Transition-metal-free PhI(OAc)2-mediated oxidative S[sbnd]S and C[sbnd]N bond formation: Regioselective synthesis of 3H-1,2,4-dithiazol-3-imines

Article abstract of DOI:10.1016/j.tetlet.2019.151424

An effective and new approach is proposed for the synthesis of regioselective 3H-1,2,4-dithiazol-3-imines through S[sbnd]S and C[sbnd]N bond formation for the first time from benzothioamides and isothiocyanates under transition-metal-free conditions. This protocol proceeds by using hypervalent iodine(III) compound of phenyliodine diacetate (PhI(OAc)₂) having additive cesium carbonate in acetonitrile solution at room temperature to provide facile access to 3H-1,2,4-dithiazol-3-imine derivatives from readily available starting materials with broad substrate scope, insensitive to air and moisture, regioselectivity and affluent up to gram scale.

Full text of DOI:10.1016/j.tetlet.2019.151424

Journal Pre-proofs
Transition-metal-free PhI(OAc)2-mediated oxidative S-S and C-N bond forma-
tion: Regioselective synthesis of 3H-1,2,4-dithiazol-3-imines
Tumula Nagaraju, Palakodety Radha Krishna
PII:
S0040-4039(19)31215-8
DOI:
https://doi.org/10.1016/j.tetlet.2019.151424
TETL 151424
Reference:
Tetrahedron Letters
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19 November 2019
Please cite this article as: Nagaraju, T., Krishna, P.R., Transition-metal-free PhI(OAc)2-mediated oxidative S-S and
C-N bond formation: Regioselective synthesis of 3H-1,2,4-dithiazol-3-imines, Tetrahedron Letters (2019), doi:
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Graphical Abstract
Transition-metal-free PhI(OAc)2-mediated oxidative
S-S and C-N bond formation: Regioselective synthesis
of 3H-1,2,4-dithiazol-3-imines
Leave this area blank for abstract info.
Tumula Nagaraju and Palakodety Radha Krishna*

1
Tetrahedron Letters
Transition-metal-free PhI(OAc)2-mediated oxidative S-S and C-N bond
formation: Regioselective synthesis of 3H-1,2,4-dithiazol-3-imines
Tumula Nagarajua, b and Palakodety Radha Krishnaa,*
aDepartment of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, India
bAcademy of Scientific and Innovative Research (AcSIR), New Delhi-110025, India
Email: prkgenius@iict.res.in
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An effective and new approach is proposed for the synthesis of regioselective 3H-1,2,4-
dithiazol-3-imines through S-S and C-N bond formation for the first time from benzothioamides
and isothiocyanates under transition-metal-free conditions. This protocol proceeds by using
hypervalent iodine(III) compound of phenyliodine diacetate (PhI(OAc)2) having additive cesium
carbonate in acetonitrile solution at room temperature to provide facile access to 3H-1,2,4-
dithiazol-3-imine derivatives from readily available starting materials with broad substrate
scope, insensitive to air and moisture, regioselectivity and affluent up to gram scale.
Available online
Keywords:
Transition-metal-free
Regioselectivity
3H-1,2,4-Dithiazol-3-imines
Scalable
2009 Elsevier Ltd. All rights reserved.
Chemistry of heterocyclic compounds is most interesting and
challenging branch in organic chemistry, in which the
heterocycles containing both sulphur and nitrogen atoms could
furnish development of new synthetic strategies and important
biological activities.1 Among the divergent heterocyclic
scaffolds, dithiazoles (both 1,2,3- and 1,2,4-) and their
derivatives provided with various interesting biological activities,
particularly, anti-microbial activity.2 Some of the important
derivatives of dithiazoles having antifungal and antibacterial
activities are shown in Figure 1. N-3-(1,2,4-Dithiazole-5-thione)-
β-resorcylcarbothioamide, 5,6-dihydro-3H-imidazo[2,l-c]-l,2,4-
dithiazole-3-thione and N-arylimino-l,2,3-dithiazoles were found
to exhibit antifungal activity,3-5 whereas, 5-(4-chloro-
bond formation of S-S for the first time using PhI(OAc)2
successfully.
[1,2,3]dithiazol-5-ylideneamino)-naphthalen-1-ol
possesses
notable antifungal as well as antibacterial activities.6 These
dithiazole compounds are reported to having various modes of
action and their targets comprise enzymes such as leucine
arylamidase, α-glucosidase, esterases, lipases, N-acetyl-β-
glucosaminidase, and alkaline phosphatase.3
Figure 1. Selective important antifungal and antibacterial
derivatives of dithiazoles.
Phenyliodine(III) diacetate (PhI(OAc)2) commonly known as
PIDA is the most important and commercially available
representative of hypervalent iodine(III) carboxylates. Recently,
important bioactive molecules of hetercyclic compounds were
successfully synthesized by using hypervalent iodine(III)
compounds. In particularly, PhI(OAc)2 has been successfully
employed in the C-C, C-N, C-O, C-S and N-S bond formation
reactions.7 Hence, the construction of efficient and sustainable
heterocyclic ring formations employing PhI(OAc)2 is still highly
desirable. Herein, we report a strategy for heteroatom-heteroatom
Due to having various pharmaceutical applications8 of 1,2,4-
dithiazoles few methods were developed as shown in Scheme 1.
Singh group reported an open pot strategy of
dimerization/deaminative cyclization cascade process from β-
ketothioamides using eosin Y as a photoinitiator for the synthesis
of 1,2,4-dithiazolidine derivatives in presence of visible-light at
ambient temperature (Scheme 1a).9 Pan and his group developed
a strategy using visible light for the synthesis of 1,2,4-dithiazoles

2
Tetrahedron Letters
from thioamides with p-quinone methides and (NH4)2S in
conditions were identified to be exploration of this protocol as
follows: 1 equiv of 1a and 1 equiv of 2a with 1 equiv of PIDA in
the presence of 1 equiv of the additive base Cs2CO3 in
acetonitrile at room temperature (Table 1, entry 8).
presence of acridinium salt (Scheme 1b).10 Kuhle group reported
a strategy for the synthesis of 1,2,4-dithiazolidine-3,5-diones
from O-alkyl esters of N-monosubstituted thiocarbamic acids and
chlorocarbonylsulfenylchloride (Scheme 1c).11 However,
majority of shortcomings of these protocols occurred due to the
general requirement of special structural features in substrates,
use of metal catalysts and harsh reaction conditions. To the best
of our knowledge, there is no transformation method available
for the synthesis of 1,2,4-dithiazoles using PhI(OAc)2. In
continuation of our previous achievements for the synthesis of
biologically important heterocyclic scaffolds,12 herein, we
propose an efficient regioselective synthesis of 3H-1,2,4-
dithiazol-3-imines employing PhI(OAc)2 from readily available
benzothioamides and isothiocyanates for the first time at ambient
temperature (Scheme 1d). This protocol constitutes an efficient
and novel access for the 3H-1,2,4-dithiazol-3-imine derivatives
and which to far has not been reported in the literature.
Table 1. Optimization of reaction conditions.a
Entry
Oxidant
(x equiv)
Base
(1 equiv)
-
Solvent
Yield
(%)b
15
20
10
30
5
70
75
90
60
20
Trace
10
1
2
3
4
5
6
7
8
9
10
11
12
13
14
PhI(OAc)2 (1)
PhI(OAc)2 (1)
PhI(OAc)2 (1)
PhI(OAc)2 (1)
PhI(OAc)2 (1)
PhI(OAc)2 (1)
PhI(OAc)2 (1)
PhI(OAc)2 (1)
PhI(OAc)2 (1)
PhI(OCOCF3)2 (1)
I2 (1)
CHCl3
DMSO
MeOH
MeCN
toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
-
-
-
-
Scheme 1. Previous reports and current approach for the
synthesis of 1,2,4-dithiazoles.
KOH
NaOH
Cs2CO3
LiOH
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
PhIO (1)
PhI(OAc)2 (1.5)
PhI(OAc)2 (0.5)
90
44
aReaction conditions: 1a (1 mmol, 1 equiv), 2a (1 mmol, 1 equiv), catalyst (x
equiv), base (1 equiv) and solvent (2 mL) at rt for 1 to 2 h.
bIsolated yield.
With the help of optimized reaction conditions, we explored
the applicability of this regioselective oxidative cyclization
strategy, and the results are summarized in Table 2. The high
efficiency shown by the model reaction was efficiently translated
to a wide variety of substituted 3H-1,2,4-dithiazol-3-imine
derivatives (3) with different benzothioamides (1) and
isothiocyanates (2) using PhI(OAc)2 oxidative system provided
good to excellent yields in all cases. Isothiocyanates having
electron-donating groups like methyl and methoxy at para-,
meta- and ortho-positions afforded the corresponding 3H-1,2,4-
dithiazol-3-imines (3b, 3c, 3f, 3g and 3i) in high yields (80-92%).
Conversely, electron-deficient halogen substituents like -Cl and -
F at para-, meta- and ortho-positions delivered respective 3H-
1,2,4-dithiazol-3-imines (3d, 3h and 3j) in good yields (78-87%).
Moreover, strong electron-withdrawing -NO2 group provides
good yield of the product 3e (70%). Interestingly, electron-
deficient disubstituted fluoro phenylisothiocyanate underwent
oxidative cyclization smoothly provided the dithiazole product 3j
in good isolated yield (80%). In addition, an alicyclic
isothiocyanate such as cyclohexyl isothiocyanate could also be
examined with the reaction conditions and furnished the
corresponding product 3k in 79% yield. It is worthy to mention
that an aliphatic propyl isothiocyanate also delivered the desired
product 3l in moderate yield. Further to extend the substrate
scope and limitations of the reaction, we studied effect of
different substituents present at the benzothioamide ring with
phenyl isothiocyanates, which proceeded proficiently to afford
the corresponding 3H-1,2,4-dithiazol-3-imines in good to
excellent yields. As shown in Table 2, benzothioamide bearing
electron-donating groups such as methyl and methoxy at para-,
meta- and ortho-positions of the phenyl ring afforded
corresponding products 3m, 3n, 3p and 3q in good to excellent
yields. Additionally, benzothioamide substituted with electron-
withdrawing group like -Cl at para-position afforded the desired
product in good yield (3o). It is notable that the reaction
We started our analysis by following the reaction of
benzothioamides 1a and isothiocyanates 2a using PhI(OAc)2 as
an oxidant (Table 1). As useful starting materials, thioamides
behave both as nucleophiles and electrophiles and widely used in
the synthesis of many heterocyclic compounds comprising
thiophene, thiazole, and pyrrole.13 When a mixture of 1a (1.0
equiv.) and 2a (1.0 equiv.) in CHCl3 using PhI(OAc)2 (1.0 equiv.)
at room temperature, satisfyingly, oxidative-cyclization
proceeded smoothly and affording desired product 1,2,4-
dithiazole (3a) through S-S and C-N bond formation in only 15%
yield (Table 1, entry 1). To increase the yield of the product, we
have monitored with several solvents such as DMSO, MeOH,
MeCN, and toluene and it was found that MeCN was worked
better than other solvents (entries 2-5). Next, to improve the yield
of the product screening of various bases as additive revealed
Cs2CO3 (1 equiv.) as the base of choice (Table 1, entry 8).14
KOH, NaOH and LiOH gave lower yields (Table 1, entries 6, 7
and 9). With these control experiments, all of the starting
materials with PhI(OAc)2 oxidant and base were essential for this
reaction. Several other oxidants PhI(OCOCF3)2, I2, and PhIO
were screened, but only lower yields of 3a could be observed in
all the cases (Table 1, entries 10-12). Further screening the
equivalence of oxidant, no affect of yield was observed when
increasing the amount of PhI(OAc)2 but the yield of the product
significantly decreased with decreasing amount of PhI(OAc)2
observed (Table 1, entries 13 and 14). Thus, the most efficient

3
successfully afforded the expected product 3r when electron-
donating group (-OMe) presenting on the both benzothioamide
and phenyl isothiocyanate substrates. Conversely, good yield of
the product 3s obtained when electron-withdrawing group (-Cl)
presenting on the both substrates. Further structural confirmation
of compound 3o was unambigiously studied by X-ray diffraction
analysis (Figure 2). It should be observed that the practical
applicability of this oxidative cyclization strategy was confirmed
successfully by the gram-scale synthesis under optimized
reaction conditions (Table 2, 3a).
Table 2. Substrate scope of the 3H-1,2,4-dithiazol-3-imines.a,b
Scheme 2. Control experiments.
Based on above experimental results and previous reports,12b,15
a possible mechanism has been proposed for the formation of 3h
as an example for this oxidative regioselective approach (Scheme
3). Initially, the benzothioamide (1a) reacts with 3-chloro phenyl
isothiocyanate (2h) in presence of Cs2CO3 to generate the
intermediate A. The intermediate A reacts with PhI(OAc)2 to
form the thiourea intermediate B, followed by intramolecular
nucleophilic attack on the sulfur atom by the another sulfur atom,
the removal of iodobenzene and acetic acid takes place to afford
the desired product 3h.
aReaction conditions: 1 (1 mmol, 1 equiv), 2 (1 mmol, 1 equiv), PhI(OAc)2 (1
equiv), Cs2CO3 (1 equiv) and MeCN (2 mL) at rt for 1 to 2 h.
bIsolated yield.
Scheme 3. Proposed reaction mechanism.
In summary, we have developed the first regioselective
oxidative cyclization of transition-metal-free strategy for the
synthesis of 3H-1,2,4-dithiazol-3-imines by using an efficient
cThe reaction was conducted on gram scale.
oxidative reagent PhI(OAc)2 from
benzothioamides and
isothiocyanates through C-N and S-S bond formation. These
compounds are the novel dithiazole heterocyclic scaffolds.
Acknowledgements
The author TN thanks the CSIR, New Delhi for financial support
in the form of fellowship. I thank Dr. Balasubramanian Sridhar
for X-ray analysis, Laboratory of X-ray Crystallography, CSIR-
IICT. (CSIR-IICT Commun. No. IICT/pubs./2019/307).
Figure 2. Crystallographic representation of compound 3o.
Next we turned to explain the possible reaction pathway, few
control experiments were performed (Scheme 2). The
experiments were conducted in the presence of free radical
trapping reagents like 2,2,6,6-tetramethylpiperidinyl-1-oxyl
(TEMPO) and p-benzoquinone (BQ) under the optimized
reaction conditions and no significant effect was noticed (Scheme
2a). These results summarized that an ionic mechanism was
probably involved in this transformation. When the
benzothioamide 1a and 3-chloro phenyl isothiocyanate 2h
undergo reaction in the presence of Cs2CO3 with the absence of
PhI(OAc)2, the intermediate A (Scheme 2b) was obtained, which
was confirmed by its charecteristic free NH protons obsereved in
1H NMR data (see Supporting Information). This intermediate A
reacts with PhI(OAc)2 to give our desired product 3h in 78%
yield (Scheme 2c).
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Information.

5
Highlights
1. Transition-metal-free
2. Phenyliodine diacetate
3. Regioselectivity
4. 3H-1,2,4-Dithiazol-3-imines
5. Scalable