Hypervalent Iodine(III)-Mediated Solvent-Free, Regioselective Synthesis of 3,4-Disubstituted 5-Imino-1,2,4-thiadiazoles and 2-Aminobenzo[d]thiazoles

Article abstract of DOI:10.1002/adsc.201800353

A convenient approach for the synthesis of 3,4-disubstituted 5-imino-1,2,4-thiadiazoles and 2-aminobenzo[d]thiazoles has been developed using phenyliodine diacetate (PIDA). This approach involves a metal-free oxidative C?N, N?S and C?S bond formations under neat conditions. High regioselectivity, solvent-free conditions, short reaction time and broad functional group compatibility are the notable features of this report. (Figure presented.).

Full text of DOI:10.1002/adsc.201800353

Title: Hypervalent Iodine(III)-Mediated Solvent-Free, Regioselective
Synthesis of 3,4-Disubstituted 5-Imino-1,2,4-thiadiazoles and 2-
Aminobenzo[d]thiazoles
Authors: Nagaraju Tumula, Palakodety Radha Krishna, Sridhar
Balasubramanian, and MANGARAO NAKKA
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800353
Link to VoR: http://dx.doi.org/10.1002/adsc.201800353

10.1002/adsc.201800353
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Hypervalent Iodine(III)-Mediated Solvent-Free, Regioselective
Synthesis of 3,4-Disubstituted 5-Imino-1,2,4-thiadiazoles and 2-
Aminobenzo[d]thiazoles
Nagaraju Tumula,a,b Radha Krishna Palakodety,a Sridhar Balasubramanianc and
Mangarao Nakkaa*
a Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007,
India.
b Academy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India.
c Center for X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, India.
Fax: +08912544683; e-mail: mangarao@csiriict.in
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
pharmaceutical areas. These heterocycles show
2- various biological activities such as antimicrobial,[6]
antidiabetic,[7] antibacterial,[8] antifungal,[9] pesticides
and corrosion inhibitors.[10] In addition, they are also
found in important drugs such as cefozopran[11] (an
antibiotic drug), zopolrestat[12] (used for the treatment
of diabetic complications), calcimycin[13] (an
Abstract. A convenient approach for the synthesis of 3,4-
disubstituted 5-imino-1,2,4-thiadiazoles and
aminobenzo[d]thiazoles has been developed using
phenyliodine diacetate (PIDA). This approach involves a
metal-free oxidative C-N, N-S and C-S bond formations
under neat conditions. High regioselectivity, solvent-free
conditions, short reaction time and broad functional group
compatibility are the notable features of this report.
ionophore
antibiotic)
and
riluzole[14]
(an
anticonvulsant drug). Despite their wide applications,
numerous protocols have been developed to construct
the 1,2,4-thiadiazoles and benzo[d]thiazoles. Classical
approaches for the synthesis of 1,2,4-thiadiazoles
involves (a) the simple oxidative dimerization of
primary thioamides using various oxidants, (b)
oxidative cyclization of imidoyl thiourea using
oxidants (Scheme 1a and 1b).[15] Whereas, (a) the
simple condensation of o-aminothiophenols with
either substituted aldehydes, carboxylic acids or esters
followed by oxidative cyclizations, (b) oxidative
cyclization of thiobenzamides with various oxidants
are common protocols for the synthesis of
benzo[d]thiazoles (Scheme 1c and 1d).[16]
Keywords:
regioselectivity;
thiadiazoles; 2-aminobenzo[d]thiazoles
Hypervalent
iodine;
solvent-free;
5-imino-1,2,4-
3,4-disubstituted
Efficient transformations carried out under metal-free
conditions have received great attention for synthesis
of bioactive molecules and pharmaceuticals. In this
context, carbon-hetero and hetero-hetero bond
formations are an important process for the
development of heterocyclic scaffolds.[1] Recently,
hypervalent iodine reagents have found a wide range
of applications in organic transformations due to their
ready availability, easy handling, low toxicity and
reactivity similar to heavy metals.[2] In particular,
phenyliodine(III) diacetate (PIDA) has been
successfully employed in the construction of C-C, C-
N, C-O, C-S and also N-S bonds.[3] On the other hand,
organic transformations under solvent-free conditions
have gained significant attention in recent years.[4]
This is because solvent-free reactions usually need
shorter reaction times, lower costs with reduced
pollution and simple workup procedures.[5]
1,2,4-Thiadiazoles and benzo[d]thiazoles are essential
heterocyclic scaffolds because of their broad
applications in the synthetic organic and
Scheme 1. Previous methods for 1,2,4-thiadiazoles and
benzo[d]thiazoles.
1
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10.1002/adsc.201800353
Advanced Synthesis & Catalysis
Recently, some metal-free transformations including raising the temperature to 65 °C showed that no
hypervalent iodine and iodide as catalysts for the improvement can be achieved (Table 1, entries 16 and
synthesis of 1,2,4-thiadiazoles and benzo[d]thiazoles 17). Thus the optimal reaction conditions were set to
were also reported.[17] However, these approaches be imidoyl thiourea (1a) (1.0 equiv.) and benzonitrile
have one or more shortcomings such as metal (2a) (1.2 equiv.) and PIDA (1.0 equiv.) at 50 °C
catalysts, use of organic solvents, lack of substrate under neat conditions.
scope and harsh reaction conditions. Thus, more
general and convenient synthetic methods for the
Table 1. Optimization of reaction conditions.
preparation
of
1,2,4-thiadiazoles
and
benzo[d]thiazoles are still in high demand. As part of
our ongoing project to investigate efficient synthetic
methods for heterocycles[18] herein, we report a metal-
free, solvent-free, regiospecific protocol for the
construction of the C-N, N-S and C-S bond by
employing PIDA under neat conditions for the
synthesis
of
3,4-disubstituted
5-imino-1,2,4-
Entry
Catalyst
(mol%)
Solvent
Temp
(°C)
Yield
thiadiazoles and 2-aminobenzo[d]thiazoles (Scheme
2).
3a
4a
(%)c
21
23
30
34
22
25
8
(%)c
55
1a
2a
PIDA (100)
PIDA (100)
PIDA (100)
PIDA (100)
PIDA (100)
PIDA (100)
PIDA (100)
DMSO
DMF
DCE
THF
MeOH
IPA
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
35
65
47
45
49
30
36
79
76
88
3a
4a
5a
6a
7a
PhCl
8a
PIDA (100) Toluene
10
--
38
21
--
--
--
--
--
Scheme 2. Synthesis of 3,4-disubstituted 5-imino-1,2,4-
thiadiazoles and 2-aminobenzo[d]thiazoles.
9b
PIDA (100)
PIFA (100)
PhIO (100)
I2 (100)
CAN (100)
PIDA (150)
PIDA (50)
PIDA (100)
PIDA (100)
neat
neat
neat
neat
neat
neat
neat
neat
neat
10b
11b
12b
13b
14b
15b
16b
17b
26
17
--
The required substrates imidoyl thioureas were
readily prepared from the corresponding amidine and
phenylisothiocynate. Initially imidoyl thiourea (1a)
(1.0 equiv.) and benzonitrile (2a) (1.0 equiv.) and
PIDA (1.0 equiv.) in DMSO at 50 °C was chosen as
model reaction to explore and optimize the reaction
conditions. Surprisingly, we observed the unexpected
minor product benzo[d]thiazole (4a) along with the
desired 1,2,4-thiadiazole (3a) under these conditions
(Table 1, entry 1). Aiming to accomplish better yield
of 3a and suppress the formation of 4a, the reaction
was screened under diverse conditions and the results
are summarized in Table 1. Performing the reaction in
the presence of various solvents, such as DMF, DCE
and THF, led to inferior results (Table 1, entries 2-4).
The reaction also failed to improve the yield of 3a
with the protic solvents such as MeOH, IPA (Table 1,
entries 5 and 6). Notably, in all cases 4a was also
observed in 21-34% yield. We examined the reaction
in chlorobenzene and toluene which offered 3a in
79% and 76% yields respectively in 1h along with 4a
in minor amount (Table 1, entries 7 and 8). To our
delight, when the reaction was carried out under neat
reaction conditions we discovered that only 3a in 88%
yield was obtained (Table 1, entry 9). In addition, we
investigated different oxidants including PIFA, PhIO,
I2 and CAN under neat condition. All these oxidants
were not suitable for this transformation (Table 1,
entries 10-13). Increasing the amount of PIDA did not
affect the product yield but when the amount of PIDA
was decreased, significantly lower yield was obtained
(Table 1, entries 14 and 15). Next, reaction
temperature affects were also studied. Poor yield was
obtained when reaction was conducted at 35 °C and
Trace
88
72
79
88
--
a) Reaction conditions: 1a (0.6 mmol, 1.0 equiv.), 2a
(0.6 mmol, 1.0 equiv.) and PIDA (1.0 equiv.)
under neat condition at 50 °C for 2 min.
b) Reaction conditions: 1a (0.6 mmol, 1.0 equiv.), 2a
(0.7 mmol, 1.2 equiv.) and PIDA (1.0 equiv.)
under neat condition at 50 °C for 2 min.
c) Isolated yield.
With the optimized reaction conditions in hand, we
then explored the scope and generality of synthetic
protocol and the results are summarized in Table 2.
As anticipated, all the benzonitriles gave the
corresponding
3,4-disubstituted
5-imino-1,2,4-
thiadiazoles in good to excellent yields. Benzonitriles
with electron-donating groups like -methyl and -
methoxy at ortho, para and meta positions gave the
corresponding products 3b, 3c, 3h and 3j in good to
high yields. It was noted that ortho-substituted
benzonitriles gave a yield similar to that of para
subsitituted benzonitrile. The reaction with halogen
substituent on benzonitriles such as -F, -Cl and -Br
afforded the products 3d-3f in good yields.
Benzonitriles with strong electron-withdrawing
groups like p-CF3 and m-NO2 generated the
corresponding thiadiazoles 3g and 3i in 78% and 80%
yields respectively. In addition, the heteronitrile such
2
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10.1002/adsc.201800353
Advanced Synthesis & Catalysis
a) Reaction conditions: 1 (0.6 mmol), 2 (0.7 mmol)
and PIDA (1.0 equiv.) under neat conditions at
50 °C for 2 min.
as thiophene-2-carbonitrile gave 3o in 79% yield.
Interestingly, alicyclic and aliphatic nitriles like
cyclohexyl, butaryl and methyl reacted smoothly to
give the desired products 3p-3v in reasonable good
yields. The structure of compounds 3j and 3s was
confirmed by single-crystal X-ray analysis (Fig. 1).19
Next, we investigated the scope of the protocol by
varying the imidoyl thiourea, which proceeded
successfully to afford the corresponding 3,4-
disubstituted 5-imino-1,2,4-thiadiazoles in moderate
to good yields. As described in Table 2, all imidoyl
thiourea substrates bearing electron-rich substituents
such as -Me and -OMe on the aryl ring and electron-
deficient substrates like -Cl, -Br and -NO2 on the aryl
ring with different nitriles gave the desired products
in moderate to good yields (Table 2, entries 3k-3n
and 3r-3v). Imidoyl thioureas bearing aryl group with
electron-withdrawing substituents gave considerably
higher yields than those with electron-donating
groups.
b) Isolated yield.
The design of molecules having potent
polyheterocyclic scaffolds that emerge as novel
drugs in discovery process is ever challange. In
light of our above successive results and advances
of polyheterocyclic compounds, we expand our
methodology towards the synthesis of 3,4-
disubstituted
2-pyridinyl
5-imino-1,2,4-
thiadiazoles (
6). We were glad to observe the
formation of desired product 6a in 90% yield.
Next, we investigated the scope and generality of
the reaction (Table 3). Benzonitriles bearing
electron-donating groups like -Me and -OMe and
electron-withdrawing groups such as -F, -Cl and -
CF3 were well tolerated and the desired products
6b-6f were obtained in good to high yields. To
our delight, alicyclic and aliphatic nitriles such as
cyclohexly, pentyl and methyl were also good
partners in this transformation (Table 3, entries
6j-6l). Furthermore, various pyridinylthioureas
with substitutents on aryl ring (R4) such as methyl,
chloro and nitro groups also were well tolerated to
yield the desired products (Table 3, entries 6g-6i).
However, the substrates possessing phenyl and
propyl group instead of pyridyl group in the
pyridinylthiourea did not provide the desired
product under the optimized conditions (Table 3,
entries 6m and 6n). The structure of compound
6h was further confirmed by X-ray analysis (Fig.
1).[19]
Table 2. Synthesis of 3,4-disubstituted 5-imino-1,2,4-
thiadiazolesa,b
3a, X = H, 88%
3b, X = Me, 90%
3c, X = OMe, 91%
3d, X = F, 86%
3e, X = Cl, 87%
3h, X = OMe, 89%
3f, X = Br, 86%
3i, X = NO2, 80%
3g, X = CF3, 78%
Table 3. Synthesis of 3,4-disubstituted 2-pyridinyl 5-
imino-1,2,4-thiadiazolesa,b
3j, 90%
3m, 84%
3p, 76%
3k, X = OMe, 78%
3l, X = NO2, 90%
6a, X = H, 90%
6b, X = Me, 91%
6c, X = OMe, 91%
6d, X = F, 85%
3n, 87%
3o, 79%
6e, X = Cl, 81%
6f, X = CF3, 74%
6g, X = Me, 87%
6h, X = Cl, 89%
6i, X = NO2, 86%
3s, X = Me, 87%
3t, X = Cl, 91%
3q, 86%
3u, 82%
3r, 88%
3v, 83%
6k, 81%
6n, 0%
6j, 78%
6m, 0%
6l, 86%
3
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10.1002/adsc.201800353
Advanced Synthesis & Catalysis
a) Reaction conditions: 1 (0.6 mmol) or 5 (0.8 mmol)
and PIDA (1.0 equiv.) under neat condition at
50 °C for 5-8 min.
a) Reaction conditions: 5 (0.8 mmol), 2 (1.0 mmol)
and PIDA (1.0 equiv.) under neat condition at
50 °C for 2 min.
b) Isolated yield.
b) Isolated yield.
In order to explore the reaction mechanism, the
radical trapping experiments were conducted in the
presence of radical inhibitor 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) and hydroquinone under the
optimized conditions and no considerable effect was
After successful implementation of this protocol
for the synthesis of 3,4-disubstituted 5-imino-
1,2,4-thiadiazoles, we focused on the byproduct
2-amino-benzo[d]thiazoles(
4). In this context, an
experiment was performed with 1a in the absence
of benzonitrile under the optimized reaction observed. These results indicated that the reaction
conditions which resulted in the corresponding 2-
amino-benzo[d]thiazole (4a) in 81% yield. The
structure of compound 4a was confirmed by
single-crystal X-ray analysis (Fig. 1).[19] With
these optimum reaction conditions in hand, we
investigated the scope of the reaction with various
substituted imidoyl thioureas (Table 4).
Fortunately, imidoyl thiourea bearing both
electron-rich and electron-deficient groups like -
Me, -OMe, -F and -Cl on aryl ring (R1 and R2)
reacted smoothly to give the corresponding
product benzo[d]thiazoles in good yields (Table
4, entries 4b-4g). Next, we turned to investigate
the scope of the reaction with pyridinyl thiourea
under the optimized reaction conditions.
Interestingly, pyridinyl 2-aminobenzo[d]thiazoles
was obtained in good yields, which was in
agreement with the literature.[20] Moreover, the
reaction of pyridinyl thiourea bearing electron
donating and withdrawing groups on aryl ring
(R4) afforded the corresponding products 7b-7e in
good to fare yields.
proceeds through an ionic mechanism (Scheme 3).
We performed a reaction between 1a and 2a in the
absence of PIDA but the reaction did not provide the
desired product.
Scheme 3. Control experiments
Fig 1. X-ray analysis
Table 4. Synthesis of 2-aminobenzo[d]thiazolesa,b
On the basis of these experimental results and
previous reports,[21] a mechanism has been
proposed for this regioselective synthesis, by
taking the formation of 3a as an example (Scheme
4). Initially, the imidoyl thiourea (1a) reacts with
4a, X = H, 81%
4b, X = Me, 83%
4c, X = OMe, 83%
4d, X = F, 74%
PIDA which provides intermediate
removal of AcOH. Intermediate
benzonitrile (2a) to afford intermediate
A
up on the
4e, 65%
A
reacts with
B
,
followed by intramolecular nucleophilic attack of
NH group on the sulfur atom with the loss of
iodobenzene and AcOH resulting in the desired
4f, 73%
4g, 72%
product 3a
.
7a, X = H, 77%
7b, X = Me, 88%
7c, X = OMe, 87%
7d, X = NO2, 54%
Scheme 4. Proposed reaction mechanism
7e, 79%
4
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10.1002/adsc.201800353
Advanced Synthesis & Catalysis
concentrated under reduced pressure to get crude. The
crude was purified by silica gel column chromatography
using EtOAc : hexane as eluents to afford corresponding
product 6a-6l.
General experimental procedure for synthesis of 2-
aminobenzo[d]thiazoles 4a-4g and 7a-7e:
To a screw cap reaction vial imidoyl thiourea (1) (0.6
mmol) or pyridinyl thiourea (5) (0.8 mmol) and PIDA (1.0
equiv.) were added. The reaction mixture was heated to 50
oC and stirred until completion. After completion of the
reaction as monitored by TLC, the reaction mixture was
quenched with a saturated aqueous solution of Na2CO3.
The organic and aqueous layers were then separated and
In conclusion, we have developed a novel and
efficient method for the synthesis of 3,4-
disubstituted 5-imino-1,2,4-thiadiazoles and 2-
aminobenzo[d]thiazoles. This method includes a
PIDA-mediated regioselective oxidative C-N, N- the aqueous layer was extracted with ethyl acetate. The
combined organic layers were dried over anhydrous
Na2SO4 and concentrated under reduced pressure to get
crude. The crude was purified by silica gel column
S and C-S bond formation under neat conditions.
This methodology proceeded with high efficiency
and wide functional group tolerance, affording the
corresponding products in good to excellent
yields. The key features such as regioselectivity,
solvent-free, metal-free, atom economy and short
reaction time make it an attractive alternative for
the preparation of 3,4-disubstituted 5-imino-1,2,4-
thiadiazoles and 2-aminobenzo[d]thiazoles.
chromatography using EtOAc : hexane as eluents to afford
corresponding products 4a-4g or 7a-7e .
Acknowledgements
The author thanks the SERB, New Delhi, India for financial
support in the form of NPDF (PDF/2016/000177). The author T.
N thank the CSIR, New Delhi for financial support in the form of
fellowships. CSIR-IICT Commun. No. IICT/pubs./2018/022.
Experimental Section
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5
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10.1002/adsc.201800353
Advanced Synthesis & Catalysis
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10.1002/adsc.201800353
Advanced Synthesis & Catalysis
COMMUNICATION
Hypervalent Iodine(III)-Mediated Solvent-Free,
Regioselective Synthesis of 3,4-Disubstituted 5-
Imino-1,2,4-thiadiazoles and 2-
Aminobenzo[d]thiazoles
Adv. Synth. Catal. Year, Volume, Page – Page
Nagaraju Tumula, Radha Krishna Palakodety,
Sridhar Balasubramanian, Mangarao Nakka*
7
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