A novel and facile synthesis of 3,5-Disubstituted isothiozoles under metal free conditions using acetophenones and dithioesters

Article abstract of DOI:10.1080/00397911.2020.1748656

A facile and conveniently simple new protocol is devised for the synthesis of 3,5-disubstituted and annulated isothiozoles under transition metal and catalyst free conditions utilizing easily available acetophenones, dithioesters and NH₄OAc. This strategy involves C=O and C=S functionalization via sequential imine formation followed by intra molecular cyclization and aerial oxidation forming consecutive C?N and S?N bonds respectively in one pot. This protocol offers a low cost, user friendly, straight forward and widely applicable approach to 3,5-disubstituted isothiazoles.

Full text of DOI:10.1080/00397911.2020.1748656

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
A novel and facile synthesis of 3,5-Disubstituted
isothiozoles under metal free conditions using
acetophenones and dithioesters
Chaithra Nagaraju , Swarup Hassan Ashok , Sadashivamurthy Shamanth ,
Sandhya C. Nagarakere , Makanahalli P. Sunilkumar , Rangappa
Kanchugarakoppal Subbegowda & Kempegowda Mantelingu
To cite this article: Chaithra Nagaraju , Swarup Hassan Ashok , Sadashivamurthy Shamanth ,
Sandhya C. Nagarakere , Makanahalli P. Sunilkumar , Rangappa Kanchugarakoppal Subbegowda
& Kempegowda Mantelingu (2020): A novel and facile synthesis of 3,5-Disubstituted isothiozoles
under metal free conditions using acetophenones and dithioesters, Synthetic Communications,
DOI: 10.1080/00397911.2020.1748656
To link to this article: https://doi.org/10.1080/00397911.2020.1748656
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https://doi.org/10.1080/00397911.2020.1748656
A novel and facile synthesis of 3,5-Disubstituted
isothiozoles under metal free conditions using
acetophenones and dithioesters
Chaithra Nagarajua, Swarup Hassan Ashoka, Sadashivamurthy Shamantha,
Sandhya C. Nagarakereb, Makanahalli P. Sunilkumara, Rangappa Kanchugarakoppal
Subbegowdaa , and Kempegowda Mantelingua
b
aSynthetic Laboratory, DOS in Chemistry, University of Mysore, Manasagangotri, India; P. G.
Department of Chemistry, St. Philomena’s College, Bannimantap, India
ABSTRACT
ARTICLE HISTORY
Received 7 February 2020
A facile and conveniently simple new protocol is devised for the syn-
thesis of 3,5-disubstituted and annulated isothiozoles under transi-
tion metal and catalyst free conditions utilizing easily available
acetophenones, dithioesters and NH4OAc. This strategy involves C¼O
and C¼S functionalization via sequential imine formation followed
by intra molecular cyclization and aerial oxidation forming consecu-
tive CꢀN and SꢀN bonds respectively in one pot. This protocol
offers a low cost, user friendly, straight forward and widely applic-
able approach to 3,5-disubstituted isothiazoles.
KEYWORDS
Air oxidation; C–N and N–S
bond formation;
intramolecular cyclization;
isothiazoles; metal and
catalyst free
GRAPHICAL ABSTRACT
Introduction
Isothiazoles represent an important class of five membered sulfur and nitrogen containing
heterocycles that are widely utilized in medicinal chemistry due to unique properties of two
electronegative sulfur and nitrogen heteroatoms in a 1,2-relationship.[1] Although synthesis
of isoxazoles,[2] and pyrazoles,[3] have been commonly developed by using easily and cheaply
available hydroxylamine and hydrazine with 1,3-dicarbonyls and equivalents, due to instabil-
ity of thiohydroxylamine,[4,5] it has always been considered as a substantial challenge to facile
synthesis of isothiazoles. Despite of these issues with the synthesis, isothiazoles, in particular
3,5-disubstituted isothiazole skeleton plays a significant role in biological activities such as
CONTACT Kempegowda Mantelingu
kmlingu@gmail.com, Rangappa Kanchugarakoppal Subbegowda
rangappaks@gmail.com Synthetic Laboratory, DOS in Chemistry, University of Mysore, Manasagangotri, Karnataka, India.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

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C. NAGARAJU ET AL.
Figure 1. Selected examples of some biologically active compounds containing isothiazole moiety.
antipyretic, analgesic, herbicidal and fungicidal properties.[6] In addition to that, core struc-
tures of pharmaceutically active molecules such as sulfasomizole, denotivir, mGluR1 antago-
nists,[7] GPR agonists,[8] antipsychotic zipracidone, tyrosine kinase c-Met,[9] and potent
inhibitors of aurora kinase,[10] containing 3,5-disubstituted isothiazole skeleton as a key
structural unit (Figure 1). Denotivir and Sulfasomizole display antiviral and antibacterial
properties respectively,[11] while GPR agonists act as an insulin regulator and also it helps to
improve the triglyceride level of cell membranes and mGluR1 antagonists is found to be
beneficial in modulating nociception preclinically. In addition to these applications in medi-
cinal chemistry, commercial importance of isothiazole derivatives are also well known, such
as kathon preservatives,[12] artificial sweeteners, inkjet inks and dyes,[13a] antifreeze composi-
tions for diesel engines,[13b] and corrosion inhibitors.[13c]
However few methods are available for the synthesis of 3,5-disubstituted isothiazoles.
Recently Wang, Ji and coworkers,[14] reported the synthesis of 3,5-disubstituted isothia-
zoles. This proposed reaction involves the addition of trisulfur radical anion to
a,b-usaturated N-sulfonylimines can furnish isothiazole. However the methods entail as
demerits as availability of starting materials, low yields, limited substrate scope and
harsh reaction conditions. As a consequence, much attention has been paid to exploring
an efficient, operationally simple and widely applicable approaches to the synthesis of
isothiazoles derivatives. To the best of our knowledge, no report has been found on the
synthesis of isothiazoles directly from dithioesters and acetophenones (Scheme 1).
Results and discussion
In continuation, of our interest in exploiting the reactivity of dithioesters and the synthesis
of bioactive heterocyclic compounds,[15,16] herein, we report a green protocol for the syn-
thesis of 3,5-disubstituted isothiazoles from acetophenones, dithioesters and NH4OAc.
In intial experiment feasibility of the reaction was checked by using 3a (crude) and
ammonia solution (1 equiv.) in the presence of AcOH (3ml) at room temperature for 24h,
no trace of product was observed (Table 1, entry 1). Upon increasing the temperature to 90 ꢁC
gratifyingly required product 4a obtained with 30% yield after 24 h (Table 1, entry 2). To

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Scheme 1. Previous strategies for the synthesis of 3,5-disustituted isothiazoles.
Table 1. Optimization of reaction 4a.
Entry
Nitrogen source
Solvent
Equivalents (w.r.t 1a)
Temp (ꢁC)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
NH3
NH3
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
DMF
THF
EtOH
H2O
AcOH
AcOH
AcOH
AcOH
1.0
1.0
2.0
2.0
3.0
4.0
5.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
RT
90
90
90
90
80
90
90
90
Reflux
90
100
110
80
24
24
24
24
10
10
7
7
7
16
7
7
–
30
40
60
70
75
75
35
20
Trace
Trace
70
65
80
(NH4)2CO3
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
9
10
11
12
13
14a
15
7
7
7
70
72
aAll reactions were carried out using acetophenones 1a (1.0 mmol) and dithioesters 2a (1.1 mmol) and NH4OAc (4 mmol
or 4 equivalents with respect to acetophenones 1) in AcOH (3 mL) at 80 ꢁC in open air, yields are obtained after col-
umn chromatography.
improve the efficiency of the reaction, further the reaction was carried out by using some other
nitrogen sources such as ammonium carbonate, significant improvement in the yield was not
obtained but surprisingly yield of the product increased to 60% when we used NH4OAc (2
equiv.) (Table 1, entries 3 and 4). Inspired by this result, the amount of NH4OAc increased
from 2 equiv. to 3 and 4 equiv., significant improvement in the yield of the product was
observed (Table 1, entries 5 and 6). Further increase in the amount of NH4OAc to 5 equiva-
lents no improvement in the yield was observed (Table 1, entry 7). Next screening of other sol-
vents like DMF, THF, EtOH and water did not provide better results (Table 1, entries 8, 9, 10,
and 11). The effect of temperature was also tested, when the temperature increased to 100 ꢁC
and 110 ꢁC no significant improvement in the yield of the product was observed (Table 1,

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C. NAGARAJU ET AL.
Scheme 2. Substrate scope of reactions.
entries 12 and 13). When the temperature was decreases from 90 ꢁC to 80ꢁC, yield of the
product was increased to 80% (Table 1, entry 14). Further decrease in the temperature did not
give better results (Table 1, entry 15). Finally, we found that reactions with 3a and NH4OAc (4
equiv.) in the presence of acetic acid at 80 ꢁC for 7 h in open air was ideal (Table 1, entry 14).
Under the above optimized reaction conditions, the versatility and efficiency of this
newly developed methodology was generalized using easily available acetophenones,
dithioesters and NH4OAc as a starting materials. After developing the optimized reac-
tion condition, subsequently we carried out a investigation of substrate scope to study
the effect of different functional groups present in the substrates (Scheme 2, 4a–4s).
The reaction was carried out with number of acetophenones and dithioesters with

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Scheme 3. Plausible mechanism for the formation of 3,5-disustituted isothiazoles.
different substituent groups like methoxy, dimethoxy, trimethoxy, methyl, halo groups
and including heterocyclic compounds like thiophenes were also tested for the construc-
tion of 3,5 disubstituted isothiazoles and in all cases reaction went smoothly to get
moderate to excellent yields.
The proposed mechanism involves the condensation reaction between 1a and 2a in the
presence of base generates intermediate 3a, which involves selective nucleophilic attack of
ammonia generated from NH4OAc (in-situ) at the carbonyl carbon of 3a gives A as an
imine intermediate. Acetate ion (generated in-situ from NH4OAc) abstract hydrogen
from intermediate A, then it undergoes intramolecular cyclization forming S–N bond
(intermediate B) followed by aerial oxidation gives the desired product 4a (Scheme 3).
Conclusion
In conclusion, we have developed an attractive and facile method for the synthesis of 3,5-
disubstituted isothiazoles under transition-metal and catalyst free condition. This method-
ology offers the formation of C–N and N–S bond followed by [4þ 1] ring annulations in a
single step. The reaction pathway follows, sequential imine formation followed by intra
molecular cyclization and aerial oxidation, leading to the elegant formation of functionalized
isothiazoles. Eco friendly, easily available starting materials, good functional group tolerance
and broad substrate scope makes this strategy more viable, when compare to previously
reported mehods and for future applications.
Experimental section
Materials and methods
All work relating to analytical thin layer chromatography were performed with E.
Merck silica gel 60 F254 aluminum plates and were visualized with UV light. The follow-
ing mobile phases were employed for TLC: chloroform, methanol, hexane, and ethyl

6
C. NAGARAJU ET AL.
acetate in different ratios. The instrumental techniques employed for the characteriza-
1
tion of the newly synthesized compounds include H and 13C NMR and mass spectros-
1
copy. H and 13C NMR spectra were recorded on a Bruker-AV (500, 400 and 126,
101 MHz, respectively) and Agilent WM (400 and 100 MHz) Fourier transforms spectro-
photometer in CDCl3 or DMSO-d6 solution using tetramethylsilane (TMS) as internal
standard. Chemical shifts were recorded in ppm relative to TMS. Mass and purity were
recorded on an LC–MSD-Trap-XCT (Agilent Technologies Inc). All the reagents and
chemicals used were from Sigma Aldrich chemicals.
General procedure for the preparation of product 4a–4s
To a solution of aryl methyl ketone 1 (1 mmol) in DMF (5 vol), NaH (1.5 mmol) and
dithioester 2 (1.1 mmol) was stirred for 3 h. Reaction was monitored by TLC. After the com-
pletion of reaction, the reaction mixture was diluted with water and then aqueous layer was
extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate then the
solvent was removed under reduced pressure to afford an intermediate 1,3-diphenyl-3-thio-
xopropan-1-one 3, which was taken to the next step without any purification.
To a solution of 3 (crude) in AcOH (3 ml), NH4OAc (4 mmol, with respect to 1) was
added and heated at 80 ꢁC for 4–7 h. After the completion of the reaction (monitored
by TLC), the mixture was diluted with ethyl acetate followed by washing with aqueous
NaHCO3 to neutralize excess of acetic acid. The organic layer was dried over anhydrous
Na2SO4 and solvent was evaporated under reduced pressure. The crude residue thus
obtained was purified by column chromatography over silica gel using increasing per-
centage of ethyl acetate in hexane as eluent to afford the pure isothiazole product 4.
Acknowledgments
We thank NMR facility, Institute of Excellence, University of Mysore, Manasagangotri, Mysore,
India for spectral data.
Funding
The author (N.C) is thankful to UGC, New Delhi, for senior research fellowships and financial
support from the DBT Glue grant [No. BT/PR23078/MED/29/1253/2017 dated-22/03/2018] and
VGST [K-FIST (L1)] grant [No. KSTePS/VGST/K-FIST(L1)/2017-18/GRD-681/79/2018-2019
dated-17/09/2018] and PURSE grant (phase 2/27(C); dated: 13/09/2019 and phase 2/27(G); dated:
01/10/2019). UOM/IOE/Project fellow/687/2019-20 dated 01/01/2020.
ORCID
Rangappa Kanchugarakoppal Subbegowda
http://orcid.org/0000-0003-0572-6305
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