Pd2(dba)3-catalyzed amination of C5-bromo-imidazo[2,1-b][1,3,4] thiadiazole with substituted anilines at conventional heating in Schlenk tube

Article abstract of DOI:10.1080/17415993.2020.1817458

An efficient Pd₂(dba)₃-catalyzed amination of C5-bromo-imidazo[2,1-b][1,3,4]thiadiazole using conventional heating is reported. The C5-bromoimidazo[2,1-b][1,3,4]thiadiazole was synthesized using a multistep approach which started by cyclization of thiosemicarbazide with a carboxylic acid to give 2-amino[1,3,4]thiadiazoles which were further treated with 2-haloketones to give imidazo[2,1-b][1,3,4]thiadiazoles. Then, the bromination of imidazothiadiazole was done using N-bromosuccinimide to give the C5-bromo-imidazo[2,1-b][1,3,4]thiadiazole. Afterward, various C-N bond-forming approaches were attempted such as S_NAr, Cu(I), Cu(II), Pd(OAc)_2, Pd₂(dba)₃ catalyst with different ligand, additive, base, solvent and temperature conditions. Out of various approaches used, only Buchwald Hartwig amination, performed with conventional heating, gave N-arylamine-5-imidazothiadiazoles. Then, 10 different anilines with different electron-withdrawing and donating groups at different positions were employed to examine the scope and limitations of the method. Salient features of this method include conventional heating in a Schlenk tube as the reaction condition, the absence of the use of toxic isocyanides, the wide nature of substituent tolerance with anilines, and moderately good product yields.

Full text of DOI:10.1080/17415993.2020.1817458

Journal of Sulfur Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/gsrp20
Pd2(dba)3-catalyzed amination of C5-bromo-
imidazo[2,1-b][1,3,4] thiadiazole with substituted
anilines at conventional heating in Schlenk tube
Ravi Rawat & Saurabh M. Verma
To cite this article: Ravi Rawat & Saurabh M. Verma (2020): Pd2(dba)3-catalyzed amination of C5-
bromo-imidazo[2,1-b][1,3,4] thiadiazole with substituted anilines at conventional heating in Schlenk
tube, Journal of Sulfur Chemistry
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JOURNAL OF SULFUR CHEMISTRY
https://doi.org/10.1080/17415993.2020.1817458
Pd2(dba)3-catalyzed amination of
C5-bromo-imidazo[2,1-b][1,3,4] thiadiazole with substituted
anilines at conventional heating in Schlenk tube
Ravi Rawat and Saurabh M. Verma
Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, India
ABSTRACT
ARTICLE HISTORY
Received 16 June 2020
Accepted 25 August 2020
An efficient Pd2(dba)3-catalyzed amination of C5-bromo-imidazo[2,
1-b][1,3,4]thiadiazole using conventional heating is reported. The
C5-bromoimidazo[2,1-b][1,3,4]thiadiazole was synthesized using a
multistep approach which started by cyclization of thiosemicar-
bazide with a carboxylic acid to give 2-amino[1,3,4]thiadiazoles
which were further treated with 2-haloketones to give imidazo[2,1-
b][1,3,4]thiadiazoles. Then, the bromination of imidazothiadiazole
was done using N-bromosuccinimide to give the C5-bromo-imidazo
[2,1-b][1,3,4]thiadiazole. Afterward, various C-N bond-forming appr-
oaches were attempted such as SNAr, Cu(I), Cu(II), Pd(OAc)2,
Pd2(dba)3 catalyst with different ligand, additive, base, solvent and
temperature conditions. Out of various approaches used, only Buch-
wald Hartwig amination, performed with conventional heating, gave
N-arylamine-5-imidazothiadiazoles. Then, 10 different anilines with
different electron-withdrawing and donating groups at different
positions were employed to examine the scope and limitations
of the method. Salient features of this method include conven-
tional heating in a Schlenk tube as the reaction condition, the
absence of the use of toxic isocyanides, the wide nature of sub-
stituent tolerance with anilines, and moderately good product yields.
KEYWORDS
C-Br amination; Buchwald
Hartwig amination;
Pd2(dba)3 catalyst;
imidazo[2,1-
b][1,3,4]thiadiazol-5-amine;
C-N bond formation
CONTACT Saurabh M. Verma
smverma@bitmesra.ac.in
Department of Pharmaceutical Sciences and
Technology, Birla Institute of Technology, Mesra, Ranchi 835215, India
Supplemental data for this article can be accessed here. https://doi.org/10.1080/17415993.2020.1817458
© 2020 Informa UK Limited, trading as Taylor & Francis Group

2
R. RAWAT AND S. M. VERMA
1. Introduction
Imidazo[2,1-b][1,3,4]thiadiazole, a bicyclic [5-5]-fuzed system having one bridgehead
nitrogen atom after being discovered in the early 1950s [1] have been significantly designed
for its application in the areas of chemistry and biology (Figure 1). Its derivatives having a
variety of substitutions at C2, C5 and/or C6 have been reported for anticancer, antibacterial,
antitubercular, antifungal, anticonvulsant, analgesic, antipyretic, diuretic, antileishmanial,
herbicidal, anthelmintic activities [2]. In recent years chemistry of this nucleus is gaining
interest from organic chemistry and pharmaceutical researchers.
The general strategy for the synthesis of imidazo[1,2-b][1,3,4]thiadiazole nucleus
involves condensation of 2-amino-5-substituted-[1,3,4]thiadiazoles with various α-
haloketones (usual acetophenones) which leads to the formation of two fuzed rings
with the desired substituents at C2 and C6 position [3–8]. In this decade, great efforts
have been directed towards developing synthetic approaches for the construction and
functionalization of imidazofused heterocycles. In the recent past, our group has pre-
sented a systematic review based on different strategies employed for C3 aroylation of
imidazo[1.2-a]pyridines [9]. Although in the case of imidazothiadiazoles, limited work
has been done to develop efficient methods for subsequent functionalization at the C5
position. In the area of drug discovery, the amino(NH)Ar group in particular is of
prime importance as it is commonly observed to participate in h-bonding during drug-
protein interaction. The only available methods for the synthesis of C5 NH-functionalized
4
3
5
N
N
6
2
N
S
1
8
7
Figure 1. Structure and IUPAC numbering of Imidazo[2,1-b][1,3,4]thiadiazole.

JOURNAL OF SULFUR CHEMISTRY
3
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Previous work
Groebke-Blackburn-Bienaymé reaction
R2
NH
R1
Microwave Assisted
N
S
Solvent -free, 120oC
N
CHO
R2
N
N
R1
CN
N
5 mins
NH2
S
2015,
Sharma et. al. RSC Adv.
5, 44353-44360.
Microwave assisted Buchwald-Hartwig cross coupling
R3
Pd2(dba)3 (5 mol%),
Br
NH2
Xantphos (10 mol%)
Cs2CO3 (3.0 equiv.)
Dry dioxane, 140oC, 30 mins
N
S
NH
N
R2
R1
R3
1.5 equiv.
N
N
N
R1
R1
Microwave Assisted
N
S
2016,
Copin et. al. Eur. J. Org. Chem.
2016(11),1958-1962.
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Figure 2. Previous work on the synthesis of imidazo[2,1-b][1,3,4]thiadiazol-5-(N-Alkyl)amine using
Groebke-Blackburn-Bienaymé reaction and microwave-assisted Buchwald Hartwig amination reaction.
imidazo[2,1-b][1,3,4]thiadiazol-5-(N-alkyl)amine are:- (1) an isocyanide-based multi-
component reaction, Groebke–Blackburn–Bienaymé reaction [10,11] and (2) Buchwald
Hartwig amination under microwave irradiation, a protocol reported by Copin et al. [12]
(Figure 2). Our challenge was to explore other strategies for the synthesis of imidazo[2,1-
b][1,3,4]thiadiazol-5-(N-aryl)amine. Herein, we are reporting a multistep synthesis of
C5-bromo-imidazo[2,1-b][1,3,4]thiadiazole followed by the final amination step which
utilized Buchwald Hartwig amination without microwave assistance at conventional heat-
ing under an inert atmosphere in Schlenk tube. The work also describes the difficulty
encountered during C-N bond formation at the C5 position of imidazothiadiazole using
various failed approaches and the scope of aniline substrates used with the ultimately
successful approach.
2. Results and discussion
The synthesis was carried by initial cyclization of thiosemicarbazide (2) with carboxylic
acids (1) by heating under reflux in phosphorus oxychloride at 80°C for 30 mins to give
2-amino-5-substituted-[1,3,4]-thiadiazoles (3) [13]. Then, intermediate (3) was treated
with 2-haloketones (4) in a sequence of 2 steps in one-pot that involved (i) heating
under reflux in acetone at 60°C for 12 h, (ii) heating under reflux in 2 N HCl at 80°C
for 2 h to give imidazo[2,1-b][1,3,4]thiadiazoles (5) [14]. Intermediate (5) was treated
with N-bromosuccinimide in dry acetonitrile at room temperature for 3–5 h to give the
C5-bromo-imidazo[1,2-b][1,3,4]thiadiazole (6) [15]. Intermediate (6) was the haloarene
reactant for reaction with anilines (7) (Figure 3).
This next step was the C-N bond-forming step between 5-bromo-2-methyl-6-
phenylimidazo[2,1-b][1,3,4]thiadiazole (6a) and aniline (7a), so various strategies were

4
R. RAWAT AND S. M. VERMA
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
4
1
O
O
X
R2
N
S
N
5
N
N
R2
R1
R1
OH
X = Cl, Br, I
R1
N
NH2
S
3
POCl3
,
(i) Acetone,
S
2
reflux, 60o
C,
reflux,
80o
H2N
C, 0.5 h
N
H
NH2
12 h
NBS
Acetonitrile,
r.t., 3-5 h
(ii) 2 N HCl,
reflux, 80o
C,
2 h
Br
N
S
N
6
R2
R1
= H, CH
= CH
R1
R2
H5 t-butyl
,
H5
3, C6
2Cl, C6
N
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Figure 3. Multistep protocol for the synthesis of C5-bromo-imidazo[1,2-b][1,3,4]thiadiazole
attempted starting with simple substitution nucleophilic aromatic (SNAr) (Table 1). The
first SNAr involving simple heating under reflux in ethanol at 80°C while monitoring
for 24 h didn’t produce any product. The second SNAr utilize K2CO3 as a base in sol-
vents such as ethanol and DMF which again failed to form the C-N bond. The SNAr
wasn’t proceeding due to the steric hindrance of approach to the C5 position of 5-bromo-
imidazothiadiazole. The next approach was then to use a metal catalyst to couple anilines
with bromo intermediate (6).
Reagents and conditions: a. (2.) K2CO3 (2 eq.); (3.) Cu(II)O (10 mol%), NMP (3 mL);
(4,5,6,7.) CuI (20 mol%), K2CO3 (3 eq.), / L-proline (40 mol%); (8,9,10.) CuI (20 mol%),
DMEDA (1 eq.) K2CO3 (3 eq.) / Cs2CO3 (3 eq.); (11,12,13,14,15.) Pd(OAc)2 (5 mol%),
Cs2CO3 (3 eq.) / Pot. t-OBu (3 eq.), / Pivalic acid (3 eq.); (16.) Pd2(dba)3 (5 mol%), Xant-
phos (10 mol %), Cs2CO3 (3 eq.). b. for all entries dry solvents were used (5 mL), c. product
was formed in 24% yield only in case of entry 16.
The first metal approach used with the Cu(II) catalyst, copper oxide in N-methyl-2-
pyrrolidone (NMP) as a basic solvent unfortunately failed. Then Cu(I) catalyst, copper
iodide was tried with different ligands, additives, bases, solvents, and reaction condi-
tions, while monitoring the reactions for 40 h, but unfortunately were also found to be
unsuccessful. Palladium was also used as a metal catalyst, first palladium acetate was
tried with different bases, with and without pivalic acid as an additive, different solvents,
and reaction conditions, and the reactions were monitored for 40 h and all failed. The
last approach was guided by work of Copin et al. [12] in the year 2016 which utilized
tris(dibenzylideneacetone)dipalladium(0) as a catalyst with conventional heating under
an inert atmosphere in Schlenk tube which did lead to product formation with a yield of
24% as mentioned in Table 1.

JOURNAL OF SULFUR CHEMISTRY
5
Table 1. Approaches attempted for C-N bond formation between 6a and 7a for the synthesis of 8a.
7a
NH2
HN
N
Br
N
S
N
S
N
N
N
Catalyst, Ligand, Base, Additive,
Solvent, Temp (o
8a
6a
C), Time (h)
Catalyst
Ligand
Base
–
Additive
Solvent
Temp (°C)
Time (h)
1.
2.
3.
4.
5.
6.
7.
8.
–
–
–
–
–
–
–
–
–
–
–
–
–
Ethanol
DMF
NMP
80
120
140
120
110
120
110
120
80
120
110
120
110
120
120
120
24
40
40
40
40
40
40
40
40
40
40
40
40
40
40
14
K2CO3
Cu(II)O
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
–
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Pot. t-OBu
Cs2CO3
Cs2CO3
Pot. t-OBu
Cs2CO3
DMSO
Toluene
DMSO
Toluene
1,4-dioxane
Acetonitrile
1,4-dioxane
Toluene
1,4-dioxane
Toluene
1,4-dioxane
1,4-dioxane
1,4-dioxane
–
L-proline
L-proline
DMEDA
DMEDA
DMEDA
–
–
–
–
9.
10.
11.
12.
13.
14.
15.
16.
–
–
–
–
–
–
Pivalic acid
Pivalic acid
Pivalic acid
–
Xantphos
Table 2. Reaction optimization of Buchwald-Hartwig amination with conventional heating under an
inert atmosphere.
7a
NH2
Br
HN
N
N
S
N
S
N
N
N
Pd
(mol%), Xantphos (mol%),
2(dba)3
Base (Concn), Solvent, Temp (o
6a
8a
C), Time (h)
Pd2(dba)3 (mol%)
Xantphos (mol%)
Base (Conc.)
Solvent
Temp (°C)
Time (h)
Yield (%)
1.
2.
3.
4.
5.
6.
7.
8.
5
5
5
5
5
10
15
10
10
10
10
10
10
10
10
10
10
10
20
30
20
20
20
20
20
20
Cs2CO3 (3 eq.)
Pot. t-OBu (2 eq.)
Pot. t-OBu (3 eq.)
K2CO3 (3 eq.)
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
acetonitrile
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
DCE
120
120
120
120
80
120
120
120
120
120
80
14
20
20
20
30
14
14
14
14
14
30
30
30
24
14
14
–
K2CO3 (3 eq.)
traces
45
48
45
30
traces
-
traces
26
Cs2CO3 (3 eq.)
Cs2CO3 (3 eq.)
Cs2CO3 (2.5 eq.)
Cs2CO3 (2 eq.)
Cs2CO3 (2.5 eq.)
Cs2CO3 (2.5 eq.)
Cs2CO3 (2.5 eq.)
Cs2CO3 (2.5 eq.)
9.
10.
11.
12.
13.
Toluene
DMSO
110
120
Afterward, the reaction in entry 16 in Table 1 was optimized using Buchwald Hartwig
amination under conventional heating. The optimization (Table 2) involved perform-
ing the reaction at different concentrations of Pd2(dba)3 with the catalyst, xantphos as
the ligand, potassium carbonate, cesium carbonate, potassium tert-butoxide as different

6
R. RAWAT AND S. M. VERMA
R3
Pd
(10 mol%),
2(dba)3
HN
N
NH2
Br
Xantphos (20 mol%),
Cs2CO3 (2.5 equiv)
N
S
N
N
8
N
R3
1,4-dioxane, 120oC, 14-20 h
N
S
7
6a
Cl
HN
HN
HN
N
S
N
N
N
N
N
N
N
S
N
S
8c (38%)
HN
8b (59%)
8a (45%)
F
S
NO2
HN
HN
N
N
S
N
N
N
S
N
N
N
N
S
8f (45%)
8e (37%)
8d (32%)
CF3
OH
HN
N
HN
HN
N
N
S
N
N
N
N
N
S
N
S
8i (40 %)
8h (34 %)
8g (35%)
O
HN
N
N
N
S
Figure 4. The substrate scope of substituted anilines (7) for the synthesis of imidazo[2,1-
b][1,3,4]thiadiazol-5-(N-aryl)amine.
bases, under different solvents at different temperatures with and without inert conditions
and reactions were monitored for a period of time. The optimized condition was used
Pd2(dba)3 as the catalyst at 10 mol% conc., xantphos as the ligand at 20 mol% conc., cesium
carbonate as the base at 2.5 eq. conc. in dry 1,4-dioxane under an inert atmosphere at 120°C
for 14 h as shown in entry 8 of Table 2. The optimized reaction condition was then evalu-
ated for substituted anilines (7a) with different electron-donating and withdrawing groups
at the ortho, meta, and para positions for evaluation of the substrate scope of the method
as shown in Figure 4. The advantages of the method are: (i) it can be used for the synthe-
sis of imidazo[2,1-b][1,3,4]thiadiazol-5-(N-aryl)amine with moderately good yields (ii) it

JOURNAL OF SULFUR CHEMISTRY
7
[Pd2(dba)3]0
Br
8
N
N
HN
Ligand exchange
N
N
N
S
[Pd(Xantphos)]0
N
6a
Oxidative addition
S
Reductive elimination
S
S
N
N
N
N
I
N
N
Ph P
Ph P
III
Pd
NH
Ph P
Ph P
Pd
Br
R
S
Cs CO
N
N
N
HCsCO
Ph P
Pd
CsBr
Ph P
CO Cs
NH
7
R
II
O
Xantphos=
Dibenzylideneacetone=
O
PPh
PPh
Figure 5. A plausible mechanism of the Buchwald Hartwig amination for the C-N bond formation
between 5-bromo-2-methyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazole (6a) and substituted anilines (7).
excludes microwave assistance by performing the reaction under an inert atmosphere in
Schlenk tube, and (iii) electron-donating and electron-withdrawing groups at the ortho,
meta and para positions are well tolerated.
Reagents and conditions: a. for all entries dry solvents were used (5 mL), b. all entries
involved the use of inert atmosphere maintained by N2 gas except for entry 10 which was
carried out in open air.
Reagent and Conditions: 5-bromo-2-methyl-6-phenyl imidazo[2,1-b][1,3,4]thiad-
iazole (6a) (1 eq.), substituted anilines (7) (1.2 equiv.), Pd2(dba)3 (10 mol %). xantphos
(20 mol%), Cs2CO3 (2.5 eq.), dry 1,4-dioxane, 120°C, 12–20 h, Yields 32–59%.
Plausible mechanism: Based on our results and previous literature reports, [15,16]
the plausible reaction mechanism for the generation of title compounds was proposed.
The active palladium species [Pd(Xantphos)]0 is generated upon coordination of ligand
(Xantphos) with Pd(0) by the replacement of dibenzylideneacetone ligands of [Pd2(dba)3]0

8
R. RAWAT AND S. M. VERMA
[12]. The oxidative addition of 5-bromo-2-phenylimidazo[2,1-b][1,3,4]thiadiazole (6a) to
[Pd(Xantphos)]0 forms intermediate I. Next, the coordination of PdII with CsCO3− occurs
after displacement of bromide, which leads to the formation of intermediate II. Subse-
quently, the displacement of CsCO3− with hydrogen from aniline (7) leads to the liberation
of cesium bicarbonate and forms intermediate III. Ultimately, the C–N bond formation
takes place while reducing PdII to Pd0 with the elimination of product (8) and subsequent
regeneration of the active Pd0 species (Figure 5)
3. Conclusion
In conclusion an efficient Pd2(dba)3-catalyzed amination of C5-bromo-imidazo[2,1-
b][1,3,4]thiadiazole under conventional heating is reported. Under this study, various
C–N bond-forming approaches were attempted such as SNAr, Cu(I), Cu(II), Pd(OAc)2,
Pd2(dba)3 catalyzed with a different combination of ligand, additive, base, solvent
and temperature conditions. Out of various approaches attempted only Buchwald
Hartwig amination performed at conventional heating resulted in desired N-arylamine-
5-imidazothiadiazoles. To examine the scope and limitations of the method, 10 different
anilines, with different electron-withdrawing and donating groups were then used. This
method’s most salient features include conventional heating in the Schlenk tube as reac-
tion condition, doesn’t involve the use of toxic isocyanides, diverse nature of substituted
aniline tolerance and moderately good product yields.
4. Experimental section
1H NMR and 13C NMR spectra were recorded using Bruker Avance DX spectrome-
1
ter at 400 and 100 MHz, respectively with TMS as an internal standard. The H NMR
and 13C NMR spectra were recorded in solvent CDCl3, at 7.26 and 77.00 ppm respec-
tively, insolvent DMSO-d6 at 2.50 and 39.51 ppm respectively and insolvent MeOD at
4.87, 3.31 and 49.1 ppm respectively. Coupling constants were reported in hertz (Hz). The
abbreviations used to characterize the signals are as follows: s = singlet, m = multiplet,
d = doublet, dd = doublet of doublet, dt = doublet of triplet, t = triplet, q = quartet.
Mass spectra were recorded using ESI mode. FTIR spectra were taken using the Atten-
uated total reflection (ATR) technique in DCM solvent. Elemental analysis was performed
using Thermo Flash 2000 CHNS elemental analyzer. TLC performed with Merck 60 F 254
silica gel plates. Column chromatography was performed using Merck silica gel (60–120
mesh).
General Procedure for the synthesis of 3 [13]
The thiosemicarbazide (2) (91 mg, 1 mmol) and carboxylic acid derivatives (1) (1 mmol)
in the presence of phosphorus oxychloride (5 mL) at 80°C for 30 mins were heated under
reflux. The reaction mixture was cooled and quenched with cold water (15 mL). The sep-
arated solid was filtered and suspended in water and basified with sodium bicarbonate.
The solid was filtered, washed with water and hexane, dried and crystallized from ethyl
acetate/hexane (10:90).

JOURNAL OF SULFUR CHEMISTRY
9
5-Methyl-1,3,4-thiadiazol-2-amine (3a)
White solid, (74 mg, 84%); IR (DCM, cm−1): 2923, 2854, 1640, 1508, 1464, 1275, 1196,
1
750; H NMR (400 MHz, DMSO-d6): δ 6.98 (s, 1H), 3.38 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) δ 168.88, 153.61, 15.79; MS (ESI-TOF) m/z: [M + H]+ calcd 116.02, found
115.89.
General Procedure for the synthesis of 5 [14]
The appropriate 5-alkyl-1,3,4-thiadiazol-2-amine (3) (1 mmol) was dissolved in 10 mL
of acetone and treated with appropriate 2-halo-acetophenones (4) (1.2 mmol). The reac-
tion mixture was heated under reflux at 60°C for 10–12 h (reaction was monitored using
TLC), the resulting reaction mixture was condensed through vacuum evaporation and then
heated under reflux at 80°C for 2 h with 20 mL of 2 N HCl. After cooling, the acidic reac-
tion mixture was neutralized by the addition of sodium bicarbonate. The resulting residue
was purified over silica gel column chromatography to get product 5. ethyl acetate/hexane
(15:85)-(35:65).
2-Methyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazole (5a)
Dusky brown solid, (94 mg, 82%); IR (DCM, cm−1): 2923, 2853, 2293, 1732, 1603, 1539,
1478, 1443, 1260, 1200, 1061, 749; 1H NMR (400 MHz, CDCl3): δ 7.99 (s, 1H), 7.85-7.83
(m, 2H), 7.45-7.41 (m, 2H), 2.73 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.33, 145.67,
133.92, 128.72, 127.49, 125.01, 109.17, 17.86; MS (ESI-TOF) m/z: [M + H]+ calcd 216.05,
found 215.99.
6-(Chloromethyl)-2-methylimidazo[2,1-b][1,3,4]thiadiazole (5b)
1
Dusky brown solid, (23 mg, 19%); H NMR (400 MHz, CDCl3): δ 7.72 (s, 1H), 4.66
(s, 2H), 2.71 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.41, 145.72, 142.41, 112.38,
40.41,17.83; MS (ESI-TOF) m/z: [M + H]+ calcd 186.99, found 186.54.
2-(tert-butyl)-6-Phenylimidazo[2,1-b][1,3,4]thiadiazole (5d)
Dusky brown solid, (102 mg, 69%); IR (DCM, cm−1): 3133, 3071, 2961, 2925, 1709,
1
1605, 1535, 1517, 1479, 1442, 1366, 1260, 1170, 1049, 1015, 722; H NMR (400 MHz,
CDCl3): δ 7.96 (s, 1H), 7.85-7.82 (d, J = 12 Hz, 2H), 7.43-7.40 (t, J = 8 Hz, 2H), 7.31-7.29
(t, J = 8, 12 Hz, 1H), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.16, 145.91, 145.68,
134.09, 128.69, 127.40, 125.07, 108.97, 37.43, 30.16; MS (ESI-TOF) m/z: [M + H]+ calcd
258.10, found 258.05.
General Procedure for the synthesis of 6a [15]
To a solution of imidazo[2,1-b][1,3,4]thiadiazole (5a) (1 mmol) in acetonitrile (5 mL)
was added NBS (1.1 mmol). After completion of stirring at room temperature (reaction
was monitored using TLC), the mixture was concentrated under reduced pressure. The
crude material was then diluted with ethyl acetate and successively washed with water.
The organic layer was dried over sodium sulfate, concentrated under reduced pressure,
and purified over silica gel column chromatography to get product 6a. ethyl acetate/hexane
(15:85)-(22:78).

10
R. RAWAT AND S. M. VERMA
5-Bromo-2-methyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazole (6a)
Amber brown solid, (178 mg, 83%); IR (DCM, cm−1): 3063, 2853, 2926, 2299, 1773,
1
1539, 1477, 1345, 1182, 768; H NMR (400 MHz, CDCl3): δ 8.04-8.03 (m, 2H), 7.49-
7.46 (m, 3H), 2.79 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.14, 144.49, 142.36, 132.95,
128.49, 128.22, 128.09, 127.88, 92.35, 17.99; MS (ESI-TOF) m/z: [M + H]+ calcd 293.97,
[M + H+2]+ calcd 295.97 found 293.92, 295.92 [M + H+2]+.
General Procedure for Buchwald–Hartwig coupling for the synthesis of 8
To a solution of 5-bromo-imidazo[2,1-b][1,3,4]thiadiazole (1 mmol), cesium carbonate
(2.5 equiv.) and aniline derivatives (1.5 eq.) in dry 1,4-dioxane (3 mL) was added inside a
15 mL Schlenk tube and degassed by nitrogen bubbling for 15 min. xantphos (20 mol%)
and Pd2dba3 (10 mol%) was then added and the mixture was heated to 120°C for 12-20 h.
The reaction mixture was then diluted in ethyl acetate and purified by silica gel column
chromatography to get product 8. ethyl acetate/hexane (22:78)-(50:50).
2-Methyl-N,6-diphenylimidazo[2,1-b][1,3,4]thiadiazol-5-
amine (8a)
Brown solid, (22 mg, 45%); m.p. = 205–207°C; IR (DCM, cm−1): 3346, 2923, 2853,
1
2299, 1598, 1527, 1496, 1462, 1330, 1247, 1178, 1103, 1027, 822, 749, 693; H NMR
(400 MHz, CDCl3): δ 7.84-7.82 (d, J = 8 Hz, 2H), 7.28-7.24 (t, J = 8 Hz, 3H), 7.22-7.12
(m, 3H), 6.81-6.77 (t, J = 8 Hz, 1H), 6.63-6.61 (d, J = 8 Hz, 2H), 5.53 (s, 1H), 2.57 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 159.77, 144.97, 142.76, 138.95, 133.50, 129.54, 128.73,
127.30, 126.02, 121.18, 120.00, 113.98, 29.73; MS (ESI-TOF) m/z: [M + H]+ calcd 307.10,
found 307.04; Elemental analysis: C17H14N4S calcd C, 66.64; H, 4.61; N, 18.29; S, 10.46
found: C, 66.54; H, 4.65; N, 18.32; S, 10.53.
N-(3,4-diMethylphenyl)-2-methyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-
amine (8b)
Brown solid, (28 mg, 59%); m.p. = 272–274°C; IR (DCM, cm−1): 3346, 2922, 2853,
1709, 1598, 1607, 1502, 1466, 1325, 1182, 1022, 813, 768, 695; 1H NMR (400 MHz, CDCl3):
δ 7.84-7.82 (d, J = 8 Hz, 2H), 7.28-7.24 (t, J = 8 Hz, 3H), 7.98-7.96 (d, J = 8 Hz, 2H), 7.39-
7.35 (t, J = 8 Hz, 2H), 7.29-7.25 (t, J = 8 Hz, 1H), 7.00-6.98 (m, 2H), 6.56-6.46 (m, 1H),
5.47 (s, 1H), 2.67 (s, 3H), 2.19 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 159.60, 142.95,
142.51, 138.85, 137.76, 133.58, 130.54, 128.58, 128.02, 127.24, 126.01, 121.56, 115.50,
111.28, 29.72; MS (ESI-TOF) m/z: [M + H]+ calcd 335.13, found 335.14; Elemental analy-
sis: C19H18N4S calcd C, 68.24; H, 5.43; N, 16.75; S, 9.59 found: C, 68.33; H, 5.47; N, 16.70;
S, 9.70.
N-(4-Chlorophenyl)-2-methyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-
amine (8c)
Brown solid, (15 mg, 38%); m.p. = 216-218°C; IR (DCM, cm−1): 3412, 2954, 2923,
1
2853, 1719, 1491, 1465, 1377, 1259, 1023, 1004, 882, 761; H NMR (400 MHz, MeOD):
δ 7.81-7.79 (m, 2H), 7.77-7.75 (2, J = 8 Hz, 1H), 7.44-7.42 (m, 1H), 7.34-7.30 (t, J = 8 Hz,
1H), 7.22-7.18 (m, 2H), 6.62-6.58 (t, J = 8 Hz, 2H), 5.33 (s, 1H), 2.67 (s, 3H); 13C NMR
(100 MHz, MeOD) δ 160.40, 131.34, 129.16, 129.08, 128.99, 128.41, 127.85, 127.45, 125.94,

JOURNAL OF SULFUR CHEMISTRY
11
118.96, 116.64, 114.87, 29.56; MS (ESI-TOF) m/z: [M + H]+ calcd 341.06, found 341.03;
Elemental analysis: C17H13ClN4S calcd C, 59.91; H, 3.84; Cl, 10.40; N, 16.44; S, 9.41 found:
C, 59.83; H, 3.70; N, 16.50; S, 9.46.
2-Methyl-N-(4-nitrophenyl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-amine (8d)
Yellow brown solid, (18 mg, 32%); m.p. = 284-286°C; IR (DCM, cm−1): 3346, 2955,
1
2922, 2853, 1709, 1639, 1459, 1377, 1260, 1081, 750; H NMR (400 MHz, CDCl3): δ
8.07-8.05 (m, 2H), 7.97-7.95 (d, J = 4 Hz, 1H), 7.76-7.74 (d, J = 8 Hz, 1H), 7.65-7.62 (d,
J = 12 Hz, 1H), 7.41-7.39 (d, J = 8 Hz, 1H), 7.31-7.27 (m, 1H), 6.98-6.93 (d, J = 20 Hz, 1
H), 6.67-6.65 (m, 1H), 6.14 (s, 1H), 2.62 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.60,
142.95, 142.59, 138.91 137.73, 133.54, 130.54, 128.58, 128.02, 127.24, 126.01, 121.56,
115.50, 111.28, 29.81, 20.13, 18.89, 17.96; MS (ESI-TOF) m/z: [M + H]+ calcd 352.08,
found 352.09; Elemental analysis: C17H13N5O2S calcd C, 58.11; H, 3.73; N, 19.93; O, 9.11;
S, 9.12 found: C, 58.19; H, 3.75; N, 19.87; S, 9.01.
2-Methyl-N-(4-(methylthio)phenyl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-
amine (8e)
Yellow brown solid, (18 mg, 37%); m.p. = 200-202°C; IR (DCM, cm−1): 3341, 2956,
2922, 1709, 1641, 1506, 1463, 1378, 1260, 750; 1H NMR (400 MHz, CDCl3): 7.92-7.91 (d,
J = 4 Hz, 2H), 7.38-7.7.22 (m, 3H), 6.96-6.92 (t, J = 8 Hz, 1H), 6.67 (s, 2H), 5.54 (s, 1H),
2.70 (s, 3H), 1.68 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 168.86, 152.91, 130.50, 128.57,
127.50, 125.98, 116.25, 116.04, 114.95, 114.67, 35.05, 18.03; MS (ESI-TOF) m/z: [M + H]+
calcd 352.47, found 395.20; Elemental analysis: C18H16N4S2 calcd C, 61.34; H, 4.58; N,
15.90; S, 18.19 found: C, 61.47; H, 4.61; N, 16.00; S, 18.12.
N-(4-Fluorophenyl)-2-methyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-
amine (8f)
Dark brown solid, (21 mg, 45%); m.p. = 225-227°C; IR (DCM, cm−1): 2924, 2854,
1736, 1586, 1505, 1466, 1444, 1377, 1344, 1213, 1180, 1098, 1046, 825, 766, 695, 661; 1H
NMR (400 MHz, CDCl3): δ 7.9 (m, 2H), 7.36-7.27 (m, 3H), 6.92 (m, 2H), 6.64 (m, 2H),
5.62 (s, 1H), 2.67 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 159.91, 158.32, 155.95, 142.67,
141.11, 138.82, 133.35, 128.60, 127.40, 126.05, 121.27, 116.19, 115.82, 114.86, 17.95; MS
(ESI-TOF) m/z: [M + H]+ calcd 325.09, found 325.06; Elemental analysis: C17H13FN4S
calcd C, 62.95; H, 4.04; F, 5.86; N, 17.27; S, 9.88 found: C, 63.04; H, 4.01; N, 17.21; S, 9.97.
2-Methyl-6-phenyl-N-(3-(trifluoromethyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-
5-amine (8g)
Dark brown solid, (17 mg, 35%); m.p. = 204-206°C; IR (DCM, cm−1): 3291, 1643,
1445, 1336, 1275, 1165, 1122, 1014, 750, 696; 1H NMR (400 MHz, CDCl3): δ 7.87-7.85 (d,
J = 8 Hz, 2H), 7.37-7.33 (t, J = 8 Hz, 2H), 7.30-7.24 (m, 2H), 7.11-7.09 (d, J = 8 Hz, 1H),
6.95 (s, 1H), 6.79-6.78 (d, J = 4 Hz, 1H), 5.82 (s, 1H), 2.66 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 160.02, 145.52, 143.05, 139.40, 133.18, 130.03, 128.65, 127.58, 125.99, 119.88,
116.73, 110.69, 17.89; MS (ESI-TOF) m/z: [M + H]+ calcd 375.08, found 375.08; Elemen-
tal analysis: C18H13F3N4S calcd C, 57.75; H, 3.50; F, 15.22; N, 14.97; S, 8.56 found: C, 57.88;
H, 3.54; N, 14.87; S, 8.62.

12
R. RAWAT AND S. M. VERMA
4-((2-Methyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)amino)phenol (8h)
Dark brown solid, (17 mg, 34%); m.p. = 275-277°C; IR (DCM, cm−1): 3311, 2951,
2838, 1649, 1449, 1112, 1014, 749; 1H NMR (400 MHz, MeOD): δ 8.64 (s, 1H), 7.81-7.77
(m, 3H), 7.44-7.42 (d, J = 1 Hz, 1H), 7.34-7.30 (t, 1H), 7.20-7.18 (m, 2H), 6.62-6.58 (t,
J = 8 Hz, 2H), 5.33 (s, 1H), 2.67 (s, 3H); 13C NMR (100 MHz, MeOD) δ 160.40, 136.34,
131.16, 129.08, 128.99, 128.41, 127.85, 127.45, 125.94, 118.96, 116.64, 114.87, 29.56; MS
(ESI-TOF) m/z: [M + H]+ calcd 323.09, found 323.04; Elemental analysis: C17H14N4OS
calcd C, 63.34; H, 4.38; N, 17.38; O, 4.96; S, 9.94 found: C, 63.40; H, 4.40; N, 17.33; S, 9.82.
N-(2,4-diMethylphenyl)-2-methyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-
amine (8i)
Dark brown solid, (20 mg, 40%); m.p. = 252-254°C; IR (DCM, cm−1): 3305, 2951,
2842, 1646, 1409, 1113, 1013; 1H NMR (400 MHz, CDCl3): δ 7.96-7.94 (d, J = 8 Hz, 2H),
7.39-7.35 (t, J = 8 Hz, 2H), 7.29-7.25 (t, J = 8 Hz, 1H), 7.10-6.98 (m, 2H), 6.56-6.46 (m,
1H), 5.53 (s, 1H), 2.70 (s, 3 H), 2.19 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 160.00, 142.95,
138.00, 136.00, 134.00, 130.54, 128.58, 128.02, 127.24, 126.01, 115.50, 111.28, 29.81, 20.13,
18.89, 17.96; MS (ESI-TOF) m/z: [M + Na]+ calcd 335.13, found 395.20; Elemental analy-
sis: C19H18N4S calcd C, 68.24; H, 5.43; N, 16.75; S, 9.59 found: C, 68.36; H, 5.40; N, 16.69;
S, 9.64.
N-(4-Methoxyphenyl)-2-methyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-
amine (8j)
Yellow brown solid, (21 mg, 43%); m.p. = 191-193°C; IR (DCM, cm−1): 3367, 2989,
2977, 1709, 1638, 1506, 1463, 1378, 1260, 750; 1H NMR (400 MHz, CDCl3): δ 7.92-7.91
(d, J = 4 Hz, 2H), 7.38-7.22 (m, 4H), 6.92 (s, 2H), 6.67 (s, 1H), 5.54 (d, 1H), 2.45 (s, 3H),
1.68 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.82, 129.53, 127.94, 126.71, 125.14, 115.53,
113.59, 34.91, 17.64; MS (ESI-TOF) m/z: [M + H]+ calcd 337.11, found 337.45; Elemental
analysis: C18H16N4OS calcd C, 64.27; H, 4.79; N, 16.65; O, 4.76; S, 9.53 found: C, 64.30; H,
4.84; N, 16.75; S, 9.46.
Acknowledgment
The authors thank Birla Institute of Technology, Mesra for providing the infrastructural facility.
Ravi Rawat is also thankful to All India Council for Technical Education, New Delhi for providing
National Doctoral Fellowship. Both authors thank AICTE, New Delhi for providing project grant
8-37/RIFD/RPS-NDF/Policy-1/2018-19 under the RPS-NDF scheme.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Funding
This work was supported by All India Council for Technical Education: [Grant Number
8-37/RIFD/RPS-NDF/Policy-1/2018-19].

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