Synthesis of novel five-membered endocyclic sulfoximines — 1-aryl-3-(arylimino)-3,5-dihydro-1,4,2-dithiazole 1-oxides

Article abstract of DOI:10.1016/j.tet.2017.05.098

A novel kind of five-membered endocyclic sulfoximines, 1-aryl-3-(arylimino)-3,5-dihydro-1,4,2- dithiazole 1-oxides, were synthesized through addition/cyclization of chloromethyl aryl sulfoximines with aryl isothiocyanates under mild reaction conditions in moderate to good yields.

Full text of DOI:10.1016/j.tet.2017.05.098

Accepted Manuscript
Synthesis of novel five-membered endocyclic sulfoximines — 1-aryl-3-(arylimino)-3,5-
dihydro-1,4,2-dithiazole 1-oxides
Yong Hua, Wenjie Zhang, Xin Wang, Zemei Ge, Runtao Li
PII:
S0040-4020(17)30607-5
10.1016/j.tet.2017.05.098
TET 28764
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 April 2017
Revised Date: 28 May 2017
Accepted Date: 31 May 2017
Please cite this article as: Hua Y, Zhang W, Wang X, Ge Z, Li R, Synthesis of novel five-membered
endocyclic sulfoximines — 1-aryl-3-(arylimino)-3,5-dihydro-1,4,2-dithiazole 1-oxides, Tetrahedron
(2017), doi: 10.1016/j.tet.2017.05.098.
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Synthesis of novel five-membered endocyclic
sulfoximines — 1-aryl-3-(arylimino)-3,5-
dihydro-1,4,2-dithiazole 1-oxides
Leave this area blank for abstract info.
Yong Hua, Wenjie Zhang, Xin Wang, Zemei Ge, Runtao Li
State Key Laboratory of Nature and Biomimetic Drugs, School of Pharmaceutical
Sciences, Peking University, Beijing 100191, China.
O
NH
O
S
N
N
S
Na CO
2 3
+
R
R
NCS
Het
R
1
S
Het
Cl
R
1
CH CN, 70℃, 20h
3
19 examples
up to 84% yield

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of novel five-membered endocyclic sulfoximines — 1-aryl-3-(arylimino)-
3,5-dihydro-1,4,2-dithiazole 1-oxides
Yong Hua, Wenjie Zhang, Xin Wang, Zemei Ge* , Runtao Li*
State Key Laboratory of Nature and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel kind of five-membered endocyclic sulfoximines, 1-aryl-3-(arylimino)-3,5-dihydro-
1,4,2- dithiazole 1-oxides, were synthesized through addition/cyclization of chloromethyl
aryl sulfoximines with aryl isothiocyanates under mild reaction conditions in moderate to
good yields.
Available online
Keywords:
Five-membered endocyclic sulfoximines
Chloromethyl aryl sulfoximines
Aryl isothiocyanates
Addition/cyclization
Synthesis
2017 Elsevier Ltd. All rights reserved
.
1. Introduction
In recent years, sulfoximines have gained considerable
attention due to their unique structure and the entensive
application in organic synthesis and medicinal chemistry.1a-b
Many efficient methods for the synthesis of sulfoximines
have been developed.2a-e Meanwhile, numerous sulfoximine
derivatives have also been prepared, especially the
endocyclic sulfoximines owing to the importance of
heterocyclic compounds in medicinal chemistry.3a-i However,
most of the methods for the synthesis of endocyclic
sulfoximines focused on the six-membered or benzo-fused
endocyclic sulfoximines,4a-l and only few on the synthesis of
five-membered endocyclic sulfoximines have been reported.
Donald J. Cram et al. first synthesized the five-membered
endocyclic sulfoximine from the reaction of p-methylphenyl
methyl sulfoximine and ethyl 2-bromoacetate in the
presence of sodium hydride, but only result in 13% yield
(Fig 1, a).5 Carsten Bolm et al. found that, when treated with
a combination of iodobenzene diacetate (PIDA) and
potassium iodide, the unsaturated NH-sulfoximines would
afford the endocyclic sulfoximine dihydro isothiazole 1-
oxides in moderate to good yields (Fig 1, b).6 More recently,
Vincent Reboul et al. developed an asymmetric synthesis of
five-membered endocyclic sulfoximines from the cyclization
of methionine derivatives by using PIDA (Fig 1, c).7 Herein,
we report the synthesis of a new kind of five-membered
endocyclic sulfoximines, 3,5-dihydro-1,4,2-dithiazole 1-
oxides, through addition/ cyclization of chloromethyl aryl
sulfoximines with aryl isothiocyanates under mild reaction
conditions in moderate to good yields (Fig 1, d).
Fig 1. Preparation of five-membered endocyclic
sulfoximines.
2. Results and discussion
In our initial attempt, chloromethyl phenyl sulfoximine
(4a) and phenyl isothiocyanate (5a) were selected as the
model substrates, with the presence of sodium carbonate in
DMF at 60oC for 20 hours to prepare the five-membered
endocyclic sulfoximine 6a. To our delight, the desired
product 6a was successfully obtained in 65% yield (Table 1
Entry 1). Encouraged by this result, further optimization of
the reaction conditions was performed next. Solvents
screening results showed that polar solvent was favorable

2
Tetrahedron
for the reaction, and acetonitrile turned out to be the best
All of them worked well and the desired products (6o-6s
)
ACCEPTED MANUSCRIPT
one with a yield of 78% (Table 1, Entries 2-6). In addition to
sodium carbonate, both organic bases and several other
inorganic bases were tested. However, none of them showed
better results than sodium carbonate (Table 1, Entries 7-10).
were formed in 48-80% yields. Additionally, all the products
6
are the mixtures of cis- and trans- isomers according to
their 1H-NMR and 13C-NMR spectra (See supporting
information), and the ratio of cis-trans isomers is related to
the kinds and positions of substituents.8
A survey of the feeding ratio of isothiocyanate (5a
)
indicated that 1.1 equivalent was the best choice to afford 6a
in 78% yield (Table 1, Entries 10-12). Finally, the effect of
reaction temperature on the reaction was examined and the
best yield of 6a was achieved at reaction temperature of
Scheme 1. Synthesis of 1-aryl-3-(arylimino)-3,5-dihydro-
1,4,2-dithiazole 1-oxides.
70 o
C
(Table 1, entries 12-14).
Table 1. Screening of Reaction Conditions.a
Entry
Solvent
Base
Temp
Ratio
(4a:5a)
Yield
(%)b
(
ꢀ
60
60
60
60
)
1
DMF
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
TEA
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.1
1:1.0
1:1.1
1:1.1
65
trace
54
2
toluene
THF
3
4
CH3CN
acetone
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
78
5
reflux
60
52
6
63
7
60
71
8
NaHCO3
DBU
60
77
9
60
trace
trace
78
10
11
12
13
Cs2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
60
60
60
75
70
80
14
reflux
77
a
Reaction was conducted with 4a (0.2 mmol) in solvent (1 mL) under
corresponding temperature.
b Isolated yields.
a Reaction was conducted for 48 h.
Based on our experimental results, a possible pathway for
this reaction is proposed in Scheme 2.9a-c First, the
nucleophilic addition between sulfoximine 4a and
isothiocyanate 5a takes place, forming the thiourea
derivatives of sulfoximine (7), which is a pair of tautomer
with 7’. Subsequently, the product 6a is generated through
the intramolecular nucleophilic substitution of 7’.
The generality of this reaction was further explored with
the optimized conditions. As exhibited in Scheme 1,
chloromethyl phenyl sulfoximine (4a) could smoothly react
with various aryl isothiocyanates
corresponding five-membered endocyclic sulfoximines
ꢁ
5
ꢂ
to afford the
6a-6l)
(
in moderate to good yields (53-84%). The position of the
substituent at the benzene ring does not have significant
effect on the reactions (6b-6d, 78-81% yields). However, the
electronic properties of the substituents on the benzene ring
have obviously effect the reactions. The electron-
withdrawing substitutes (6j, 4-NO2, 84% yield; 6k, 4-CF3,
82% yield) are more favorable for the reactions than the
electron-donating substitutes (6e, 4-Me, 60% yield; 6i, 4-
OMe, 53% yield). 3-Pyridyl isothiocyanate also got a good
yield (6l, 70%). However, ethyl isothiocyanate and 1-
naphthyl isothiocyanate only gave a trace of the desired
products (6m and 6n), which maybe due to the low
reactivity and large steric effect respectively. Subsquently,
representative substituted aryl or heteroaryl chloromethyl
sulfoximines (4-a-f) were allowed to react with phenyl
isothiocyanate (5a) under the optimized reaction conditions.
Scheme 2. Possible Reaction Pathway.

3
(Chloromethyl)(imino)(thiophen-2-yl)-λ6-sulfan-one (4f)
3. Conclusion
ACCEPTED MANUSCRIPT
was afforded as a pale yellow oil (76%). 1H NMR (400 MHz,
CDCl3) δ 7.81 – 7.76 (m, 2H), 7.20 (t, J = 4.3 Hz, 1H), 4.74 –
4.65 (m, 2H), 3.45 (s, 1H). 13C NMR (100 MHz, CDCl3) δ
139.06, 135.93, 135.68, 128.26, 62.00.
In summary, we have developed an efficient method for the
synthesis of a novel five-membered endocyclic sulfoximines
through addition/cyclization of chloromethyl aryl sulfoximines
with aryl isocyanates. A series of 1-aryl-3-(arylimino)-3,5-
dihydro-1,4,2-dithiazole 1-oxides were prepared in moderate to
good yields by this method. Due to the unique properties of
sulfoximine group and the importance of heterocyclic
compounds in medicinal chemistry, this novel kind of endocyclic
sulfoximines will be of great interest to medicinal chemists. The
biological activities of these compounds are currently under
investigation in our laboratory.
4.3 General procedure for the preparation of compounds (6a-6s)
To a solution of chloromethyl aryl sulfoximine 4 (0.2 mmol)
in acetonitrile (1 mL) was added Na2CO3 (0.22 mmol) and
isothiocyanate 5 (0.22 mmol). The resulting mixture was stirred
at 70 C for 20 hours. After completion of the reaction, the
solvent was evaporated and then 10 mL of water was added. The
mixture was extracted with DCM. The combined organic layers
o
were washed by brine, dried over anhydrous Na
2
SO . filtered and
4
4. Experimental section
then concentrated under reduced pressure The residue was
.
4.1 General
purified by silica gel column chromatography using petroleum
ether/ethyl acetate to give the desired product (6a-6s).
1H-NMR and 13C-NMR spectra were recorded on a Bruker
AVANCE 400 MHz and 600 MHz spectrometer using CDCl3 or
4.3.1 1-Phenyl-3-(phenylimino)-3,5-dihydro-1,4,2-dithiazole 1-
oxide (6a)
1
DMSO-d6 as solvent. The H-NMR chemical shifts (in ppm)
were referenced to tetramethylsilane. The 13C-NMR chemical
shifts were given using solvent (CDCl3 or DMSO-d6) as the
internal standard. High resolution mass spectra were recorded
using LCMS–IT–TOF technique (Shimadzu). Unless otherwise
noted, materials obtained from commercial suppliers were used
without further purification. Column chromatography was carried
out on silica gel (particle size 200-300 mesh ASTM).
1
White solid, Rf=0.24 (EtOAc 1:2 Hex); Yield 80%; H NMR
(600 MHz, CDCl3) δ 8.09 (d, J = 7.6 Hz, 2H), 7.96 (d, J = 7.7 Hz,
1H), 7.79 (t, J = 7.5 Hz, 1H,), 7.75 (t, J = 7.5 Hz, 0.5H), 7.67 (t, J
= 7.9 Hz, 2H), 7.63 (t, J = 7.9 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H,),
7.33 – 7.27 (m, 1H), 7.14 (t, J = 7.4 Hz, 1H), 7.05 (d, J = 7.4 Hz,
2.5H), 4.78 (d, J = 11.5 Hz, 1H), 4.74 (d, J = 11.5 Hz, 0.5H),
4.56 (d, J = 11.5 Hz, 0.5H), 4.50 (d, J = 11.5 Hz, 1H). 13C NMR
(150 MHz, CDCl3) δ 159.3, 159.0, 150.1, 148.6, 135.4, 135.4,
135.3, 134.8, 130.0, 129.9, 129.2, 129.1, 128.8, 128.5, 124.3,
123.8, 123.0, 121.6, 58.9, 57.1; ES-HRMS: Calcd for
C14H13N2OS2 [M+H]+, 289.0464, Found 289.0470.
4.2 Preparation of chloromethyl aryl sulfoximines (4a-4d)
Typical procedure:2e Chloromethyl phenyl sulfide (10 mmol)
was dissolved in methanol (25 mL), and PhI(OAc)2 (25 mmol),
NH2COONH4 (20 mmol) was added. The mixture was reacted at
room temperature for 3 hours. After completion, the solvent was
evaporated and then 20 mL of water was added. The mixture was
extracted with DCM and the combined organic phase were dried
4.3.2ꢃ 3-((4-Chlorophenyl)imino)-1-phenyl-3,5-dihydro-1,4,2-
dithiazole 1-oxide (6b)
1
White solid, Rf=0.22 (EtOAc 1:2 Hex); Yield 81%; H NMR
over anhydrous Na SO4. After removal of solvents, the residue
2
(400 MHz, CDCl3) δ 8.10 (d, J = 7.8 Hz, 2H), 7.97 (d, J = 7.8 Hz,
1.48H), 7.83 – 7.76 (m, 1.74H), 7.72 – 7.63 (m, 3.48H), 7.31 (d,
J = 8.5 Hz, 2H), 7.28 (d, J = 8.8 Hz, 1.48H), 7.24 (d, J = 8.8 Hz,
1.48H), 6.99 (d, J = 8.5 Hz, 2H), 4.81 (d, J = 11.4 Hz, 1H), 4.75
(d, J = 11.5 Hz, 0.74H), 4.56 (d, J = 11.5 Hz, 0.74H), 4.52 (d, J =
11.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 159.5, 148.6, 147.2,
135.6, 135.6, 135.3, 134.7, 130.1, 130.1, 129.6, 129.3, 129.2,
129.0, 128.9, 128.6, 124.5, 123.1, 59.0, 57.2; ES-HRMS: Calcd
for C14H12ClN2OS2 [M+H]+, 323.0074, Found 323.0073.
was purified by silica gel column chromatography using
petroleum ether/ethyl acetate (4:1) to afford the desired product
(Chloromethyl)(imino)(phenyl)-λ6-sulfanone (4a) as
yellow oil (1.57 g, 83%). H NMR (400 MHz, CDCl3) δ 8.06 (d,
J = 7.5 Hz, 2H), 7.70 (t, J = 7.3 Hz, 1H), 7.60 (t, J = 7.5 Hz, 2H),
4.59 (s, 2H), 3.18 (s, 1H).
a pale
1
With
the
same
method,
(Chloromethyl)(imino)(4-
methoxyphenyl)- λ6-sulfanone (4b) was afforded as a pale yellow
oil (82%). 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.7 Hz, 2H),
7.04 (d, J = 8.7 Hz, 2H), 4.55 (s, 2H), 3.90 (s, 3H), 3.08 (s, 1H).
13C NMR (100 MHz, CDCl3) δ 164.2, 131.6, 128.7, 114.5, 61.5,
55.8;
4.3.3ꢃ 3-((2-Chlorophenyl)imino)-1-phenyl-3,5-dihydro-1,4,2-
dithiazole 1-oxide (6c)
1
White solid, Rf=0.22 (EtOAc 1:2 Hex); Yield 78%; H NMR
(4-Bromophenyl)(chloromethyl)(imino)-λ6-sulfanone (4c) was
afforded as a pale yellow oil (80%). 1H NMR (400 MHz, CDCl3)
δ 7.95 – 7.88 (m, 2H), 7.77 – 7.68 (m, 2H), 4.57 (s, 2H), 3.01 (s,
1H). 13C NMR (100 MHz, CDCl3) δ 136.6, 132.6, 131.0, 129.7,
61.1;
(Chloromethyl)(4-fluorophenyl)(imino)-λ6-sulfanone (4d) was
afforded as a pale yellow oil (82%). 1H NMR (400 MHz, CDCl3)
δ 8.27 – 7.82 (m, 2H), 7.45 – 6.98 (m, 2H), 4.58 (s, 2H), 3.13 (s,
1H). 13C NMR (100 MHz, CDCl3) δ 167.5, 165.0, 133.5, 133.4,
132.4, 132.3, 116.7, 116.4, 61.3;
(Chloromethyl)(imino) (pyridin-2-yl)-λ6-sulfanone (4e) was
afforded as a pale yellow oil (78%). 1H NMR (400 MHz, CDCl3)
δ 8.78 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 7.9 Hz, 1H), 8.00 (t, J =
7.8 Hz, 1H), 7.59 (dd, J = 7.0, 5.3 Hz, 1H), 4.95 (q, J = 11.9 Hz,
2H), 3.31 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 155.83, 150.33,
138.21, 127.47, 123.82, 57.93.
(400 MHz, CDCl3) δ 8.08 (d, J = 7.7 Hz, 2H), 7.97 (d, J = 7.8 Hz,
1.6H), 7.83 – 7.72 (m, 1.8H), 7.70 –7.60 (m, 3.6H), 7.41 (d, J =
7.9 Hz, 1H), 7.34 (d, J = 7.9 Hz, 0.8H), 7.25 – 7.14 (m, 2.6H),
7.10 – 7.04 (m, 2H), 6.99 – 6.93 (m, 0.8H), 4.80 (d, J = 11.6 Hz,
1.8H), 4.64 (d, J = 11.6 Hz, 0.8H), 4.58 (d, J = 11.6 Hz, 1H). 13
C
NMR (100 MHz, CDCl3) δ 160.6, 147.3, 147.1, 135.6, 135.5,
135.2, 135.0, 130.2, 130.1, 123.0, 129.5, 129.2, 129.1, 128.9,
128.6, 127.4, 127.0, 126.8, 126.5, 125.3, 124.4, 123.3, 123.1,
59.2, 58.1; ES-HRMS: Calcd for C14H12ClN2OS2 [M+H]+,
323.0074, Found 323.0070.
4.3.4ꢃ 3-((3-Chlorophenyl)imino)-1-phenyl-3,5-dihydro-1,4,2-
dithiazole 1-oxide (6d)
1
White solid, Rf=0.22 (EtOAc 1:2 Hex); Yield 79%; H NMR
(400 MHz, CDCl3) δ 8.10 (d, J = 7.5 Hz, 2H), 7.97 (d, J = 7.5 Hz,
1.4H), 7.83 – 7.76 (m, 1.7H), 7.72 – 7.63 (m, 3.4H), 7.36 – 7.34
(m, 0.7H),7.30 – 7.24 (m, 1.4H), 7.22 – 7.18 (m, 1H), 7.14 – 7.09

4
Tetrahedron
1
(m, 1H), 7.06 (t, J = 1.9 Hz, 1H), 7.02 (dt, J = 7.1, 2.0 Hz,
White solid, Rf=0.24 (EtOAc 1:2 Hex); Yield 53%; H NMR
(400 MHz, CDCl3) δ 8.11 (d, J = 8.0 Hz, 2H), 7.99 (d, J = 7.8 Hz,
1.2H), 7.83 –7.74 (m, 1.6H), 7.71 – 7.62 (m, 3.2H), 7.36 (d, J =
8.4 Hz, 1.2H), 7.00 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.3 Hz, 2H),
6.84 (d, J = 8.4 Hz, 1.2H), 4.78 (d, J = 11.3 Hz, 1H), 4.72 (d, J =
11.6 Hz, 0.6H), 4.53 (d, J = 11.3 Hz, 0.6H), 4.49 (d, J = 11.4 Hz,
1H), 3.82 (s, 3H), 3.78 (s, 1.8H). 13C NMR (100 MHz, CDCl3) δ
156.6, 156.2, 143.6, 141.8, 135.6, 135.4, 135.4, 134.9, 130.0,
130.0, 129.3, 128.9, 124.3, 122.6, 114.3, 113.7, 58.8, 57.0, 55.5,
55.4; ES-HRMS: Calcd for C15H15N2O2S2 [M+H]+, 319.0569,
Found 319.0568.
ACCEPTED MANUSCRIPT
0.7H), 6.94 (d, J = 7.9 Hz, 1H), 4.81 (d, J = 11.4 Hz, 1H), 4.76 (d,
J = 11.5 Hz, 0.7H), 4.57 (d, J = 11.5 Hz, 0.7H), 4.53 (d, J = 11.5
Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 159.7, 151.3, 135.6,
135.5, 134.7, 134.5, 134.0, 130.2, 130.1, 130.1, 129.5, 129.3,
128.9, 124.4, 123.9, 123.2, 122.0, 121.5, 120.0, 59.1, 57.2; ES-
HRMS: Calcd for C14H12ClN2OS2 [M+H]+, 323.0074, Found
323.0069.
4.3.5ꢃ1-Phenyl-3-(p-tolylimino)-3,5-dihydro-1,4,2-dithiazole 1-
oxide (6e)
1
White solid, Rf=0.23 (EtOAc 1:2 Hex); Yield 60%; H NMR
4.3.10ꢃ 3-((4-Nitrophenyl)imino)-1-phenyl-3,5-dihydro-1,4,2-
dithiazole 1-oxide (6j)
(400 MHz, CDCl3) δ 8.12 (d, J = 7.4 Hz, 2H), 7.99 (d, J = 7.4 Hz,
1H), 7.85 – 7.75 (m, 1.5H), 7.72 – 7.62 (m, 3H), 7.25 (d, J = 8.3
Hz, 1H), 7.17 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.1 Hz, 1H), 6.97
(d, J = 8.2 Hz, 2H), 4.80 (d, J = 11.4 Hz, 1H), 4.75 (d, J = 11.4
Hz, 0.5H), 4.56 (d, J = 11.4 Hz, 0.5H), 4.51 (d, J = 11.4 Hz, 1H),
2.37 (s, 3H), 2.31 (s, 1.5H). 13C NMR (100 MHz, CDCl3) δ 158.9,
158.7, 147.7, 146.2, 135.5, 135.4, 135.4, 134.9, 133.9, 133.4,
130.0, 129.7, 129.3, 129.2, 128.9, 122.8, 121.4, 58.9, 57.1, 21.0;
ES-HRMS: Calcd for C15H15N2OS2 [M+H]+, 303.0620, Found
303.0616.
Yellow solid, Rf=0.21 (EtOAc 1:2 Hex); Yield 84%; 1H NMR
(600 MHz, DMSO-d6) δ 8.16 (s, 2H), 8.07 (s, 2H), 7.91 (t, J =
7.4 Hz, 1H), 7.78 (t, J = 7.4 Hz, 2H), 7.33 (s, 1H), 7.19 (s, 1H),
5.44 (d, J = 12.2 Hz, 1H), 5.33 (d, J = 10.0 Hz, 1H). 13C NMR
(150 MHz, DMSO-d6) δ 163.2, 160.1, 156.3, 155.5, 143.3, 142.6,
135.8, 133.8, 130.1, 129.0, 125.1, 124.9, 124.5, 123.4, 122.4,
57.3, 55.7; ES-HRMS: Calcd for C14H12N3O3S2 [M+H]+,
334.0315, Found 334.0313.
4.3.6ꢃ 3-((4-Fluorophenyl)imino)-1-phenyl-3,5-dihydro-1,4,2-
dithiazole 1-oxide (6f)
4.3.11ꢃ 1-Phenyl-3-((4-(trifluoromethyl)phenyl)imino)-3,5-
dihydro-1,4,2-dithiazole 1-oxide (6k)
1
1
White solid, Rf=0.22 (EtOAc 1:2 Hex); Yield 82%; H NMR
White solid, Rf=0.22 (EtOAc 1:2 Hex); Yield 82%; H NMR
(400 MHz, CDCl3) δ 8.12 (d, J = 8.1 Hz, 2H), 8.00 (d, J = 8.1 Hz,
1.4H), 7.85 – 7.77 (m, 1.7H), 7.73 – 7.65 (m, 3.4H), 7.36 – 7.32
(m, 1.4H), 7.09 – 6.95 (m, 5.4H), 4.82 (d, J = 11.4 Hz, 1H), 4.76
(d, J = 11.5 Hz, 0.7H), 4.58 (d, J = 11.5 Hz, 0.7H), 4.53 (d, J =
11.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 159.2, 158.7,
146.3, 144.6, 135.6, 135.5, 135.4, 134.8, 130.1, 130.0, 129.3,
128.9, 124.5, 124.4, 123.0, 122.9, 115.9, 115.7, 115.2, 115.0,
59.0, 57.1; ES-HRMS: Calcd for C14H12FN2OS2 [M+H]+,
307.0370, Found 307.0370.
(400 MHz, CDCl3) δ 8.13 (d, J = 7.7 Hz, 2H), 7.99 (d, J = 7.6 Hz,
1.7H), 7.87 – 7.78 (m, 1.85H), 7.75 – 7.65 (m, 3.7H), 7.62 (d, J =
7.6 Hz, 2H), 7.56 (d, J = 7.6 Hz, 1.7H), 7.38 (d, J = 7.9 Hz, 1.7H),
7.16 (d, J = 7.7 Hz, 2H), 4.85 (d, J = 11.9 Hz, 1H), 4.80 (d, J =
11.7 Hz, 0.85H), 4.61 (d, J = 12.0 Hz, 0.85H), 4.57 (d, J = 11.6
Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 153.0, 152.0, 141.3,
135.7, 135.1, 134.5, 130.2, 130.1, 129.3, 128.8, 126.4, 126.4,
125.8, 125.8, 123.1, 121.9, 59.1, 57.3; ES-HRMS: Calcd for
C15H12N2F3OS2 [M+H]+, 357.0338, Found 357.0341.
4.3.7ꢃ 3-((4-Bromophenyl)imino)-1-phenyl-3,5-dihydro-1,4,2-
dithiazole 1-oxide (6g)
4.3.12ꢃ 1-Phenyl-3-(pyridin-3-ylimino)-3,5-dihydro-1,4,2-
dithiazole 1-oxide (6l)
1
Yellow solid, Rf=0.23 (EtOAc 1:2 Hex); Yield 65%; 1H NMR
(400 MHz, CDCl3) δ 8.10 (d, J = 7.8 Hz, 2H), 7.97 (d, J = 7.9 Hz,
1.46H), 7.85 – 7.75 (m, 1.73H), 7.72 – 7.63 (m, 3.46H), 7.45 (d,
J = 8.5 Hz, 2H), 7.39 (d, J = 8.6 Hz, 1.46H), 7.21 (d, J = 8.6 Hz,
1.46H), 6.93 (d, J = 8.5 Hz, 2H), 4.81 (d, J = 11.4 Hz, 1H), 4.75
(d, J = 11.5 Hz, 0.73H), 4.56 (d, J = 11.5 Hz, 0.73H), 4.52 (d, J =
11.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 159.4, 149.1, 147.8,
135.6, 135.6, 135.3, 134.7, 132.2, 131.5, 130.1, 130.1, 129.3,
128.9, 124.9, 123.5, 117.4, 116.9, 59.0, 57.2; ES-HRMS: Calcd
for C14H12BrN2OS2 [M+H]+, 366.9569, Found 366.9568.
White solid, Rf=0.20 (EtOAc); Yield 70%; H NMR (400
MHz, CDCl3) δ 8.54 (s, 1H), 8.35 (d, J = 4.7 Hz, 1H), 8.33 (s,
1H), 8.23 (d, J = 4.7 Hz, 1H), 8.06 (d, J = 8.0 Hz, 2H), 7.94 (d, J
= 8.1 Hz, 2H), 7.77 (dd, J = 17.8, 7.8 Hz, 2H), 7.71 – 7.59 (m,
5H), 7.38 – 7.32 (m, 1H), 7.26 (dd, J = 10.1, 5.3 Hz, 1H), 7.18
(dd, J = 8.1, 4.8 Hz, 1H), 4.85 (d, J = 11.6 Hz, 1H), 4.79 (d, J =
11.6 Hz, 1H), 4.66 – 4.57 (m, 2H). 13C NMR (100 MHz, CDCl3)
δ 161.44, 160.69, 146.15, 145.44, 145.42, 144.90, 144.70, 143.44,
135.70, 135.69, 134.92, 134.40, 130.14, 130.10, 129.87, 129.20,
129.00, 128.79, 123.63, 123.27, 59.10, 57.31; ES-HRMS: Calcd
for C13H12N3OS2 [M+H]+, 290.0422, Found 290.0417.
4.3.8ꢃ 3-((4-Iodophenyl)imino)-1-phenyl-3,5-dihydro-1,4,2-
dithiazole 1-oxide (6h)
4.3.13ꢃ 1-(4-Methoxyphenyl)-3-(phenylimino)-3,5-dihydro-
1,4,2-dithiazole 1-oxide (6o)
Yellow solid, Rf=0.23 (EtOAc 1:2 Hex); Yield 63%; 1H NMR
(400 MHz, CDCl3) δ 8.09 (d, J = 8.0 Hz, 2H), 7.96 (d, J = 8.0 Hz,
1.48H), 7.84 – 7.74 (m, 1.74H), 7.72 – 7.65 (m, 3.48H), 7.64 (d,
J = 8.3 Hz, 2H), 7.57 (d, J = 8.3 Hz, 1.48H), 7.08 (d, J = 8.3 Hz,
1.48H), 6.82 (d, J = 8.2 Hz, 2H), 4.81 (d, J = 11.5 Hz, 1H), 4.75
(d, J = 11.5 Hz, 0.74H), 4.56 (d, J = 11.6 Hz, 0.74H), 4.52 (d, J =
11.5 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 209.3, 159.4, 149.7,
148.5, 138.1, 137.5, 135.6, 135.2, 134.7, 130.1, 130.1, 129.3,
128.9, 125.3, 123.9, 88.2, 87.8, 59.0, 57.2; ES-HRMS: Calcd for
C14H12IN2OS2 [M+H]+, 414.9430, Found 414.9425.
1
White solid, Rf=0.24 (EtOAc 1:2 Hex); Yield 79%; H NMR
(400 MHz, CDCl3) δ 8.01 (d, J = 8.9 Hz, 2H), 7.88 (d, J = 8.9 Hz,
1H), 7.37 – 7.27 (m, 4H), 7.17 – 7.03 (m, 6.5H), 4.75 (d, J = 11.3
Hz, 1H), 4.71 (d, J = 11.4 Hz, 0.5H), 4.50 (d, J = 11.3 Hz, 0.5H),
4.45 (d, J = 11.3 Hz, 1H), 3.93 (s, 1H), 3.90 (s, 1H). 13C NMR
(100 MHz, CDCl3) δ 165.4, 150.2, 131.7, 131.3, 129.1, 128.5,
125.0, 124.3, 123.8, 123.1, 121.7, 115.3, 59.1, 58.4, 57.4, 56.0;
ES-HRMS: Calcd for C15H15N2O2S2 [M+H]+, 319.0569, Found
319.0570.
4.3.9ꢃ 3-((4-Methoxyphenyl)imino)-1-phenyl-3,5-dihydro-1,4,2-
dithiazole 1-oxide (6i)
4.3.14ꢃ 1-(4-Bromophenyl)-3-(phenylimino)-3,5-dihydro-1,4,2-
dithiazole 1-oxide (6p)

5
Yellow solid, Rf=0.23 (EtOAc 1:2 Hex); Yield 78%; 1H NMR
(400 MHz, CDCl3) δ 7.94 (d, J = 8.4 Hz, 2H), 7.83 – 7.73 (m,
3.84H), 7.34 (t, J = 7.6 Hz, 2H), 7.30 – 7.27 (m, 1.84H), 7.14 (t,
J = 7.3 Hz, 1H), 7.08 – 7.04 (m, 0.46H), 7.02 (d, J = 8.0 Hz, 2H),
4.79 (d, J = 11.5 Hz, 1H), 4.74 (d, J = 11.5 Hz, 0.46H), 4.55 (d, J
= 11.5 Hz, 0.46H), 4.49 (d, J = 11.5 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ 158.7, 158.7, 150.0, 148.6, 133.4, 131.4, 130.8,
130.4, 129.2, 128.6, 124.5, 124.0, 123.0, 121.6, 59.0, 57.2; ES-
HRMS: Calcd for C14H12BrN2OS2 [M+H]+, 366.9569, Found
366.9575.
Bull, J. A. Angew Chem Int Ed Engl. 2016, 55, 7203-7207; (d)
Mancheno, O. G.; Bistri, O.; Bolm, C. Org Lett. 2007, 9(19),
3809-3811; (e) Tota, A.; Zenzola, M.; Chawner, S. J.; St John-
ACCEPTED MANUSCRIPT
Campbell, S.; Carlucci, C.; Romanazzi, G.; Degennaro, L.; Bull, J.
A.; Luisi, R. Chem Commun. 2017, 53(2), 348-351.
3. (a) Siemeister, G.; Lücking, U.; Wengner, A. M.; Lienau, P.;
Steinke, W.; Schatz, C.; Mumberg, D.; Ziegelbauer, K. Mol
Cancer Ther. 2012, 11, 2265; (b) Satzinger, G. Drug News
Perspect. 2001, 14, 197-207; (c) Bartoszyk, G. D.;Dooley, D. J.;
Barth, H.; Hartenstein, J.; Satzinger, G. J Pharm Pharmacol. 1987,
39, 407-408; (d) Barnes, A. C.; Hairsine, P. W.; Matharu, S. S.;
Ramm, P. J.; Taylor, J. B. J Med Chem. 1979, 22, 418-424; (e) Lu,
D.; Vince, R. Bioorg Med Chem Lett. 2007, 17, 5614-5619; (f)
Siemeister, G.; Lücking, U.; Wengner, A. M.; Lienau, P.; Steinke,
W.; Schatz, C.; Mumberg, D.; Ziegelbauer, K. Mol Cancer Ther.
2012, 11, 2265-2273; (g)Nishimura, N.; Norman, M. H.; Liu, L.;
Yang, K. C.; Ashton, K. S.; Bartberger, M. D.; Chmait, S.; Chen,
J.; Cupples, R.; Fotsch, C.; Helmering, J.; Jordan, S. R.; Kunz, R.
K.; Pennington, L. D.; Poon, S. F.; Siegmund, A.; Sivits, G.;
Lloyd, D. J.; Hale, C.; St Jean, D. J. J Med.Chem. 2014, 57, 3094-
3116; (h) Gutmann, B.; Elsner, P.; O'Kearney-McMullan, A.;
Goundry, W.; Roberge, D. M.; Kappe, C. O. Org Process Res Dev.
2015, 19, 1062-1067; (i) Oost, T.; Fiegen, D.; Gnamm, C.
WO2014/029830, 2014.
4.3.15ꢃ 1-(4-Fluorophenyl)-3-(phenylimino)-3,5-dihydro-1,4,2-
dithiazole 1-oxide (6q)
1
White solid, Rf=0.22 (EtOAc 1:2 Hex); Yield 77%; H NMR
(400 MHz, CDCl3) δ 8.13 (dd, J = 8.6, 4.9 Hz, 2H), 7.99 (dd, J =
8.6, 4.8 Hz, 0.92H), 7.38 – 7.28 (m, 6.76H), 7.15 (t, J = 7.3 Hz,
1H), 7.07 (t, J = 7.3 Hz, 0.46H), 7.04 (d, J = 8.0 Hz, 2H), 4.80 (d,
J = 11.4 Hz, 1H), 4.75 (d, J = 11.5 Hz, 0.46H), 4.55 (d, J = 11.5
Hz, 0.46H), 4.49 (d, J = 11.4 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ 168.4, 165.8, 158.7, 150.0, 148.7, 132.5, 132.4, 132.1,
132.0, 130.5, 130.5, 129.1, 128.6, 124.4, 124.0, 123.0, 121.6,
117.6, 117.4, 110.0, 59.1, 57.3; ES-HRMS: Calcd for
C14H12FN2OS2 [M+H]+, 307.0370, Found 307.0365.
4.
(a) Harmata, M.; Pavri, N. Angew Chem Int Ed Engl. 1999,
38(16), 2419-2421; (b) Dong, W. R.; Wang, L.; Parthasarathy, K.;
Pan, F. F.; Bolm, C. Angew Chem Int Ed Engl. 2013, 52(44),
11573-11576; (c) Chinnagolla, R. K.; Vijeta, A.; Jeganmohan, M.
Chem Commun. 2015, 51(65), 12992-12995; (d) Cheng, Y. and
Bolm, C. Angew Chem Int Ed Engl. 2015, 54(42), 12349-12352;
(e) Harmata, M. and Hong, X. C. J Am Chem Soc. 2003, 125(19),
5754-5756; (f) Cheng, Y.; Dong, W. R.; Parthasarathy, K.; Bolm,
C. Org Lett. 2017, 19(3), 726-729; (g) Bohmann, R. A.; Unoh, Y.;
Miura, M.; Bolm, C. Chem–Eur J. 2016, 22(20): 6783-6786; (h)
Harmata, M.; Cai, Z. X.; Chen, Y. G. J Org Chem. 2009, 74(15),
5559-5561; (i) Le, T. N.; Diter, P.; Pegot, B.; Bournaud, C.;
Toffano, M.; Guillot, R.; Giang, V. T.; Magnier, E. Org Lett.
2016, 18(19), 5102-5105; (j) Battula, S. R. K.; Subbareddy, G. V.;
Chakravarthy, I. E.; Saravanan, V. RSC Adv. 2016, 6(61), 55710-
55714; (k) Kuhl, J.; Reggelin, M. Synthesis-Stuttgart. 2017, 49(2):
403-408; (l) Bizet, V.; Hendriks, C. M. M.; Bolm, C. Chem Soc
Rev. 2015, 44, 3378–3390.
4.3.16ꢃ 3-(Phenylimino)-1-(pyridin-2-yl)-3,5-dihydro-1,4,2-
dithiazole 1-oxide (6r)
1
White solid, Rf=0.50 (EtOAc); Yield 54%; H NMR (400
MHz, CDCl3) δ 8.80 (d, J = 4.5 Hz, 1H), 8.78 (d, J = 4.5 Hz,
0.47H), 8.35 (d, J = 7.9 Hz, 1H), 8.22 (d, J = 7.8 Hz, 0.47H),
8.08 (t, J = 7.8 Hz, 1H), 8.03 (t, J = 7.8 Hz, 0.47H), 7.69 – 7.58
(m, 1.47H), 7.35 (t, J = 7.6 Hz, 2H), 7.30 – 7.23 (m, 1.88H), 7.15
(t, J = 7.3 Hz, 1H), 7.04 (d, J = 7.8 Hz, 2.47H), 5.35 – 5.29 (m,
1.47H), 4.72 (d, J = 11.6 Hz, 1H), 4.64 (d, J = 11.5 Hz, 0.47H).
13C NMR (100 MHz, CDCl3) δ 158.74, 158.45, 154.44, 154.37,
150.91, 150.81, 150.06, 148.84, 138.85, 138.73, 129.05, 128.47,
128.42, 128.38, 124.31, 123.92, 123.81, 123.76, 122.94, 121.70,
54.12, 52.44; ES-HRMS: Calcd for C13H12N3OS2 [M+H]+,
290.0422, Found 290.0420.
5. Williams, T. R.; Cram, D. J. J Am Chem Soc. 1971, 93(26), 7333-
7335.
6. Wang, H.; Frings, M.; Bolm, C. Org Lett. 2016, 18(10), 2431-
2434.
7. Marzag, H.; Schuler, M.; Tatibouet, A.; Reboul, V. Eur J Org
Chem. 2017, 4, 896-900.
4.3.17ꢃ 3-(Phenylimino)-1-(thiophen-2-yl)-3,5-dihydro-1,4,2-
dithiazole 1-oxide (6s)
8. Lanyon-Hogg, T.; Ritzefeld, M.; Masumoto, N.; Magee, A. I.;
Rzepa, H. S.; Tate, E. W. J Org Chem. 2015, 80(9), 4370-4377.
9. (a) Fortin, S.; Wei, L. H.; Moreau, E.; Lacroix, J.; Cote, M. F.;
Petitclerc, E.; Kotra, L. P.; C-Gaudreault, R. J Med Chem. 2011
54(13), 4559-4580; (b) Le, T. N.; Diter, P.; Pegot, B.; Bournaud,
C.; Toffano, M.; Guillot, R.; Vo-Thanh, G.; Yagupolskii, Y.;
Magnier, E. J Fluorine Chem. 2015, 179, 179-187; (c) Saha, P.;
Ramana, T.; Purkait, N.; Ali, M. A.; Paul, R.; Punniyamurthy, T. J
Org Chem. 2009, 74(22), 8719-8725.
Yellow solid, Rf=0.25 (EtOAc 1:2 Hex); Yield 48%; 1H NMR
(400 MHz, CDCl3) δ 7.97 (d, J = 3.5 Hz, 1H), 7.94 (d, J = 4.9
Hz, 1H), 7.90 (d, J = 4.9 Hz, 0.45H), 7.85 (d, J = 3.4 Hz, 0.45H),
7.35 (t, J = 7.4 Hz, 2H), 7.31 –7.27 (m, 2.8H), 7.24 (t, J = 4.0 Hz,
0.45H), 7.15 (t, J = 7.3 Hz, 1H), 7.09 –7.06 (m, 0.45H), 7.04 (d, J
= 7.8 Hz, 2H), 4.88 (d, J = 11.3 Hz, 1H), 4.84 (d, J = 11.6 Hz,
0.45H), 4.69 (d, J = 11.2 Hz, 0.45H), 4.63 (d, J = 11.2 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 157.71, 157.50, 149.91, 148.67,
137.97, 137.84, 137.77, 137.31, 135.13, 134.36, 129.17, 129.13,
128.57, 124.45, 124.00, 122.93, 121.57, 59.98, 58.35; ES-HRMS:
Calcd for C12H11N2OS3 [M+H]+, 295.0034, Found 295.0031.
Acknowledgements
We are grateful for financial support from the National
Natural Science Foundation of China (No. 81673287).
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