A practical method, NaOCl-mediated, to prepare thiabendazoles via intramolecular amination reaction

Article abstract of DOI:10.1016/j.tetlet.2017.07.086

A series of new chlorinated thiabendazoles (6a–m) have been synthesized from readily available anilines and 4-cyanothiazole in moderate to good yields. All synthesized compounds were fully characterized using ¹H NMR, ¹³C NMR, IR, and mass spectrometry. Additionally, the structure of the compound (6f) was confirmed by single-crystal X-ray diffraction. In addition, synthesis of 2-substituted benzimidazoles and 2-phenyl benzothiazole was investigated using our optimized conditions and the outcome is presented herein.

Full text of DOI:10.1016/j.tetlet.2017.07.086

Accepted Manuscript
A Practical Method, NaOCl-Mediated, to Prepare Thiabendazoles via Intramo-
lecular Amination Reaction
Vikrant Patil, Enrique Barragan, Shivaputra A. Patil, Siddappa A. Patil,
Alejandro Bugarin
PII:
S0040-4039(17)30944-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.086
TETL 49168
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 June 2017
15 July 2017
24 July 2017
Please cite this article as: Patil, V., Barragan, E., Patil, S.A., Patil, S.A., Bugarin, A., A Practical Method, NaOCl-
Mediated, to Prepare Thiabendazoles via Intramolecular Amination Reaction, Tetrahedron Letters (2017), doi:
http://dx.doi.org/10.1016/j.tetlet.2017.07.086
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A Practical Method, NaOCl-Mediated, to
Prepare Thiabendazoles via Intramolecular
Amination Reaction
Vikrant Patila, Enrique Barraganb, Shivaputra A. Patilc, Siddapa A. Patila*, and Alejandro Bugarinb*
aCentre for Nano & Material Sciences, Jain University, Jain Global Campus, Bangalore 562112, Karnataka,
INDIA
bDepartment of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, TX 76019, USA
cPharmaceutical Sciences Department, College of Pharmacy, Rosalind Franklin University of Medicine and
Science, 3333 Green Bay Road, North Chicago, IL 60064, USA
R1
N
Cl
H
N
R1
S
N
N
N
N
N
1. NaOCl (1.5 equiv)
2. NaH, alkyl halides
S
N
R2
NH•HCl
S
17 examples
chlorinated adducts
* Metal-free reaction conditions
* Intramolecular amination
* Easy access to thiabendazoles
N
Cl

1
Tetrahedron Letters
journal homepage: www.els evier.com
A Practical Method, NaOCl-Mediated, to Prepare Thiabendazoles via Intramolecular
Amination Reaction
Vikrant Patila, Enrique Barraganb, Shivaputra A. Patilc, Siddappa A. Patila*, Alejandro Bugarinb∗
aCentre for Nano & Material Sciences, Jain University, Jain Global Campus, Bangalore 562112, Karnataka, INDIA.
bDepartment of Chemistry & Biochemistry, University of Texas at Arlington, Arlington, TX 76019, USA.
cPharmaceutical Sciences Department, College of Pharmacy, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL
60064, USA.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A series of new chlorinated thiabendazoles (6a-m) have been synthesized from readily available
anilines and 4-cyanothiazole in moderate to good yields. All synthesized compounds were fully
characterized using 1H NMR, 13C NMR, IR, and mass spectrometry. Additionally, the structure
of the compound (6f) was confirmed by single-crystal X-ray diffraction. In addition, synthesis of
2-substituted benzimidazoles and 2-phenyl benzothiazole was investigated using our optimized
conditions and the outcome is presented herein.
Available online
Keywords:
2017 Elsevier Ltd. All rights reserved.
Thiabendazole
Bleach
Synthesis
Characterization
Single-crystal X-ray diffraction
Heterocyclic compounds are a class of cyclic molecules that
have at least two different elements in their ring system.1
Therefore, heterocycles represent what is possible the largest and
more diverse class of organic compounds.2 Heterocycles have
found many miscellaneous applications including; ligands for
transition state metals,3 organocatalysts,4 building blocks for
bioactive molecules and pharmaceuticals,5 solvents (e.g., THF,
pyridine, and dioxanes), etc.6
have synthesized thiabendazoles and study their biological
activities. For example, Meng and co-workers, in 2015, reported
the biological evaluation and synthesis of thiabendazoles via
condensation of 1,2-diaminobenezene with
a thiazole-4-
carboxaldehyde derivative.8 Another direct route towards
thiabendazoles appeared in a U.S. patent back in 1961, which
uses bleach (sodium hypochlorite).13 However, the patent lacks
reaction yields and a reliable protocol. Months later, the same
group documented a small study on the antiparasitic properties
of these compounds14 and in 1970, they reported a broader
biological spectrum.15 Furthermore, Sletzinger and co-authors
reported the synthesis of two thiabendazole derivatives utilizing
similar protocol, albeit using a stepwise procedure, in 1965.16 In
view of these statements, it was thought worthwhile to further
develop the bleach mediated synthesis of thiabendazoles, in
order to investigate it scope and limitations, while analyzing the
effects of chlorine atoms selectively placed on the final
thiabendazole adducts.
N
N
N
N
S
N
H
N
H
S
Benzimidazole
Thiazole
Thiabendazole
Figure 1. Structures of benzimidazole, thiazole, and thiabendazole
Among the vast classes of heterocyclic compounds, organic
molecules containing benzimidazole and thiazole backbones in
their structure (Figure 1) are of high importance in medicinal
chemistry, due to their large pharmacological spectrum in both
humans and animals.7 They are valuable intermediates in the
synthesis of many bioactive molecules, including thiabendazoles
(Figure 1). Benzimidazole and thiazole derivatives have
displayed a wide range of biological activities such as;
antiangiogenesis,8 anticancer,9 antifungal and antibacterial.10
Also, it has been reported that keratitis due to the fungus
Aspergillus flavus can be treated using thiabendazole.11 Across
the globe, several research groups have reported assorted
benzimidazole and thiazole derivatives as promising
Herein, a simple method is described for the synthesis of
chlorinated thiabendazoles (Tables 1 and 2). In brief, our
synthetic strategy was based on reacting substituted anilines (1a-
d) with 4-cyanothiazole (2) in the presence of dry HCl gas to
form the corresponding amidine derivative (3a-d), which were in
turn cyclized to 2-(thiazol-4-yl)-1H-benzoimidazole derivatives
(4a-d) via intramolecular amination reaction using
stoichiometric amounts of bleach (Table 1).17 In order to make
our study more meaningful, aniline 1a plus three more anilines
bearing a chlorine atom at ortho, meta, and para positions 1b-c
antimicrobial agents.10, 12 On the other hand, only a few groups
———
∗ Corresponding author. Tel.: +1-817-272-9399; fax: +1-817-272-3808; e-mail address: bugarin@uta.edu (A. Bugarin)

2
Tetrahedron Letters
were selected. All anilines afforded their expected product in
adducts, 6a and 6b, in moderate to good yields (45% and 63%,
respectively). The ortho substituted thiabendazole 4b was
reacted with six different alkyl halides to afford products 6c to
6h in moderate yields. In addition, the meta chlorinated
thiabendazole 4c was reacted with four different alkyl halides to
produce adducts 6i to 6l in moderate yields. Finally, the para
chlorinated thiabendazole 4d was reacted with benzyl chloride to
produce adducts 6m in 29% yields. The low yields for these
substitution reactions are attributed to two main factors, the
utilization of alkyl chlorides and to over-alkylation, which
formed undesired byproducts. These side products were difficult
to characterize; however, we believe they are mixtures of
ammonium salts.19 Although the yields are moderate, the
observed functional group tolerance is good. For example,
conditions tolerated halides, heterocycles, benzylic protons, and
cyano groups. Therefore, this work should generate interest in
the chemistry community for the synthesis of more complex or
further functionalized thiabendazoles.
moderate to good yields, with aniline 1c producing a lower yield
due to the presence of product 4b in the reaction mixture.
Aniline 1c afforded 40% yield of product 4c and 17% yield of
adduct 4b. Nonetheless, both adducts were easily separated by
column chromatography (Table 1).
Table 1.
Synthesis of thiabendazoles (4a-d)a
Table 2.
Alkylation of thiabendazoles (6a-m)a,b
aReaction conditions for step 1. Solvent = 1,2-dichlorobenzene, temp = 135
°C, aniline (1a-d) (49 mmol), 4-cyanothiazole (45 mmol), then dry HCl.
Step 2. Solvent: methanol/water 1:1, amidine hydrochloride (3a-d) (31
mmol), sodium carbonate (31 mmol), NaOCl (31 mmol).
bYield of purified products (average of 2-3 runs).
The observed thiabendazole adducts and reactivity suggests
that the mechanism follows an oxidative cyclization process, as
depicted on Scheme 1. First, sodium carbonate helps to
dissociate the ammonium salt and release amidine I, which in
turn reacts with sodium hypochlorite to form N-chloro
carboximidamide II. Then, this intermediate undergoes a 5-exo-
tet cyclization to afford intermediate III that quickly re-
aromatizes in the presence of base, to produce thiabendazole
4a.18 This represents a metal-free intramolecular amination
reaction. Although, our mechanistic interpretation proposes two-
electron sequences, a radical pathway it is also plausible.
However, further studies, to be published later, will help to
support or refuse this hypothesis.
aReaction conditions: solvent = DMF, temp = 25 °C, ratios: 2-(thiazol-4-yl)-
1H-benzoimidazole (2.5 mmol)/ alkyl halide (2.7 mmol) / sodium hydride
(3.0 mmol).
bYield of purified products (average of 2-3 runs).
Scheme 1. Proposed mechanism
The structures of all synthesized thiabendazoles (6a-m) were
1
confirmed by H NMR, 13C NMR, IR and mass spectrometry
With the four different thiabendazoles (4a-d) on hand, we
proceeded to investigate the scope of these thiabendazoles under
alkylation conditions. The outcome is reported in Table 2. For
thiabendazole 4a, two alkyl halides were employed, a pyridine
and bisphenyl derivatives, both affording their respective
techniques. All 1H NMR spectra of the chlorinated
thiabendazoles (6a-m) present a singlet peak in the range 6.03-
6.22 ppm assigned to the methylene (CH2) protons of benzyl
moiety attached to the benzimidazole nitrogen atom. This
indicated a successful alkylation reaction. Likewise, 13C NMR

3
spectra of all thiabendazoles (6a-m) revealed the presence of
peaks in the range δ = 45.74-49.15 ppm attributed to the
methylene (CH2) carbon atom. Conversely, the IR spectra of all
chlorinated thiabendazoles (6a-m) displayed a strong absorption
band around 1304–1573 cm-1, correspond to the ν(C=N) stretching
vibrations and a sharp band of medium intensity at 2923–3126
cm–1, attributed to the aromatic ν(C–H) stretching vibrations.
Furthermore, the results obtained from the mass spectrometry are
in good agreement with the proposed structures of the
chlorinated thiabendazoles (6a-m).
the aliphatic nitrile (n-butyronitrile) was employed as starting
material.23 To complete this study, the synthesis of 2-phenyl
benzothiazole24 8f was attempted using benzonitrile and
thiophenol. Unfortunately, not even the phenyl benzimidothioate
salt of step 1 was observed (Table 3).
Table 3.
Approach towards benzimidazoles and a benzothiazolea
In addition, single crystals of compound (6f) suitable for X-
ray diffraction analysis were obtained by slow evaporation in
chloroform. A perspective view of compound (6f) is depicted in
Figure 2. Compound (6f) crystallized in the monoclinic space
group P 21/n with four motifs in a unit cell. Crystal structure of
compound (6f) revealed that the molecule is co-planar in nature.
The crystals of compound (6f) do not have any organic solvent
molecules or lattice held water molecules in the unit cell of the
determined structure. The C-C bond distances in phenyl ring are
in the normal range of 1.35 – 1.48 Å, which is characteristic of
delocalized aromatic rings. The C-C-C bond angles in phenyl
°
ring are close to 120 , it suggests that carbon atoms are sp2
aReaction conditions for step 1. Solvent = 1,2-dichlorobenzene, temp = 135
°C, aniline (1a) (49 mmol), nitrile (7) (45 mmol), then dry HCl. Step 2.
Solvent: methanol/water 1:1, all amidine hydrochloride obtained (1
equiv), sodium carbonate (1 equiv), NaOCl (1 equiv).
hybridized. The compound (6f) lies in three planes with plane I
[C(1) C(2) C(3) C(4) C(20) C(21) C(5) Cl(1) N(1) C(14) N(2)
C(22) N(4) C(23) Cl(24) and S(1)] making a dihedral angle of
75.59° and 60.92°with plane II [C(6) C(7) C(8) C(9) C(16) and
C(15)], and plane III [N(3) C(19) C(18) C(10) C(17) C(13)
C(12), and C(11)], whereas the plane II forms a dihedral angle of
47.00° with plane III. The molecular packing diagram shows
four layers of molecules, which are independently arranged in
the unit cell. In each layer, the molecules are alternatively
parallel. The molecular packing diagram did not show
involvement of intramolecular or intermolecular hydrogen
bonding. Hence, molecules forming each layer are not connected
through intermolecular hydrogen bonding.
bYield of product calculated by 1H and 13C NMR.
cThiophenol was used instead of aniline.
In conclusion, we have developed
a
simple and
complementary method for the synthesis of several
miscellaneous thiabendazoles from inexpensive starting
materials and reagents. The significant advantages of this
methodology are simplicity of operation, cost effectiveness, easy
availability of starting materials and metal-free condition, with
moderate to good yields of products. Hence, this approach is an
attractive method for the synthesis of different types of
substituted thiabendazoles for both academia and industrial
settings. Regrettably, the reported conditions are not compatible
with other aromatic or aliphatic nitriles, as well as, thiophenol.
Acknowledgements
The University of Texas at Arlington and the UTA Research
Enhancement Program, partially financed this project. The
authors also acknowledge Dr. Delphine Gout for X-ray data
collection and the NSF grants (CHE-0234811 and CHE-
0840509) for additional instrumentation. The authors also thank
DST-Nanomission, India (SR/NM/NS-20/2014), DST-SERB,
India (SERB/F/7013/2015-16) and Jain University, India for
financial support. Antimicrobial screening was performed by
CO-ADD (The Community for Antimicrobial Drug Discovery),
funded by the Wellcome Trust (UK) and The University of
Queensland (Australia).
Figure 2. ORTEP representation of the X-ray crystal structure of 6f
showing atom labeling. 50% probability amplitude displacement ellipsoids
are shown.20
Having optimized the reaction conditions for the synthesis
of chlorinated thiabendazoles (Tables 1 and 2). It was suggested
that other aromatic and aliphatic nitriles should be compatible to
the reaction conditions (Table 3). In order to support of refuse
this hypothesis, we first reacted aniline 1a and benzonitrile 7a
under the standard reaction conditions. We were surprise to
observe only traces of the final 2-phenyl benzimidazole 8a21
adduct. However, we decided to continue our study using other
aromatic nitriles, both electron-rich and electron-poor. The
electron-rich 4-methoxybenzonitrile substrate afforded the
expected product 8d,21 albeit in only 10% yield. For the electron-
poor (4-CF3, 4-NO2) benzonitriles, only traces were observed
again.22 Unfortunately, the same outcome was experienced when
Supplementary Material
Supplementary data [experimental procedures, H, 13C NMR
data of all the compounds (6a-m), crystallographic data for (6f),
and bioassays details] associated with this article can be found,
in the online version, at http://
1
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17. General procedure for the synthesis of thiabendazoles (4a-d): To a
solution of 4-cyanothiazole (5.0 g, 45.0 mmol) in o-dichlorobenzene
(40.0 mL) was added the respective aniline (1a-d) (49.0 mmol). The
reaction mixture was heated at 135 °C with purging excess dry HCl for
3 h. Then, cooled the reaction mixture to 40 °C and the resulting solids
were filtered, washed with more o-dichlorobenzene (10.0 mL). The
solids were dried at 90 °C under vacuum to give amidine
hydrochlorides adducts. Then, to (31.0 mmol) of amidine hydrochloride
in water (35.0 mL) was added methanol (35.0 mL) at room
temperature. Cooled the reaction mixture to 0-5 °C, added sodium
carbonate (3.4 g, 31.0 mmol) and stirred the reaction mixture for 20
minutes. To the reaction mixture was added NaOCl (31.0 mmol, 12%
w/v) (1.9 mL) at 5-10 °C. Then, the reaction mixture was heated to 60-
65 °C and stirred for 2 h. Water (25.0 mL) was added to the reaction
mixture and extracted with EtOAc (100 mL). The organic layer was
concentrated under reduce pressure to get crude thiabendazoles.
Finally, the crude compounds were purified by column chromatography
using 9:1 DCM/EtOAc, affording pure thiabendazoles (4a-d).
18. Baldwin, J. E. J. Chem. Soc., Chem. Commun .1976, 734-736.
19. Addition of NaI or use of alkyl bromides resulted on similar yields due
to over-alkylation adducts.

5
A Practical Method, NaOCl-Mediated,
to Prepare Thiabendazoles via
Intramolecular Amination Reaction
Vikrant Patila, Enrique Barraganb, Shivaputra A.
Patilc, Siddappa A. Patila*, Alejandro Bugarinb
HIGHLIGHTS:
1. A practical method for the synthesize
several thiabendazole derivatives
2. A metal-free protocol is documented
3. Good functional group tolerance
4. Easy access to structurally complex
heterocyles
5. Fully characterized adducts are reported