A catalyst-free method for the synthesis of 1,4,2-dithiazoles from isothiocyanates and hydroxylamine triflic acid salts

Article abstract of DOI:10.1039/d1ob00938a

A catalyst-free method for the preparation of 1,4,2-dithiazoles is developed by reactions of isothiocyanates with hydroxylamine triflic acid salts. This reaction achieves C-S, C-N, and S-N bond formation, and a range of products are obtained in moderate to good yields. The obvious feature is using shelf-stable hydroxylamine triflic acid salts as a N source to synthesize heterocycles under mild conditions.

Full text of DOI:10.1039/d1ob00938a

Organic &
Biomolecular Chemistry
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A catalyst-free method for the synthesis of
,4,2-dithiazoles from isothiocyanates and
hydroxylamine triflic acid salts†
1
Cite this: Org. Biomol. Chem., 2021,
9, 6206
1
Received 13th May 2021,
Accepted 24th June 2021
a
a
b
a
a
Zhenyu An, ‡ Ting Wang,‡ Yafeng Liu, Yi Ren and Rulong Yan
*
DOI: 10.1039/d1ob00938a
rsc.li/obc
A catalyst-free method for the preparation of 1,4,2-dithiazoles is fully developed, almost all strategies for producing these pro-
developed by reactions of isothiocyanates with hydroxylamine ducts required unavailable starting materials, multiple steps,
triflic acid salts. This reaction achieves C–S, C–N, and S–N bond and harsh reaction conditions. Therefore, the synthesis of
formation, and a range of products are obtained in moderate to 1,4,2-dithiazoles with simple substrates is still challenging and
good yields. The obvious feature is using shelf-stable hydroxyl- attractive.
amine triflic acid salts as a N source to synthesize heterocycles
Hydroxylamine triflic acid salts have recently emerged as an
under mild conditions.
NH or NH source to achieve C–H amination of arenes, difunc-
2
tionalization of alkenes, thiol amino-oxidation, and sulfur imi-
Dithiazoles, as five-membered heterocycles with nitrogen and
two sulfur atoms, have attracted considerable attention
because of their frequent appearance in a large number of
natural products and biologically active molecules.
Furthermore, these molecules (1,2,3-, 1,2,4-, and 1,4,2-dithia-
zoles) often exhibit a broad spectrum of biological activities,
10
11
12
dation (Scheme 1). In recent years, Morandi, Jiao, Ritter,
13
and Falck successively described direct radical aromatic
amination reactions using hydroxylamine triflic acid salts as
1
14
aminating reagents. Morandi also reported some general
strategies to access amines through iron-catalyzed difunctiona-
15
lization of alkenes. In 2021, Morandi designed an iron-cata-
2
3
such as antitubercular, antifungal, and anticancer activities
lyzed reaction for the selective amino-oxidation of thiols to
4
(
Fig. 1). Particularly, 1,4,2-dithiazole analogues have also been
proved to be useful for the treatment of cancer and identified
as novel inhibitors of West Nile virus (WNV) replication.
16
unprotected sulfinamides. Bolm discovered an iron-catalyzed
5
a
synthesis of NH sulfoximines from sulfoxides and arylhydroxy-
lamine triflic acid. However, using hydroxylamine triflic acid
salts as a N source to construct heterocyclic compounds is less
studied. Herein, we report a novel and facile procedure to
build N-phenyl-5-(phenylimino)-1,4,2-dithiazol-3-amines from
5
b
Despite the promising applications, 1,4,2-dithiazoles still
are rare skeletons with limited reports on their synthesis
6
7
methods. In 1998, Mloston described a fast [3 + 2] cyclo-
addition of the fluorinated thione S-imide with aromatic thio-
ketones for the synthesis of 1,4,2-dithiazolidines. In 2007,
isothiocyanates and [MsONH ]OTf under catalyst- and addi-
3
tive-free conditions.
In recent years, hexafluoroisopropanol (HFIP) has received
increasing attention as a catalyst, solvent, or co-solvent in
8
Yadav reported an approach to produce 1,4,2-dithiazole-fused
heterocycles through cyclization reaction of (methylsulfinyl)
9
methyl carbamimidothioates. Recently, Shao disclosed a
novel synthetic methodology to generate 1,4,2-dithiazoles by
reactions of phenylthioureas with 1,1-dichloro-2-nitroethene.
Although some methods toward 1,4,2-dithiazoles were success-
a
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and
Chemical Engineering, Lanzhou University, Lanzhou 730000, China.
E-mail: yanrl@lzu.edu.cn
b
Chemical Science and Engineering College, North Minzu University, Yinchuan
750000, China
†
Electronic supplementary information (ESI) available: Experimental pro-
cedures, spectroscopic data and X-ray data. CCDC 2032219. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/d1ob00938a
‡
These authors contributed equally to this work.
Fig. 1 Bioactive compounds containing dithiazoles.
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when TFE, MeCN, EtOH, DCM, and THF were used as solvents,
no desired product was detected (Table 1, entries 6–10). The
results indicated that HFIP was crucial for this process
1
8
because HFIP might form radical species. A screen of temp-
erature indicated that 30 °C was superior to others, giving
product 3a in 83% yield (Table 1, entries 11–13). It was found
that an adjustment of the amount of 2a led to lower yields
(
Table 1, entries 14 and 15). Moreover, air conditions gener-
ated 3a in a slightly lower yield (Table 1, entry 16). So, the opti-
mized reaction system was established as shown in Table 1,
entry 12.
With the optimized reaction conditions in hand, we first
examined the scope of isothiocyanatobenzenes. As shown in
Table 2, a variety of electron-donating and electron-withdraw-
ing group-substituted isothiocyanatobenzenes were efficiently
engaged in this reaction to provide various 1,4,2-dithiazoles in
moderate to good yields. This reaction had no obvious steric
effect of the substituents, and the ortho-, meta-, and para-
methylphenyl-substituted 1,4,2-dithiazoles (3b, 3c, and 3d)
were afforded in 70%, 80%, and 86% yields, respectively.
Dimethyl-substituted isothiocyanatobenzenes 1e–1g produced
the corresponding products 3e–3g in 65%–79% yields under
Scheme 1 Reactions of hydroxylamine triflic acid salts.
1
7
organic synthesis owing to its unique features. So, our initial
efforts were focused on the reaction of isothiocyanatobenzene
1
a with [MsONH ]OTf 2a using HFIP as a solvent under argon.
3
The desired product 3a was obtained in 56% yield (Table 1,
entry 1). Subsequently, several analogous hydroxylamine triflic
acid salts were examined and [MsONH ]OTf 2a was proved to
be the most effective hydroxylamine triflic acid salt (Table 1,
entries 2–5). Further optimization of solvents showed that
3
a
Table 2 Scope of substituted isothiocyanatobenzenes
a
Table 1 Optimization of the reaction conditions
b
Entry
N source
Solvent
Temp. (°C)
Yield (%)
1
2
3
4
5
6
7
8
9
2a (0.7)
2b (0.7)
2c (0.7)
2d (0.7)
2e (0.7)
2a (0.7)
2a (0.7)
2a (0.7)
2a (0.7)
2a (0.7)
2a (0.7)
2a (0.7)
2a (0.7)
2a (0.5)
2a (1.5)
2a (0.7)
HFIP
HFIP
HFIP
HFIP
HFIP
TFE
MeCN
EtOH
DCM
THF
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
60
60
60
60
60
60
60
60
60
60
20
30
100
30
30
30
56
35
42
38
c
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
69
83
Trace
71
1
1
1
1
1
1
1
0
1
2
3
4
5
6
38
76
d
a
Reaction conditions: 1a (0.2 mmol), N source, and solvent (2 mL)
b
c
d
under argon for 3 h. Isolated yield. n.d. = not detected. Under air.
TFE = 2,2,2-trifluoroethanol. The entry in bold highlights the opti-
a
Reaction conditions: 1 (0.20 mmol) and 2a (0.14 mmol) in HFIP
1
mized reaction conditions, and the reaction time was monitored by (2 mL) at 30 °C under argon for 3 h. The ratio was determined by
H
TLC.
NMR analysis.
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the standard conditions. On the other hand, halogen substitu-
ents (F, Cl, and Br) on the aromatic ring were well tolerated,
furnishing 3l–3q in moderate yields. In addition, substrates 1r
and 1s bearing 3-fluoro-5-methyl and 3-chloro-4-methyl groups
gave products 3r and 3s in 67% and 69% yields, respectively.
Substrate 1t could successfully be converted into the desired
product 3t, albeit with a diminished yield. Unfortunately, the
use of (isothiocyanatomethyl)benzene 1u led to a trace amount
of the desired product.
To gain insight into the mechanism, several control experi-
ments were carried out, as shown in Scheme 2. Radical scaven-
gers TEMPO (2,2,6,6,-tetramethylpiperidinooxy) and BHT (2,6-
di-tert-butyl-4-methyl-phenol) were tested for this transform-
ation, and the product 3a was obtained in 5% and 9% yields,
respectively. In addition, when 1,1-diphenylethylene was
added under the standard conditions, the product 3a was
obtained in 13% yield. Moreover, an electron paramagnetic
resonance (EPR) experiment was performed using 5,5-dimethy-
Scheme 3 Proposed mechanism.
zation to give intermediate C. Subsequently, intermediate C
reacts with another isothiocyanatobenzene to form intermedi-
ate D. Intermediate E, which is generated from intermediate D
via a resonated procedure, can be transformed into intermedi-
ate F through intramolecular radical cyclization addition.
Finally, intermediate G, which is formed by the oxidation of
MsO· to intermediate F, produces the product 3a by the elimin-
ation of a proton.
1
-pyrroline-N-oxide (DMPO) as a radical probe. As shown in
Fig. 2, some radical signals were detected after a reaction
mixture of 1a and 2a in HFIP was stirred at ambient tempera-
ture for 5 min in the presence of DMPO. These results indi-
cated that the reactions involved radical-mediated pathways.
On the basis of the above results and literature reports, a
possible
Scheme 3.
mechanism
is
proposed,
as
shown
in
1
0–12,19
Initially, HFIP promotes the decomposition
In conclusion, we have developed a method for the syn-
thesis of 1,4,2-dithiazole derivatives via the cyclization reaction
of isothiocyanates with hydroxylamine triflic acid salts. The
features of our presented methodology are mild reaction con-
ditions and catalyst-free, additive-free, and simple operation.
This transformation presents good functional group tolerance,
and a series of N-phenyl-5-(phenylimino)-1,4,2-dithiazol-3-
amines are obtained in moderate to good yields.
of [MsONH
3
]OTf to generate MsOH and ammoniumyl radical
A. The reaction of ammoniumyl radical A with isothiocyanato-
benzene 1a leads to intermediate B, which undergoes isomeri-
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Scheme 2 Control experiments.
This work was supported by the National Natural Science
Foundation of China (21672086).
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