A Facile Approach to the Synthesis of Benzothiazoles from N-Protected Amino Acids

Article abstract of DOI:10.1134/S1070428020020190

Abstract: –A simple trituration method for the synthesis of 2-substituted benzothiazoles derived from N-protected amino acids and 2-aminothiophenol using molecular iodine as a mild Lewis acid catalyst has been proposed. The reaction occurs in one step for 20–25 min in solve-free conditions and provides the target products in excellent yields.

Full text of DOI:10.1134/S1070428020020190

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 2, pp. 292–297. © Pleiades Publishing, Ltd., 2020.
A Facile Approach to the Synthesis of Benzothiazoles
from N-Protected Amino Acids
M. Arfana,*, A. Tahiraa, A. Mannanb, and T. Fatimac
a Department of Chemistry, School of Natural Sciences, National University of Sciences and Technology,
Islamabad, 44000 Pakistan
b Department of Pharmacy, COMSATS University, Abbottabad Campus, Abbottabad, 22010 Pakistan
c Department of Chemistry, COMSATS University, Islamabad Campus, Islamabad, 44000 Pakistan
*e-mail: marfan@sns.nust.edu.pk
Received August 21, 2019; revised October 25, 2019; accepted December 20, 2019
Abstract––A simple trituration method for the synthesis of 2-substituted benzothiazoles derived from N-protect-
ed amino acids and 2-aminothiophenol using molecular iodine as a mild Lewis acid catalyst has been proposed.
The reaction occurs in one step for 20–25 min in solve-free conditions and provides the target roducts in excellent
yields.
Keywords: benzothiazole, N-protected amino acids, Lewis acid catalyst
DOI: 10.1134/S1070428020020190
Among the known heterocycles benzothiazole is one
ofthemostbiologicallyandchemicallyactivemoiety,due
to which it has found a large number of pharmaceutical
and industrial applications [1–4]. Over the past decade,
rapidly increasing application of benzothiazoles in
medicinal and pharmaceutical chemistry has been
observed, and a large number of methods have been
reported for their synthesis. However, the methods
available in literature have such limitations as the use of
metal catalysts, expensive reagents, and toxic solvents,
as well as long reaction times, high temperatures, and
low yields [5–11].
versatility. They are known to serve as important starting
materials for the synthesis of a variety of molecules,
regulate key metabolic pathways and processes, and
play a role in the health, growth, homeostasis, and
reproduction of living organisms [19].
As part of our studies for the development of new
methodology, herein we now describe a new approach
for the synthesis of 2-substituted benzothiazoles in a
single step, with an excellent yield, a shorter reaction
time, without the use of any costly or toxic reagent and
using iodine as a Lewis acid catalyst.
The six amino acids used in this study, namely
glycine, leucine, proline, tryptophan, valine and
phenylalanine, were first benzoyl and Boc-protected
following published procedures [20] (Schemes 1 and 2,
respectively).
Inthepresentstudyforthesynthesisofbenzothiazoles
we developed a method that overcomes all the above-
mentioned limitations. We employed iodine as a
catalyst, the reaction was carried out without the use
of any solvent, at room temperature, and was complete
in 20–25 min. The efficiency of iodine catalysis in
benzothiazole synthesis has been repeatedly mentioned
in the literature [12–18].
The synthesis of benzothiazoles was carried out
by the procedure in [13] by trituration of N-protected
amino acids with 2-aminothiophenol in the presence of
molecular iodine as a catalyst. The reaction is novel in
the sense that up to date N-protected amino acids have
never been involved in such reaction as a reactant for the
synthesis of benzothiazoles. In 2013, Panda et al. [21]
used N-protected aminoacylbenzotriazole or N-protected
peptidylbenzotriazole for the synthesis of benzothiazoles
In this work we synthesized 2-substituted
benzothiazoles using N-protected amino acids as
substrates for the first time. For the protection of the
amino group, the benzoyl and Boc protecting groups
were selected. Amino acids were selected as substrates
as they show remarkable metabolic and regulatory
292

A FACILE APPROACH TO THE SYNTHESIS OF BENZOTHIAZOLES
293
Scheme 1. Synthesis of N-benzoyl-protected amino acids 1a–1f.
OH
O
HN
O
Cl
O
1. 10% NaOH
2. Ice, dil. HCl
H2N
+
R
OH
O
R
1a–1f
R = H (a), –CH2CH(CH3)2 (b),
(c),
(d), CH(CH3)2 (e),
(f).
HN
N
H
Scheme 2. Synthesis of N-Boc-protected amino acids 2a–2f.
OH
O
C
O
C
O
1. Dioxane
2. 1M NaOH, H2O
O
HN
H2N
O
+
OH
3. dil. KHSO4
O
O
O
R
O
R
2a–2f
R = H (a), –CH2CH(CH3)2 (b),
(c),
(d), CH(CH3)2 (e),
(f).
HN
N
H
in noncatalytic conditions under microwave irradiation,
and the maximum yield of the target products was 89%.
However, by our procedure we obtained yields of up
to 98% not using microwave irradiation and in half the
reaction time in [21]. Furthermore, we used N-protected
amino acids rather than N-protected benzotriazoles.
spectroscopy and mass spectrometry. The FTIR spectra
of all the products showed a characteristic benzothiazole
C=N absorption band in the region of 1600 cm–1
[22, 23]. The absence of a broad OH stretching band at
3200–3400 cm–1 was considered as further evidence for
the formation of the target products.
The reaction of N-benzoyl-protected amino acids
1a–1f with 2-aminothiophenol gave the corresponding
2-substituted benzothiazoles 3a–3f (Scheme 3). The
synthesized compounds were characterized by FTIR
Scheme 4 shows the mass spectral fragmentation
pathway of compound 3a (as a representative of the
series), which is confirmative of the structure of the
product.
Scheme 3. Synthesis of benzothiazoles 3a–3f from N-benzoyl-protected amino acids 1a–1f.
OH
N
O
O
HN
HN
NH2
SH
I2 trituration
rt, 20–25 min
O
S
+
R
R
1a–1f
3a–3f
R = H (a), –CH2CH(CH3)2 (b),
(c),
(f).
(d), CH(CH3)2 (e),
HN
N
H
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ARFAN et al.
Scheme 4. Mass spectral fragmentation pattern of compound 3a.
N
S
HN
O
N
N
S
O
HN
NH
–C6H5
–CHO
S
m/z 191
m/z 163
m/z 268
–NH
N
S
N
S
CH2
–CN
–CH2
S
m/z 134
m/z 148
m/z 108
The reaction of N-Boc-protected amino acids 2a–2f
The study resulted in the successful development
of a facile synthesis of 2-substituted benzothiazoles
from N-benzoyl- and N-Boc-protected amino acids,
using molecular iodine as a catalyst. Twelve previously
unknown benzothiazoles were synthesized, and their
structures were confirmed by FTIR spectroscopy and
GCMS analysis.
with 2-aminothiophenol resulted in the synthesis of
the corresponding 2-substituted benzothiazoles 4a–4f
(Scheme 5). The FTIR spectra of the products and the
mass spectrum of compound 4a as a representative of
the series (Scheme 6) confirm the formation of the target
products.
Scheme 5. Synthesis of benzothiazoles 4a–4f from N-BOC-protected amino acids 2a–2f.
OH
N
O
O
NH2
SH
HN
HN
I2 trituration
rt, 20–25 min
O
+
S
R
O
R
O
2a–2f
4a–4f
R = H (a), –CH2CH(CH3)2 (b),
(c),
(f).
(d), CH(CH3)2 (e),
HN
N
H
Scheme 6. Mass spectral fragmentation pattern of compound 4a.
N
S
O
N
S
HN
MacLaf
O
HN
O
OH
m/z 264
m/z 208
MacLaf 1
N
N
S
N
S
CH2
NH2
–NH2
–CH2
–CN
S
S
m/z 164
m/z 148
m/z 134
m/z 108
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A FACILE APPROACH TO THE SYNTHESIS OF BENZOTHIAZOLES
295
N-(1,3-Benzothiazol-2-ylmethyl)benzamide (3a)
was prepared by the general procedure using amino
acid 1a. Yield 76%, mp 110–111°C, Rf. IR spectrum,
ν, cm–1: 1613 (C=O), 1600 (C=N), 1582 (C=C), 700
(C–S). Mass spectrum, m/z (Irel, %): 268 [M]+, 191 [M –
C6H5]+, 163 [M – C6H5CO]+, 148 [M – C6H5CONH]+,
134 [C7H4NS], 108 [C6H4S].
EXPERIMENTAL
All chemicals of analytical grade were purchased
from Sigma–Aldrich and used without further
purification. The melting points were determined on an
SMP10 melting point apparatus and are uncorrected.
The reaction progress was monitored by TLC on
plates (eluent), spots visualization under UV light.
The FTIR spectra were recorded on a Bruker ATR
FTIR spectrophotometer in the range 4000–500 cm–1.
Recrystallized samples were analyzed by GCMS on a
Perkin Elmer Clarus 600 GC coupled with 600c MS
Quadrupole EI (dimensions Elite-5 column, carrier gas
He, 1 mL/min).
N-[1-(1,3-Benzothiazol-2-yl)-3-methylbutyl]-
benzamide (3b) was prepared by the general procedure
using amino acid 1b. Yield 86%, mp 118–119°C, Rf
0.63. IR spectrum, ν, cm–1: 1703 (C=O), 1603 (C=N),
1578 (C=C), 710 (C–S). Mass spectrum, m/z: 324
[M]+, 247 [M – C6H5]+, 219 [M – C6H5CO]+, 204 [M –
C6H5CONH2]+, Second Route: 281 [M – CH3CH2CH3]+,
176 [281 – C6H5CO], 134 [C7H4NS], 108 [C6H4S].
N-Benzoyl-protected amino acids 1a–1f (general
procedure).Asolution of 0.5g (6.66 mmol) of amino acid
in 0.4 mL of 10% aqueous NaOH was stirred for 30 min,
after which 0.68 mL of benzoyl chloride was added
dropwise in five portions, and stirring was continued for
an additional 30 min. The progress of the reaction was
monitored byTLC.After the reaction had been complete,
ice was added, and the pH of the mixture was adjusted
to 2–3 by carefully adding dilute HCl. The crystals that
formed were filtered off, washed with cold water, dried,
boiled in CCl4 for 5 min to remove excess benzoic acid,
washed with water, and recrystallized from methanol.
[2-(1,3-Benzothiazol-2-yl)pyrrolidin-1-yl]-
(phenyl)methanone (3c) was prepared by the general
procedure using amino acid 1c. Yield 91%, mp 101–
102°C, Rf 0.59. IR spectrum, ν, cm–1: 1680(C=O), 1600
(C=N), 1575 (C=C), 712 (C–S). Mass spectrum, m/z:
308 [M]+, 231 [M – C6H5]+, 203 [M – C6H5CO]+, 175
[C10H10NS], 134 [C7H4NS], 108 [C6H4S].
N-[1-(1,3-Benzothiazol-2-yl)-2-(1H-indol-3-yl)-
ethyl]benzamide (3d) was prepared by the general
procedure using amino acid 1d. Yield 82%, mp 122–
125°C, Rf 0.70. IR spectrum, ν, cm–1: 1713 (C=O),
1614 (C=N), 1539 (C=C), 710 (C–S). Mass spectrum,
m/z: 397 [M]+, 320 [M – C6H5]+, 292 [M – C6H5CO]+,
277 [M – C6H5CONH]+, 281 [M – C8H6N]+, 267 [M –
C8H6NCH2]+, 34 [C7H4NS].
N-Boc-protected amino acids 2a–2f (general
procedure). Amino acid (4.3 g, 37.4 mmol) was
dissolved in dioxane (75 mL) and after 30 min 1 M
NaOH (38 mL) and H2O (38 mL) were added followed
by (Boc)2O (9 g, 41.4 mmol). The reaction mixture was
stirred for 1 h and concentrated under reduced pressure
to about 30–40 mL, after which ice and a little of ethyl
acetate. A dilute KHSO4 solution was then added very
carefully to the reaction mixture to adjust its pH to 2–3.
The solution was then washed with brine and the product
was extracted with ethyl acetate and dried over MgSO4.
The solvent was evaporated under reduced pressure.
N-[1-(1,3-Benzothiazol-2-yl)-2-methylpropyl]-
benzamide (3e) was prepared by the general procedure
using amino acid 1e. Yield 97%, mp 92–94°C, Rf 0.77.
IR spectrum, ν, cm–1: 1678 (C=O), 1603 (C=N), 1565
(C=C), 700 (C–S). Mass spectrum, m/z: 310 [M]+, 190
[M – C6H5CO]+, 134 [C7H4NS], 108 [C6H4S].
N-[1-(1,3-Benzothiazol-2-yl)-2-phenylethyl]ben-
zamide (3f) was prepared by the general procedure
using amino acid 1f. Yield 66%, mp 144–146°C, Rf
0.66. IR spectrum, ν, cm–1: 1700 (C=O), 1608 (C=N),
1573 (C=C), 715 (C–S). Mass spectrum, m/z: 358
[M]+, 281 [M – C6H5]+, 253 [M – C6H5CO]+, 267 [M –
CH2C6H5]+, 134 [C7H4NS].
Benzothiazoles 3a–3f and 4a–4f from N-protected
amino acids (general procedure). The reaction
between protected amino acid (500 mg, 2.7 mmol) and
2-aminothiophenol (0.67 mL, 5.3 mmol) in the presence
of iodine (223 mg, 1.8 mmol) as a catalyst was carried
out following the procedure described in [14]. The
reaction was complete (TLC monitoring) in 20 min. The
product was washed with aqueous Na2S2O3 to remove
unreacted iodine and purified by recrystallization from a
70 : 30 ethanol–water mixture.
tert-Butyl
(1,3-benzothiazol-2-ylmethyl)carba-
mate (4a) was prepared by the general procedure
using amino acid 2a. Yield 78%, mp 139–141°C, Rf
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ARFAN et al.
0.75. IR spectrum, ν, cm–1: 1600 (C=O), 1582 (C=N),
1570 (C=C), 1308 [C(CH3)3], 1300 (C–O), 712 (C–S).
Mass spectrum, m/z: 264 [M]+, 208 [MacLafferty], 164
[MacLafferty 1], 148 [C8H6NS], 134 [C7H4NS], 108
[C6H4S].
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tert-Butyl [1-(1,3-benzothiazol-2-yl)-3-methylbu-
tyl]carbamate (4b) was prepared by the general
procedure using amino acid 2b. Yield 96%, mp 89–
91°C, Rf 0.84. IR spectrum, ν, cm–1: 1735 (C=O),
1605 (C=N), 1600 (C=C), 1298 [C(CH3)3], 1300 (C–
O), 710 (C–S). Mass spectrum, m/z: 320 [M]+, 277
[M – CH(CH3)2]+, 263 [M – CH2CH(CH3)2]. Second
Route: 264 [MacLafferty], 220 [MacLafferty 1], 204
[C12H15NS], 134 [C7H4NS].
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tert-Butyl
2-(1,3-benzothiazol-2-ylmethyl)pyr-
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rolidine-1-carboxylate (4c). Yield 98%, mp 95–99°C,
Rf 0.81. IR spectrum, ν, cm–1: 1717 (C=O), 1600 (C=C),
1614 (C=N), 1280 [C(CH3)3], 1100 (C–O), 710 (C–S).
Mass spectrum, m/z: 304 [M]+, 248 [MacLafferty], 204
[C11H12N2S], 190 [C10H10N2S], 134 [C7H4NS].
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tert-Butyl
[1-(1,3-benzothiazol-2-yl)-2-(4-hyd-
roxyphenyl)ethyl]carbamate (4d). Yield 92%, mp
135–137°C, Rf 0.76. IR spectrum, ν, cm–1: 1680 (C=O),
1603 (C=N), 1582 (C=C), 1305 (C–O), 714 (C–S).
Mass spectrum, m/z: 393 [M]+, 263 [M – C8H6N]+, 337
[MacLafferty 1], 293 [MacLafferty], 134 [C7H4NS].
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and Lang, S., J. Org. Chem., 2013, vol. 78, p. 1471.
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tert-Butyl
[1-(1,3-benzothiazol-2-yl)-2-methyl-
propyl]carbamate (4e). Yield 54%, mp 138–140°C, Rf
0.70. IR spectrum, ν, cm–1: 1735 (C=O), 1604 (C=N),
1578 (C=C), 1299 [C(CH3)3], 1241 (C–O), 700 (C–S).
Mass spectrum, m/z: 306 [M]+, 250 [MacLafferty 1], 206
[MacLafferty], 190 [C9H6NS(CH3)3], 134 [C7H4NS],
108 [C6H4S].
tert-Butyl
[1-(1,3-benzothiazol-2-yl)-2-phenyl-
ethyl]carbamate (4f). Yield 90%, mp 80–84°C, Rf
0.65. IR spectrum, ν, cm–1: 1693 (C=O), 1607 (C=N),
1506 (C=C), 1366 [C(CH3)3], 1156 (C–O), 715 (C–S).
Mass spectrum, m/z: 354 [M]+, 298 (MacLafferty), 238
[C7H4NSC8H8], 134 [C7H4NS], 254 [MacLafferty 2],
207 [M – C(CH3)3CH2C6H5]+.
https://doi.org/10.1021/ol400773k
CONFLICT OF INTEREST
The authors declare no conflict of interest.
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