β-CD/CuI catalyzed regioselective synthesis of iodo substituted 1,2,3-triazoles, imidazo[1,2-a]-pyridines and benzoimidazo[2,1-b]thiazoles in water and their functionalization

Article abstract of DOI:10.1016/j.tet.2017.05.081

An environment benign process has been developed for the regioselective synthesis of 5-iodo-1,4-disubstituted-1,2,3-triazoles catalyzed by CuI/β-CD in water. Moreover, the process was manifested for the efficient synthesis of 2-iodo-imidazo[1,2-a]pyridine

Full text of DOI:10.1016/j.tet.2017.05.081

Accepted Manuscript
β-CD/CuI catalyzed regioselective synthesis of iodo substituted 1,2,3-triazoles,
imidazo[1,2-a]-pyridines and benzoimidazo[2,1-b]thiazoles in water and their
functionalization
Divya Dheer, Ravindra K. Rawal, Virender Singh, P.L. Sangwan, Parthasarathi Das,
Ravi Shankar
PII:
S0040-4020(17)30590-2
10.1016/j.tet.2017.05.081
TET 28747
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 18 March 2017
Revised Date: 25 May 2017
Accepted Date: 26 May 2017
Please cite this article as: Dheer D, Rawal RK, Singh V, Sangwan PL, Das P, Shankar R, β-CD/CuI
catalyzed regioselective synthesis of iodo substituted 1,2,3-triazoles, imidazo[1,2-a]-pyridines and
benzoimidazo[2,1-b]thiazoles in water and their functionalization, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.05.081.
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β-CD/CuI catalyzed regioselective synthesis
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of iodo substituted 1,2,3-triazoles, imidazo[1,
2-a]-pyridines
b]thiazoles
and
benzoimidazo[2,1-
and their
in
water
functionalization
Divya Dheer, Ravindra K. Rawal, Virender Singh, P. L. Sangwan, Parthasarathi Das and Ravi Shankar

1
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Tetrahedron
journal homepage: www.elsevier.com
β-CD/CuI catalyzed regioselective synthesis of iodo substituted 1,2,3-triazoles,
imidazo[1,2-a]-pyridines and benzoimidazo[2,1-b]thiazoles in water and their
functionalization
Divya Dheer,a,b Ravindra K. Rawal,c,* Virender Singh,d P. L. Sangwan,a Parthasarathi Dasa and Ravi
a,b,
Shankar
*
aBio-Organic Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Jammu 180001, India. E-mail: rshankar@iiim.ac.in
bAcademy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India.
CDepartment of Pharmaceutical Chemistry, Indo-Soviet Friendship College of Pharmacy (ISFCP), Moga-142002, India.E-mail: rawal.ravindra@gmail.com
dDepartment of Chemistry, National Institute of Technology (NIT) Jalandhar, 144011, Punjab, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An environment benign process has been developed for the regioselective synthesis of 5-iodo-
1,4-disubstituted-1,2,3-triazoles catalyzed by CuI/β-CD in water. Moreover, the process was
manifested for the efficient synthesis of 2-iodo-imidazo[1,2-a]pyridines and 2-iodo-
benzoimidazo[2,1-b]thiazoles in aqueous medium. Additionally, the iodinated derivatives were
successfully modified via palladium catalyzed coupling reactions. The salient features of this
methodology are in-situ formation of 1-iodoalkyne & alkyl/aryl azide under mild reaction
conditions, high regio-selectivity and use of water as a greener solvent.
Available online
Keywords:
β-Cyclodextrin
Iodo-imidazo[1,2-a]pyridines
Iodo-triazoles
2009 Elsevier Ltd. All rights reserved
.
Iodo-benzoimidazo[2,1-b]thiazoles
1. Introduction
potent scaffold to discover bioactive compounds and drug
intermediates.5
Halogenated aromatic compounds embrace a major class of
building blocks for the synthesis of heterocycles and
employed as active pharmaceutical ingredients (APIs). Due
to the versatility of the C−X group, these participate in a
variety of functionalization reactions,1 especially cross-
coupling reactions.2
Scheme 1: Selective approach for the synthesis of iodo
Figure 1: Heterocyclic compound based Drugs and bioactive
molecules
substituted 1,2,3-triazoles, imidazo[1, 2-
a
]-pyridines and
benzoimidazo[2,1- ]thiazoles
b
The 1,2,3-triazole moiety bears an integral part of many
modified nucleosides as well as carbanucleosides with
antiviral, anti-HIV or cytostatic activities.3 Nevertheless, a
large number of 1,2,3- triazoles exhibit various
pharmacological properties e.g. antitubercular, antibacterial,
antifungal and anticancer.4 1,2,3-Triazole skeleton act as a
Similarly,
benzoimidazo[2,1-
exploited for several biological therapeutics such as
antiviral, antibacterial and anti-inflammatory (Figure 1).6,7
It was found that several efforts have been made for the
synthesis of 5-iodo-1,2,3-triazoles and 2-iodo-imidazo[1,2-
a
number of imidazo[1,2-
a
]pyridines and
b]thiazoles derived analogues have been

2
Tetrahedron
11d
CuI + β-CD
H2O
I2
60
30
a
]pyridines. Recently, iodotriazoles have been synthesized
ACCEPTED MANUSCRIPT
12
13
14
CuI + β-CD
CuI + β-CD
β-CD
H2O
H2O
H2O
NIS
NBS
I2
20
20
n.o.
50
60
n.o.
by copper(I)-catalyzed cycloaddition of organic azides with
terminal alkynes in the presence of an electrophilic
iodinating agent or cycloaddition with 1-iodoalkyne
15
16
CuI + β-CD
CuI + β-CD
H2O
-
n.o.
n.o.
70
60
(Scheme 1), as
a
passionate area of research.8-12
EtOH
I2
Correspondingly, water is an attractive reaction medium for
researchers nowadays because it’s not only economical and
environmental friendly, but also shows unique reactivity. Even
one of the principles of green chemistry promotes the idea of
using water as a safer and environmentally benign solvent.
Several recent reports have demonstrated water as a precise
solvent and a suitable reaction media.13 Nevertheless, the use of
water as a reaction medium is a great challenge for synthetic
organic chemists being the less solubility of organic compounds
17
CuI + β-CD
DMSO
I2
30
40
[a]Reaction conditions: Phenylacetylene (1.0 mmol), benzyl
bromide (1.0 mmol), sodium azide (2.0 mmol), iodine source
(1.5 mmol), catalyst (10 mol%), solvent (5 mL), open flask, 90
oC, 2-4 h. bβ-CD (1.0 mol%) was also used. Iodine : 1.0 mmol.
c
dIodine (2.0 mmol). eIsolated yields. *n.o. : not observed.
1,4-disubstituted-1,2,3-triazoles (4a) as the minor product
(Table 1, entry 1).The spectroscopic data revealed the structure of
products as (3a) and (4a) which was in accordance with the
literature reports.16-17 Infact, same reaction when carried out at
room temperature, yielded no product. Subsequently, a number
of catalysts such as Cu(OAc)2, CuSO4.5H2O, Cu(OTf)2, CuI,
CuBr2 and CuCl were investigated in the presence of 1.5 mmol of
I2 in acetonitrile (Table 1, entries 2-7), but CuI was found most
suitable catalyst in terms of yield (Table 1, entry 5). With the
objective to develop a greener method, a number of experiments
were performed using water as the reaction medium under
different conditions (Table 1, entries 8-15).When water was used
as a solvent instead of acetonitrile, only 20% conversion was
observed (Table 1, entry 8). β-CD are known to provide water-
soluble medium for organic materials by making complexation
with organic compounds, therefore it has appeared an effective
method for enhancing dissolution properties of poorly soluble
organic materials.14 Owing to the mentioned properties of β-CD,
it was envisaged to explore it as a phase transfer catalyst for the
designed organic synthesis (Table 1, entries 9-17). Expectedly,
when the reaction was executed in the presence of β-CD (1.0 mol
%), 3a was obtained in 79% yield with 4a (13%) within 2 h. The
optimization of I2 loading revealed that 1.5 mmol of iodine
produced the best yield of the desired product (Table, entries 9-
11). These reactions when observed at room temperature yielded
only without iodo-product with unconsumed iodo-
phenylacetylene, i.e., 4a (80%). Other source of iodine like NIS
was also examined for this transformation (Table 1, entry 12),
however, molecular I2 provided better results. Similarly, NBS
also furnished the desired product in lower yield (Table 1, entry
13). In order to confirm the role of CuI and I2, control
experiments were performed without CuI and I2 (Table 1, entries
14-15), formation of desired product was not observed. The
reactions were also carried out in ethanol and DMSO (Table 1,
entries 16-17), however, satisfactory results were not obtained.
in water. Shin et al also showed an example of β-CD/copper-
catalyzed azide-alkyne cycloaddition to form 1,4-disubstituted-
1,2,3-triazoles, according to above studies, the reduced amount of
β-CD, yielded products upto 97% compared to α- and γ- CD.14
Apart from above, β-CD is the cheapest and readily used catalyst
in many other applications. Thus, based on the findings, we
herein reported CuI/ β-CD-catalyzed regioselective synthesis of
5-iodo-1,2,3-triazoles,
2-iodoimidazopyridines,
and
2-
iodobenzoimidazothiazoles in water. This multi-component
reaction forms iodoalkynes in situ and undergoes cycloaddition
under relatively mild conditions. The supplementary advantages
of the method are simplicity of the operation, high yields, good
substrate generality and applicability of water as a greener
solvent.
2. Results and Discussion
As a part of our continuing interest15 in the improvement of the
practicability and eco-friendliness synthesis of important APIs,
we report herein a simple, eco-friendly, multi-component one pot
approach for the synthesis of 5-iodo-1,4-disubstituted-1,2,3-
triazoles from aryl/alkyl halides, terminal alkynes, I2 and NaN3 in
water, via in-situ formation of 1-iodoalkyne and alkyl azide/aryl
azide which are catalyzed by CuI/β-CD. Additionally, β-CD
could be easily recovered from the reaction mixture by simple
filtration and also avoids the drawbacks of using a special
halogenating reagent for the synthesis of 1-haloalkyne and
tedious workup procedures. To the best of our knowledge, there
is no report for the one-pot synthesis of 5-iodo-1,4-disubstituted-
1,2,3-triazoles, 2-iodo-imidazo[1,2-a]pyridines and 2-iodo-
benzoimidazo[2,1-b]thiazoles derivatives in water. The
optimization of reaction was initiated with phenylacetylene (1a),
benzyl bromide (2a) and sodium iodide, by using copper(II)
perchlorate, and DMAP in CH3CN at 90 oC in open air condition
(Table 1, entry 1) and the desired product, 5-iodo-1,4-
disubstituted-1,2,3-triazoles (3a) was obtained in 57% yield with
According to literature the formation of 5-H-triazoles are not
exceptional, under optimized condition we also observed such
by-products, 5-H-triazoles (4a) as the minor compound.8,18 To
verify the same, two controlled reactions were performed where
in first experiment, benzyl bromide, terminal alkyne, NaN3 and I2
were mixed in water without any time gap in the presence of
CuI/β-CD. It was found that 5-H-triazole (4a) was the major
product that may be formed from terminal alkyne which was not
completely transformed into 1-iodoalkyne. To confirm this
Table 1: Optimization of the reaction condition for synthesis of 5-
Iodo-1,2,3-triazoles[a]
Br
I
2a
Conditions
N
N
N
N
+
+
N
N
1a
NaN3
3a
(Major)
4a
(Minor)
Entry
Catalyst
Solvent
Iodine
(%)Yielde
source
3a
57
50
4a
hypothesis,
another
reaction
was
employed
where
1a
2a
Cu(ClO4)2
Cu(OAc)2
CH3CN
CH3CN
NaI
I2
25
10
phenylacetylene and I2 were stirred in water in the presence of
CuI/β-CD for 30 min and then confirmed the formation of 1-
iodophenylacetylene by TLC analysis. After that benzyl bromide
and sodium azide were added in the same flask and the reaction
temperature was raised up to 90 oC. According to literature, β-CD
has indigent water solubility at room temperature but when used
1.0 mol%, it became fully soluble along with raising reaction
temperature. Expectedly, 5-iodo-1,2,3-triazoles was yielded as
3a
CuSO4.5H2O
CH3CN
I2
54
29
4a
Cu(OTf)2
CuI
CH3CN
CH3CN
I2
I2
33
80
60
10
5a
6a
7a
8a
CuBr2
CuCl
CuI
CH3CN
CH3CN
H2O
I2
I2
I2
n.o.*
n.o.
n.o.
30
30
20
9b
CuI + β-CD
CuI + β-CD
H2O
I2
79
13
10c
H2O
I2
60
20

3
major compound and this controlled experiment suggested the in-
situ formation of iodoalkyne (Scheme 2).
Scheme 2: Control experiments
substituted-1,2,3-triazole (3b, 78%) as a major compound with
ACCEPTED MANUSCRIPT
1,2,3-triazole (4b, 12%) in minor quantity. Also, pyridine
substituent’s revealed poor conversions (3o, 0%) as well as (4o
0%). Standardized method was also demonstrated with 1-butyn-
3-ol (3p, 76%) and ester (3q, 73%) to explore method’s
applicability.
Recently, we reviewed the pharmacology and synthetic
advancement of imidazo[1,2-a]pyridine14h-i derivatives which
revealed that this framework display an array of biological
properties such as anticancer, antiviral, antibacterial and anti-
inflammatory2 e.g. alpidem,3 zolpidem,4 necopidem and
saripidem (Figure 1). Therefore, it was envisaged to expand the
scope of the present methodology for the synthesis of
imidazo[1,2-a]pyridine derivatives by using 2-aminopyridine (5)
as the precursor in replace of alkyl/aryl halide/azide (Table 3).
Accordingly, 2-aminopyridines were reacted with substituted
acetylenes (CuI/β-CD in presence of 1.5 equiv of I2 in acetonitrile
at 90 oC. It was pleasing that all the substrates responded
positively to the previously optimized conditions and the
designed 2-iodoimidazo[1,2-a]pyridine derivatives (6a-6i) were
obtained in 65%-85% yields (Table 3).
The scope of the reaction was explored by using substituted
benzyl bromides and acetylenes (involving 10 mol% of CuI and
1.5 mmol of I2 and β-CD in water at 90 oC. The desired products,
5-iodo-1,4-disubstituted-1,2,3-triazoles (3a-3n, Scheme 3) were
obtained in major quantity with 1,4-disubstituted-1,2,3-triazoles
as a minor product (4a-4n, Table 2). In general, substituted
phenylacetylene reacted smoothly with in-situ synthesized benzyl
azide to furnish the triazole derivatives (3a-3j) in 64-86% yield.
It was observed that aliphatic halides were moderately reactive as
compared to benzyl halides which furnished the products (3k-3n)
in moderate to lower yields (64%-66%).
Table 3: Synthesis of 2-iodoimidazo[1,2-a]pyridinesb
Table 2: Synthesis of 5-iodo-1,4-disubstituted-1,2,3-triazolesa
b
Reaction Conditions: Aminopyridine
5
(1.0 mmol),
Phenylacetylene 1 (1.0 mmol), Iodine (1.5 mmol), CuI (10 mol%), β
-CD (1.0 mol%), Water, 90 oC , 2-4 h.
Apart from this, a wide range of compounds possessing
benzo[d]imidazo-[2,1-b]thiazole scaffold have been well
exploited in many biological activities,19 thus development of
new synthetic routes for such heterocyclic moieties has been an
intense area of research.20 To our gratification, the current
optimized method was examined for the synthesis of 2-
iodobenzoimidazo-thiazole derivatives. Recently, Hajra group
disclosed a Cu(OAc)2·H2O (10 mol%) catalyzed synthesis of 2-
halobenzo-imidazothiazole derivatives using 1,2-dichlorobenzene
as the reaction medium. Fortunately, 2-aminobenzothiazoles
reacted well under the present reaction conditions to afford the
corresponding 2-iodobenzo[d]imidazo[2,1-b]thiazoles derivatives
in good yields after 2-4 h (8a-c). The structure of 2-
iodobenzo[d]imidazo[2,1-b]thiazole (8a) was confirmed by
evaluation with reported data.21
a
Reaction conditions: Phenylacetylene 1 (1.0 mmol), Aryl/alkyl
halide 2 (1.0 mmol), NaN3 (2.0 mmol), CuI (10 mol%), β-CD (1.0
mol%), I2 (1.5 mmol), Water (5 mL), 90 oC, 2-4 h. n.f. : not found
Table 4: Synthesis of 2-iodobenzoimidazo[2,1-b]thiazolesc
However, in substituted benzyl halides we didn’t observe a major
effect on yield. Similarly, phenylacetylene with an electron
donating group reacted better at a faster rate to yield the halo-

4
Tetrahedron
iodophenylacetylene formed two hydrogen bond (2.61 and 1.93
ACCEPTED MANUSCRIPT
Å) with the water molecules present within the cavity of β-CD
hydrate and with the -CH2OH group located near the wider side
(secondary hydroxy rim) (Figure 3). The benzyl azide formed
two hydrogen bonds (1.62 and 2.12 Å) similarly as in the case of
1-iodophenylacetylene, one with the water molecules present
within the cavity of β-CD hydrate and other with the -CH2OH
group located on the periphery of the β-CD (Figure 4). Whereas
2-aminopyridine formed five hydrogen bonds (1.62, 1.83, 2.06,
2.81 and 2.83 Å) with the water molecules and with the -CH2OH
group present on the periphery of the cavity of β-CD hydrate
(Figure 5). Pyridine ring nitrogen formed two hydrogen bonds
(1.62 and 1.83Å) with water molecule present within the cavity
of β-CD hydrate whereas 2-amino group formed three hydrogen
bonds (2.06, 2.81 and 2.83 Å), two hydrogen bonds formed with
the peripheral -CH2OH group of β-CD and one with water
molecule present within the β-CD cavity. Hydrogen bonding of
the –NH2 group of 2-aminopyridine and azide group of benzyl
azide with the peripheral –CH2OH and water molecules inside
the cavity of β-CD hydrate as a consequence of inclusion might
cReaction Conditions: Aminobenzothiazole
7
(1.0 mmol),
Phenylacetylene 1 (1.0 mmol), Iodine (1.5 mmol), CuI (10 mol%), β-
CD (1.0 mol%), Water, 90 oC , 2-4 h.
Next, we investigated the role of β-CD in the reaction with the
1
help of H NMR. Accordingly, the NMR spectrum of β-CD was
recorded in the presence and absence of starting materials.
Unfortunately, the starting materials were not soluble in water
without β-CD in order to understand if they are encapsulated by
β-CD or not. The NMR spectrum (500 MHz, D2O) of the β-CD–
increase their nucleophilic property. As
a consequence,
nucleophilic attacks by benzyl azide and 2-aminopyridine with 1-
iodophenylacetylene are facilitated. On the basis of the
aforementioned experimental findings, the vital presence of β-CD
hydrate for the above mentioned chemical transformation is fairly
evident.
benzyl azide complex, β-CD-2-aminopyridine mixtures, and free
14
β-CD 22 are depicted in Figure 2
.
Figure 3: The most stable complex of 1-iodophenylacetylene docked
into the β-CD cavity
Figure 2: Comparative 1H NMR spectra of i) β-CD-benzyl
azide complex and ii) β-CD–2-aminopyridine mixtures iii) pure
β-CD showing β-CD regions
Figure 4: The most stable complex of benzyl azide docked into the
β-CD cavity
Upfield shifts of H-3 (0.08 ppm, 0.02 ppm) and H-5 (0.13, 0.09
ppm) protons of β-cyclodextrin in the β-CD–2-aminopyridine
mixtures and β-CD-1-benzyl azide were observed compared to
the spectrum of free β-CD (H-6 & H-3 were merged). These
shifts indicate that the benzyl azide and 2-aminopyridine are
ideally encapsulated in the β-CD cavity. Thus, it is suggested that
there action is accelerated and eventually the activation of
starting materials during the reaction.
The cavity of β-CD is hydrated due to the presence of water
molecules inside the cavity. It was hypothesized that the
hydrogen bonding interaction between the water and guest
molecules might assist the formation of inclusion complex within
the host cavity. From the molecular docking experiments (PDB
ID: BCD), it was observed that 1-iodophenylacetylene, benzyl
azide and 2-aminopyridine (5) had different affinity to β-CD
hydrate with a preferred orientation of the ligands inside its
cavity: Benzyl azide and 2-aminopyridine were more included
than 1-iodophenylacetylene within the β-CD cavity. The 1-
Figure 5: The most stable complex of 2-aminopyridine docked into
the β-CD cavity
Halogenated aromatics are known to convert into the
corresponding aryl, alkenyl or alkynyl group under cross-
coupling condition. To investigate the scope of the coupling
reactions, we further functionalized 5-Iodo-1,2,3-triazoles and 2-
iodo-imidazo[1,2-a]pyridines in some important analogues (9,
10, 11, 12, 13 and 14) respectively in excellent yields through
Suzuki,23 Heck,24 and Sonogashira25 reaction (Scheme 3).

5
Scheme 3: Synthetic utility of the 5-Iodo-1,2,3-triazoles and 2-
iodobenzoimidazo[2,1-b]thiazoles
substituted terminal alkyne and produced 1-iodoalkyne complex
ACCEPTED MANUSCRIPT
(b) Cu(I) phenylethyne (a) as shown scheme 4. The
cycloaddition between terminal alkyne and azide complex
afforde iodotriazole(3a) via copper(I) triazole(d) intermediate.
3. Conclusions
In summary, we have developed an, environmental friendly
process for the synthesis of 5-iodo-triazoles, 2-iodo-imidazo[1, 2-
a]pyridines and 2-iodobenzoimidazo[2,1-b]thiazoles catalyzed by
CuI/β-CD in aqueous medium. The salient features of this
methodology are in-situ formation of 1-iodoalkyne, alkyl/aryl
azide in mild reaction conditions and high regioselectivity by
using water as a greener .Finally the scope of iodo substrate were
successfully extend with palladium catalyzed coupling
methodologies. In addition, molecular docking and 1H NMR
studies was performed to demonstrate the role of β-CD in
developed method.
4. Experimental Section
4.1 General Information
1H and 13C NMR spectra in CDCl3 were recorded on Bruker
Avance III-400 MHz, using (CH3)4Si as an internal standard.
Chemical shifts (δ) are expressed in parts per million referenced
to the residual solvent (i.e., 1H 7.24 ppm, 13C 77.1 ppm for
1
Based on experimental and literature evidence studies,26 we
proposed a plausible mechanism for the β-CD/CuI-catalyzed
synthesis of 5-iodo-1,2,3-triazoles and 2-iodo-imidazo[1,2-a]-
pyridine in H2O via β-CD/CuI promoted oxidative cyclization as
displayed in Scheme 4.
CDCl3; H 3.35, 4.78 ppm). Signal multiplicity is expressed as
follows: s (singlet), br s (broad singlet), d (doublet), t (triplet), q
(quartet), m (multiplet). J values are given in hertz (Hz). For the
HRMS measurement, Q-TOF, Agilent Technologies 6540
instrument was used and IR was recorded on FT-IR Bruker (270-
30) spectrophotometer. All reactions and purity of the
synthesized compounds were monitored by TLC using silica gel
60 F254 aluminium plates. Visualization was accomplished by
UV light, exposure to iodine vapours and by treating the plates
with dragendorff reagent followed by heating. Unless otherwise
indicated, materials and solvents were purchased and used
without further purification.
Scheme 4: Proposed Mechanism for β-CD/CuI-catalyzed synthesis
of 5-Iodo-1,2,3-triazoles and 2-iodo-imidazo[1, 2-a]-pyridines
4.2 General Procedure for the synthesis of 1,4-
disubstituted-1,2,3-triazoles (3a-3n
& 4a-4n):
A suspension of phenylacetylene (50 mg, 1.0 mmol) and
1
iodine (124 mg, 1.5 mmol) was added to a mixture of CuI
(10 mol %) and β–cyclodextrin (1.0 mol %) dissolved in
water (5 mL) and stirred for 30 min at room temperature. A
red homogeneous solution was formed, which confirmed the
formation of 1-iodophenylacetylene as revealed by TLC
analysis. Thereafter, benzyl bromide
2 (84 mg, 1.0 mmol)
and sodium azide (64 mg, 2.0 mmol) were added to the
reaction mixture and reaction temperature raised up to 90 oC
for 4 h. After completion of reaction as monitored by TLC,
the reaction mixture was diluted with water (20 mL). The
aqueous solution was extracted with EtOAc (3 x 10 mL) and
combined organic layer was washed with saturated Na2S2O3
solution, dried over anhydrous Na2SO4, and evaporated in
vacuum. The residue was purified by column
chromatography using (10% EtOAc: petroleum ether) to
afford the desired product.
The catalytic activity of β-CD for these reactions, initially,
activate the formation of complexation of substituted terminal
alkyne with β–CD/CuI/I2 gives crude adduct 1-iodoalkynes (b)
via Cu(I) phenylethyne (a). Oxidative addition of haloalkyne
leads to a Cu-chelated (e) complex generating a Cu(III) complex
(f), which undergoes reductive elimination of Cu(III) to Cu(I) to
provide desired cyclised compound (6a) in water. Though
cyclodextrins are known to form inclusion complexes with aryl
halides, in the present study it is postulated that bulk of the
reaction takes place inside the β-CD cavity that increases the
capability for water solubility and reaction in water. The
iodotriazole (3a) formation start from complexation of
1-Benzyl-5-iodo-4-phenyl-1H-1,2,3-triazole (3a
)
The compound 3a was prepared according to the general
procedure starting from phenylacetylene (50 mg, 1.0 equiv);
Yield: 79% (140 mg); Rf (10% EtOAc: petroleum ether) 0.46;
IR (KBr, cm-1): 2957, 2851, 2920, 1606, 1433, 1446, 1230,
1
1079, 1024, 987, 725; H NMR (400 MHz, CDCl3) δ 7.87
(d,
J = 8.4 Hz, 2H), 7.40-7.36 (m, 2H), 7.28-7.26 (m, 6H),

6
Tetrahedron
ACCEPTED MANUSCRIPT
5.60 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 150.23 (C),
(C), 137.77 (C), 134.56 (C), 129.14 (2CH), 128.79 (CH),
134.30(C), 130.21 (C), 128.94 (2CH), 128.63 (CH), 128.56
(2CH), 128.52 (CH), 127.83 (2CH), 127.46 (2CH), 76.45
(C), 54.42 (CH2); HRMS [ESI]: m/z calculated for C15H12IN3
[M+H]+ 362.0109, found: 362.0129.
128.45 (2CH), 128.16 (2CH), 127.95 (2CH), 127.80 (CH),
122.46 (CH), 72.62 (CH2), 63.73 (CH2), 54.19 (CH2);
HRMS [ESI]: m/z calculated for C17H17N3O [M+H]+
280.1405, found: 280.1435.
4.2.1
1-Benzyl-4-phenyl-1H-1,2,3-triazole(4a
)
4.2.6
1-(4-Bromobenzyl)-5-iodo-4-phenyl-1H-1,2,3-
triazole (3d
)
The compound 4a was prepared by the same procedure as
described for 3a; Yield: 13% (30 mg); Rf (10% EtOAc:
petroleum ether) 0.34; IR (KBr, cm-1): 3129, 3051, 2950,
The compound 3d was prepared according to the general
procedure starting from phenylacetylene (50 mg, 1.0 equiv)
and 4-bromobenzyl bromide (120 mg, 1.0 equiv); Yield:
72% (155 mg); Rf (10% EtOAc: petroleum ether) 0.41; IR
(KBr, cm-1): 2921, 2851, 2350, 1446, 1227, 1065, 1010,
1
2271, 1463, 1223, 1075, 1050; H NMR (400 MHz, CDCl3)
δ 7.81 – 7.78 (m, 2H), 7.66 (s, 1H), 7.41-7.36 (m, 5H), 7.33-
7.30(m, 3H), 5.57 (s, 2H); 13C NMR (101 MHz, CDCl3) δ
148.26 (C), 134.72 (C), 130.58 (C), 129.16 (2CH), 128.79
(3CH), 128.15 (CH), 128.06 (2CH), 125.72 (2CH), 119.45
(CH), 54.24 (CH2); HRMS [ESI]: m/z calculated for
C15H13N3 [M+H]+ 236.1143, found: 236.1189.
770; 1H NMR (400 MHz, CDCl3) δ 7.93 (d,
J
= 7.1 Hz, 2H),
7.47-7.40 (m, 5H), 7.19 (d,
J
= 8.4 Hz, 2H), 5.62 (s, 2H); 13
C
NMR (125 MHz, CDCl3) δ 150.39(C), 133.30(C), 132.14
(2CH), 130.03(C), 129.54 (2CH), 128.71(CH), 128.59
(2CH), 127.44 (2CH), 122.71(C), 76.31 (C), 53.78 (CH2);
HRMS [ESI]: m/z calculated for C15H11BrIN3 [M+H]+
439.9215, found: 439.9262.
4.2.2
1-Benzyl-5-iodo-4-(p-tolyl)-1H-1,2,3-triazole (3b):
The compound 3b was prepared according to the general
procedure starting from 4-ethynyltoluene (50 mg, 1.0 equiv);
Yield: 78% (126 mg); Rf (10% EtOAc: petroleum ether)
4.2.7
1-(4-Bromobenzyl)-4-phenyl-1H-1,2,3-triazole (4d)
0.48; IR (KBr, cm-1): 3031, 2917, 1910, 1573, 1454, 1226,
The compound 4d was prepared by the same procedure as
described for 3d; Yield: 11% (17 mg); Rf (10% EtOAc:
petroleum ether) 0.31; IR (KBr, cm-1): 2920, 1489, 1218,
1074, 1015, 807, 767, 695; H NMR (400 MHz, CDCl3) δ
7.82 – 7.77 (m, 2H), 7.66 (s, 1H), 7.51 (d,
1
988, 821, 723; H NMR (400 MHz, CDCl3) δ 7.82 (d,
J =
8.1 Hz, 2H), 7.35-7.29 (m, 5H), 7.26 (d,
J = 7.3 Hz, 2H),
5.65 (s, 2H), 2.39 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
150.30 (C), 138.52 (C), 134.42 (C), 129.24 (2CH), 128.90
(2CH), 128.47 (CH), 127.82 (2CH), 127.36 (2CH), 76.11
(C), 54.37 (CH2), 21.35 (CH3); HRMS [ESI]: m/z calculated
for C16H14IN3 [M+H]+ 376.0266, found: 376.0272.
1
J
= 8.4 Hz, 2H),
7.42-7.38 (m, 2H), 7.32 (dd,
J
= 11.7, 4.3 Hz, 1H), 7.18 (d, J
= 8.4 Hz, 2H), 5.52 (s, 2H); 13C NMR (125 MHz, CDCl3) δ
148.46 (C), 133.70 (C), 132.35 (2CH), 130.34 (C), 129.67
(2CH), 128.87 (2CH), 128.32 (CH), 125.73 (2CH), 122.98
(C), 119.45 (CH), 53.68(CH2); HRMS [ESI]: m/z calculated
for C15H12BrN3 [M+H]+ 314.0248, found: 314.0312.
4.2.3
1-Benzyl-4-(p-tolyl)-1H-1,2,3-triazole (4b)
The compound 4b was prepared by the same procedure as
described for 3b; Yield: 12% (13 mg); Rf (10% EtOAc:
petroleum ether) 0.37; IR (KBr, cm-1): 3144, 2920, 2851,
1458, 1349, 1222, 1047; 1H NMR (400 MHz, CDCl3) δ 7.68
4.2.8
1-(4-Bromobenzyl)-5-iodo-4-(p-tolyl)-1H-1,2,3-
triazole (3e
)
(d,
J
= 8.1 Hz, 2H), 7.61 (s, 1H), 7.39-7.37 (m, 3H), 7.33 –
The compound 3e was prepared according to the general
procedure starting from 4-ethynyltoluene (50 mg, 1.0 equiv)
and 4-bromobenzyl bromide (107 mg, 1.0 equiv); Yield:
77% (150 mg); Rf (10% EtOAc: petroleum ether) 0.43; IR
7.29 (m, 2H), 7.20 (d,
J
= 7.9 Hz, 2H), 5.57 (s, 2H), 2.36 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 148.34 (C), 138.04 (C),
134.74 (C), 129.50 (2CH), 129.17 (2CH), 128.79 (CH),
128.09(2CH), 127.70(C), 125.61 (2CH), 119.15 (CH), 54.23
(CH2), 21.30 (CH3); HRMS [ESI]: m/z calculated for
C16H15N3 [M+H]+ 250.1300, found: 250.1358.
(KBr, cm-1)
:
2917, 2851, 1486, 1377, 1229, 1066, 1010,
820; 1H NMR (400 MHz, CDCl3) δ 7.81 (d,
= 8.1 Hz, 2H),
7.48 (d, = 7.8 Hz, 2H), 7.26 (d, = 7.9 Hz, 2H), 7.18 (d,
J
J
J
J
= 8.1 Hz, 2H), 5.59 (s, 2H), 2.39 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 150.43 (C), 138.65 (C), 133.39 (C), 132.11
(2CH), 129.56 (2CH), 129.29 (2CH), 127.34 (2CH),
127.20(C), 122.66 (C), 76.15 (C), 53.73 (CH2), 21.39 (CH3);
HRMS [ESI]: m/z calculated for C16H13BrIN3 [M+H]+
453.9371, found: 453.9404.
4.2.4
1-Benzyl-4-((benzyloxy)methyl)-5-iodo-1H-1,2,3-
triazole (3c
)
The compound 3c was prepared according to the general
procedure starting from benzyl protected propargyl alcohol
(50 mg, 1.0 equiv); Yield: 79% (110 mg); Rf (10% EtOAc:
petroleum ether) 0.42; IR (KBr, cm-1): 2922, 2852, 1747,
4.2.9
1-(4-Bromobenzyl)-4-(p-tolyl)-1H-1,2,3-triazole
4e
1
1454, 1219, 1094, 725; H NMR (400 MHz, CDCl3) δ 7.43
(
)
– 7.22 (m, 10H), 5.59 (s, 2H), 4.61 (s, 2H), 4.59 (s, 2H); 13
C
NMR (125 MHz, CDCl3) δ 148.86 (C), 137.70 (C), 134.13
(C), 128.94 (2CH), 128.57 (CH), 128.41 (2CH), 128.06
(2CH), 127.91 (2CH), 127.80 (CH), 80.50 (C), 72.46 (CH2),
63.20 (CH2), 54.27 (CH2); HRMS [ESI]: m/z calculated for
C17H16IN3O [M+H]+ 406.0372, found: 406.0407.
The compound 4e was prepared by the same procedure as
described for 3e; Yield: 9% (13 mg); Rf (10% EtOAc:
petroleum ether) 0.35; IR (KBr, cm-1): 2924, 2853, 1747,
1
1650, 1221, 1182, 1072, 811, 753; H NMR (400 MHz,
CDCl3) δ 7.68 (d,
J = 8.1 Hz, 2H), 7.62 (s, 1H), 7.51 (d, J =
8.4 Hz, 2H), 7.19 (dd,
J
= 13.7, 8.2 Hz, 4H), 5.51 (s, 2H),
2.36 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 138.16(C),
133.78(C), 132.33 (2CH), 129.65(2CH), 129.52(2CH),
127.55 (C), 125.63 (2CH), 122.94(C), 119.07 (CH), 53.51
(CH2), 21.28 (CH3); HRMS [ESI]: m/z calculated for
C16H14BrN3 [M+H]+ 328.0405, found: 328.0458.
4.2.5
1-Benzyl-4-((benzyloxy)methyl)-1H-1,2,3-triazole
4c
(
)
The compound 4c was prepared by the same procedure as
described for 3c. Yield: 7% (7 mg); Rf (10% EtOAc:
petroleum ether) 0.33; IR (KBr, cm-1): 3031, 2863, 1496,
1455, 1218, 1132, 1091, 745; 1H NMR (400 MHz, CDCl3) δ
7.45 (s, 1H), 7.37 – 7.25 (m, 10H), 5.50 (s, 2H), 4.66 (s,
2H), 4.58 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 145.68
4.2.10 4-((Benzyloxy)methyl)-1-(4-bromobenzyl)-5-iodo-
1H-1,2,3-triazole (3f
)

7
The compound 3f was prepared according to the general
(d, J = 7.7 Hz, 1H), 7.41 – 7.15 (m, 7H), 6.63 (d, J = 7.3
ACCEPTED MANUSCRIPT
procedure starting from benzyl protected propargyl alcohol
(50 mg, 1.0 equiv) and 4-bromobenzyl bromide (85 mg, 1.0
equiv); Yield: 68% (112 mg); Rf (10% EtOAc: petroleum
ether) 0.47; IR (KBr, cm-1) 3063, 2855, 1516, 1495, 1473,
1303, 1221, 1093, 824; 1H NMR (400 MHz, CDCl3) δ 7.48 (d,
J = 8.4 Hz, 2H), 7.39 – 7.27 (m, 5H), 7.15 (d, J = 8.5 Hz, 2H),
5.53 (s, 2H), 4.60 (s, 2H), 4.59 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 149.04 (C), 137.71 (C), 133.14 (C), 132.12 (2CH),
129.59 (2CH), 128.41 (2CH), 128.00 (2CH), 127.78 (CH),
122.74 (C), 80.28 (C), 72.49 (CH2), 63.19 (CH2), 53.58 (CH2);
HRMS [ESI]: m/z calculated for C17H15BrIN3O [M+H]+
483.9477, found: 483.9489.
Hz, 1H), 5.68 (s, 2H), 4.64 (s, 2H), 4.61 (s, 2H); 13C NMR
(125 MHz, CDCl3) δ 149.04 (C), 137.74 (C), 133.78 (C),
132.98 (CH), 129.84 (CH), 128.45 (2CH), 128.38(CH),
128.06 (2CH), 127.82 (CH), 122.37 (C), 81.41 (C), 72.46
(CH2), 63.24 (CH2), 53.98 (CH2); HRMS [ESI]: m/z
calculated for C17H15BrIN3O [M+H]+ 483.9477, found:
483.9534.
4.2.15 5-Iodo-1-(4-methoxybenzyl)-4-phenyl-1H-1,2,3-
triazole (3i
)
The compound 3i was prepared according to the general
procedure starting from phenylacetylene (50 mg, 1.0 equiv)
and 4-methoxybenzyl bromide (97 mg, 1.0 equiv); Yield:
72% (138 mg); Rf (10% EtOAc: petroleum ether) 0.39; IR
(KBr, cm-1): 2921, 2848, 1611, 1512, 1247, 987, 764, 694,
4.2.11 4-((benzyloxy)methyl)-1-(4-bromobenzyl)-1H-1,2,3-
triazole (4f)
1
The compound 4f was prepared by the same procedure as
described for 3f; Yield: 16% (20 mg); Rf (10% EtOAc:
petroleum ether) 0.36; IR (KBr, cm-1): 3087, 2922, 2801,
1917, 1721, 1587, 1454, 1362, 1055, 741, 699; 1H NMR (500
MHz, CDCl3) δ 7.47-7.45 (m, 3H), 7.33 – 7.24 (m, 5H), 7.11 (d,
J = 8.3 Hz, 2H), 5.42 (s, 2H), 4.64 (s, 2H), 4.57 (s, 2H); 13C NMR
(125 MHz, CDCl3) δ 145.80 (C), 137.75 (C), 133.70 (C), 132.25
(2CH), 129.77 (2CH), 128.47 (2CH), 127.95 (2CH), 127.84(CH),
122.87 (C), 122.57 (CH), 72.66 (CH2), 63.69 (CH2), 53.39 (CH2);
HRMS [ESI]: m/z calculated for C17H15BrIN3O [M+H]+
358.0510, found: 358.0535.
538; H NMR (400 MHz, CDCl3) δ 7.91 – 7.89 (m, 2H),
7.46-7.39 (m, 1H), 7.28 (d, J = 8.7 Hz, 2H ), 6.87 (d, J = 8.7
Hz, 2H), 5.59 (s, 2H), 3.78 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 159.75 (C), 150.21 (C), 130.19 (C), 129.44 (2CH),
128.53 (2CH), 127.84 (CH), 127.50 (2CH), 126.34 (C),
114.27 (2CH), 76.24 (C), 55.33 (OCH3), 54.05 (CH2);
HRMS [ESI]: m/z calculated for C16H14IN3O [M+H]+
392.0215, found: 392.0250.
4.2.16 1-(4-Methoxybenzyl)-4-phenyl-1H-1,2,3-triazole
(4i)
The compound 4i was prepared by the same procedure as
described for 3i; Yield: 16% (21 mg). Rf (10% EtOAc:
petroleum ether) 0.29; IR (KBr, cm-1): 3131, 2961, 1612,
1462, 1249, 1034, 827, 759, 691; H NMR (400 MHz,
CDCl3) δ 7.81 – 7.76 (m, 2H), 7.62 (s, 1H), 7.40-7.36 (m,
4.2.12 1-(2-Bromobenzyl)-5-iodo-4-phenyl-1H-1,2,3-
triazole (3g
)
1
The compound 3g was prepared according to the general
procedure starting from phenylacetylene (50 mg, 1.0 equiv)
and 2-bromobenzyl bromide (120 mg, 1.0 equiv); Yield:
64% (138 mg); Rf (10% EtOAc: petroleum ether) 0.44; IR
2H), 7.33 – 7.29 (m, 1H), 7.26 (d, J = 8.7 Hz, 2H), 6.90 (d, J
= 8.7 Hz, 2H), 5.49 (s, 2H), 3.80 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 159.99 (C), 148.12 (C), 130.66 (C), 129.76
(2CH), 128.80 (2CH), 128.13 (CH), 126.65 (C), 125.69
(2CH), 119.32 (CH), 114.53 (2CH), 55.36 (OCH3), 53.78
(CH2); HRMS [ESI]: m/z calculated for C16H15N3O [M+H]+
266.1249, found: 266.1289.
(KBr, cm-1)
:
2923, 2852, 1439, 1232, 1026, 987, 767, 737;
1H NMR (400 MHz, CDCl3) δ 8.00 (dd,
= 8.3, 1.2 Hz,
2H), 7.62 (dd, = 7.8, 1.3 Hz, 1H), 7.48 (dd, = 11.8, 3.0
Hz, 2H), 7.43 – 7.38 (m, 1H), 7.28 – 7.16 (m, 2H), 6.67 (dd,
= 7.6, 1.5 Hz, 1H), 5.77 (s, 2H); 13C NMR (125 MHz,
J
J
J
J
CDCl3) δ133.94 (C), 132.97 (C), 130.09 (C), 129.78 (CH),
128.75(CH), 128.62 (2CH), 128.18 (CH), 128.06(CH),
127.39 (2CH), 122.28 (C), 77.13 (C), 54.20 (CH2); HRMS
[ESI]: m/z calculated for C15H11BrIN3 [M+H]+ 439.9215,
found: 439.9275.
4.2.17 5-Iodo-1-(4-methoxybenzyl)-4-(p-tolyl)-1H-1,2,3-
triazole (3j
)
The compound 3j was prepared according to the general
procedure starting from 4-ethynyltoluene (50 mg, 1.0 equiv)
and 4-methoxybenzyl bromide (86 mg, 1.0 equiv); Yield:
86% (150 mg); Rf (10% EtOAc: petroleum ether) 0.40; IR
(KBr, cm-1): 2922, 2852, 1739, 1611, 1512, 1245, 1181, 822,
4.2.13 1-(2-Bromobenzyl)-4-phenyl-1H-1,2,3-triazole (4g
)
The compound 4g was prepared by the same procedure as
described for 3g; Yield: 10% (15 mg); Rf (10% EtOAc:
petroleum ether) 0.34; IR (KBr, cm-1): 2923, 2852, 2350,
726; 1H NMR (400 MHz, CDCl3) δ 7.81 (d,
J = 8.1 Hz, 2H),
7.31 – 7.23 (m, 4H), 6.87 (d, J = 8.7 Hz, 2H), 5.59 (s, 2H),
3.79 (s, 3H), 2.39 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
159.71(C), 150.26(C), 138.47(C), 129.43 (2CH), 129.22
(2CH), 127.41 (C), 127.36(2CH), 126.46 (C), 114.24 (2CH),
75.79 (C), 55.31 (OCH3), 53.95 (CH2), 21.35 (CH3); HRMS
[ESI]: m/z calculated for C17H16IN3O [M+H]+ 406.0372,
found: 406.0434.
1
1741, 1463, 1183, 1028, 764, 694; H NMR (400 MHz,
CDCl3) δ 7.84 – 7.80 (m, 2H), 7.78 (s, 1H), 7.64 (d,
J = 7.9
Hz, 1H), 7.43-7.39 (m, 2H), 7.34-7.30 (m, 2H), 7.25 – 7.17
(m, 2H), 5.72 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 147.68
(C), 133.77 (C), 132.74 (CH), 129.96(C), 129.91(CH),
129.80(CH), 128.32 (2CH), 127.78(CH), 127.71(CH),
125.27 (2CH), 122.94 (C), 119.31 (CH), 53.38 (CH2);
HRMS [ESI]: m/z calculated for C15H12BrN3 [M+H]+
314.0248, found: 314.0319.
4.2.18 1-(4-Methoxybenzyl)-4-(p-tolyl)-1H-1,2,3-triazole
(4j):
The compound 4j was prepared by the same procedure as
described for 3j; Yield: 9% (11 mg); Rf (10% EtOAc:
petroleum ether) 0.31; IR (KBr, cm-1): 3130, 2935, 1611,
1515, 1222, 1182, 1025, 814, 767, 521; 1H NMR (400 MHz,
4.2.14 4-((Benzyloxy)methyl)-1-(2-bromobenzyl)-5-iodo-
1H-1,2,3-triazole (3h
)
The compound 3h was prepared according to the general
procedure starting from benzyl protected propargyl alcohol
(50 mg, 1.0 equiv) and 2-bromobenzyl bromide (85 mg, 1.0
equiv); Yield: 75% (124 mg); Rf (10% EtOAc: petroleum
CDCl3) δ 7.67 (d,
J = 8.2 Hz, 2H), 7.57 (s, 1H), 7.29 – 7.23
(m, 2H), 7.19 (d,
J = 8.3 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H),
5.49 (s, 2H), 3.80 (s, 3H), 2.35 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 159.96(C), 148.22(C), 137.94 (C), 129.67 (2CH),
129.46 (2CH), 127.81 (C), 126.72 (C), 125.60 (2CH),
ether) 0.46; IR (KBr, cm-1)
1058, 1026, 745, 697; H NMR (400 MHz, CDCl3) δ 7.60
:
3030, 2920, 2854, 1572, 1440,
1

8
Tetrahedron
118.91 (CH), 114.52 (2CH), 55.35 (OCH3), 53.76 (CH2),
2H), 2.01 – 1.92 (m, 2H), 1.41 – 1.36 (m, 4H), 0.93 (t, J =
ACCEPTED MANUSCRIPT
21.26 (CH3); HRMS [ESI]: m/z calculated for C17H17N3O
7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 149.69(C),
130.40(C), 128.52 (3CH), 127.51 (2CH), 76.78 (CH), 50.96
(CH2), 29.65 (CH2), 28.54 (CH2), 22.14 (CH2), 13.87 (CH3);
HRMS [ESI]: m/z calculated for C13H16IN3 [M+H]+
342.0422, found: 342.0486.
[M+H]+ 280.1405, found: 280.1457.
4.2.19 5-Iodo-4-phenyl-1-propyl-1H-1,2,3-triazole (3k
)
The compound 3k was prepared according to the general
procedure starting from phenylacetylene (50 mg, 1.0 equiv)
and 1-iodopropane (82 mg, 1.0 equiv); Yield: 66% (101
mg); Rf (10% EtOAc: petroleum ether) 0.45; IR (KBr, cm-1):
4.2.24 5-Iodo-1-pentyl-4-(p-tolyl)-1H-1,2,3-triazole (3n
)
The compound 3n was prepared according to the general
procedure starting from 4-ethynyltoluene (50 mg, 1.0 equiv)
and 1-iodopentane (85 mg, 1.0 equiv); Yield: 64% (98 mg);
Rf (10% EtOAc: petroleum ether) 0.42; IR (KBr, cm-1):
1
2961, 2927, 2874, 1448, 1228, 985, 766, 696; H NMR (400
MHz, CDCl3) δ 7.94 (dd,
(m, 2H), 7.42 – 7.37 (m, 1H), 4.44 – 4.39 (m, 2H), 2.00 (q,
= 14.8, 7.4 Hz, 2H), 1.02 (t,
= 7.4 Hz, 3H); 13C NMR (125
J = 8.3, 1.3 Hz, 2H), 7.50 – 7.44
J
1
J
2921, 2851, 1739, 1510, 1463, 1182, 1105, 823, 772; H NMR
MHz, CDCl3) δ 149.21 (C), 129.90 (C), 128.01 (3CH),
127.02 (2CH), 75.57 (C), 51.94 (CH2), 22.91 (CH2), 10.50
(CH3); HRMS [ESI]: m/z calculated for C11H12IN3 [M+H]+
314.0109, found: 314.0155.
(400 MHz, CDCl3) δ 7.82 (d, J = 8.2 Hz, 2H), 7.27 (d, J =
9.5 Hz, 2H), 4.45 – 4.41 (m, 2H), 2.40 (s, 3H), 1.97-1.95 (m,
2H), 1.42 – 1.36 (m, 4H), 0.93 (t,
(125 MHz, CDCl3) δ 127.48 (d,
J
= 7.0 Hz, 3H); 13C NMR
J = 19.1 Hz), 149.79(C),
138.38(C),
128.19(3CH),
127.56(C),
127.41(2CH),
4.2.20 4-Phenyl-1-propyl-1H-1,2,3-triazole (4k
)
75.63(C), 50.91 (CH2), 29.63(CH2), 28.54 (CH2), 22.14
(CH2), 21.30(CH3), 13.82 (CH3); HRMS [ESI]: m/z
calculated for C14H18IN3 [M+H]+ 356.0579, found: 356.0618.
The compound 4k was prepared by the same procedure as
described for 3k; Yield: 8% (7 mg); Rf (10% EtOAc:
petroleum ether) 0.35; IR (KBr, cm-1): 3131, 2961, 1462,
1218, 1075, 829, 762, 695, 521; 1H NMR (400 MHz,
4.2.26 2-(1-Benzyl-5-iodo-1H-1,2,3-triazol-4-yl)ethanol
(3p)
CDCl3) δ 7.83 (d,
7.6 Hz, 2H), 7.32 (t,
2H), 1.96 (dd,
J = 8.2 Hz, 2H), 7.75 (s, 1H), 7.41 (t, J =
J
= 7.3 Hz, 1H), 4.34 (t,
J
J
= 6.5 Hz,
= 7.3 Hz,
The compound 3p was prepared according to the general
procedure starting from 3-butyn-1-ol (50 mg, 1.0 equiv.);
Yield: 76% (178 mg); Rf (10% MeOH: DCM) 0.51; IR
(KBr, cm-1): 3284, 2924, 2853, 1442, 1218, 1052, 723, 697;
J
= 14.1, 6.9 Hz, 2H), 0.97 (t,
3H); 13C NMR (125 MHz, CDCl3) δ 147.70 (C), 130.74 (C),
128.83 (2CH), 128.08 (CH), 125.69 (2CH), 119.52 (CH),
52.00 (CH2), 23.76 (CH2), 11.08 (CH3); HRMS [ESI]: m/z
calculated for C11H13N3 [M+H]+ 188.1143, found: 188.1182.
1H NMR (400 MHz, CDCl3) δ 7.34 (t,
J
=6.6 Hz, 3H), 7.29-
=6.0 Hz,
7.25 (m, 2H), 5.57 (s, 2H), 3.99 (s, 2H), 2.88(t,
J
2H); 13C NMR (101 MHz, CDCl3) δ 150.30 (C), 134.21 (C),
128.93 (2CH), 128.55(CH), 127.87 (2CH), 79.01 (C), 61.13
(CH2), 54.30 (CH2), 29.17 (CH2); HRMS [ESI]: m/z
calculated for C11H12IN3O [M+H]+ 330.0059, found:
330.0095.
4.2.21 5-Iodo-1-propyl-4-(p-tolyl)-1H-1,2,3-triazole (3l
)
The compound 3l was prepared according to the general
procedure starting from 4-ethynyltoluene (50 mg, 1.0 equiv)
and 1-iodopropane (73 mg, 1.0 equiv); Yield: 65% (92 mg);
Rf (10% EtOAc: petroleum ether) 0.41; IR (KBr, cm-1):
1
4.2.27 Ethyl
2-(5-iodo-4-phenyl-1H-1,2,3-triazol-1-
)
2974, 2876, 1650, 1418, 1384, 1220, 984, 823, 729; H
yl)acetate (3q
NMR (400 MHz, CDCl3) δ 7.82 (d,
J
= 8.2 Hz, 2H), 7.27 (d,
= 8.6 Hz, 2H), 4.44 – 4.36 (m, 2H), 2.40 (s, 3H), 1.98 (dt,
= 14.8, 7.4 Hz, 2H), 1.02 (t,
= 7.4 Hz, 3H); 13C NMR
J
J
The compound 3q was prepared according to the general
procedure starting from phenylacetylene (50 mg, 1.0 equiv.)
and ethyl chloroacetate (60 mg, 1.0 equiv.); Yield: 73% (128
mg); Rf (30% EtOAc: petroleum ether) 0.51; IR (KBr, cm-1):
2917, 1744, 1374, 1215, 985; 1H NMR (400 MHz, CDCl3) δ
8.01-7.94 (m, 2H), 7.53-7.38 (m, 3H), 5.27 (s, 2H), 4.31 (q,
J
(125 MHz, CDCl3) δ 149.79 (C), 138.38 (C), 129.19 (2CH),
127.95(C), 127.48 (2CH), 75.72 (C), 52.40 (CH2), 23.40
(CH2), 21.29 (CH3), 10.99 (CH3); HRMS [ESI]: m/z
calculated for C12H14IN3 [M+H]+ 328.0266, found: 328.0324.
J
=7.1 Hz 2H), 1.32(t, J
=7.1 Hz, 3H); 13C NMR (101 MHz,
4.2.22 1-Propyl-4-(p-tolyl)-1H-1,2,3-triazole (4l
)
CDCl3) δ 165.55 (CO), 150.25 (C), 130.06 (C), 128.73(CH),
128.58 (2CH), 127.46 (2CH), 77.54 (C), 62.54 (CH2), 51.66
(CH2), 14.11 (CH3); HRMS [ESI]: m/z calculated for
C12H12IN3O2 [M+H]+ 358.0008, found: 358.0035.
The compound 4l was prepared by the same procedure as
described for 3l; Yield: 10% (8 mg); Rf (10% EtOAc:
petroleum ether) 0.32; IR (KBr, cm-1): 2963, 1643, 1633,
1
1352, 1219, 1109, 1050, 812, 772; H NMR (400 MHz,
4.3 General procedure and characterization data for the 2-
iodoimidazo[1,2-a]pyridines as listed in Table 3 is
CDCl3) δ 7.72 (d,
7.9 Hz, 2H), 4.36 (t,
= 14.5, 7.3 Hz, 2H), 1.00 (t,
J
= 8.1 Hz, 2H), 7.69 (s, 1H), 7.23 (d,
J
=
J
J
= 7.2 Hz, 2H), 2.38 (s, 3H), 1.99 (dt,
= 7.4 Hz, 3H); 13C NMR (125
exemplified for 6a
:
J
MHz, CDCl3) δ 137.89 (C), 129.48 (C), 127.96 (2CH & C),
125.62 (2CH), 119.01 (CH), 51.97 (CH2), 23.74 (CH2),
21.24 (CH3), 11.07 (CH3); HRMS [ESI]: m/z calculated for
C12H15N3 [M+H]+ 202.1300, found: 202.1341.
A suspension of 2-aminopyridine
5
(50 mg, 1.0 mmol),
phenylacetylene (54 mg, 1.0 mmol), iodine (187 mg, 1.5
1
mmol), CuI (10 mol %) in β–cyclodextrin (1.0 mol %) and
water (5 mL) was stirred for 30 min at room temperature, a
red homogeneous solution was formed, which was
4.2.23 5-Iodo-1-pentyl-4-phenyl-1H-1,2,3-triazole (3m
)
o
transferred to heating at 90 C for 4 h. After the completion
The compound 3m was prepared according to the general
procedure starting from phenylacetylene (50 mg, 1.0 equiv)
and 1-iodopentane (95 mg, 1.0 equiv); Yield: 65% (108 mg);
Rf (10% EtOAc: petroleum ether) 0.43; IR (KBr, cm-1):
of reaction as monitored by TLC, the reaction was further
diluted with water (10 mL). The aqueous solution was
extracted with EtOAc (3 x 10 mL) and combined organic
layer was washed with saturated Na2S2O3 solution, dried
over anhydrous Na2SO4, and evaporated in vacuum. The
residue was purified by column chromatography (silica gel,
1
2926, 2853, 1747, 1447, 1224, 1152, 1097, 767, 695. H
NMR (400 MHz, CDCl3) δ 7.94 (dt,
J = 8.2, 1.7 Hz, 2H),
7.49 – 7.43 (m, 2H), 7.42 – 7.36 (m, 1H), 4.46 – 4.41 (m,

9
30:70, v/v, EtOAc in petroleum ether) to afford the desired
product.
The compound 6e was prepared according to the general
ACCEPTED MANUSCRIPT
procedure starting from 2-amino-5-chloropyridine (50 mg,
1.0 equiv) and 4-ethynyltoluene (44 mg, 1.0 equiv); Yield:
65% (93 mg); Rf (30% EtOAc: petroleum ether) 0.65; IR
(KBr, cm-1): 2922, 2851, 1643, 1320, 1018, 770, 666, 507;
4.3.1
2-Iodo-3-phenylimidazo[1,2-a]pyridine (6a)
The compound 6a was prepared according to the general
procedure starting from 2-aminopyridine (50 mg, 1.0 equiv)
and phenylacetylene (54 mg, 1.0 equiv); Yield: 80% (136
mg); Rf (30% EtOAc: petroleum ether) 0.58; IR (KBr, cm-1):
1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.54 (d,
J
= 9.4
Hz, 1H), 7.39 (t,
J = 5.7 Hz, 4H), 7.14 (d, J = 11.2 Hz, 1H),
2.47 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 145.16 (C),
139.75 (C), 130.14 (2CH), 129.90 (2CH), 127.58 (C),
126.16 (CH), 124.64 (C), 121.40 (C), 121.07 (CH), 117.47
(CH), 94.31 (C), 21.51 (CH3); HRMS [ESI]: m/z calculated
for C14H10ClIN2 [M+H]+ 368.9611, found: 368.9635.
1
2924, 2852, 1465, 1312, 1298, 1185, 1074, 737, 698; H
NMR (400 MHz, CDCl3) δ 8.07 (d,
J
= 6.9 Hz, 1H), 7.64 (d,
J
= 9.1 Hz, 1H), 7.58 – 7.48 (m, 5H), 7.23 – 7.18 (m, 1H),
6.77 (t,
J
= 7.3 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
146.8 (C), 130.1 (2CH), 129.2 (2CH), 128.2 (C), 127.1 (C),
125.2 (CH), 123.2 (CH), 117.1 (CH), 113.0 (CH), 93.26 (C);
HRMS [ESI]: m/z calculated for C13H9IN2 [M+H]+ 320.9844,
found: 320.9854.
4.3.6
3-((benzyloxy)methyl)-6-chloro-2-iodoimidazo[1,2-
a]pyridine (6f
)
The compound 6f was prepared according to the general
procedure starting from 2-amino-5-chloropyridine (50 mg,
1.0 equiv) and benzyl protected propargyl alcohol (55 mg,
1.0 equiv); Yield: 70% (155 mg); Rf (30% EtOAc:
petroleum ether) 0.62; IR (KBr, cm-1): 2851, 1491, 1323,
4.3.2
2-iodo-3-(p-tolyl)imidazo[1,2-a]pyridine (6b)
The compound 6b was prepared according to the general
procedure starting from 2-aminopyridine (50 mg, 1.0 equiv)
and 4-ethynyltoluene (62 mg, 1.0 equiv).Yield: 65% (115
mg); Rf (30% EtOAc: petroleum ether) 0.55; IR (KBr, cm-1):
1
1306, 1218, 1064, 805, 743, 696; H NMR (400 MHz,
CDCl3) δ 8.16 (d,
J
= 1.2 Hz, 1H), 7.50 (d,
J = 9.5 Hz, 1H),
7.32 (dt, = 8.0, 5.1 Hz, 5H), 7.18 (dd,
J
J
= 9.5, 2.0 Hz, 1H),
1
2923, 2854, 1633, 1496, 1311, 1298, 1226, 829, 750; H
4.82 (s, 2H), 4.51 (s, 2H); 13C NMR (125 MHz, CDCl3) δ
145.92 (C), 137.19 (C), 128.56 (2CH), 128.11 (CH), 128.06
(2CH), 126.82 (CH), 123.21 (C), 122.05 (CH), 121.36 (C),
117.21 (CH), 96.64 (C), 71.95 (CH2), 61.71 (CH2); HRMS
[ESI]: m/z calculated for C15H12ClIN2O [M+H]+ 398.9716,
found: 398.9758.
NMR (400 MHz, CDCl3) δ 8.04 (d,
= 9.0 Hz, 1H), 7.42 (d, = 7.8 Hz, 2H), 7.36 (d,
Hz, 2H), 7.19 – 7.14 (m, 1H), 6.73 (t, = 6.8 Hz, 1H), 2.45
J
= 6.9 Hz, 1H), 7.60 (d,
J
J
J
= 7.7
J
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 146.82 (C), 139.27
(C), 129.96 (4CH), 127.07 (C), 125.26 (C), 124.84 (CH),
123.24 (CH), 117.11 (CH), 112.75 (CH), 93.53 (C), 21.50
(CH3); HRMS [ESI]: m/z calculated for C14H11IN2 [M+H]+
335.0000, found: 335.0048.
4.3.7
2-iodo-6-methyl-3-phenylimidazo[1,2-a]pyridine
6g
(
)
4.3.3
3-((benzyloxy)methyl)-2-iodoimidazo[1,2-
a]pyridine (6c
The compound 6g was prepared according to the general
procedure starting from 2-amino-5-methylpyridine (50 mg,
1.0 equiv) and phenylacetylene (47 mg, 1.0 equiv); Yield:
85% (131 mg); Rf (30% EtOAc: petroleum ether) 0.54; IR
(KBr, cm-1): 2923, 2853, 1741, 1444, 1405, 1227, 1158,
)
The compound 6c was prepared according to the general
procedure starting from 2-aminopyridine (50 mg, 1.0 equiv)
and benzyl protected propargyl alcohol (77 mg, 1.0 equiv);
Yield: 70% (135 mg); Rf (30% EtOAc: petroleum ether)
0.52; IR (KBr, cm-1): 2923, 2853, 1633, 1495, 1453, 1307,
1
1074, 799, 757, 700, 596; H NMR (400 MHz, CDCl3) δ
7.83 (s, 1H), 7.59 – 7.51 (m, 6H), 7.04 (d,
J = 9.2 Hz, 1H),
2.28 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 145.99 (C),
130.16 (2CH), 129.22 (2CH), 129.11 (CH), 128.48 (C),
128.34 (C), 128.25 (CH), 122.73 (C), 120.81 (CH), 116.39
(CH), 92.92 (C), 18.24 (CH3); HRMS [ESI]: m/z calculated
for C14H11IN2 [M+H]+ 335.0000, found: 335.0037.
1
1339, 1216, 1060, 747, 698; H NMR (400 MHz, CDCl3) δ
8.17 (d,
J
= 6.9 Hz, 1H), 7.58 (d,
J
= 9.1 Hz, 1H), 7.36 –
= 6.8 Hz, 1H),
7.28 (m, 5H), 7.25 – 7.20 (m, 1H), 6.83 (t,
J
4.87 (s, 2H), 4.50 (s, 2H); 13C NMR (126 MHz, CDCl3) δ
147.62 (C), 137.46 (C), 128.49 (2CH), 127.98 (2CH),
127.96 (CH), 125.53 (CH), 124.09 (CH), 122.54 (C), 116.97
(CH), 112.92 (CH), 96.10 (C), 71.67 (CH2), 61.99 (CH2);
HRMS [ESI]: m/z calculated for C15H13IN2O [M+H]+
365.0106, found: 365.0112.
4.3.8
2-iodo-6-methyl-3-(p-tolyl)imidazo[1,2-a]pyridine
(6h)
The compound 6h was prepared according to the general
procedure starting from 2-amino-5-methylpyridine (50 mg,
1.0 equiv) and 4-ethynyltoluene (53 mg, 1.0 equiv); Yield:
70% (112 mg); Rf (30% EtOAc: petroleum ether) 0.56; IR
(KBr, cm-1): 2923, 2853, 1505, 1332, 1297, 1225 965, 819,
4.3.4
6-chloro-2-iodo-3-phenylimidazo[1,2-a]pyridine
6d
(
)
The compound 6d was prepared according to the general
procedure starting from 2-amino-5-chloropyridine (50 mg,
1.0 equiv) and phenylacetylene (40 mg, 1.0 equiv); Yield:
75% (103 mg); Rf (30% EtOAc: petroleum ether) 0.69; IR
(KBr, cm-1): 3072, 2957, 1493, 1319, 1292, 1223, 1069,
1
798; H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.50 (s,
1H), 7.41 (d,
J = 8.1 Hz, 2H), 7.36 (d, J = 7.9 Hz, 2H), 7.01
(dd,
J
= 9.2, 1.5 Hz, 1H), 2.46 (s, 3H), 2.26 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 145.97 (C), 139.13 (C), 130.03
(2CH), 129.93 (2CH), 127.91 (CH), 126.67 (C), 125.53 (C),
122.47 (CH), 120.86 (CH), 116.42 (CH), 93.15 (C), 21.51
(CH3), 18.25 (CH3); HRMS [ESI]: m/z calculated for
C15H13IN2 [M+H]+ 349.0157, found: 349.0196.
798; 1H NMR (400 MHz, CDCl3) δ 8.10 (d,
J = 1.8 Hz, 1H),
7.61 – 7.54 (m, 6H), 7.19 – 7.16 (m, 1H); 13C NMR (125
MHz, CDCl3) δ 145.25 (C), 130.02 (2CH), 129.58 (CH),
129.44 (2CH), 127.69 (C), 127.54 (C), 126.34 (CH), 121.51
(C), 121.01 (C), 117.52 (CH), 94.41 (C); HRMS [ESI]: m/z
calculated for C13H8ClIN2 [M+H]+ 354.9454, found:
354.9506.
4.3.9
3-((benzyloxy)methyl)-2-iodo-6-methylimidazo[1,2-
a]pyridine (6i
)
The compound 6i was prepared according to the general
procedure starting from 2-amino-5-methylpyridine (50 mg,
1.0 equiv) and benzyl protected propargyl alcohol (67 mg,
1.0 equiv); Yield: 80% (140 mg); Rf (30% EtOAc:
4.3.5
6-chloro-2-iodo-3-(p-tolyl)imidazo[1,2-a]pyridine
6e
(
)

10
Tetrahedron
petroleum ether) 0.57; IR (KBr, cm-1): 2923, 2853, 1674,
equiv); Yield: 70% (91 mg); Rf (30% EtOAc: petroleum
ACCEPTED MANUSCRIPT
1
1581, 1453, 1311, 1228, 1123, 1084, 801; H NMR (400
MHz, CDCl3) δ 7.90 (s, 1H), 7.47 (d, = 9.1 Hz, 1H), 7.33
(t, = 6.1 Hz, 5H), 7.07 (d, = 9.1 Hz, 1H), 4.84 (s, 2H),
4.50 (s, 2H), 2.33 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
146.66 (C), 137.61 (C), 128.02 (dd, = 16.4, 2.8 Hz),
ether) 0.69; IR (KBr, cm-1): 2955, 2852, 1741, 1470, 1210,
1
J
1178, 823, 745, 661; H NMR (400 MHz, CDCl3) δ 7.67 (d,
J
J
J
= 7.9 Hz, 1H), 7.42 (d,
Hz, 2H), 7.29 (d, = 7.4 Hz, 1H), 7.22 – 7.17 (m, 1H), 7.09
(d,
= 8.1 Hz, 1H), 2.49 (s, 3H); 13C NMR (125 MHz,
J = 8.0 Hz, 2H), 7.36 (d, J = 7.9
J
J
J
122.69 (C), 121.79 (CH), 116.22 (CH), 93.36 (C), 71.58
(CH2), 61.85 (CH2), 18.19 (CH3); HRMS [ESI]: m/z
calculated for C16H15IN2O [M+H]+ 379.0263, found:
379.0302.
CDCl3) δ 148.20 (C), 139.69 (C), 132.28 (C), 131.12 (C),
130.67 (2CH), 129.89 (C), 129.66 (2CH), 125.83 (CH),
125.72 (C), 124.94 (CH), 124.22 (CH), 113.73 (CH), 89.18
(C), 21.60 (CH3); HRMS [ESI]: m/z calculated for
C16H11IN2S [M+H]+ 390.9721, found: 390.9752.
4.4 General Procedure and Characterization Data for the
2-iodobenzoimidazo[2,1-b]thiazoles Listed in Table 4
as exemplified for 8a
4.5 1-Benzyl-4-((benzyloxy)methyl)-5-phenyl-1H-1,2,3-
triazole (9)
A suspension of 2-aminobenzothiazole
7
(50 mg, 1.0 mmol),
A mixture of 3c (50 mg, 1 equiv), phenylboronic acid (23 mg, 1.5
equiv), K2CO3 (43 mg, 2.5 equiv), and Pd(PPh3)2Cl2 (9 mg, 0.1
equiv) in DMF:H2O (2.5:0.5, 3 mL) was stirred for 4 h at 80 °C.
Then the resultant mixture was poured into H2O (15 mL) and was
extracted with CH2Cl2 (3 × 15 mL). The combined organic layers
were washed with brine (15 mL) and dried over Na2SO4. The
solvent was removed under vacuum, and the residue was purified
by column chromatography [silica gel, 30% EtOAc in petroleum
ether] to give 9; Yield: 87% (38 mg); Rf (30% EtOAc:
petroleum ether) 0.52; IR (KBr, cm-1): 3031, 2924, 2858,
phenylacetylene (34 mg, 1.0 mmol), iodine (84 mg, 1.5
1
mmol) and CuI (10 mol %) and β–cyclodextrin (1.0 mol %)
in water (5 mL) was stirred for 30 min at room temperature,
a red homogeneous solution was formed, after that reaction
o
temperature was raised up to 90 C for 4h (reaction progress
was monitored by TLC). After reaction was finished, the
mixture was quenched with water. The aqueous solution was
extracted with EtOAc (3 x 10 mL) and combined organic
layer was washed with saturated Na2S2O3 solution, dried
over anhydrous Na2SO4, and evaporated in vacuum. The
residue was purified by column (silica gel, 30:70 v/v EtOAc
in petroleum ether) to afford the desired product.
1
1721, 1496, 1454, 1363, 1073, 733, 698; H NMR (400
MHz, CDCl3) δ 7.44-7.37 (m, 4H), 7.28 (d,
7.26 – 7.23 (m, 8H), 7.06-7.03 (m, 2H), 5.46 (s, 2H), 4.56
(d,
= 7.8 Hz, 4H); 13C NMR (125 MHz, CDCl3) δ 142.50
J = 2.2 Hz, 1H),
J
(C), 138.03 (C), 137.08 (C), 135.42 (C), 129.72 (2CH),
129.56 (CH), 128.86 (2CH), 128.77 (2CH), 128.32 (2CH),
128.15 (CH), 127.91 (2CH), 127.58 (CH), 127.36 (2CH),
126.63 (C), 72.24 (CH2), 62.70 (CH2), 52.07 (CH2); HRMS
[ESI]: m/z calculated for C23H21N3O [M+H]+ 356.1718,
found: 356.1753.
2-Iodo-3-phenylbenzo[d]imidazo[2,1-b]thiazole (8a
)
The compound 8a was prepared according to the general
procedure starting from 2-aminobenzothiazole (50 mg, 1.0
equiv) and phenylacetylene (34 mg, 1.0 equiv); Yield: 80%
(100 mg); Rf (30% EtOAc: petroleum ether) 0.65; IR (KBr,
cm-1): 2922, 2851, 1653, 1479, 1469, 1180, 1018, 702, 635;
1H NMR (400 MHz, CDCl3) δ 7.70 – 7.67 (m, 1H), 7.57-
4.6 1-Benzyl-4-((benzyloxy)methyl)-5-styryl-1H-1,2,3-
triazole (10
)
7.55 (m, 5H), 7.29 (t,
J = 7.1 Hz, 1H), 7.20 (t, J = 7.2 Hz,
A mixture of 3c (50 mg, 1 equiv), Na2CO3 (40 mg, 3 equiv), n-
Bu4NBr (40 mg, 1 equiv), Pd (OAc)2 (4 mg, 0.05 equiv), PPh3 (3
mg, 0.1 equiv) and styrene (16 mg, 1.2 equiv) in DMF (2 mL),
was stirred for 12 h at 85 °C under N2. Then the resultant mixture
was poured into H2O (15 mL) and was extracted with CH2Cl2 (3
× 15 mL). The combined organic layers were washed with brine
(15 mL) and dried over Na2SO4. The solvent was removed under
vacuum, and the residue was purified by column chromatography
[silica gel, 30% EtOAc in petroleum ether] to give 10; Yield:
90% (42 mg); Rf (30% EtOAc: petroleum ether) 0.58; IR
(KBr, cm-1): 2924, 2854, 1739, 1496, 1454, 1362, 1066, 727,
695; 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.29 (m, 13H), 7.24 -
7.19 (m, 3H), 6.76 (d, J = 16.3 Hz, 1H), 5.60 (s, 2H), 4.76 (s,
2H), 4.64 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 141.96 (C),
137.90 (C), 137.04 (CH), 136.07 (C), 134.85 (C), 134.41 (C),
129.12 (2CH), 128.94 (CH),128.83 (2CH), 128.47 (3CH),
128.10 (2CH), 127.77 (CH), 127.19 (2CH), 126.89 (2CH),
111.19 (CH), 72.22 (CH2), 63.71 (CH2), 52.40 (CH2); HRMS
[ESI]: m/z calculated for C25H23N3O [M+H]+ 382.1875,
found: 382.1878.
1H), 7.07 (d,
J
= 7.6 Hz, 1H); 13C NMR (125 MHz, CDCl3)
δ 132.28 (C), 131.07 (C), 130.86 (2 CH), 129.97 (C), 129.60
(C), 128.91 (2CH), 128.86 (C), 125.86 (CH), 124.98 (CH),
124.27 (CH), 113.70 (CH), 89.30 (C); HRMS [ESI]: m/z
calculated for C15H9IN2S [M+H]+ 376.9564, found:
376.9608.
4.4.1
3-((Benzyloxy)methyl)-2-iodobenzo[d]imidazo[2,1-
b]thiazole (8b
)
The compound 8b was prepared according to the general
procedure starting from 2-aminobenzothiazole (50 mg, 1.0
equiv) and 4-ethynyltoluene (39 mg, 1.0 equiv); Yield: 75%
(105 mg); Rf (30% EtOAc: petroleum ether) 0.67; IR (KBr,
cm-1): 2923, 2855, 1653, 1578, 1453, 1361, 1217, 1123,
1
1021, 819; H NMR (400 MHz, CDCl3) δ 7.92 (d,
J
= 8.0
Hz, 1H), 7.68 (d,
J = 8.0 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H),
7.37 – 7.33 (m, 1H), 7.33 – 7.26 (m, 5H), 4.92 (s, 2H), 4.59
(s, 2H); 13C NMR (125 MHz, CDCl3) δ 149.72 (C), 137.45
(C), 132.22 (C), 129.70 (C), 128.39 (2CH), 127.99 (2CH),
127.87 (CH), 126.92 (C), 126.48 (CH), 125.13 (CH), 123.97
(CH), 114.74 (CH), 92.07 (C), 71.53 (CH2), 62.21 (CH2);
HRMS [ESI]: m/z calculated for C17H13IN2OS [M+H]+
420.9827, found: 420.9837.
4.7 1-Benzyl-4-((benzyloxy)methyl)-5-(phenylethynyl)-1H-
1,2,3-triazole (11
)
A mixture of 3c (50 mg, 1 equiv), phenylacetylene (15 mg, 1.2
equiv), Pd(PPh3)2Cl2 (9 mg, 0.1 equiv) and CuI (2 mg, 0.1 equiv)
in Et3N (2 mL) was stirred for 12 h at 80 °C under N2( reaction
progress was monitored by TLC). Then the resultant mixture was
poured into H2O (15 mL) and was extracted with CH2Cl2 (3 × 15
mL). The combined organic layers were washed with brine (15
mL) and dried over Na2SO4. The solvent was removed under
4.4.2
2-Iodo-3-(p-tolyl)benzo[d]imidazo[2,1-b]thiazole
8c
(
)
The compound 8c was prepared according to the general
procedure starting from 2-aminobenzothiazole (50 mg, 1.0
equiv) and benzyl protected propargyl alcohol (48 mg, 1.0

11
vacuum, and the residue was purified by column chromatography
[silica gel, 30% EtOAc in petroleum ether] to give desired
compound 11; Yield: 85% (40 mg); Rf (30% EtOAc:
petroleum ether) 0.55; IR (KBr, cm-1): 2923, 1723, 1649,
mL). The combined organic layers were washed with brine
ACCEPTED MANUSCRIPT
(15 mL) and dried over Na2SO4. The solvent was removed under
vacuum, and the residue was purified by column chromatography
[silica gel, 30% EtOAc in petroleum ether] to give desired
compound 14.Yield: 85% (40 mg); Rf (20% EtOAc:
petroleum ether) 0.53; IR (KBr, cm-1): 2920, 1731, 1494,
1
1454, 1071, 757, 733, 697; H NMR (400 MHz, CDCl3) δ
7.44 – 7.33 (m, 14H), 7.27 – 7.25 (m, 1H), 5.61 (s, 2H), 4.72
(s, 2H), 4.64 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 146.99
(C), 137.91 (C), 134.56 (C), 131.67 (2CH), 129.70 (CH),
128.90 (2CH), 128.59 (2CH), 128.56 (CH), 128.37 (2CH),
128.21 (2CH), 127.92 (2CH), 127.66 (CH), 121.29 (C),
120.73 (C), 101.94 (CH), 73.70 (CH), 72.47 (CH2), 62.66
(CH2), 53.07 (CH2); HRMS [ESI]: m/z calculated for
C25H21N3O [M+H]+ 380.1718, found: 380.1727.
1
1363, 1210, 1187, 968, 757, 667; H NMR (400 MHz,
CDCl3) δ 7.70 (d,
J = 7.6 Hz, 1H), 7.61 (d, J = 7.7 Hz, 2H),
7.45 – 7.28 (m, 10H), 2.49 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 147.73 (C), 147.67 (C), 147.14 (2CH), 139.27
(CH), 139.23 (C), 138.60 (C), 138.51 (C), 131.52 (CH),
129.81 (CH), 129.40 (CH), 128.23 (CH), 128.13 (C), 125.77
(C), 124.93 (C), 124.50 (2CH), 124.01 (2CH), 119.16
(2CH), 114.10 (2CH), 22.72 (CH3); HRMS [ESI]: m/z
calculated for C24H16N2S [M+H]+ 365.1068, found 365.1103.
4.8 2-Phenyl-3-(p-tolyl)benzo[d]imidazo[2,1-b]thiazole
(12)
4.11Molecular docking simulation
A mixture of 8c (50 mg, 1 equiv), phenylboronic acid (24 mg, 1.5
equiv), K2CO3 (42 mg, 2.5 equiv), and Pd(PPh3)2Cl2 (9 mg, 0.1
equiv) in DMF:H2O (2.5:0.5, 3 mL) was stirred for 4 h at 80 °C.
Then the resultant mixture was poured into H2O (15 mL) and was
extracted with CH2Cl2 (3 × 15 mL). The combined organic layers
were washed with brine (15 mL) and dried over Na2SO4. The
solvent was removed under vacuum, and the residue was purified
by column chromatography [silica gel, 20% EtOAc in petroleum
ether] to give 12; Yield: 90% (39 mg); Rf (20% EtOAc:
petroleum ether) 0.56; IR (KBr, cm-1): 2921, 1512, 1493,
1368, 1024, 961, 829, 694; 1H NMR (400 MHz, CDCl3) δ 7.66
(d, J = 8.0 Hz, 1H), 7.59 (d, J = 7.3 Hz, 2H), 7.44 (d, J = 7.9 Hz,
2H), 7.36 (d, J = 7.8 Hz, 2H), 7.26 – 7.22 (m, 3H), 7.20 – 7.12
(m, 2H), 6.86 (d, J = 8.2 Hz, 1H), 2.51 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 146.96 (C), 143.22 (C), 139.47 (C), 134.34
(C), 133.20 (C), 131.16 (2CH), 130.58 (C), 130.09 (2CH),
128.22 (2CH), 127.30 (C), 126.93 (2CH), 126.89 (CH),
125.69 (CH), 124.44 (C), 124.37 (CH), 124.19 (CH), 113.47
(CH), 21.57 (CH3); HRMS [ESI]: m/z calculated for
C22H16N2S [M+H]+ 341.1068, found: 341.1099.
The Molecular docking studies of the inclusion complexes
of β-CD hydrate with guests were performed using
Molecular Operating Environment 2008.10 (MOE.
https://www.chemcomp.com/MOE). For the Docking study,
the coordinates of 2-aminopyridine, benzyl azide and
phenylacetylene iodide were build using builder module the
geometry of 2-aminopyridine, benzyl azide and
phenylacetylene iodide were optimized by applying
MMFF94x force field in MOE 2008.10, and the crystal
structure of the β-CD (PDB ID: BCD) was downloaded
from the protein data bank (http://www.rcsb.org./pdb). As
PDB for β- CD hydrate is not available in the Protein Data
Bank, native structure of β- CD was taken from the Protein
Data Bank having PDB ID: BCD. The 3D structure of β- CD
hydrate was generated from it by performing necessary
modification i.e., additions of five water molecules within
the cavity of β- CD hydrate. The optimized structure 2-
aminopyridine, benzyl azide and phenylacetylene iodide
were used as ligand and hydrated β-CD was used as
receptor. The β-CD hydrate molecule was kept as a fixed
truncated-cone and guest were allowed to freely move.
Structure refinement and energy minimization were
performed with MOE. Docking calculation results for each
guest molecule were clustered into different groups in the
form of inclusion complex. The lowest energy host–guest
inclusion complex conformation was selected and analyzed.
All calculations were carried out on an Intel I3, 2.2 GHz
based machine with MS Windows 7 as operating system.
Visualization of the docked pose and molecular graphics has
been done by using MOE 2008.10
4.9 2-Styryl-3-(p-tolyl)benzo[d]imidazo[2,1-b]thiazole (13
)
A mixture of 8c (50 mg, 1 equiv), Na2CO3 (38 mg, 3 equiv), n-
Bu4NBr (39 mg, 1 equiv), Pd(OAc)2 (4 mg, 0.05 equiv), PPh3 (3
mg, 0.1 equiv) and styrene (15 mg, 1.2 equiv) in DMF (2 mL),
was stirred for 12 h at 85 °C under N2. Then the resultant mixture
was poured into H2O (15 mL) and was extracted with CH2Cl2 (3
× 15 mL). The combined organic layers were washed with brine
(15 mL) and dried over Na2SO4. The solvent was removed under
vacuum, and the residue was purified by column chromatography
[silica gel, 30% EtOAc in petroleum ether] to give 13; Yield:
95% (45 mg); Rf (20% EtOAc: petroleum ether) 0.58; IR
(KBr, cm-1): 2921, 1594, 1488, 1466, 1309, 841, 751, 667,
5
Acknowledgements
576; 1H NMR (400 MHz, CDCl3) δ 7.66 (d,
7.50-7.38 (m, 7H), 7.31 – 7.23 (m, 4H), 7.21 – 7.17 (m, 2H),
6.91 (d,
= 15.9 Hz, 1H), 2.51 (s, 3H); 13C NMR (125 MHz,
J = 7.8 Hz, 1H),
Divya Dheer thank to CSIR, New Delhi, India for her research
fellowship. This research work was financially supported by CSIR-
New Delhi. R. S. and V. S. gratefully acknowledges the financial
support by DST (EMR/2016/002304) and CSIR (02(0202)/14/EMR-
II) New Delhi, India in the form of research grant. CSIR-IIIM
communication no. IIIM/2031/2017.
J
CDCl3) δ 148.36 (C), 142.89 (C), 139.20 (C), 137.57 (C),
132.88 (C), 130.69 (2CH), 130.30 (C), 129.64 (2CH),
128.85 (CH), 128.53 (2CH), 127.26 (CH), 126.44 (2CH),
126.34 (C), 125.74 (CH), 125.66 (C), 124.45 (CH), 124.25
(CH), 118.71 (CH), 113.52 (CH), 21.51 (CH3); HRMS
[ESI]: m/z calculated for C22H16N2S [M+H]+ 367.1224, found
367.1261.
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Supplementary Material
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
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