Free Radical Synthetic Protocol for Benzothiazoles via Ring Opening of Benzotriazole: A Two-step Organic Chemistry Experiment for Undergraduate and Postgraduate Students

Article abstract of DOI:10.1002/jhet.3405

The utility and advantages of benzotriazole methodology have been described for the practical synthesis of benzothiazoles. The two-step synthetic procedure includes nucleophilic acyl substitution followed by benzotriazole ring cleavage under the free radical condition and subsequent cyclization via elimination of molecular nitrogen (N₂). This protocol requires cheap and readily available reagents, and moreover easy to handle, thus can be used to teach undergraduate and postgraduate students about the importance of benzotriazole moiety in organic synthesis, ring cleavage chemistry, cyclization reactions, and use of industrial waste in free radical reactions. Students can also learn some important and common techniques useful in organic chemistry such as monitoring of organic reaction using thin-layer chromatography and UV, microwave (MW) technique for the synthesis, and column chromatography for the product isolation and structure determination through NMR, MS, and IR spectral analysis of the pure compounds.

Full text of DOI:10.1002/jhet.3405

Month 2018
Free Radical Synthetic Protocol for Benzothiazoles via Ring Opening of
Benzotriazole: A Two-step Organic Chemistry Experiment for
Undergraduate and Postgraduate Students
Anoop S. Singh, Nidhi Mishra, Mangal S. Yadav, and Vinod K. Tiwari*
Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
*
E-mail: tiwari_chem@yahoo.co.in; vtiwari@ucdavis.edu
Received July 12, 2018
DOI 10.1002/jhet.3405
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
The utility and advantages of benzotriazole methodology have been described for the practical synthesis
of benzothiazoles. The two-step synthetic procedure includes nucleophilic acyl substitution followed by
benzotriazole ring cleavage under the free radical condition and subsequent cyclization via elimination of
2
molecular nitrogen (N ). This protocol requires cheap and readily available reagents, and moreover easy
to handle, thus can be used to teach undergraduate and postgraduate students about the importance of
benzotriazole moiety in organic synthesis, ring cleavage chemistry, cyclization reactions, and use of
industrial waste in free radical reactions. Students can also learn some important and common techniques
useful in organic chemistry such as monitoring of organic reaction using thin-layer chromatography and
UV, microwave (MW) technique for the synthesis, and column chromatography for the product isolation
and structure determination through NMR, MS, and IR spectral analysis of the pure compounds.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
antimicrobial, and antifungal activities [5]. The
immunosuppressive drug frentizole, the antiparasitic
Benzotriazole methodology has emerged as a promising
and successful tactic in synthetic chemistry [1,2]. Along
with ease in introduction and removal, the compatibility of
benzotriazole moiety with various reaction conditions
tioxidazole, a human CCR1 and CCR3 receptor
antagonist, the calcium channel blocker fostedil, and
many others are the representative examples of drugs
that consist of benzothiazole skeleton. These fascinating
features of benzothiazole derivatives have compelled the
chemists to develop new methodologies for their
synthesis. Several earlier reported methods include
K [Fe (CN) ] mediated cyclization of arylthioamide
2
makes it an ideal group for substitution reactions. On the
other hand, the rupture of benzotriazole ring via breaking
of N–N and C–N bonds with assistance of suitable
reagents leads to formation of different aromatic
compounds such as benzothiazoles, amides, benzoxazoles,
indoles, and benzimidazoles [3]. In addition to be a
nontoxic, low-cost, and stable moiety, other advantages
associated with benzotriazole such as simple introduction
to a molecule, easy elimination, α-cation stabilization, and
promotion of an anion or free radical formation at the
α-position make the benzotriazole methodology even
better than other synthetic techniques practiced so far. The
wide substrate scope of this methodology has provided
convenient and high-yielding synthesis of many valuable
heterocyclic systems and other biologically significant
molecules. Due to potential results and high yields
associated with benzotriazole ring cleavage (BtRC)
methodology, this protocol has been elaborately explored
in synthesis of benzothiazoles by our group during past
few years [4].
3
6
(Jacobson’s method) [6], condensation of carbonyl
compounds with 2-aminothiophenol [7], transition-metal
catalyzed cyclization of thioformanilides under aromatic
nucleophilic substitution [8] or radical conditions [9],
and via thioamide intermediates derived from halo
amides using P4S10 or Lawesson’s reagent [10]. Some
disadvantages associated with these methods are use of
toxic reagents, harsh reaction conditions, difficult work-
up process, and toxic reaction wastes. Whereas BtRC
mediated benzothiazole synthesis includes metal-free
environmentally benign mild reaction conditions with
easy work-up procedure and high yields.
Benzotriazole ring cleavage (BtRC) can take place
either via Dimroth rearrangement or via free radical
mechanism [11,12]. In Dimroth rearrangements,
benzotriazole containing an electron withdrawing
group at 1-position exists in thermal equilibrium with
diazonium intermediate which participates in product
formation via nucleophilic substitution. On the other
Benzothiazole heterocycles have extensively been
used as a core moiety of different pharmaceutically
relevant compounds particularly known for antidiabetic,
©
2018 Wiley Periodicals, Inc.

A. S. Singh, N. Mishra, M. S. Yadav, and V. K. Tiwari
Vol 000
hand, the free radical path involves the generation of free
radical with assistance of an initiator followed by
eradication of nitrogen gas. The benefit of free radical
process over Dimroth rearrangement comprises no need
of electron withdrawing group.
Present scheme of benzothiazole synthesis via BtRC
route consists of two successive reactions. In the first step,
the substitution of one of the two benzotriazole rings of
bis-(benzotriazole) methanethione with pyrrolidine ring in
basic medium proceeds rapidly to produce (1H-benzo[d]
second lab session, the second step (BtRC) of two-step
synthesis is started and the reaction is monitored by
TLC (Rf = 0.5, 35% ethyl acetate/n-hexane). In the
third lab session, work-up is performed and product is
purified by column chromatography. After drying and
1
weighing, the isolated product is analyzed by H-NMR
13
and
C-NMR spectroscopy, IR spectroscopy, and
melting point determination for identity and purity. The
yield of each step as well as the overall yield is calculated.
See Supporting Information for experimental details.
[1,2,3]triazol-1-yl)(pyrrolidin-1-yl)
methanethione
in
Synthesis
of
1-(1-pyrrolidinyl
thioxomethyl)-1H-
excellent yield. The second step includes free radical
cleavage of benzotriazole ring initiated through tributyltin
benzotriazole 3. A synthetic scheme for the first step
of two-step synthetic route is shown in Scheme 1 and
Scheme 2. Students are familiar with the concept of
nucleophilic acyl substitution reaction and the role of
an easily substituted group to facilitate this reaction
[14]. Here, we used pyrrolidine as a nucleophile in the
presence of triethylamine to substitute one of the easily
removable benzotriazole moieties of bis(benzotriazolyl)
methanethione 2. Thus, thiocarbamoyltion reaction of
secondary amine pyrrolidine 1 (1.0 equiv) with bis-
benzotriazole methanethione 2 (1.0 equiv) in the presence
of Et N (0.2 equiv) in anhydrous CH Cl at room
hydride (Bu SnH) in the presence of radical initiator
3
azobisisobutyronitrile (AIBN). The resulting free radical
gets cyclized by elimination of molecular nitrogen (N ). In
2
place of Bu SnH or TMS-H, poly(methylhydrosiloxane),
3
an industrial waste can also be used as a radical reagent
[
13]. Although there are a number of addition [14],
substitution [15], elimination [16], and free radical reactions
17] available in literature for chemistry education point of
[
view which can be performed by the students in laboratory,
none of them envelopes the main concepts of organic
reactions to the benefits of undergraduate and postgraduate
students. For improving the basic concept of organic
chemistry among undergraduate students, there are only
limited studies dealing with the cyclization reactions, for
example, cyclization of the monoterpene citronellal to
isopulegol [18]. Furthermore, for introducing the concept
of the ring cleavage chemistry, a separate reaction, that is,
the electrocyclic ring opening of halocyclopropanes is
performed by students [19]. In contrast to the earlier
practiced experiments, the present scheme includes an
easy experimental demonstration of free radical reaction
for undergraduate students and embraces substitution
reaction, ring cleavage chemistry, free radical reaction,
elimination, and cyclization, all in a single reaction
protocol, which we wish to report herein.
3
2
2
temperature leads to synthesis of 1-(1-pyrrolidinyl
thioxomethyl)-1H-benzotriazole 3 in quantitative yield in
a very short span of time (10–15 min) (Scheme 1). The
resulting adduct 1-(1-pyrrolidinyl thioxomethyl)-1H-
benzotriazole 3 is highly stable and can be easily
controlled for the attack by another amine molecule. Thus,
no bi-substituted product is observed in this first step. The
structure of compound 1-(1-pyrrolidinyl thioxomethyl)-
1H-benzotriazole 3 is elucidated using extensive spectral
1
13
studies (IR, MS, H-NMR, and C-NMR).
BtRC route for the cyclization via free radical mechanism
leading to benzothiazoles.
The triazole ring of
benzotriazole moiety undergoes ring cleavage by free
radical mechanism. Moreover, the generated free radical can
Scheme 1. Synthesis
benzotriazole 3.
of
1-(1-pyrrolidinyl
thioxomethyl)-1H-
EXPERIMENTAL
Students may work alone or with lab mates. This
laboratory exercise can easily be performed in three 2- to
3-h lab sessions. Basic requirements of the reaction
setup, safety precautions, and reaction metrics are
introduced in a pre-lab session. In the first lab session, a
Scheme 2. Synthesis of 2-(pyrrolidin-1-yl)benzo[d]thiazole
4 via
15-min nucleophilic substitution reaction is carried out,
benzotriazole ring cleavage (BtRC) under conventional and microwave
irradiation (MW) route. [Color figure can be viewed at
wileyonlinelibrary.com]
and the product is isolated after an easy work-up and
column chromatographic purification (SiO ). The reaction
2
product is dried and weighed and % yield is calculated.
The product is analyzed by melting point determination
and by extensive spectroscopic techniques including
1
13
H-NMR and C-NMR and IR spectroscopy. In the
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Benzotriazole Ring Cleavage Chemistry
be cyclized again by an intramolecular attack of a free radical
site to afford another hetrocyclic moiety. This concept has
been used to synthesize 2-(pyrrolidin-1-yl)benzo[d]thiazole
thioamide bond by nucleophilic acyl substitution reaction
of pyrrolidine and bis(benzotriazolyl)methanethione, role
of AIBN and tributyl tin hydride (Bu SnH) in free radical
3
4
via free radical ring cleavage followed by cyclization of
generation, free radical opening of benzotriazole ring via
β-scission of N–N bond and ring closure by cyclative
molecular nitrogen elimination leading to formation of
benzothiazole ring.
1-(1-pyrrolidinyl thioxomethyl)-1H-benzotriazole.
Thus, a reaction of 1-(1-pyrrolidinyl thioxomethyl)-1H-
benzotriazole 3, Bu SnH (2.2 equiv), and AIBN (5 mol%)
3
in toluene as solvent at 100°C produces a biradical
via β-scission of N–N bond of benzotriazole and
affords 2-(pyrrolidin-1-yl)benzo[d]thiazole 4 via cyclative
First of all, AIBN initiates the process by the generation
of 2-cyanoprop-2-yl radical, which rapidly reacts with
•
Bu SnH producing a tin radical (Bu Sn ) [20]. This
3
3
elimination of molecular nitrogen (N ) (Scheme 2).
newly formed radical attacks on thione functionality of
thiocarbonyl and generates radical intermediate A. The
intermediate A further generates a radical intermediate B
2
This BtRC methodology shows notable compatibility
with microwave conditions. The reaction of
benzotriazolemethanethione 3 with stannanyl/silyl hydride
•
by consequently introduction of a tin radical and H .
(
2.2 equiv) and AIBN (5 mol %) in anhydrous toluene
under microwave irradiation (CEM Discover LabMate) at
00°C for 10 min affords corresponding benzothiazole 4.
Intermediate B, on benzotriazole ring opening transforms
into biradical intermediate C, which on elimination of
nitrogen molecule and subsequent attack of sulfur,
1
The reaction mixture is concentrated in vacuo, extracted
produces D [21]. Loss of molecular hydrogen (H ) from
2
with CH Cl , washed with water, and dried over
intermediate D through oxidative aromatization at the
cost of 2σ-bond to a resulted π-bond in final product
produces title benzothiazole (Scheme 4). The mechanism
of this BtRC reaction leading to benzothiazole is also
supported by density functional theory (DFT) [4b].
2
2
anhydrous Na SO . The organic layer is concentrated in
2
4
vacuo and purified by flash column chromatography
SiO ) to afford benzothiazole 4 in pure form. Spectral
(
2
data and m.p. of the isolated product 4 are matched with
the previous one obtained under conventional heating
condition. Thus, the reaction completes within 10 min
under microwave irradiation and is considered important
one for the radical cyclization.
SAFETY PRACTICE AND SUSPECTED HAZARDS
An inexpensive, biodegradable, and nontoxic
polymethylhydrosiloxane, which is a silicon industry
by-product, has been considered as a green alternative
reagent for the wide applications in organic synthesis
Protective equipments such as safety goggles, lab coat,
and gloves must be used while performing experiments.
All the reactions should be carried out using standard
laboratory safety precautions in a fume hood. Reagents,
solvents, products, and wastes must be manipulated
and dispensed in a fumehood. Bis(1-benzotriazolyl)
methanethione is harmful if swallowed; causes skin,
eye, and respiratory irritation. Triethylamine is a highly
flammable liquid. It is harmful if swallowed, in contact
with skin causes severe burns, if inhaled causes
respiratory irritation, and causes damage in contact with
eyes. Toluene is a highly flammable liquid and may
be fatal if inhaled. It causes skin irritation and may
cause drowsiness or dizziness. Chloroform-d and
dichloromethane are fatal if swallowed or inhaled, cause
skin and eye irritation, and are suspected of causing
cancer. Tributyltin hydride is a flammable liquid and toxic
if swallowed, harmful in contact with skin, causes skin
and eye irritation, and causes damage to organs through
prolonged or repeated exposure. AIBN may cause fire,
fatal if swallowed, and it is harmful to aquatic life with
long lasting effect. Silica gel causes irritation to respiratory
track and digestive track and should never be used without
mask and other safety measures. Prolonged or extensive
exposure to silica gel may cause Silicosis. Iodine vapors
cause skin and eye irritation and are corrosive in nature.
UV rays cause skin and eye irritation and are responsible
[14]. Thus, the BtRC reaction of 1-(1-pyrrolidinyl
thioxomethyl)-1H-benzotriazole 3 in the presence of
poly(methylhydrosiloxane) (2.0 equiv of weight) and
AIBN (5 mol%) in toluene as solvent at 100°C affords
2-(pyrrolidin-1-yl)benzo[d]thiazole
4
via cyclative
elimination of molecular nitrogen (N2) in almost
quantitative yield (Scheme 3). This methodology may
be considered as environmentally benign.
MECHANISM
Mechanism of the two-step synthetic route is explained
in a pre-lab session which highlights the formation of
Scheme 3. Synthesis of 2-(pyrrolidin-1-yl)benzo[d]thiazole
benzotriazole ring cleavage (BtRC) with an use of poly
methylhydrosiloxane). [Color figure can be viewed at
wileyonlinelibrary.com]
4 via
(
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. S. Singh, N. Mishra, M. S. Yadav, and V. K. Tiwari
Vol 000
Scheme 4. Reaction mechanism leading to benzothiazole from corresponding thioacyl benzotriazole derivative via cleavage of benzotriazole ring (BtRC)
under free radical condition. [Color figure can be viewed at wileyonlinelibrary.com]
for skin cancer and many ocular disorders. Ethyl acetate and
hexane are highly flammable solvents and must be kept
away from any source of heat and spark.
group, free radical reaction and mechanism of free radical
cyclative cleavage of benzotriazole ring is assessed
through pre-lab exercises completed by students. Also, it
helps students to take interest in independent consultation
of chemical literature for useful information. The
experiment was made to perform by five batches of 10
students each since last 2.5 years, and we could
successfully achieve these pedagogical goals in 80–90%
cases in each batch.
The handout provided in Supporting Information
contains information about chemicals and equipments
related to this synthetic protocol, probable hazards, and
the experimental procedures.
RESULTS AND DISCUSSION
The pedagogic goals of this experiment are mainly
focused on (1) understanding of basic protocols of organic
synthesis, discussion, and comprehension of chemical
literature for information and carrying out a chemical
synthesis task as a team work for UG and PG students; (2)
understanding of some basic concepts of organic
chemistry such as nucleophilic acyl substitution, free
radical mechanism, ring cleavage, and cyclization; (3)
understanding of feasible role and importance of some
reagents and groups in organic synthesis such as tributyl
tinhydride and AIBN for free radical reactions and
benzotriazole as good leaving group; (4) understanding
the concepts of green chemistry to know the significance
of utilization of industrial waste in organic synthesis; and
Synthesis
of
1-(1-pyrrolidinyl
thioxomethyl)-1H-
benzotriazole: a nucleophilic acyl substitution. Thin-layer
chromatography (TLC) analysis (30% ethyl acetate/n-
hexane) of the reaction mixture under UV/iodine showed
gradual disappearance of the starting material spot
(Rf = 0.7) and appearance of a new product spot
(Rf = 0.5) with time. This TLC analysis helped students to
observe consumption of starting material bis-benzotriazole
methanethione (BtCSBt, 2) and formation of the reaction
product with time. The absence in the TLC (using solvent
system, 30% ethyl acetate/hexane) of a spot from the
starting material after 15 min gives evidence that the
starting material has been consumed. After completion of
reaction, the purification of product was performed by
(
5) application of column chromatography (SiO ) for the
2
purification of developed organic compound.
To achieve these goals, the pre-lab and post-lab exercises
(
(
Supporting Information), answering questions in a handout
Supporting Information) as well as the two-step synthesis
experiment is mandatory for every student. Through the
answers given by students and the experimental results
achieved by them, the assessment of the extent of success
of our pedagogic aims can be performed. A detailed
knowledge of nucleophilic acyl substitution reaction, role,
and importance of benzotriazole moiety as a good leaving
flash chromatography (SiO ). Isolated yield of reaction
2
product was achieved by students in the range of 81–98%.
The structure of product 3 was confirmed after analysis of
1
13
H-NMR and C-NMR spectra, IR spectra, and melting
point determination.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Benzotriazole Ring Cleavage Chemistry
Free radical ring cleavage followed by cyclization. The
progress of reaction was observed by students by means
of TLC analysis (35% ethyl acetate/n-hexane) under
UV or iodine by disappearance of 1-(1-pyrrolidinyl
thioxomethyl)-1H-benzotriazole spot (Rf = 0.6) and
appearance of new benzothiazole product 4 spot (at
Rf = 0.5, 35% ethyl acetate/n-hexane). Students reported
the full consumption of starting compound after 2 h.
Toluene in reaction mass was removed using rotary
evaporator at 55°C temperature and 100-mbar pressure.
Students isolated the product in the next lab session by
flash chromatography and reported yields ranging
reaction product 3 (Step 1) simply reveals about the
appearance of supplementary signals in compound 3 at δ
4.01 and 3.86 (each t, J = 6.6 Hz) attributed to methylene
protons (2 x NCH ) in addition to two more signals at δ
2
2.10 and 1.98 each correspond for two protons (2 x
NCH CH ) that confirm about the successful conversion
2
2
of starting material 1 to its coupling product 3. Likewise,
1
appearance of signals in H-NMR of benzothiazole
product 4 in different pattern both in aromatic region
(attributed to four aryl protons) and at δ 3.53 (t,
J = 6.6 Hz, 4H) and δ 2.01 (m, 4H) attributed to eight
pyrrolidine protons (2 x CH ) was found in close
2
7
0–89%. The structure of product 4 was confirmed by
agreement about the successful conversion of compound
3 to 4 via BtRC under free radical condition (Step 2).
Thus, both the steps can be easily analyzed, and reaction
product has been well characterized by careful
1
13
students analyzing H-NMR and C-NMR spectra, IR
spectra, and melting point determination.
1
A careful comparison of the H-NMR (300 MHz,
1
CDCl ) of bis-benzotriazole methanethione (1) and its
comparison of H-NMR (CDCl3, 300 MHz) of
3
compounds 1, 3, and 4 (Fig. 1) (see Supporting
Information for the characterization of developed
compounds by extensive spectral analysis).
A brief discussion on the role of benzotriazole moiety
in organic synthesis was conducted, and most of the
students were able to properly understand the significance
of benzotriazole methodology in the synthesis of
heterocyclic compounds. The use of AIBN and tributyltin
hydride in free radical reactions and mechanism of ring
cleavage and cyclization reaction was also discussed well
with students. A discussion on mechanism of this
reaction exhibited the level of interest and analytical
approach of students. Some students proposed really
appreciating alternatives of the cyclization step using
Lewis acid instead of tributyltin hydride and AIBN.
In post-lab sessions, all the students could give correct
details of mechanistic consideration of the two reactions.
After consulting chemical literature, majority students
considered the benzotriazole moiety as an efficient,
promising, and versatile tool in organic synthesis, and
most of them understood significance of benzothiazole
1
13
synthesis. By considering the H-NMR and C-NMR
spectra of developed compounds students determined
the number of signals, multiplicity, and coupling
constants. All the students could appropriately assign the
characteristic peaks of the compounds using a chemical
shift table provided to them, and they successfully
differentiated the NMR and IR spectra of compounds 3
and 4 on the basis of characteristic peaks (Supporting
Information).
CONCLUSIONS
1
Benzotriazole methodology is a facile, inexpensive,
and promising method for the synthesis of heterocyclic.
This experiment offers an exposure for students
Figure 1. H-NMR (300 MHz, CDCl
2
com]
3
) of compound 1, coupling product
and BtRC product 4. [Color figure can be viewed at wileyonlinelibrary.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. S. Singh, N. Mishra, M. S. Yadav, and V. K. Tiwari
Vol 000
towards understanding of role of benzotriazole moiety in
synthesis of benzothiazole ring via mode of nucleophilic
acyl substitution, free radical ring cleavage, and
cyclization reactions. A group of students became aware
of role of AIBN and tributyltin hydride in free radical
reactions and understood their mechanisms. This
experiment provided an opportunity for students to learn
organic synthesis skills, ability of analytical thinking and
solving synthesis problems independently as well as by
team work.
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Acknowledgments. VKT gratefully acknowledge Science and
Engineering Research Board (SERB), New Delhi (grant no.
EMR/2016/001123) for the funding. The authors sincerely
thank CISC-Banaras Hindu University for providing
spectroscopic studies of the developed molecules. VKT thank
all his students and staff who directly or indirectly supported the
investigation on benzotriazole ring cleavage (BtRC) chemistry.
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SUPPORTING INFORMATION
[
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet