate requirements in TAD formation.
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Scheme 3. Substrate investigation on the formation of TAD 4
When studying asymmetrical DPTUs 2u and 2v, the issue of regioselectivity arose from the
possibility of forming two different regioisomers (Scheme 4).23 Regioselectivity tends to be
steered by the intrinsic electronic effects of the substrate, in particular the substituent
influences. In evaluating DPTU 2u with methyl and bromo substituents at each of phenyl
rings, a mixture of 3u and 3U or 4u and 4U were separated in a total yield of 45% and 74%,
respectively. This observation can be rationalized by the slight difference between methyl and
bromo in the electronic contributions. For DPTU 2v with strong electronꢀwithdrawing nitro
group at one end, the CꢀN bond formation was preferred for the less electronꢀrich nitrogen,
resulting in the isolation of pure major isomer 4V (53%) whose structure was established by
Xꢀray diffraction analysis. By applying the optimal conditions favoring the DTA formation,
2v provided 3V as the sole product. Although the desired single crystal structure for Xꢀray
diffraction was not obtained, its structure can be deduced according to the regioselectivity in
the formation of 4V. The 2Z,4Z configuration for 4V was assigned according to the steric
effect of the adjacent phenyl substituent.
Scheme 4. Selectivity investigation on the asymmetrical diphenylthioureas.
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Based on the clues afforded by the above experimental observations, a plausible reaction
pathway was proposed (Scheme 5) exemplified by substrate 2v. Electrophilic attack of DCNE
to DPTU 2v afforded intermediate A. Intramolecular cyclization of A occurred in ethanol
generating the fourꢀmembered product. While, intermolecular attack of A by another
molecule of 2v gave intermediate B which further underwent cyclization delivering the
fiveꢀmembered compound. The regioselectivity for the asymmetrical DPTU can be explained
by the fact that the C=N double bond in transition state A was prone to form with the
electronꢀrich nitrogen. Besides the formation of DTA, side product diphenylurea D was also
separated, which generated by intermediate C formed in the reaction. While for the
phenylthiourea 2i, cyanamide E and phenylurea F were detected as the side products (Scheme
5). The nitro olefin may exist in trans or cis configuration, however, only one thermal stable
isomer were observed and no transꢀcis isomerization occurred during the store or analysis of
the compounds.
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CONCLUSIONS
We have disclosed a novel synthetic methodology for access of 1,4,2ꢀdithiazolidines or
1,3ꢀthiazetidines from 1,1ꢀdichloroꢀ2ꢀnitroethene and phenylthioureas. The products can be
obtained independently with a high selectivity under the control of solvent. Given the simplicity
and generality, we expect this protocol would have wide application for the preparation of
functional molecules.
Scheme 5. Proposed mechanism and side products for the formation of DTA and TAD.
EXPERIMENTAL SECTION
General information
Chromatographic analysis was performed using an ACQUITY UPLCꢀH Class system, equipped
with BEH C18 reversed phase column. The mobile phase was a mixture of MilliQ ultrapure water
with 0.01% trifluoroacetic acid (A) and acetonitrile (B). The following elution gradient totally
lasted 15 min: initial mobileꢀphase composition, 90:10 (v/v) phase A: B; 0ꢀ8 min, linear change
from 10 to 100% B; 8ꢀ10 min 100% B; 10ꢀ11 min, 90:10 (v/v) phase A: B. The detectors of
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products 3 and 4 were set at 426 nm and 365 nm respectively. Synthesis of
4
5
1,1-dichloro-2-nitroethene
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Hydrochloric acid (41.7 g, 0.411 mol, 36%) and nitric acid (39.8 g, 0.411 mol, 65%) were added to
the flask, drop added the 1,1-dichloroethylene (31.0 g, 0.315 mol) in 3 h, and kept at 20-25 °C.
The mixture was continuously stirred for 1 h, then washed with water, and extracted by CHCl3,
collected the organic phase, then added it to 235 mL 4% NaOH solution in the ice bath, after
simple separation and chloroform washing, the organic phase was concentrated, and dried with
anhydrous magnesium sulfate, then obtained pure product.
Isolated yield: 66% (29.5 g, 0.208 mol). Yellow oily liquid; 1H NMR (400 MHz, CDCl3): δ = 7.64
(s, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ = 136.5, 136.4 ppm. HRMS (ESI): m/z calcd for
C2H35Cl2NO2 (M+H)+, 140.9384; found, 140.9382; calcd for C2H35Cl37ClNO2 (M+H)+, 142.9355;
found, 142.9356.
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General procedure for the synthesis of 1,3-diphenylthiourea derivatives 2a-f
Aniline compounds (50 mmol) was dissolved in C2H5OH (30 mL), CS2 (75 mL) was added to the
stirred solution. The reaction mixture was stirred under reflux until the reaction was complete as
monitored by TLC. The precipitate was collected by filtration and recrystallized by hot ethanol to
give the pure product (yield: 60ꢀ80%).
General procedure for the synthesis of 1-phenylthiourea derivatives 2g-m
Benzoyl chloride (50 mmol) was dissolved in acetone (20 mL), stirred at room temperature.
NH4SCN (62.5 mmol) was dissolved in acetone (10 mL), then added dropwise to the reaction
mixture, stirred for 15 min. The precipitate was moved by filtration, then the filtrate was dissolved
in ethyl acetate (20 mL). Aniline compounds (50 mmol) was dissolved in ethyl acetate (10 mL),
then added dropwise to the reaction mixture at room temperature, stirred until the reaction was
complete as monitored by TLC. The white precipitate was collected by filtration and dissolved in
C2H5OH (30 mL). NaOH solution (100 mmol) was added dropwise to the reaction mixture, stirred
at room temperature until the reaction was complete as monitored by TLC. The reaction mixture
was adjusted pH to 7 by HCl, stirred under iceꢀbath. Filtered to afford product (yield: 80ꢀ85%).
General procedure for the synthesis of compounds 3
Compounds 2aꢀm (3 mmol) and tetrabutyl ammonium fluoride (783 mg, 3 mmol) were stirred in
CHCl3 (15 mL) at ꢀ10 oC, 1,1ꢀdichloroꢀ2ꢀnitroethene (255 mg, 1.8 mmol) were added to the stirred
o
solution. The reaction mixture was stirred at ꢀ10 C until the reaction was complete as monitored
by TLC. After being cooled to room temperature, the reaction mixture was diluted with water and
extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated.
The crude product was further purified by column chromatography (petroleum ether and ethyl
acetate (6:1 v/v)).
(3Z,5Z)-5-(nitromethylene)-N,2-diphenyl-1,4,2-dithiazolidin-3-imine (3a): Isolated yield: 51%
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o
1
(252 mg, 0.77 mmol). Yellow solid; mp: 124.9‒126.4 C; H NMR (400 MHz, DMSOꢀd6): δ =
8.28 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.38 (t, J =
7.8 Hz, 1H), 7.14 (t, J = 7.4 Hz, 1H), 6.97 (d, J = 7.5 Hz, 1H) ppm; 13C NMR (100 MHz,
DMSOꢀd6): δ = 160.2, 150.7, 149.8, 136.3, 129. 8, 129.8, 128.5, 127.5, 124.6, 121.0, 121.0 ppm.
HRMS (ESI): m/z calcd for C15H12N3O2S2 (M+H)+, 330.0371; found, 330.0370.
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(3Z,5Z)-5-(nitromethylene)-N,2-di-p-tolyl-1,4,2-dithiazolidin-3-imine (3b): Isolated yield: 55%
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(295 mg, 0.83 mmol). Yellow solid; mp: 124.3‒125.6 oC; H NMR (400 MHz, DMSOꢀd6): δ =
8.28 (s, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H), 6.84 (d, J
= 8.2 Hz, 2H), 2.36 (s, 3H), 2.28 (s, 3H) ppm; 13C NMR (100 MHz, DMSOꢀd6): δ = 160.4, 149.8,
148.4, 138.2, 133.6, 133.6, 130.2, 130.2, 127.4, 120.8, 120.8, 20.7, 20.4 ppm. HRMS (ESI): m/z
calcd for C17H16N3O2S2 (M+H)+, 358.0684; found, 358.0685.
(3Z,5Z)-N,2-bis(4-methoxyphenyl)-5-(nitromethylene)-1,4,2-dithiazolidin-3-imine
(3c):
Isolated yield: 56% (327 mg, 0.84 mmol). Yellow solid; mp: 130.2‒131.6 oC; 1H NMR (400 MHz,
DMSOꢀd6): δ = 8.28 (s, 1H), 7.58 (d, J = 7.6 Hz, 2H), 7.10 (d, J = 7.2 Hz, 2H), 6.98ꢀ6.80 (m, 4H),
3.82 (s, 3H), 3.74 (s, 3H) ppm; 13C NMR (100 MHz, DMSOꢀd6): δ = 160.5, 159.2, 156.2, 149.4,
144.2, 129.4, 128.4, 122.0, 120.8, 115.0, 114.9, 55.5, 55.2 ppm. HRMS (EI): m/z calcd for
C17H15N3O4S2 [M]+, 389.0504; found, 389.0505.
(3Z,5Z)-N,2-bis(3-methoxyphenyl)-5-(nitromethylene)-1,4,2-dithiazolidin-3-imine
(3d):
Isolated yield: 40% (234 mg, 0.60 mmol). Yellow solid; mp: 132.2‒133.6 oC; 1H NMR (400 MHz,
DMSOꢀd6): δ = 8.28 (s, 1H), 7.47 (t, 1H), 7.34ꢀ7.20 (m, 3H), 7.04 (d, 1H), 6.72 (d, J = 6.0 Hz,
1H), 6.61ꢀ6.50 (m, 2H), 3.81 (s, 3H), 3.74 (s, 3H) ppm; 13C NMR (100 MHz, DMSOꢀd6): δ =
160.4, 160.4, 160.1, 152.0, 145.0, 137.2, 130.6, 130.6, 120.9, 119.4, 114.2, 113.3, 112.9, 110.4,
106.5, 55.5, 55.1 ppm. HRMS (ESI): m/z calcd for C17H16N3O4S2 [M+H]+, 390.0583; found,
390.0582.
(3Z,5Z)-N,2-bis(4-chlorophenyl)-5-(nitromethylene)-1,4,2-dithiazolidin-3-imine (3e): Isolated
o
1
yield: 43% (257 mg, 0.65 mmol). Yellow solid; mp: 134.8‒135.6 C; H NMR (400 MHz,
DMSOꢀd6): δ = 8.32 (s, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.4 Hz,
2H), 7.01 (d, J = 8.4 Hz, 2H) ppm; 13C NMR (100 MHz, DMSOꢀd6): δ = 150.0, 150.6, 149.4,
135.0, 132.9, 129.7, 129.7, 129.3, 128.7, 122.9, 121.2 ppm. HRMS (ESI): m/z calcd for
C15H10N3O2S235Cl2 (M+H)+, 397.9592; found, 397.9690. calcd for C15H10N3O2S235Cl37Cl (M+H)+,
399.9562; found, 399.9554.
(3Z,5Z)-N,2-bis(4-bromophenyl)-5-(nitromethylene)-1,4,2-dithiazolidin-3-imine (3f): Isolated
o
1
yield: 36% (263 mg, 0.54 mmol). Yellow solid; mp: 151.7‒153.4 C; H NMR (400 MHz,
DMSOꢀd6): δ = 8.24 (s, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.69ꢀ7.55 (m, 4H), 7.11 (d, J = 8.2 Hz, 2H)
ppm; 13C NMR (100 MHz, DMSOꢀd6): δ = 154.2, 144.4, 142.8, 133.2, 132.7, 132.5, 125.6, 123.6,
120.8, 118.8, 116.2 ppm. HRMS (EI): m/z calcd for C15H9N3O2S279Br2 [M]+, 484.8503, found
484.8496. calcd for C15H9N3O2S279Br81Br [M]+ 486.8483; found, 486.8490.
(Z)-5-(nitromethylene)-N-phenyl-1,4,2-dithiazol-3-amine (3g): Isolated yield: 54% （205 mg,
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0.81 mmol）. Yellow solid; mp: 201.9‒203.5 C; H NMR (400 MHz, DMSOꢀd6): δ = 10.90 (s,
1H), 8.35 (s, 1H), 7.65 (d, 2H), 7.43 (t, J = 16.5, 8.8 Hz, 2H), 7.14 (t, J = 7.3 Hz, 1H) ppm; 13C
NMR (100 MHz, DMSOꢀd6): δ = 171.2, 155.7, 139.3, 129.1, 123.4, 118.1, 117.4 ppm. HRMS (EI):
m/z calcd for C9H7N3O2S2 [M]+, 252.9980; found, 252.9982.
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(Z)-5-(nitromethylene)-N-(o-tolyl)-1,4,2-dithiazol-3-amine (3h): Isolated yield: 43% (173 mg,
0.65 mmol). Yellow solid; mp: 133.4‒134.8 oC; 1H NMR (400 MHz, DMSOꢀd6): δ = 10.12 (s, 1H),
8.27 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.27 (t, J = 11.0, 6.2 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.15
(t, J = 7.3 Hz, 1H), 2.25 (s, 3H) ppm; 13C NMR (100 MHz, DMSOꢀd6): δ = 172.2, 158.7, 137.5,
131.3, 130.8, 126.6, 125.8, 123.7, 117.2, 17.8 ppm. HRMS (EI): m/z calcd for C10H9N3O2S2 [M]+,
267.0136; found, 267.0137.
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(Z)-N-(4-methoxyphenyl)-5-(nitromethylene)-1,4,2-dithiazol-3-amine (3i): Isolated yield: 58%
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(246 mg, 0.87 mmol). Yellow solid; mp: 214.9‒216.1 C; H NMR (400 MHz, DMSOꢀd6): δ =
10.72 (s, 1H), 8.28 (s, 1H), 7.49 (d, 2H), 6.95 (d, 2H), 3.74 (s, 3H) ppm; 13C NMR (100 MHz,
DMSOꢀd6): δ = 171.6, 156.4, 155.5, 132.6, 120.2, 117.2, 114.3, 55.2 ppm. HRMS (ESI): m/z calcd
for C10H10N3O3S2 (M+H)+, 284.0164; found, 284.0164.
(Z)-N-(2-methoxyphenyl)-5-(nitromethylene)-1,4,2-dithiazol-3-amine (3j): Isolated yield: 45%
o
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(191 mg, 0.68 mmol). Yellow solid; mp: 177.1‒179.1 C; H NMR (400 MHz, DMSOꢀd6): δ =
10.27 (s, 1H), 8.29 (s, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.11 (d, J = 6.9 Hz, 2H), 6.98 (t, J = 6.5 Hz,
1H), 3.84 (s, 3H) ppm; 13C NMR (100 MHz, DMSO): δ = 172.3, 157.1, 149.4, 129.2, 128.1, 124.8,
120.5, 117.0, 111.4, 55.8 ppm. HRMS (EI): m/z calcd for C10H9N3O3S2 [M]+, 283.0085; found,
283.0086.
(Z)-N-(4-chlorophenyl)-5-(nitromethylene)-1,4,2-dithiazol-3-amine (3k): Isolated yield: 44%
o
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(190 mg, 0.66 mmol). Yellow solid; mp: 245.6‒246.8 C; H NMR (400 MHz, DMSOꢀd6): δ =
10.96 (s, 1H), 8.30 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H) ppm; 13C NMR (100
MHz, DMSOꢀd6): δ = 170.9, 155.5, 138.3, 129.0, 126.8, 119.6, 117.5 ppm. HRMS (ESI): m/z
calcd for C9H7N3O2S235Cl [M+H]+, 287.9668; found, 287.9665. calcd for C9H7N3O2S237Cl[M+H]+,
289.9639; found, 289.9634.
(Z)-N-(4-bromophenyl)-5-(nitromethylene)-1,4,2-dithiazol-3-amine (3l): Isolated yield: 41%
o
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(205 mg, 0.62 mmol). Yellow solid; mp: 162.6‒163.7 C; H NMR (400 MHz, DMSOꢀd6): δ =
10.94 (s, 1H), 8.30 (s, 1H), 7.54 (s, 4H) ppm; 13C NMR (100 MHz, DMSOꢀd6): δ = 170.9, 1554,
138.7, 131.9, 119.9, 117.5, 114.8 ppm. HRMS (ESI): m/z calcd for C9H7N3O2S279Br [M+H]+,
331.9163; found, 331.9166. calcd for C9H7N3O2S281Br [M+H]+, 333.9143; found, 333.9153.
(Z)-5-(nitromethylene)-N-(4-nitrophenyl)-1,4,2-dithiazol-3-amine (3m): Isolated yield: 31%
o
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(139 mg, 0.47 mmol). Yellow solid; mp: 223.7‒225.4 C; H NMR (400 MHz, DMSOꢀd6): δ =
11.52 (s, 1H), 8.34 (s, 1H), 8.27 (d, J = 9.2 Hz, 2H), 7.80 (d, J = 9.2 Hz, 2H) ppm; 13C NMR (100
MHz, DMSOꢀd6): δ = 170.4, 154.9, 145.1, 141.9, 125.4, 118.0, 117.6 ppm. HRMS (EI): m/z calcd
for C9H6N4O4S2 [M]+, 297.9830; found, 297.9832.
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Synthesis of compound 3n
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1ꢀBenzoylꢀ2ꢀThiourea (0.541 g, 3 mmol) and Tetrabutyl ammonium fluoride (0.783 g, 3 mmol)
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were stirred in CHCl3 (15 mL) at ꢀ10 C, 1,1ꢀdichloroꢀ2ꢀnitroethene (0.255 g, 1.8 mmol) were
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added to the stirred solution. The reaction mixture was stirred at ꢀ10 C until the reaction was
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complete as monitored by TLC. After being cooled to room temperature, the reaction mixture was
diluted with water and extracted with CH2Cl2. The combined organic layers were dried over
Na2SO4 and concentrated. The crude product was further purified by column chromatography
(petroleum ether and ethyl acetate (6:1 v/v)).
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(Z)-N-(5-(nitromethylene)-1,4,2-dithiazol-3-yl)benzamide (3n): Isolated yield: 37% (156 mg,
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0.56 mmol). Yellow solid; mp: 245.8‒246.3 C; H NMR (400 MHz, DMSOꢀd6): δ = 13.22 (s,
1H), 8.41 (s, 1H), 8.08 (d, J = 7.7 Hz, 2H), 7.70 (t, J = 7.2 Hz, 1H), 7.58 (t, J = 7.6 Hz, 2H) ppm;
13C NMR (100 MHz, DMSOꢀd6): δ = 172.0, 165.9, 155.2, 133.5, 130.5, 128.7, 128.6, 117.8 ppm.
HRMS (EI): m/z calcd for C10H7N3O3S2 [M]+, 280.9929; found, 280.9934.
Synthesis of compound 3o
Thiobenzamide (0.412 g, 3 mmol) and Tetrabutyl ammonium fluoride (0.783 g, 3 mmol) were
stirred in CHCl3 (15 mL) at ꢀ10 oC, 1,1ꢀdichloroꢀ2ꢀnitroethene (0.255 g, 1.8 mmol) were added to
o
the stirred solution. The reaction mixture was stirred at ꢀ10 C until the reaction was complete as
monitored by TLC. After being cooled to room temperature, the reaction mixture was diluted with
water and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and
concentrated. The crude product was further purified by column chromatography (petroleum ether
and ethyl acetate (6:1 v/v)).
(Z)-5-(nitromethylene)-3-phenyl-1,4,2-dithiazole (3o): Isolated yield: 46% (165 mg, 0.69
mmol). Yellow solid; mp: 188.4‒190.1 oC; 1H NMR (400 MHz, DMSOꢀd6): δ = 8.48 (s, 1H), 7.92
(d, J = 7.3 Hz, 2H), 7.66 (t, 1H), 7.59 (t, J = 16.6, 9.6 Hz, 2H) ppm; 13C NMR (100 MHz,
DMSOꢀd6): δ = 170.9, 165.2, 132.7, 130.5, 129.7, 127.9, 119.1 ppm. HRMS (EI): m/z calcd for
C9H6N2O2S2 [M]+, 237.9871; found, 237.9873.
Synthesis of compound 3V
1ꢀ(4ꢀnitrophenyl)ꢀ3ꢀ(4ꢀtolyl)thiourea (0.862 g, 3 mmol) and Tetrabutyl ammonium fluoride (0.783
o
g, 3 mmol) were stirred in CHCl3 (15 mL) at ꢀ10 C, 1,1ꢀdichloroꢀ2ꢀnitroethene (0.255 g, 1.8
o
mmol) were added to the stirred solution. The reaction mixture was stirred at ꢀ10 C until the
reaction was complete as monitored by TLC. After being cooled to room temperature, the reaction
mixture was diluted with water and extracted with CH2Cl2. The combined organic layers were
dried over Na2SO4 and concentrated. The crude product was further purified by column
chromatography (petroleum ether and ethyl acetate (6:1 v/v)).
(3Z,5Z)-5-(nitromethylene)-N-(4-nitrophenyl)-2-(p-tolyl)-1,4,2-dithiazolidin-3-imine
(3V):
Isolated yield: 33% (193 mg, 0.50 mmol). Yellow solid; mp: 142.9‒143.4oC; 1H NMR (400 MHz,
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DMSOꢀd6): δ = 8.35 (s, 1H), 8.24 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 7.7 Hz, 2H), 7.37 (d, J = 7.6 Hz,
2H), 7.22 (d, J = 8.4 Hz, 2H), 2.32 (s, 3H). 13C NMR (101 MHz, DMSOꢀ d6): δ = 159.6, 156.3,
150.9, 143.6, 138.8, 133.0, 130.3, 127.5, 125.6, 122.1, 121.2, 20.7. HRMS (EI): m/z calcd for
C16H12N4O4S2 [M]+, 388.0300; found, 388.0299.
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Diphenylthiourea derivatives (3 mmol) were added in C2H5OH (15 mL) at ꢀ25 oC,
1,1ꢀdichloroꢀ2ꢀnitroethene (0.511 g, 3.6 mmol) were added to the stirred solution. The reaction
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mixture was stirred at ꢀ25 C until the reaction was complete as monitored by TLC. After being
cooled to room temperature, the solvent was removed by vacuum and the solid was diluted with
water and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and
concentrated. The crude product was further purified by column chromatography.
(2Z,4Z)-4-(nitromethylene)-N,3-diphenyl-1,3-thiazetidin-2-imine (4a): Isolated yield: 68%
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(607 mg, 2.04 mmol). Yellow solid; mp: 121.9‒123.2 C; H NMR (400 MHz, DMSOꢀd6): δ =
8.14 (s, 1H), 7.69 (d, J = 7.8 Hz, 2H), 7.56 (t, J = 7.9 Hz, 2H), 7.48ꢀ7.41 (m, 3H), 7.28 (t, J = 7.4
Hz, 1H), 7.16 (d, J = 7.5 Hz, 2H) ppm; 13C NMR (100 MHz, DMSOꢀd6): δ = 154.9, 143.8, 143.6,
134.1, 129.9, 129.6, 128.1, 126.3, 123.5, 121.4, 115.7 ppm. HRMS (EI): m/z calcd for
C15H11N3O2S [M]+, 297.0572; found, 297.0574.
(2Z,4Z)-4-(nitromethylene)-N,3-di-p-tolyl-1,3-thiazetidin-2-imine (4b): Isolated yield: 60%
(586 mg, 1.8 mmol). Yellow solid; mp: 128.7‒130.2 oC; 1H NMR (400 MHz, DMSOꢀd6): δ = 8.06
(s, 1H), 7.55 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.04 (d, J =
8.1 Hz, 2H), 2.36 (s, 3H), 2.31 (s, 3H) ppm; 13C NMR (100 MHz, DMSOꢀd6): δ = 155.3, 143.2,
141.0, 137.9, 135.7, 131.7, 130.3, 123.0, 123.6, 121.3, 115.3, 20.7, 20.5 ppm. HRMS (EI): m/z
calcd for C17H15N3O2S [M]+, 325.0885; found, 325.0884.
(2Z,4Z)-N,3-bis(4-methoxyphenyl)-4-(nitromethylene)-1,3-thiazetidin-2-imine (4c): Isolated
o
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yield: 73% (783 mg, 2.19 mmol). Yellow solid; mp: 151.1‒151.8 C; H NMR (400 MHz,
DMSOꢀd6): δ = 7.95 (s, 1H), 7.58 (d, J = 8.7 Hz, 2H), 7.09 (dd, J = 8.3, 4.9 Hz, 4H), 7.00 (d, J =
8.7 Hz, 2H), 3.82 (s, 3H), 3.77 (s, 3H) ppm; 13C NMR (100 MHz, DMSOꢀd6): δ = 158.9, 157.7,
156.1, 142.6, 136.3, 126.9, 125.9, 122.7, 115.1, 114.8, 114.7, 55.5, 55.3 ppm. HRMS (EI): m/z
calcd for C17H15N3O4S [M]+, 357.0783; found, 357.0782.
(2Z,4Z)-N,3-bis(4-chlorophenyl)-4-(nitromethylene)-1,3-thiazetidin-2-imine (4d): Isolated
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yield: 81% (890 mg, 2.43 mmol). Yellow solid; mp: 166.7‒169.5 C; H NMR (400 MHz,
DMSOꢀd6): δ = 8.24 (s, 1H), 7.71 (d, J = 9.6 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.9 Hz,
2H), 7.18 (d, J = 8.6 Hz, 2H) ppm; 13C NMR (100 MHz, DMSOꢀd6): δ = 154.3, 144.5, 142.4,
132.8, 132.4, 130.6, 129.8, 129.6, 125.5, 123.3, 116.2 ppm. HRMS (EI): m/z calcd for
C15H9N3O2S35Cl2 [M]+, 364.9793; found, 364.9785. calcd for C15H9N3O2S35Cl37Cl [M]+, 366.9763;
found, 366.9760.
(2Z,4Z)-N,3-bis(4-bromophenyl)-4-(nitromethylene)-1,3-thiazetidin-2-imine (4e): Isolated
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yield: 83% (1133 mg, 2.49 mmol). Yellow solid; mp: 183.5‒184.9 C; H NMR (400 MHz,
DMSOꢀd6): δ = 8.24 (s, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.64 (t, 4H), 7.11 (d, J = 8.6 Hz, 2H) ppm;
13C NMR (100 MHz, DMSOꢀd6): δ = 154.2, 144.4, 142.8, 133.2, 132.7, 132.5, 125.6, 123.6, 120.8,
118.8, 116.2 ppm. HRMS (EI): m/z calcd for C15H9N3O2S79Br2 [M]+, 452.8782; found, 452.8779.
calcd for C15H9N3O2S79Br81Br[M]+, 454.8762; found, 454.8770.
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(2Z,4Z)-N,3-bis(2-chlorophenyl)-4-(nitromethylene)-1,3-thiazetidin-2-imine (4f): Isolated
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yield: 72% (791 mg, 2.16 mmol). Yellow solid; mp: 128.3‒130.9 C; H NMR (400 MHz,
DMSOꢀd6): δ = 7.99 (s, 1H), 7.86 (d, J = 7.3 Hz, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.68ꢀ7.53 (m, 3H),
7.41 (t, J = 7.6 Hz, 1H), 7.32ꢀ7.21 (m, 2H) ppm; 13C NMR (101 MHz, DMSOꢀd6): δ = 155.1,
145.4, 140.8, 132.3, 131.3, 130.7, 130.6, 130.4, 130.1, 128.6, 128.5, 127.4, 126.7, 121.4, 116.6
ppm. HRMS (EI): m/z calcd for C15H9N3O2SCl2 [M]+, 364.9793; found, 364.9790. calcd for
C15H9N3O2S35Cl37Cl [M]+, 366.9763; found, 366.9745.
(2Z,4Z)-N,3-bis(3-chlorophenyl)-4-(nitromethylene)-1,3-thiazetidin-2-imine (4g): Isolated
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yield: 76% (835 mg, 2.28 mmol). Yellow solid; mp: 116.2‒118.1 C; H NMR (400 MHz,
DMSOꢀd6): δ = 8.32 (s, 1H), 7.81 (t, J = 1.8 Hz, 1H), 7.65 (d, 1H), 7.57 (t, J = 8.0 Hz, 1H),
7.54ꢀ7.43 (m, 2H), 7.34 (dd, 1H), 7.24 (t, J = 1.9 Hz, 1H), 7.13 (dd, 1H) ppm; 13C NMR (100
MHz, DMSOꢀd6): δ = 153.9, 145.1, 145.1, 135.0, 134.1, 133.8, 131.5, 131.2, 128.2, 126.1, 123.5,
122.3, 121.6, 119.9, 116.6 ppm. HRMS (EI): m/z calcd for C15H9N3O2SCl2 [M]+, 364.9793; found,
364.9791. calcd for C15H9N3O2S35Cl37Cl [M]+, 366.9763; found, 366.9768.
(2Z,4Z)-4-(nitromethylene)-3-(4-nitrophenyl)-N-(p-tolyl)-1,3-thiazetidin-2-imine
(4V):
Isolated yield: 53% (567 mg, 1.59 mmol). Yellow solid; mp: 132.9‒134.3oC; 1H NMR (400 MHz,
DMSOꢀd6): δ = 8.46 (s, 1H), 8.36 (d, J = 8.9 Hz, 2H), 7.99 (d, J = 8.9 Hz, 2H), 7.27 (d, J = 7.9 Hz,
2H), 7.07 (d, J = 8.0 Hz, 2H), 2.33 (s, 3H). 13C NMR (100MHz, DMSOꢀd6): δ = 154.0, 145.1,
142.9, 140.7, 139.4, 136.0, 130.4, 125.0, 123.4, 121.3, 117.0, 20.5. HRMS (EI): m/z calcd for
C16H12N4O4S[M]+, 356.0579; found, 356.0580.
ASSOCIATED CONTENT
Supporting information
The Supporting Information is available free of charge on the ACS Publications website including
optimization of the formation of TAD 4a, Copies of NMR spectra.
Crystallography
CCDC: 1423225 (3g), 1423226 (4e) and 1423227 (4V) contain the supplementary
crystallographic data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
AUTHOR INFORMATION
Corresponding Authors
∗ Eꢀmail: shaoxusheng@ecust.edu.cn; Phone: (+86) 21ꢀ64253967
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‡ These authors contributed equally to this work.
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Notes
The authors declare no competing financial interest.
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This work was financial supported by National Natural Science Foundation of China
(21372079, 21472046), Shanghai Pujiang Program (14PJD012).
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