Design and evaluation of 1,2,3-dithiazoles and fused 1,2,4-dithiazines as anti-cancer agents

Article abstract of DOI:10.1016/j.bmcl.2021.128078

Heteroatom rich 1,2,3-dithiazoles are relatively underexplored in medicinal chemistry. We now report screening data on a series of structurally diverse 1,2,3-dithiazoles and electronically related 1,2,4-dithiazines with the aim of identifying interesting starting points for potential future optimisation. The 1,2,3-dithiazoles, were obtained via a number of different syntheses and screened on a series of cancer cell lines. These included breast, bladder, prostate, pancreatic, chordoma and lung cancer cell lines with an additional skin fibroblast cell line as a toxicity control. Several low single digit micromolar compounds with promising therapeutic windows were identified for breast, bladder and prostate cancer. Furthermore, key structural features of 1,2,3-dithiazoles are discussed, that show encouraging scope for future refinement.

Full text of DOI:10.1016/j.bmcl.2021.128078

Bioorg. Med. Chem. Lett. 43 (2021) 128078
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and evaluation of 1,2,3-dithiazoles and fused 1,2,4-dithiazines as
anti-cancer agents
,
,
Kaitlyn A. Maffuida e, Maria Koyionib e, Chad D. Torricea, William A. Murphya,
Heemaja K. Mewadaa, Panayiotis A. Koutentisb, Daniel J. Cronaa c, Christopher R.M. Asquithd
,
,*
a Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599,
USA
b Department of Chemistry, University of Cyprus, P. O. Box 20537, 1678 Nicosia, Cyprus
c Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
d Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
A R T I C L E I N F O
A B S T R A C T
Keywords:
Heteroatom rich 1,2,3-dithiazoles are relatively underexplored in medicinal chemistry. We now report screening
data on a series of structurally diverse 1,2,3-dithiazoles and electronically related 1,2,4-dithiazines with the aim
of identifying interesting starting points for potential future optimisation. The 1,2,3-dithiazoles, were obtained
via a number of different syntheses and screened on a series of cancer cell lines. These included breast, bladder,
prostate, pancreatic, chordoma and lung cancer cell lines with an additional skin fibroblast cell line as a toxicity
control. Several low single digit micromolar compounds with promising therapeutic windows were identified for
breast, bladder and prostate cancer. Furthermore, key structural features of 1,2,3-dithiazoles are discussed, that
show encouraging scope for future refinement.
1,2,3-Dithiazole
Breast cancer
Bladder cancer
Prostate cancer
Pancreatic cancer
Chordoma
Нeteroatom rich 1,2,3-dithiazoles are relatively underexplored in
medicinal chemistry with the 1,2,4-dithiazine core even rarer.1 This
despite a number of reports on interesting biological applications
(Fig. 1) including activity against bacteria,2–5 fungi/weeds,6–11 vi-
ruses12,13 and cancers.14–16 Most 1,2,3-dithiazole chemistry revolves
around 4,5-dichloro-1,2,3-dithiazolium chloride, known as ‘Appel salt’,
which can be readily prepared from chloroacetonitrile and disulfur
dichloride.17
arrays of compounds on a series of cancer cell lines. These included
breast, bladder, prostate, pancreatic, chordoma and lung cancer cell
lines with an additional skin fibroblast cell line as a toxicity control.24–27
These cancer cell lines each presents a different drug resistance profiles
and when combined in a panel, each represents a distinct therapeutic
challenge to overcome.28 We synthesized a series of more common 5H-
1,2,3-dithiazolimines (8–25) via a nucleophilic displacement of the C-5
chloride of Appel salt 7 using various substituted anilines (Scheme
1).29–32
The versatile chemistry of Appel salt and the interesting physical/
biological properties of its derivatives, have led to a diverse series of
compounds being produced but generally around small, focused li-
braries. To date, 1,2,3-dithiazole chemistry has centered around the ring
systems susceptibility to attack by nucleophiles at the S-1, S-2, and C-5
atoms.18 These reaction pathways also present opportunities to target
biological processes that are historically difficult to target, including
proteins, protein–protein interactions and attempt to address issues of
selectivity within protein families by irreversible binding to
cysteine.19–23
We then converted three 1,2,3-dithiazoles 24, 26 & 27 using dieth-
ylamine and Hünig’s base in acetonitrile at ca. 20 ◦C, followed by
treatment with concentrated sulfuric acid to afford their respective
1,2,4-dithiazines 28–30 in good yields (Scheme 2).33 Additional struc-
tural diversity was achieved by modifying the C-4 position of dithiazo-
limines 31–34 (Scheme 3).34–37 Treatment of dithiazolimines 31–34
with DABCO in chlorobenzene at ca. 131 ◦C to afford a series of N-(2-
chloroethyl)-piperazin-1-yl-substituted 1,2,3-dithiazoles 35–38.38 The
available N-chloroethyl moiety was then further modified by nucleo-
philic substitution of the chloride using a variety of oxygen, sulfur and
nitrogen based nucleophiles to give a series of structurally diverse
To further explore the structural requirements for anti-cancer ac-
tivity within the 1,2,3-dithiazole scaffold, we profiled several focused
* Corresponding author.
E-mail address: chris.asquith@unc.edu (C.R.M. Asquith).
e
Contributed equally.
https://doi.org/10.1016/j.bmcl.2021.128078
Received 25 February 2021; Received in revised form 18 April 2021; Accepted 26 April 2021
Available online 2 May 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.

K.A. Maffuid et al.
Bioorganic & Medicinal Chemistry Letters 43 (2021) 128078
Scheme 3. Synthetic procedure to afford 39–46.17,38 Reagent and Conditions:
31–32 (X = ArN): a) ArNH2 (2 equiv), DCM, rt, 2 h; b) pyridine (2 equiv), rt, 1
h. 33 (X = S): H2S (g), MeCN, rt. 34 (X = O): HCO2H, rt, 2 h. b) DABCO (2
equiv), PhCl, 131 ◦C, 76–85%. c) NucH, MeCN, reflux, 72–98%.
two chordoma lines.
The 4-methylthiophenyl 15 was toxic with non-specific inhibition of
the toxicity control, this was consistent with findings in the previously
reported in vivo pigment study.39 The 4-bromophenyl 16 showed inhi-
bition of breast cancer (IC50 = 11 µM) with weaker activity across the
other cancer cell lines apart from lung cancer cell line. The 3-bromo-
phenyl 17 had a similar profile to the 4-bromophenyl 16, but showed
just under a 2-fold increase in potency against breast cancer (IC50 = 6.7
µM) with no increase in toxicity. The introduction of an ortho-nitrile to
the 3-bromophenyl analogue 18 reduced activity on the breast cancer
cell line by 4-fold but demonstrated a 3- and 4-fold increase activity on
bladder and pancreatic cancer, respectively. The final two analogues of
this series 19 and 20 contained para-substituted sulfonamide groups.
The N-(thiazol-2-yl)sulfonamide 19 showed only limited activity, but
the N-(pyrimid-2-yl)sulfonamide 20 showed potent activity against
breast cancer (IC50 = 3.0 µM) and some activity against the difficult to
treat,25–26,40 patient-derived chordoma cell line UCH-2 (IC50 = 19 µM).
It is currently unclear if this activity is related to the pyrimidine sub-
tituent, the 1,2,3-dithiazole or both parts of the molecule.
Fig. 1. Examples of biologically active 1,2,3-dithiazoles.
Scheme 1. Nucleophic displacement from Appel salt (7) to afford 8–25. Re-
agent and Conditions: for 8–21: a) ArNH2 (1 equiv), DCM, rt, 2 h; b) pyridine (2
equiv), rt, 1 h; 23–98%. Then for 21–25: a) ArNH2 (1 equiv), HCl (g), DCM, rt,
12 h; b) lutidine (2 equiv), rt, 3 h; 17–92%.
We then made a small series of small heteroaryl amine derivatives
21–25 (Table 2). The first analogue with a N-(thiazol-2-yl) 21, an
analogue of 19 was toxic across all cell lines including WS-1 with little
differentiated activity between the cell lines. The second analogue N-(3-
methyl-1H-pyrazol-5-yl) 22, also showed some toxicity (WS-1; IC50
=
40 µM), but showed a 2-fold improvement over 21, with some activity
against the panel of cancer cell lines. However, with an increase in size
of the C-3 substituent from methyl 22 to phenyl 23, the toxicity can be
tuned out, as in the case of 23 (WS-1; IC50 = >100 µM). The reduction in
toxicity did not compromise inhibition activity with breast, bladder,
prostate, pancreatic cancers, all having IC50’s below 25 µM and breast
Scheme 2. Synthetic procedure to afford 28–30. Reagent and Conditions: a)
Et2NH (3 equiv), i-Pr2NEt (1 equiv), MeCN, rt, 25 min; b) concd H2SO4 (5
equiv), MeCN, rt, 5 min.
analogues 39–46.38
Initial screening focused on the simpler substituted phenyl analogues
based on the (Z)-4-chloro-N-phenyl-5H-1,2,3-dithiazol-5-imines scaffold
8–20 (Table 1). The first compound screened, the (Z)-N-[4-(benzyloxy)
phenyl]-4-chloro-5H-1,2,3-dithiazol-5-imine (8) is known to cause a loss
of pigmentation in melanophores and the retinal pigment epithelium
(RPE) of developing Xenopus laevis embryos.39 In our cell line screening,
dithiazolimine 8 showed limited activity across the cancer cell lines, the
most potent activity was an IC50 of 13 µM against bladder cancer, with
no associated toxicity (WS-1; IC50 = >100 µM). Interestingly, the cor-
responding analogue switching from the benzyl 8 to the phenyl 9 in a
previously reported study yielded a toxic compound,39 whereas no
toxicity (WS-1; IC50 = >100 µM) was observed in our screening and only
limited anti-cancer activity across the cell line panel. The 4-(n-butyl)-
substituted dithiazolimine 10 showed weaker activity (IC50 = 18 µM) on
the bladder cancer cell line, but still without any associated toxicity.
The 4-trifluoromethoxy analogue with the additional diversity of a 2-
methyl group (11) showed a 4-fold drop in bladder cancer inhibition but
an increase of 4-fold for prostate cancer inhibition. Additional modifi-
cation of the 4-trifluoromethoxyphenyl 11 included analogues that
lacked the 2-methyl group but included halo substitution at the 3-posi-
tion (12–13) but these showed no improvement. Interestingly, the fused
methylene 3,4-catechol 14 showed the same potency as the dithiazole
11 on the prostate cancer cell line and a small hint of inhibition on the
cancer inhibition in the single digit micromolar range (IC50 = 9.3 μM).
–
The blocking of the N H of pyrazolyl 23 with a benzyl group 24,
reduced activity against breast cancer by 4-fold, but maintained activity
across bladder, prostate, pancreatic cancers, while showing no toxicity.
However, reverting to a methyl group on C-3 25, led to a potent a
compound against bladder cancer (IC50 = 2.1 µM) and prostate cancer
(IC50 = 10 µM), but also resulted in a compound with increased toxicity
in WS-1 (IC50 = 15 µM).
We then converted three 1,2,3-dithiazoles to fused 1,2,4-dithiazines
28–30 to look at the effect of shifting to an electronically and chemicaly
different disulfide bridge system (Table 3).38 The 5,7-dimethyl-5H-
pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitrile (28) was near inactive.
However, the extension of the pendant substituent pattern of the 5-
benzyl-7-phenyl-substituted dithiazine 29 allowed for a 10-fold in-
crease of inhibition on the bladder cancer cell line to single digit
micromolar with only mild associated toxicity (WS-1; IC50 = 51 μM)
with respect to 28. Interestingly, the symmetrical 5,7-diphenyl-
substituted dithiazine 30 modulated the anti-cancer activity with im-
provements on both breast and prostate cancer inhibition potency (IC50
= <20
with no tocivty in WS-1 (IC50 = >100 µM).
The encouraging preliminary data from the earlier screening, led us
μM) and maintained bladder cancer inhibition (IC50 = 14 μM)
2

K.A. Maffuid et al.
Bioorganic & Medicinal Chemistry Letters 43 (2021) 128078
Table 1
Results of a series of N-(aryl)-4-chloro-5H-1,2,3-dithiazol-5-imines (8–20).a
Name
R1
R2
R3
MCF7
5637
DU145
PANC1
UCH1
UCH2
A431
WS-1
8
BnO
H
H
H
H
Cl
Br
H
50
35
42
43
88
73
19
36
11
6.7
28
49
3.0
13
35
18
47
33
36
32
34
36
53
14
27
39
45
>100
52
18
32
52
17
14
48
27
42
92
29
>100
55
44
30
54
57
36
34
28
38
43
40
39
30
34
>100
33
48
87
43
85
22
37
51
59
65
36
19
>100
>100
>100
>100
>100
100
>100
>100
>100
>100
>100
>100
84
9
PhO
H
10
11
12
13
14
15
16
17
18
19
20
n-BuO
F3CO
F3CO
F3CO
H
>100
76
Me
H
>100
>100
24
H
–OCH2O–
H
95
MeS
Br
H
H
H
86
51
66
H
H
35
>100
>100
>100
>100
>100
>100
94
Br
Br
H
H
38
H
CN
H
13
>100
>100
>100
2-thiazolyl-NHSO2
2-pyrimidyl-NHSO2
97
H
H
37
a
Results are a mean average of 4 replicates.
Table 2
Results of a small series 5-membered N-hetaryl-substituted 1,2,3-dithiazolimines (21–25).a
Name
X1
X2
R1
X3
MCF7
5637
DU145
PANC1
UCH1
UCH2
A431
WS-1
21
22
23
24
25
S
H
N
N
N
N
H
N
H
H
H
H
45
18
9.3
30
18
15
20
16
16
2.1
8.1
14
11
14
10
24
27
23
18
26
10
33
59
30
33
22
18
38
52
30
17
24
NH
NH
N-Bn
N-Bn
Me
Ph
Ph
Me
69
40
>100
>100
27
>100
>100
15
a
Results are a mean average of 4 replicates.
Table 3
Results of a small series of 1,2,4-dithiazines (28–30).a
Name
R1
R2
MCF7
5637
DU145
PANC1
UCH1
UCH2
A431
WS-1
28
29
30
Me
Bn
Ph
Me
Ph
Ph
>100
54
81
8.7
14
40
32
16
>100
>100
75
>100
>100
55
>100
>100
68
>100
54
>100
51
36
72
>100
a
Results are a mean average of 4 replicates.
to test more divergent substitution patterns, changing both the 5- and 4-
position of the 1,2,3-dithiazole. We reacted a selection of 5-substituted
1,2,3-dithiazoles with DABCO to gain an additional point of variation.
The ring opened N-(2-chloro-ethyl)piperazin-1-yl derivatives 31–34
were then reacted with nucelophies to afford a series of diverse ana-
logues. The final compounds 39–46 afford a range of results (Table 4).
The first analogue an ester, (Z)-2-{4-[5-(phenylimino)-5H-1,2,3-dithia-
zol-4-yl]piperazin-1-yl}ethyl benzoate (39), had low micromolar activ-
ity against breast and bladder cancer in addition to chordoma. However,
39 also unfortunately, displayed some mild toxicity (WS-1; IC50 = 38
both chordoma cell lines. The thiocyanate analogue 41, showed broadly
similar activity with no toxicity. There was one anomalous difference,
compound 41 showed reduced inhibition on the bladder cancer cell line,
the reason for this is currently unclear.
We then tested (Z)-5-bromo-2-({4-[4-(2-chloroethyl)-piperazin-1-
yl]-5H-1,2,3-dithiazol-5-ylidene}amino)benzonitrile (42), that con-
tained several structural point changes compared with 39–41. Com-
pound 42 showed encouraging results particularly towards inhibition of
breast (IC50 = 4.1 μM) and bladder (IC50 = 8.0 μM) cancers with lower
single digit micromolar potencies.41
μ
M). The corresponding anilino derivative 40, slightly reduced this
Compound 42 also showed good potency on prostate and chordoma
toxicity, while maintaining potency against breast, bladder cancer and
cancer with no toxicity observed (WS-1; IC50 = >100 μM). This 20- to
3

K.A. Maffuid et al.
Bioorganic & Medicinal Chemistry Letters 43 (2021) 128078
Table 4
Results of a series of ring opened N-(2-chloroethyl)piperazin-1-yl derivatives (39–46).a
Name
X
R
MCF7
5637
DU145
PANC1
UCH1
UCH2
A431
WS-1
39
40
41
42
43
N-Ph
OBz
NH-Ph
SCN
Cl
17
10
32
4.1
51
13
18
93
8.0
25
30
55
14
15
23
60
67
16
18
73
23
25
38
32
46
34
36
38
N-Ph
21
87
55
N-Ph
38
>100
>100
>100
>100
>100
>100
N-Ph(2-CN, 4-Br)
23
S
>100
44
O
9.9
33
22
77
25
31
90
92
45
46
O
O
N(Me)-Ph
SCN
2.2
5.4
12
39
4.4
3.3
21
11
12
12
17
14
17
25
20
17
a
Results are a mean average of 4 replicates.
25-fold toxicity window was encouraging and demonstrated that the
activities observed were not the result of a generic toxicity phenotype.
Switching to the 5-thione 4-phthalimido derivative 2-{2-[4-(5-thioxo-
5H-1,2,3-dithiazol-4-yl)piperazin-1-yl]ethyl}isoindoline-1,3-dione
(43), led to a net drop in inhibition across the panel of cell lines, with no
toxicity observed. The ketone derivative 4-{4-[2-(benzo[d]thiazol-2-
ylthio)ethyl]piperazin-1-yl}-5H-1,2,3-dithiazol-5-one (44), showed
mild inhibition across all cancer cell lines with no toxicity observed. The
switch to the N-methylaniline analogue 45 and thiocyanate analogue 46
both had similar biological profiles, potent across the cancer cell line
panel with a moderate amount of toxicity observed.
and Biotronics Ltd. Furthermore, we thank the A. G. Leventis Foundation
for helping to establish the NMR facility at the University of Cyprus. We
also thank Dr. Brandie Ehrmann and Ms. Diane E. Wallace for for LC-
MS/HRMS support provided by in the Mass Spectrometry Core Labo-
ratory at the University of North Carolina at Chapel Hill. The core is
supported by the National Science Foundation under Grant No. (CHE-
1726291).
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2021.128078.
The 1,2,3-dithiazole core have previously been shown to have some
activity against breast cancer, but this is the first report of a broader
screening against multiple cancer cell lines.14 Within this screening we
have identified several low single digit micromolar compounds for
breast, bladder and prostate cancer all with low relative toxicity. We
have highlighted a series of modifications and demonstrated the effect of
key structural features on the 1,2,3-dithiazole scaffold.
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4

K.A. Maffuid et al.
Bioorganic & Medicinal Chemistry Letters 43 (2021) 128078
After 1 hour 2,6-lutidine (111.2 L, 0.96 mmol) was added dropwise. The reaction
23 Isham CR, Tibodeau JD, Jin W, Xu R, Timm M, Bible KC. Blood. 2007;109:
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μ
mixture was adsorbed onto silica after a further 2 hours and purified by flash
chromatography to afford the corresponding [(4-chloro-5H-1,2,3-dithiazol-5-
ylidene)amino]arene. Represenative example: (Z)-5-Bromo-2-[(4-chloro-5H-1,2,3-
dithiazol-5-ylidene)amino]benzonitrile (32). Yellow needles (72%), mp (DSC)
onset: 167.5 ◦C, peak max: 168.3 ◦C (from cyclohexane/DCE); (found: C, 32.6; H,
1.0; N, 12.6. C9H3BrClN3S2 requires C, 32.5; H, 0.9; N, 12.6%); λmax(DCM)/nm 230
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27 Cell culture method: U-CH1 and U-CH2 cell lines were cultured in 4:1 IMDM:RPMI-
1640 medium supplemented with 10% fetal bovine serum (FBS), 1% penicillin/
streptomycin in gel-coated flasks. A-431, PANC-1, and WS1 cell lines were cultured
in DMEM medium supplemented with 10% FBS and 1% penicillin/streptomycin.
DU145 and MCF-7 cells were cultured in MEM medium supplemented with 10% FBS
and 1% penicillin/streptomycin. 5637 cells were cultured in RPMI-1640 medium
supplemented with 10% FBS and 1% penicillin/streptomycin. Cells were seeded in
384 well plates and were treated with test compound in quadruplicate 24 hours after
plating. Cell viability was assessed at 72 hours using alamarBlue (ThermoFisher,
USA). Fluorescence was measured using Tecan Infinite 200 PRO plate reader with an
excitation at 535 nM and emission at 590 nM. IC50 values were determined by
nonlinear regression using GraphPad PrismTM software. (Positive controls: MCF7,
lapatinib IC50 = 6.3 µM42; 5637, pazopanib IC50 = 15 µM43; PANC1, panobinostat
(log
ε
3.14), 250 (3.08), 314 (2.50), 383 (2.88), 419 inf (2.65); νmax/cmꢀ 1 3080w (Ar
CH), 3063w, 2232w (C≡N), 1585m, 1560s, 1545m, 1489s, 1476s, 1458m, 1389w,
1269w, 1233w, 1182w, 1148m, 1126m, 1074m, 880m, 864s, 812m, 795m, 770m;
1H NMR (500 MHz, CDCl3) δ 7.87 (1H, d, J 2.0, H-6), 7.78 (1H, dd, J 8.5, 2.0, H-4),
7.21 (1H, d, J 9.0, H-3); 13C NMR (125 MHz, CDCl3) δ 161.9 (s), 125.1 (s), 148.2 (s),
137.5 (d), 136.4 (d), 119.1 (d), 118.8 (s), 114.9 (s), 108.1 (s); m/z (EI) 335 (M++4,
7%), 333 (M++2, 24), 331 (M+, 17), 272 (22), 270 (22), 240 (4), 238 (4), 234 (3),
232 (3), 208 (3), 206 (3), 182 (3), 180 (3), 159 (8), 127 (12), 125 (6), 115 (4), 100
(20), 93 (5), 88 (4), 75 (9), 70 (4), 66 (9), 64 (100), 50 (8). (Z)-5-Bromo-2-({4-[4-
(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}amino)
benzonitrile (42). To a stirred solution of 5-bromo-[N-(4-chloro-5H-1,2,3-dithiazol-
5-ylidene)amino]benzonitrile (33.3 mg, 0.1 mmol) in PhCl (1 mL) at ca. 20 ◦C was
added in one portion DABCO (13.5 mg, 0.12 mmol). The mixture was then heated at
ca. 131 ◦C for 1 h and then left to cool to ca. 20 ◦C. The mixture was poured onto a
packed column of silica and eluted with n-hexane. Subsequent elution (n-hexane/
Et2O, 70:30) gave 42 as yellow needles (37.5 mg, 84%), mp (DSC) onset: 144.4 ◦C,
IC50 = 1.0 µM44; DU145, docetaxel IC50 = 5 nM45; UCH1, gefitinib IC50 = 1.4 µM25
;
UCH2, gefitinib IC50 = 23 µM25; A431, lapatinib IC50 = 100 nM46; WS-1, lapatinib
IC50 = 13 µM25).
28 Gillet J, Varma S, Gottesman MM. J Natl Cancer Inst. 2013;105:452–458.
29 Kim K. Phosphorus Sulfur Silicon Relat Elem. 1997;120:229–244.
30 Kim K. Sulfur Rep. 1998;21:147–207.
peak max: 145.4 ◦C (from c-hexane); λmax (DCM)/nm 321 (log
ε 2.86), 321 inf (2.73);
νmax/cmꢀ 1 3026w, 2953w, 2882w, 2833w, 2778w, 2228w (C≡N), 1575s, 1547m,
1504m, 1470m, 1462m, 1437m, 1385m, 1369m, 1350w, 1333w, 1306m, 1294m,
1273m, 1252m, 1223m, 1200w, 1170m, 1142m, 1128m, 1121m, 1099w, 1076m,
1061w, 1051w, 1032w, 997s, 953m, 881m, 872m, 851m, 835m, 824s, 797m, 766m,
729m; 1H NMR (500 MHz, CDCl3) δ 7.83 (1H, d, J 2.0), 7.75 (1H, dd, J 8.8, 2.3), 7.30
(1H, d, J 9.0), 3.81 (4H, t, J 4.8), 3.61 (2H, t, J 6.8), 2.78 (2H, t, J 7.0), 2.69 (4H, t, J
5.0); 13C NMR (125 MHz, CDCl3) δ 163.1 (s), 158.5 (s), 153.0 (s), 137.4 (d), 136.1
(d), 119.4 (d), 117.8 (s), 115.7 (s), 108.5 (s), 59.7 (t), 52.8 (t), 48.6 (t), 40.8 (t);
MALDI-TOF MS (m/z): 448 (МН++4, 52%), 446 (МН++2, 100), 444 (МН+, 86), 410
(МН+-Cl, 30), 339 (80), 105 (57). HRMS m/z [M+H]+ calcd for C15H16N5S2ClBr:
443.9719, found 443.9707.
31 Konstantinova LS, Rakitin OA. Russ Chem Rev. 2008;77:521–546.
32 Rakitin OA. In Comprehensive Heterocyclic Chemistry III; Katritzky AR, Ramsden
CA, Scriven EFV, Taylor RJK, Zhdankin VV, Eds.; Elsevier: Oxford, 2008; vol. 6,
Chapter 6.01, pp 1ꢀ 36.
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36 Besson T, Rees CW. J Chem Soc, Perkin Trans 1. 1996:2857–2860.
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37 Besson T, Guillard J, Rees CW, Thiery V. J Chem Soc, Perkin Trans 1. 1998:889–892.
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41 General procdure for [(4-chloro-5 H-1,2,3-dithiazol-5-ylidene)amino]arenes:
Aminoarene (0.48 mmol) was added to a stirred suspension of 4,5-dichloro-1,2,3-
dithiazolium chloride (100 mg, 0.48 mmol) in dichloromethane (4 mL) at ca. 20 ◦C.
5