Cleaner and greener synthesis of 3H-benzothiazole-2-thione and its derivatives

Article abstract of DOI:10.1080/17415993.2020.1803321

A cleaner and greener method of synthesis of 3H-benzothiazole-2-thione is being reported in this communication. In this method, various o-iodoaniline derivatives are reacted with carbon disulfide in the presence of Cs₂CO₃ and tetramethyl ammonium bromide (TMAB) to give 3H-benzothiazole-2-thione and its derivatives in higher yields.

Full text of DOI:10.1080/17415993.2020.1803321

Journal of Sulfur Chemistry
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Cleaner and greener synthesis of 3H-
benzothiazole-2-thione and its derivatives
Nitin Srivastava & Ram Kishore
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of 3H-benzothiazole-2-thione and its derivatives, Journal of Sulfur Chemistry, DOI:
10.1080/17415993.2020.1803321
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JOURNAL OF SULFUR CHEMISTRY
https://doi.org/10.1080/17415993.2020.1803321
BRIEF REPORT
Cleaner and greener synthesis of 3H-benzothiazole-2-thione
and its derivatives
Nitin Srivastava and Ram Kishore
Department of Chemistry, Amity University Uttar Pradesh Lucknow Campus, Lucknow, India
ABSTRACT
ARTICLE HISTORY
Received 24 March 2020
Accepted 26 July 2020
A cleaner and greener method of synthesis of 3H-benzothiazole-2-
thione is being reported in this communication. In this method, vari-
ous o-iodoaniline derivatives are reacted with carbon disulfide in the
presence of Cs2CO3 and tetramethyl ammonium bromide (TMAB) to
give 3H-benzothiazole-2-thione and its derivatives in higher yields.
KEYWORDS
3H-benzothiazole-2-thione;
carbon disulfide; tetramethyl
ammonium bromide;
o-iodoaniline
1. Introduction
3H-benzothiazole-2-thiones are significant synthons forming the basic structures used in
pharmaceuticals. They have shown potential fungicidal [1], anti-yeast [2,3], anti-candida
[4,5], anti-bacterial [6], anti-inflammatory [7], anti-hypertension [8], anti-tumor [9] activ-
ities, etc. Earlier investigations have revealed that 2nd, 5th, and 6th substitutions in
benzothiazole and 2-mercaptobenzothiazole have shown significant fungicidal and micro-
bicidal properties. It has also been revealed that if 6th position is substituted with electron
withdrawing groups like halogens, trifluoromethyl, nitro, amino, fungicidal, and microbi-
cidal activities are enhanced [10]. Azam and Suresh [11] in their literature review have
mentioned that the pharmacological activity of these systems has been widely investi-
gated and is found to be efficient. In a very early study, Halasa and Smith suggested
CONTACT Nitin Srivastava
nitinsriv5@gmail.com
Department of Chemistry, Amity University Uttar Pradesh
Lucknow Campus, Lucknow 226 028, India
© 2020 Informa UK Limited, trading as Taylor & Francis Group

2
N. SRIVASTAVA AND R. KISHORE
Figure 1. Tautomeric forms of the benzothiazole-2-thiol ring system.
Figure 2. Some bioactive benzothiazole derivatives.
that the benzothiazole-2-thiol ring system is in a tautomeric form with benzothiazole-2-
thione (Figure 1) and Michael/Mannich reactions could easily be performed to produce
N-substituted benzothiazole-2-thione compounds [12,13] (Figure 2).
The traditional methods for the synthesis of 3H-benzothiazole-2-thione made the use
of the reactions between N,N-diphenylthioureas and sulfur. In the other ways, its synthesis
was done by the reaction of carbon disulfide with 2-aminobenzenethiols under extreme

JOURNAL OF SULFUR CHEMISTRY
3
pressure [14]. Later these classes of compounds were synthesized by nucleophilic aro-
matic substitution (SNAr) reaction O-ethyldithiocarbonate anion with an o-haloaniline
and subsequently ring closure [15]. These methods involve extreme conditions [16], toxic
chemicals, tiring workup, and lesser yields [17]. So owing to the significance of 3H-
benzothiazole-2-thione in various fields, a better, cleaner, and greener method with high
yield is always welcomed. Here, an effort to prepare different 3H-benzothiazole-2-thione
is being reported. This method is cleaner and greener compared to the existing methods.
2. Results and discussion
All the chemicals used in this process are either easily available in the market or may be
easily synthesized in the laboratory. In this method, an easily available carbon disulfide,
2-iodo- or 2-bromoanilines are employed as starting materials and gives the correspond-
ing 3H-Benzothiazole-2-thione in higher yields in mild conditions in easier and simpler
method. The reaction with 2-iodoaniline derivatives proceeded easily as compared to 2-
bromoaniline derivatives. So in order to make the process energy efficient and enhance
general suitability, 2-iodoaniline derivatives were used for the synthesis. During the per-
formance of the process, it was found that 2-chloroaniline derivatives did not reacted with
the CS2 in the presence of Cs2CO3 and tetramethyl ammonium bromide (TMAB) even
on increasing the temperature to 200°C. On the basis of such screening, we found that the
2-iodoaniline derivatives are more suitable for a cleaner and greener process and so we
proceeded with 2-iodoanilines. Here the reaction was carried under the inert atmosphere.
The phase transfer catalyst enhances the mutual interaction among the reactants and is
easily removed from the product. Cs2CO3 was chosen because it is cheap, mild base, easily
available, highly soluble in both polar and non-polar solvents and easily separated from
the reaction mixture.
According to the planned reaction, we took 2-IC6H4NH2 in a 50 mL sealing tube and
added tetramethyl ammonium bromide (TMAB), CS2 and Cs2CO3 to it. Now 10 mL of
DMSO was added under inert atmosphere and was thoroughly mixed for 30 min. Further,
this was stirred at higher temperature of 100°C for 08 h after sealing. Now the tube was
cooled to room temperature and further added with some water. Then the organic com-
pound was extracted, concentrated, and purified. Compounds formed (entry 3a, Table 2)
were identified by spectral and physical data. IR spectrum of 3a showed absorption band
representing unsaturation at 1602 cm−1, C=S at 1340 and 1185 cm−1. Proton spectra of
entry 3a showed broad peak at δ = 13.76 (N–H), aromatic protons multiplet in the range
δ = 6.30–6.93. The 13C spectra also confirmed the presence of C=S, C–S, C–N bonds
in the synthesized compounds. The mass and elemental constitution of the product con-
firmed by HRMS (m/e) = 167.9938(obs.), 167.9931(calc). Thus the compound formed
was confirmed as 3H-Benzothiazole-2-thione.
The outcome of this product (entry 3a, Table 2) was evaluated with various phase
transfer catalyst by reacting o-iodoaniline with carbon disulfides in different phase trans-
fer catalyst. We tried many phase transfer catalyst like tetra-n-butyl ammonium chloride
(TBAC), tetramethyl ammonium bromide (TMAB), tetra-n-butyl ammonium bromide
(TBAB), tetra-n-butyl ammonium iodide (TBAI), tetra-n-butyl ammonium hydrogen car-
bonate (TBAHC), tetra-n-butyl ammonium hydrogen sulfate (TBAHS), Triton-B, crown

4
N. SRIVASTAVA AND R. KISHORE
Table 1. Effect of different catalyst on time and yield of the
product.
S. no.
Phase transfer catalyst
TBAC
TMAB
TBAB
TBAHC
TBAHS
Triton-B
Crown ether (18 Crown 6)
Time (h)
% Yield
1
2
3
4
5
6
7
10.0
8.0
9.0
12.0
14.0
9.0
72
80
75
72
70
75
72
11.0
Scheme 1. Synthesis of 3H-benzothiazole-2-thiones.
ether (18 crown 6), etc. It was found that tetramethyl ammonium bromide (TMAB) served
well in getting high yield of the desired 3H-benzothiazole-2-thione (Table 1).
After optimizing the reaction conditions o-iodoanilines with different substituent on the
aromatic ring and N-substituted o-iodoanilene with different groups like alkyl (primary,
secondary, tertiary), alicyclic, aromatics were employed in tetra methyl ammonium bro-
mide and CS2 system in DMSO to get various benzothizole-2-thiones. It was also observed
that electron releasing group on the aromatics ring gave better yield and in lesser time as
compared to the electron withdrawing groups attached to aromatic ring. Here in this reac-
tion several products were formed which involved weak electron-attracting groups (e.g.
–Br) to strong electron-attracting groups (e.g Fluoro), along with electron-repelling sub-
stituents like CH3 in the para-position. The substituents in para and ortho position with
respect to NH2 group gave higher yields of the corresponding product (entries 3d and 3e).
To study the effect of various N-substituted anilines on the product, we tried various o-
iodoanilines in which one of the H of amino group substituted with 1°, 2°, 3° alkyl group,
phenyl, benzylic and cyclic groups and reacted them with CS2 in the presence of TMAB and
CS2CO3. It was found that with N-substituted iodoanilines the yield was also very good.
N-methyl iodoaniline gave 3-methyl-3H-benzothiazole-2-thione 3i, the yield was 94% at
100°C (Scheme 1). Same method yielded 84% of 3-ethyl-3H-benzothiazole-2-thione 3j.
It can be stated here that electron releasing group at N gave higher yield in lesser time.
Simultaneously crowding at N decreases the yield and increases the time of the reaction.
The spectral characterization of all benzothiazoles and their substituted analogues were
confirmed through the standard data available for the existing compounds in the literature
[18–21]. Various synthesized compounds are summarized in Table 2.

JOURNAL OF SULFUR CHEMISTRY
5
Table 2. Synthesized 3H-benzothiazole-2-thione and its derivatives.
Entry
o-iodoaniline
Product
Time (h)
8.0
% Yield
80
3a
3b
3c
8.0
9.2
78
92
3d
3e
11.5
11.0
91
93
3f
14.0
13.0
86
88
3g
3h
3i
15.0
8.0
84
94
(continued).

6
N. SRIVASTAVA AND R. KISHORE
Table 2. Continued.
Entry
o-iodoaniline
Product
Time (h) % Yield
3j
9.0
84
3k
3l
11.5
11.0
80
80
3m
3n
3o
20.0
10.0
28.0
70
80
85
3. Possible mechanism
The probable mechanism of the reaction of iodo anilines with carbon disulfide is given in
Scheme 2.

JOURNAL OF SULFUR CHEMISTRY
7
Scheme 2. Possible mechanism of the reaction.
Here the lone pair of e− on N atom of aniline attacks the electrophilic site generated on
the CS2 due to the displacement of the electron to more electronegative Sulfur atom and
subsequent intramolecular SNAr reaction forms Benzothiazole-2-thione [22].
4. Experimental
All chemicals used in the reaction were procured from Fluka, Merck, and Sigma Aldrich.
No further purification of the procured reagents was done. Silica gel (10–40 mm particle
size) was used for column chromatography. 1H NMR and 13C NMR spectra were recorded
on Bruker advance DPX instrument at 400, 100 MHz respectively at room temperature
in CDCl3. X-4 digital melting point apparatus with microscope was used to ascertain the
melting points of the compounds. Bruker Esquire ion-trap mass spectrometer was used to
register mass spectra.
4.1. Typical procedure for 3H-benzothiazole-2-thione
1.095 g (5 mmol) of 2-IC6H4NH2 was taken in a 50 mL sealed tube and added with 1.5
mL (10.0 mmol) tetramethyl ammonium bromide (TMAB), 1.0 mL (15 mmol) CS2, and
10 mmol of Cs2CO3. 10 mL of DMSO was added under inert atmosphere and was thor-
oughly mixed for 30 min. Further, this was stirred at higher temperature of 100°C for 8 h
after sealing. Now the tube was cooled room temperature and further added with 20 mL
H2O. Then the organic compound was extracted with 3 × 20 mL of ethyl ethanoate and
the extracts thus obtained were dried with Na2SO4 (anhyd.) which was further concen-
trated over rotatory evaporator and chiller plant. Now the organic compound was finally
obtained in pure form by silica gel packed column chromatography in which the column
was eluated with hexane–ethyl ethanoate in the ratio of 5:1. The filtrate on concentration
gave benzothiazole-2-thione.

8
N. SRIVASTAVA AND R. KISHORE
4.2. Data analysis for synthesized 3H-benzothiazole-2-thione and its derivatives
1. 3H-Benzothiazole-2-thione [18] (3a)
White compound; Yield (0.667 g, 80%), melts at 188–189°C; 1H NMR, δ = 13.76 (br s, 1
H), 6.30–6.93 (4H aromatic); 13C NMR, δ = 189.8, 141.3, 129.4, 127.2, 124.3, 121.8, 112.5;
HRMS (m/z) for [C7H5NS2 + H+] = 167.9938 (Obs.), 167.9931.
2. 6-Methyl-3H-benzothiazole-2-thione [18] (3b)
1
White compound; Yield (0.70 g, 78%), melts at 179–180°C; H NMR, δ = 13.68 (s, br,
NH), 7.44 (s, 1 H), 7.20 (s, 2H), 2.29 (s, CH3); 13C NMR δ = 189.2, 138.8, 134.0, 129.5,
127.9, 121.6, 112.2, 20.8; HRMS (m/z) for [C8H7NS2 + H+] = 182.0088 (obs.), 182.0093
(calc.).
3. 4,6-Dimethyl-3H-benzothiazole-2-thione [19] (3c)
White compound; Yield (0.89 g, 92%), melts at 184–185°C; 1H NMR, δ = 13.64 (br, 1H,
NH), 6.54 (1H singlet aromatic), 6.40 (1H singlet aromatic), 2.35 (6H singlet,); 13C NMR
δ = 196.1, 137.8, 134.7, 133.7, 129.1, 127.2, 127.0, 21.1, 11.7; HRMS (m/z) for [C9H9NS2
+ H+] = 195.0245 (obs.), 196.0248 (calc.).
4. 6-Ethyl-3H-benzothiazole-2-thione [15(d)] (3d)
1
Yellow oil; Yield (0.78 g, 80%); H NMR, δ = 7.48, 7.29, 7.21, 4.41, 1.78-1.84 (m, 2H),
1.42–1.48 (2H, m), 1.35–1.38 (2H, m), 1.27–1.34 (m, 6H), 0.88; 13C NMR, δ = 188.9,
141.5, 127.9, 126.8, 124.5, 121.3, 112.3, 46.4, 29.2, 29.1, 26.8, 26.7, 22.5, 13.9; HRMS (m/z)
for [C9H9NS2 + H+] = 196.2027 (obs.), 196.2038(calc.).
5. 6-Iso propylbenzo thiazole-2(3H)-thione [15(d)] (3e)
Yellow oil; Yield (0.83 g, 80%); 1H NMR, δ = 13.68 (s, broad N–H), 6.80–6.22
(aromatic, multiplet), 3.12 (multiplet, 2H), 1.29 (singlet 6H terminal); 13C NMR,
δ = 196.1, 145.0, 137.3, 129.0, 125.3, 123.4, 31.7, 24.4; HRMS (m/z) for [C10H11NS2+
H+] = 209.0333(obs.), 209.0321(calc.).
6. 6-Fluorobenzo thiazole-2(3H)-thione [19] (3f)
White compound; Yield (0.79 g, 86%), melts at 204.6–205.9°C; 1H NMR, δ = 13.84 (s, N-
H), 7.69 (doublet, 1H), 7.35 (double doublet, 1H), 7.28 (s, 1H); 13C NMR, δ = 191.4, 142.7,
132.3, 128.7, 124.5, 123.7, 112.4; HRMS (m/z) for [C7H4FNS2+ H+] = 185.9838 (obs.),
185.9841(calc.). Consider reference no [19].
7. 7-Chlorobenzo thiazole-2(3H)-thione [15(b)] (3g)
1
White compound; Yield (0.85 g, 85%); melts at 204.6–205.9oC; H NMR, δ = 13.79 (s,
NH), 7.72 (1H, d), 7.35 (dd, 1H), 7.28 (1H, s); 13C NMR, δ = 191.4, 142.7, 132.3, 128.7,
124.5, 123.7, 112.4; HRMS (m/z) for [C7H4ClNS2+ H+] = 201.9474 (obs.), 201.9468
(calc.).
8. 6-Chloro-4-Fluoro benzothiazole thione [19] (3h)
White compound; Yield (0.91 g, 84%); melts at 210–211°C; 1H NMR, δ = 14.12 (br s, 1 H),
7.71–7.90 (m, 1 H), 7.48–7.71 (m, 1 H); 13C NMR, δ = 190.8, 133.1, 128.7, 129.7, 120.7,
120.7, 117.7, 114.1; HRMS (m/z) for [C7H3ClFNS2+ H+] Mw = 219.9441(obs), 219.9452
(calc.).

JOURNAL OF SULFUR CHEMISTRY
9
9. 3-Methyl-3H-benzothiazole-2-thione [19] (3i)
1
White compound; Yield (1.029 g, 94%); melts at 100.3–101.9°C; H NMR, δ = 7.51
(d, 1H), 7.40–7.43 (1H, m), 7.27–7.32 (1H, m), 7.20 (d, 1H), 3.84 (s, 3H); 13C NMR,
δ = 189.2, 141.8, 127.3, 126.8, 124.8, 121.2, 112.2, 33.1; HRMS (m/z) for [C8H7NS2+
H+] = 182.0012 (obs.), 182.0020 (calc.).
10. 3-Ethyl-3H-benzothiazole-2-thione [18] (3j)
Grey Solid (0.78 g, 80%) melts at 96–98°C; 1H NMR, δ = 6.96–6.27 (multiplet aromatic,
4H), 3.10 (quartet, 2H), 1.13 (triplet 3H terminal); 13C NMR, δ = 193.4, 140.1, 129.3,
129.5, 125.6, 124.8, 46.3, 12.1; HRMS: (m/z) for [C9H9NS2+ H+] = 196.0176 (obs.),
196.0168 (calc.).
11. 3-Pentyl-3H-benzothiazole-2-thione [18] (3k)
Yellow oil (0.83 g, 80%); 1H NMR, δ = 6.96–6.27 (multiplet, 4H aromatic), 3.06 (NCH2
triplet), 1.56 (2H multiplet CH2), 1.33 (2H multiplet CH2), 1.29 (2H multiplet CH2), 0.96
(t, 3H); 13C NMR, δ = 193.4, 140.1, 129.3, 129.5, 125.6, 124.8, 53.5,29.3, 28.1, 22.8, 14.0;
HRMS: (m/z) for [C12H15NS2+ H+] = 238.0722 (obs.), 238.0720 (calc.).
12. 3-Isopropyl-3H-benzothiazole-2-thione [21] (3l)
Yellow oil (0.83 g, 80%); 1H NMR (CDCl3, 400 MHz) δ = 6.96–6.27 (multiplet, 4H aro-
matic), 2.97 (NCH multiplet), 1.18 (6H multiplet terminal CH3); 13C NMR (CDCl3,
100 MHz) δ = 193.4, 140.1, 129.3, 129.5, 125.6, 124.8, 49.4, 20.4; HRMS: (m/z) for
[C10H11NS2+ H+] = 210.0336 (obs.), 210.0327 (calc.).
13. 3-Cyclohexyl-3H-benzothiazole-2-thione [18] (3m)
Husk color solid (0.87 g, 70%) melts at 114–116°C;C13H15NS2; H NMR (CDCl3, 400
1
MHz) δ = 1.44 (6H multiplet), 1.63 (4H multiplet), 2.64 (1H multiplet C–H), 6.19–6.99
(4H, multiplet, aromatic); 13C NMR (CDCl3, 100 MHz) δ = 193.4, 140.1, 129.3, 129.5,
125.6, 124.8, 53.2, 29.9, 27.1, 22.3; HRMS (m/z) for [C13H15NS2+ H+] = 250.0639 (obs.),
250.0646 (calc.).
14. 3-Phenyl-3H-benzothiazole-2-thione [18] (3n)
1
Pale yellow oil (0.972 g, 80%); C13H9NS2; H NMR (CDCl3, 400 MHz) δ = 6.39–7.03
(5H multiplet aromatic), 6.28–6.88(4H multiplet aromatic); 13C NMR (CDCl3, 100
MHz) δ = 189.4, 143.8, 130.1, 126.3, 121.9, 118.2, 143.1, 129.4, 118.2; HRMS: (m/z) for
[C13H9NS2 + H+] = 244.0176 (obs.), 244.0167 (calc.).
15. 3-(Naphthalen-2-ylmethyl)-3H-benzothiazole-2-thione [18] (3o)
Yellowish compound (1.30 g, 85%) melts at 163–164°C; C17H11NS2; 1H NMR (CDCl3, 400
MHz) δ = 6.29–6.98 (4H, multiplet, aromatic), 7.08–7.75 (7H multiplet, aromatic), 4.68
(2H singlet); 13C NMR (CDCl3, 100 MHz) δ = 193.5, 140.1, 139.5, 125.6, 124.8, 135.2,
133.5, 131.6, 127.3, 125.7, 124.8, 123.4, 118.7, 109.4 59.4; HRMS (m/z) for [C18H13NS2 +
H+] = 308.0559 (obs.), 308.0562 (calc.).
Disclosure statement
No potential conflict of interest was reported by the author(s).

10
N. SRIVASTAVA AND R. KISHORE
ORCID
Nitin Srivastava http://orcid.org/0000-0002-4167-0807
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