On water catalyst-free synthesis of benzo[: D] imidazo[2,1- b] thiazoles and novel N -alkylated 2-aminobenzo [d] oxazoles under microwave irradiation

Article abstract of DOI:10.1039/c9ra08929b

A highly efficient unprecedented catalyst-free microwave-assisted procedure for synthesizing benzo[d]imidazo[2,1-b]thiazoles and N-alkylated 2-aminobenzo[d]oxazol in green media was developed. The transformation provided rapid access to functionalized ben

Full text of DOI:10.1039/c9ra08929b

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PAPER
On water catalyst-free synthesis of benzo[d]
imidazo[2,1-b] thiazoles and novel N-alkylated 2-
aminobenzo[d]oxazoles under microwave
irradiation†‡
Cite this: RSC Adv., 2020, 10, 770
*
Narasimharao Mukku and Barnali Maiti
A highly efficient unprecedented catalyst-free microwave-assisted procedure for synthesizing benzo[d]
imidazo[2,1-b]thiazoles and N-alkylated 2-aminobenzo[d]oxazol in green media was developed. The
transformation provided rapid access to functionalized benzo[d]imidazo[2,1-b]thiazoles from 2-
aminobenzothiazole and N-alkylated 2-aminobenzo[d]oxazole from 2-aminobenzoxazole scaffolds
under mild transition-metal-free conditions. This synthetic manipulation is expected to greatly expand
the repertoire of reaction types in heterocyclic chemistry and pave the way for new syntheses of
bioactive compounds.
Received 30th October 2019
Accepted 10th December 2019
DOI: 10.1039/c9ra08929b
rsc.li/rsc-advances
derivatives have been used to treat interval loss of nerve func-
tion (F) (Fig. 1).22,23
Introduction
The extraordinarily satisfying properties of the benzo[d]imi-
dazo[2,1-b]thiazole- and benzo[d]oxazole-related drugs have
motivated organic chemists to set out to synthesize, using
simple methodologies, a great number of novel chemothera-
peutic agents. In recent years, the syntheses of benzo[d]imidazo
[2,1-b]thiazoles and benzo[d]oxazole derivatives have attracted
much attention.
Syntheses of nitrogen-containing fused heterocyclic small
molecules are attracting increasing attention in medicinal
chemistry, drug design, and advanced materials due to their
structural complexities.1–4 These architecturally complex mole-
cules are frequently used as biological probes in living systems
as well as drugs in medicine because their diverse heteroatoms
can bind different locations of biological macromolecules.
Researchers in pharmaceutical industries and academicians are
highly interested in the synthesis of fused heterocyclic small
molecules owing to their pharmaceutical activities and thera-
peutic potential. For studying cell biology and the treatment of
diseases, diverse heterocyclic small molecules are extremely
important as they modulate the function of enzymes and
receptors.5–8 In this context, benzo[d]imidazo[2,1-b]thiazoles
and benzo[d]oxazole derivatives are members of an essential
class of heterocycles that have gained signicant attention
owing to their broad spectrum of important bioactivities. Benzo
[d]imidazo[2,1-b]thiazoles have been reported to serve as
a potent non-sedative anxiolytic (A),9,10 powerful anticancer
agent (B),11–14 PET imaging probe of b-amyloid plaques in the
brains of Alzheimer's patients (C),15–17 kinase inhibitor (D),18–20
and antimicrobially active molecule (E),21 while benzo[d]oxazole
A careful literature survey revealed many reports on the
designs of heteroannulation reactions of 2-aminobenzothiazoles
with a-bromoketones in organic solvents.24–27 For instance, Hajra
et al. developed an elegant protocol for iron-catalyzed syntheses
of benzo[d]imidazo[2,1-b]thiazoles from reactions of 2-amino-
benzothiazoles with ketones/chalcones.28 Furthermore, in 2016,
the research groups of Jeong developed FeCl3-catalyzed reactions
of 2-aminobenzothiazoles with aldehydes and nitro alkane to
produce fused heterocycles.29 In 2015, Zhu et al. established
Cu(OAc)2-promoted cycloaddition reactions of a-methylenyl iso-
cyanides with 2-methyl benzothiazole to produce benzo[d]imi-
dazo[2,1-b]thiazoles.30 Similarly, Meshram et al. developed Cu(II)
and ionic liquid co-catalysed syntheses of fused heterocycles.31 In
2017, Volkova et al. synthesized diverse benzo[d]imidazo[2,1-b]
thiazoles by performing copper (I, II)-catalysed reactions of
2-aminobenzothiazoles with aldehydes and alkynes in a contin-
uous-ow reactor.32 Subsequently, Deng et al. developed metal-
free syntheses of benzo[d]imidazo[2,1-b]thiazoles from 2-amino-
benzothiazoles with cyclic ketones and elemental sulfur and
oxygen.33 In the same year, Zhang et al. developed a catalytic
oxidative cyclisation of 2-aminobenzothiazole with 2-phenox-
yacetophenone under oxygen using a CuI catalyst.34 Recently,
Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology,
Vellore-632014, India. E-mail: barnalimaiti.m@gmail.com
† The article is dedicated to Prof. Chung Ming Sun for his contributions to
diversity-oriented synthesis.
‡ Electronic supplementary information (ESI) available: 1H and 13CNMR, GCMS,
IR, HRMS spectra of compounds 3a–3l, and 5a–5d ESI page no 2–33. See DOI:
10.1039/c9ra08929b
´
a one-pot GroebkeꢀBlackburnꢀBienayme synthetic protocol was
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Fig. 1 Selected biologically active benzo[d]imidazo[2,1-b]thiazoles and benzo[d]oxazole derivatives.
´
˜
employed by Sharada et al. and the Gamez-Montan group to a continuation of our quest to develop new synthetic method-
synthesize these privileged heterocycles (Scheme 1).35–37 ologies using sustainable chemistry,47–50 we developed in the
Although the above methodologies are impressive, the currently described work a simple and facile procedure for the
development of an efficient and transition-metal-free approach transition-metal-free synthesis of benzo[d]imidazo[2,1-b]thia-
for the diversity-oriented synthesis of both benzo[d]imidazo[2,1- zoles and novel N-alkylated 2-aminobenzo[d]oxazoles in H2O-
b]thiazoles and novel N-alkylated 2-aminobenzo[d]oxazoles IPA under microwave irradiation.
derivatives using a simple methodology remains a challenging
yet attractive task. Most of the syntheses developed so far suffer
serious drawbacks such as the use of transition metals, harsh
Results and discussion
reaction conditions, use of toxic solvents, long reaction times
At the outset, we employed 2-aminobenzothiazole 1 with 2-
and limited substrate scope.38–42 Therefore, it is warranted to
bromoacetophenone 2 as a suitable substrate, for reaction
devise a new strategy to construct these privileged scaffolds in
discovery and optimization, results of which are shown in Table
a sustainable pathway, which forms the core of modern organic
1. Carrying out the reaction in a room-temperature solvent-free
synthesis. The application of microwave (MW) irradiation
condition for 6 h did not yield any benzo[d]imidazo[2,1-b]thia-
together with green solvents has gained signicant attention in
zole product 3 (Table 1, entry 1). However, upon increasing the
recent years because of the extremely rapid growth in the
reaction temperature to 100 ꢁC, the product yield of compound
generation of products in non-ammable, nontoxic environ-
3 improved to 50% (Table 1, entry 2). Next we tested performing
ments of green solvents. MW irradiation offers several advan-
the reaction in polar aprotic solvents such as CH2Cl2 and
tages such as rapid and instantaneous heating, high
CH3CN at their reuxing temperatures for 6 h; little improve-
homogeneity of temperature, and decreased formation of side
ment in the product yield of 3 was found (Table 1, entry 3, 4).
products. By choosing appropriate MW irradiation parameters,
Even performing the heterocyclisation reaction in a high-
reaction selectivity can be attained and the rates of reactions
ꢁ
boiling-point solvent like DMSO at 100 C for 6 h did not have
can be increased. Compounds in polar solvents can more
much of an impact on the product yield of 3 (Table 1, entry 5).
quickly absorb MW energy than can compounds in relatively
Interestingly, the product yield of 3 dramatically increased to
apolar solvents.43–46 In an effort to solubilize organic
65% when we performed the reaction in a polar protic solvent
compounds in water, isopropyl alcohol (IPA) as a polar protic
such as reuxing ethanol (Table 1, entry 6). And when we per-
organic co-solvent is used as a reaction medium that can easily
formed the same set of reactions in an H2O-IPA medium as
absorb microwave power for efficient product generation.
a green solvent at 100 ꢁC for 2 h, the yield of the product 3 was
Moreover IPA is a powerful, nontoxic, unusual ‘green’ solvent
observed to be 90% (Table 1, entry 7). And when subsequently
that can easily solubilize organic compounds and efficiently
ꢁ
applying microwave irradiation at a temperature of 100 C and
absorb MW power. In our research, we set out to develop
pressure of 15 bar, the yield of product 3 increased dramatically
expedient catalyst-free green chemical syntheses of benzo[d]
to 95% in 15 minutes of reaction time (Table 1, entry 8). The
imidazo[2,1-b]thiazoles and novel N-alkylated 2-aminobenzo[d]
advantages of microwave irradiation combined with H2O-IPA as
oxazoles using H2O-IPA as the preferred reaction medium under
a reaction medium included a reduction of the reaction time
MW irradiation. This synthetic methodology was found to offer
along with the elimination of side product formation, showing
several advantages in comparison to the already reported
the process to be environmentally benign and economical. Next
synthesis protocols, such as excellent yields with high purity,
we evaluated the scope of the reaction by employing substituted
avoidance of toxic transition-metal catalysts, a broad substrate
2-aminobenzothiazoles 1 and phenacyl bromides 2. Interest-
scope, and green and economical process resulting from the use
ingly, for both 1 and 2, the product yield was not affected by the
of
a combination of H2O-IPA with MW irradiation. In
substituent group. Whether electron-withdrawing or electron-
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Scheme 1 Heterocyclisation of 2-aminobenothiazole: previous and present work.
donating substituents were used, efficient heterocyclisation in reduced pressure, extraction, and solvent evaporation, all without
the microwave irradiation conditions occurred smoothly to the use of column chromatography.
result in the corresponding benzo[d]imidazo[2,1-b]thiazole
products 3 in excellent yields.
Finally the identities of the puried products were conrmed
1
by characterizing them spectroscopically, specically using H
All of these reactions were performed under high-pressure NMR, 13C NMR, and mass spectroscopy (MS).
microwave conditions in typically 12–15 minutes. Table 2 shows
To further examine the efficiency of this heterocyclisation
the substrate scope for the efficient synthesis of substituted benzo reaction and to swily expand our unique compound library, we
[d]imidazo[2,1-b]thiazoles in green media. Aer completion of the extended the substrate scope to 2-aminobenzoxazoles 4 as
reactions, the corresponding benzo[d]imidazo[2,1-b]thiazole suitable substrates. We reacted the 2-aminobenzoxazole 4 with
derivatives were obtained with excellent yields and then simple a-bromoketone 2a in the same microwave irradiation condition
work-ups were carried out involving removal of solvents under as described above for 15 minutes, and this reaction only
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Table 1 Optimization of the heterocyclisation reactiona
Entry
Solvent
Temperature
rt
Time (h)
Yieldc (%)
1
2
3
4
5
6
7
8
Neat
Neat
6
6
6
6
6
6
2
0.25
0
100 ꢁ
C
50
15
10
15
65
90
95
CH2Cl2
CH3CN
DMSO
EtOH
H2O-IPA
H2O-IPA
Reux
Reux
100 ꢁ
C
80 ꢁ
C
100 ꢁ
C
MW, 100b ꢁC
a
b
Reaction was performed using 1a (1 mmol), 2a (1 mmol), H2O-IPA (4 ml, 1 : 1). Microwave reaction were carried out in Biotage Initiator
Microwave Synthesizer operated at 2450 MHz at 15 bar pressure. c Yield of the isolated product.
produced the N-alkylated 2-amino benzo[d]oxazoles 5a, and did localization of the lone pair of electrons of oxygen on the oxygen
so in 90% yield, as shown in Scheme 2.
atom of the 2-amino benzo[d]oxazole moiety further deactivated
Furthermore, to obtain the cyclised benzo[d]imidazo[2,1-b] the nitrogen atom of the amine group to attack the adjacent
oxazoles 6, we tested various polar aprotic and polar protic carbonyl moiety. Finally using the variously substituted a-bro-
solvents in various conditions as outlined in Table 1; here, no moketones 2, we obtained N-alkylated 2-amino benzo[d]oxazole
cyclised product 6 was found. This result was probably due to products 5 in good yield, as shown in Table 3.
the oxygen atom of the 2-amino benzo[d]oxazole moiety being
Next, to evaluate the drug-like properties of the synthesized
more electronegative than the sulphur atom of 2-amino- compounds in our libraries, we applied Lipinski's rule of ve by
benzothiazole. Furthermore, the presumably relatively high calculating the molecular weight, clog P, the number of
Table 2 Substrate scope for the syntheses of substituted benzo[d]imidazo[2,1-b]thiazoles 3
Entry
R1
(C6H5)R2
Yielda
LRMSb
H-bond donor
H-bond acceptor
clog Pc
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
H
H
H
H
H
7-OEt
7-OEt
7-OEt
7-NO2
7-NO2
C6H5
95
94
93
95
96
92
90
94
94
92
90
92
250
264
280
246
275
318
295
308
362
330
295
363
0
0
0
0
0
0
0
0
0
0
0
0
2
2
3
4
3
2
3
3
3
3
4
4
4.86
5.36
4.87
2.94
4.29
5.74
4.60
5.90
6.28
5.69
4.61
5.50
4-(C6H5)CH3
4-(C6H5)OCH3
–CO2Et
4-(C6H5)CN
4-(C6H5)–CF3
4-(C6H5)NO2
4-(C6H5)CH3
4-(C6H5)–CF3
2,4-(C6H5)(F)2
C6H5
3j
3k
3l
4-(C6H5)CF3
a
Isolated yields. b LMRS was recorded by using the GC-MS method. c clog P estimated by using by ChemBioOffice 2010.
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Scheme 2 Attempted synthesis of substituted benzo[d]imidazo[2,1-b]oxazoles in green media.
Table 3 Substrate scope for the synthesis of N-alkylated 2-amino benzo[d]oxazoles 5
Entry
R1
(C6H5)R2
Yielda
LRMSb
H-bond donor
H-bond acceptor
clog Pc
5a
5b
5c
5d
5e
5f
H
H
H
H
H
5-CI
C6H5
94
93
94
94
92
93
253
283
287
321
289
317
1
1
1
1
1
1
4
5
4
4
4
5
ꢀ0.39
ꢀ0.17
0.39
4-(C6H5)OCH3
4-(C6H5)CI
4-(C6H5)CF3
2,4-(C6H5)(F)2
4-(C6H5)OCH3
0.62
ꢀ0.45
0.39
a
Isolated yields. b LRMS was recorded by using the GC-MS method. c clog P estimated by using by ChemBioOffice 2010.
hydrogen bond donors and acceptors and the number of present synthetic protocol for large-scale syntheses of benzo[d]
rotatable bonds of each member of the library. The rule predicts imidazo[2,1-b]thiazole scaffolds.
than an organic molecule can have drug-like physical properties
Based on the experimental results of the reaction, a plausible
if its molecular weight is less than 500, its clog P value is not mechanistic pathway for this heteroannulation reaction was
more than 5, and it has no more than 10 and 5 hydrogen bond derived, and this pathway is outlined in Scheme 4. According to
acceptors and donors, respectively. However, a molecule this proposed pathway, the reaction occurred via a sequence of
violating just one of the Lipinski rules may still be considered as steps involving a nucleophilic bromo-substitution by the N-
a potential drug candidate. Fortunately the predicted values of atom of 2-amino benzothiazole to lead to the N-alkylated adduct
drug-like properties for these synthesized compounds were a, which on liberation of HBr formed the intermediate b fol-
found to be within the accepted limits of Lipinski's rule of ve, lowed by an intramolecular cyclization to obtain intermediate c.
as shown in Tables 2 and 3.
The nal step of the reaction involved the elimination of a water
In addition, we have demonstrated the potential utility of molecule from intermediate c to afford benzo[d]imidazo[2,1-b]
this synthetic protocol on the gram scale by using the model thiazole 3 derivatives. Furthermore, according to the proposed
reaction. As shown in Scheme 3, the reaction afforded 1.5 g of 3a mechanism, the reactions of 2-aminobenzoxazole with a-bro-
in 95% yield, demonstrating the potential applications of the moketones involved selective substitution by the secondary
amine of 2-aminobenzo[d]oxazol, leading to the N-alkylated 2-
Scheme 3 Gram-scale catalyst-free synthesis of benzo[d]imidazo[2,1-b] thiazole 3a.
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Scheme 4 A plausible mechanism for the syntheses of benzo[d]imidazo[2,1-b]thiazole derivatives.
aminobenzo[d]oxazol derivatives. The lack of any observed a PerkinElmer Clarus 600 GC MS spectrometer. IR spectra were
hetero annulation was attributed to the greater electronegativity recorded using a Bomen DA8 3 FTS spectrometer. Microwave
of oxygen than of sulphur resulting in the electron pair on the reactions were carried out in a 2011 model Biotage Initiator
oxygen atom being more localized and hence further deacti- Microwave Synthesizer, SW version: 4.1.3. Build 11768 using an
vating the benzoxazole moiety for hetero cyclisation. In addi- IR sensor as internal probe for the control of temperature and
tion, an attempted reaction in a sealed tube with microwave compressed air system for cooling.
irradiation for a long time did not facilitate the hetero-
annulation reactions, indicative of a relative lack of delocal-
ization of the benzoxazole moiety oxygen electron pair for
heterocyclisation compared to that of the benzothiazole moiety
sulphur electron pair.
Representative procedure for the synthesis of benzo[d]
imidazo[2,1-b]thiazole 3a
In a 10 ml microwave vial, 2-aminobenzothiazole 1a (0.125 mg,
0.83 mmol, 1.0 equiv.) and 2-bromo acetophenone 2a (0.165 mg,
0.83 mmol, 1.0 equiv.) were added to 4 ml of H2O-IPA (1 : 1). The
reaction mixture was irradiated with microwaves for 15 min at
100 ꢁC and 15 bar pressure. Aer completion of the reaction as
monitored using TLC, the reaction mixture was cooled to room
temperature and the solvent was removed under reduced
pressure. The precipitated solid product was ltered and
washed with ice-cooled ether (10 ml) and dried under vacuum to
obtain benzo[d]imidazo[2,1-b]thiazole 3a in 95% yield.
Conclusions
In summary, we have demonstrated a novel green methodology
for the syntheses of benzo[d]imidazo[2,1-b]thiazoles and N-
alkylated 2-aminobenzo[d]oxazoles from 2-amino benzothia-
zoles and 2-aminobenzoxazoles with a-haloketone under
microwave irradiation in a green medium. The prominent
features of this approach include green reaction environments,
high atom economy, single synthetic operation, relatively short
reaction time, high yield, and the lack of any need to perform
chromatographic purication. These features coupled with the
reaction being conducted under microwave irradiation and
without the use of toxic transition-metal catalysts as well as
being operationally simple and involving the use of inexpensive
starting materials make the method potentially scalable and
useful for the preparation of a wide range of analogues.
Representative procedure for the synthesis of 2-amino-3-(2-(4-
methoxyphenyl)-2-oxoethyl)benzo[d]oxazol-3-ium 5a
In a 10 ml microwave vial, 2-aminobenzoxazole 4a (0.134 mg,
1.00 mmol, 1.0 equiv.) and 2-bromo acetophenone 2a (0.198 mg,
1.00 mmol, 1.0 equiv.) were added to 4 ml of H2O-IPA (1 : 1). The
reaction mixture was irradiated with microwaves for 15 min at
100 ꢁC and 15 bar pressure. Aer completion of the reaction as
monitored using TLC, the reaction mixture was cooled to room
temperature and the solvent was removed under reduced
pressure. The precipitated solid product was ltered and
washed with ice-cooled ether (10 ml) and dried under vacuum to
Experimental section
Substituted 2-aminobenzothiazoles, 2-aminobenzoxazoles and
substituted 2-bromo acetophenones purchased from Sigma
Aldrich and solvents from commercial suppliers were used
obtain
2-amino-3-(2-(4-methoxyphenyl)-2-oxoethyl)benzo[d]
oxazol-3-ium 5a in 95% yield.
1
without further purication. H NMR and 13C NMR data were
2-Phenylbenzo[d]imidazo[2,1-b]thiazole (3a)28
recorded using a Bruker DRX400 spectrometer (400 MHz).
Chemical shis are reported in ppm relative to an internal Yield: 95%, white solid; mp: 88–90 C, Rf: 0.5% (40% EtOAc/n-
ꢁ
1
standard. Coupling constant (J) values are given in Hz. Multi- Hexane); H NMR (400 MHz, CDCl3) 7.87 (s, 1H), 7.79 (d, J ¼
plicities of peaks are given as d (doublet), m (multiplet), s 7.52 Hz, 2H), 7.60 (d, J ¼ 7.96 Hz, 1H), 7.50 (d, J ¼ 8.0 Hz, 1H),
(singlet), and t (triplet). Mass spectra were recorded using 7.37–7.32 (m, 3H), 7.24–7.18 (m, 2H); 13C NMR (100 MHz,
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2-(4-Nitrophenyl)benzo[d]imidazo[2,1-b]thiazole (3g)30
CDCl3) d 148.1, 147.7, 133.8, 132.1, 130.3, 128.7, 127.5, 126.2,
125.2, 124.9, 124.4, 112.6, 106.9. MS (GC-MS): 250; IR
(KBr, cmꢀ1): 3134, 1599, 1580, 1490, 1256.
ꢁ
Yield: 90%; brown solid; mp: 250–252 C, Rf: 0.6 (40% EtOAc/n-
hexane); 1H NMR (400 MHz, DMSO-d6) d 9.03 (s, 1H), 8.28 (d, J ¼
8.8 Hz, 1H), 8.24 (m, 1H), 8.10 (d, J ¼ 8.8 Hz, 2H), 8.00 (dd, J ¼ 8.0,
1.6 Hz, 2H), 7.57 (t, J ¼ 7.2 Hz, 1H), 7.46–7.42 (m, 1H), 13C NMR
(400 MHz, DMSO-d6) d 146.5, 145.8, 145.6, 141.9, 140.9, 137.2,
132.0, 130.0, 129.9, 127.1, 126.0, 125.6, 125.4, 114.0, 112.3; MS
(GC-MS): 295; IR (KBr, cmꢀ1): 3148, 1595, 1492, 1323, 1103, 852.
2-(p-Tolyl)benzo[d]imidazo[2,1-b]thiazole (3b)28
Yield: 94%; brown solid; mp: 105–107 ꢁC, Rf: 0.4 (30% EtOAc/n-
1
hexane); H NMR (400 MHz, CDCl3) d 7.86 (s, 1H), 7.69 (d, J ¼
8.0 Hz, 2H), 7.62 (d, J ¼ 8.0 Hz, 1H), 7.52 (d, J ¼ 8.0 Hz, 1H),
7.40–7.36 (m, 1H), 7.28–7.24 (m, 1H), 7.16 (d, J ¼ 8.0 Hz, 1H),
2.31 (s, 3H). 13C NMR (100 MHz, CDCl3) d 148.0, 147.8, 137.3,
132.2, 131.1, 130.3, 129.4, 126.2, 125.1, 124.8, 124.4, 112.6,
106.4, 21.3; MS (GC-MS): 264; IR (KBr, cmꢀ1): 3139, 1550, 1485,
1253, 821, 725.
7-Ethoxy-2-(p-tolyl)benzo[d]imidazo[2,1-b]thiazole (3h)
Yield: 94%; brown solid; mp: 175–177 ꢁC; Rf: 0.6 (40% EtOAc/n-
1
hexane); H NMR (400 MHz, CDCl3) d 7.78 (s, 1H), 7.67 (d, J ¼
8.0 Hz, 2H), 7.42–7.38 (m, 1H), 7.16 (s, 1H), 7.14–7.11 (m, 1H),
4.03–3.94 (m, 2H), 2.30 (s, 3H), 1.39 (t, J ¼ 7.2 Hz, 3H).13C NMR
(100 MHz, CDCl3) d 156.5, 147.3, 137.2, 131.4, 131.1, 129.4,
127.0, 126.3, 125.0, 114.0, 113.0, 109.4, 106.4, 64.3, 21.3, 14.8.
HRMS (ESI, m/z): calcd for C18H16N2OSH [M + H]+: 309.1062.
Found: 309.1064, IR (KBr, cmꢀ1) 2974, 1601, 1548, 1498, 1260,
1244, 1056, 825.
2-(4-Methoxyphenyl)benzo[d]imidazo[2,1-b]thiazole (3c)28
ꢁ
Yield: 93%; white solid; mp: 168–170 C; Rf: 0.6 (40% EtOAc/n-
1
hexane); H NMR (400 MHz, CDCl3) d 7.88 (s, 1H), 7.80 (d, J ¼
8.5 Hz, 2H), 7.69 (d, J ¼ 8.0 Hz, 1H), 7.59 (d, J ¼ 8.0 Hz, 1H), 7.45
(t, J ¼ 7.7 Hz, 1H), 7.33 (t, J ¼ 7.7 Hz, 1H), 6.96 (d, J ¼ 8.5 Hz,
2H), 3.85 (s, 3H); 13C NMR (100 MHz, CDCl3) d 159.4, 147.9,
147.6, 132.3, 130.2, 126.7, 126.5, 126.2, 124.7, 124.4, 114.2,
112.6, 105.9, 55.3. MS (GC-MS): 280; IR (KBr, cmꢀ1): 2835, 1545,
1485, 1398, 1238, 831.
7-Ethoxy-2-(4-(triuoromethyl)phenyl)benzo[d]imidazo[2,1-b]
thiazole (3i)
ꢁ
Yield: 94%; white solid; mp: 177–180 C, Rf: 0.5 (60% EtOAc/n-
1
hexane); H NMR (400 MHz, CDCl3) d 7.94 (s, 1H), 7.87 (d, J ¼
8.0 Hz, 2H), 7.57 (d, J ¼ 8.4 Hz, 2H), 7.44 (d, J ¼ 8.8 Hz, 1H), 7.13
(d, J ¼ 2.4 Hz, 1H), 6.95 (d, J ¼ 8.8, 2.4 Hz, 1H), 4.00 (q, J ¼ 7.2 Hz,
2H), 1.39 (t, J ¼ 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 156.9,
147.9, 145.5, 137.2, 131.5, 128.9, 126.0, 125.7 (d, JCF ¼ 3.8 Hz),
125.1, 114.2, 113.3, 109.4, 107.9, 64.4, 14.8. HRMS (ESI, m/z):
calcd for C18H13F3N2OSH [M + H]+: 363.0779. Found: 363.0775, IR
(KBr, cmꢀ1) 1614, 1500, 1475, 1317, 1161, 1105, 1060, 833.
Ethyl benzo[d]imidazo[2,1-b]thiazole-2-carboxylate (3d)25
Yield: 95%; white solid; mp: 95–97 ꢁC, Rf: 0.6 (30% EtOAc/n-
hexane); 1H NMR (400 MHz, DMSO-d6) d 9.03 (s, 1H), 8.16 (d, J ¼
8.0 Hz, 1H), 8.04 (d, J ¼ 8.0 Hz, 1H), 7.57 (t, J ¼ 7.7 Hz, 1H), 7.48
(t, J ¼ 7.7 Hz, 1H), 4.30 (q, J ¼ 7.2 Hz, 2H), 1.32 (t, J ¼ 7.2 Hz,
3H). 13C NMR (100 MHz, DMSO-d6) d 162.3, 148.0, 137.8, 131.8,
130.3, 127.3, 126.7, 125.5, 119.6, 114.8, 60.7, 14.8. MS (GC-MS):
246; IR (KBr, cmꢀ1): 3125, 1786, 1703, 1525, 1496, 1296, 1232,
1020.
2-(2,4-Diuorophenyl)-7-ethoxybenzo[d]imidazo[2,1-b]
thiazole (3j)
Yield: 92%; white solid; mp: 164–166 ꢁC;, Rf: 0.4 (40% EtOAc/n-
hexane); 1H NMR (400 MHz, CDCl3) d 8.20–8.14 (m, 1H), 7.97 (d,
J ¼ 3.8 Hz, 1H), 7.47 (d, J ¼ 8.8 Hz, 1H), 7.16 (d, J ¼ 2.4 Hz, 1H),
6.98–6.93 (m, 2H), 6.90–6.84 (m, 1H), 4.05 (q, J ¼ 6.9 Hz, 2H),
1.44 (t, J ¼ 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 163.0 (d, JCF
¼ 12 Hz), 160.5 (q, JCF ¼ 12 Hz), 158.2 (d, JCF ¼ 12 Hz), 156.7,
147.1, 139.7, 131.4, 128.7 (q, JCF ¼ 5 Hz), 126.2, 118.2 (q, JCF ¼ 4
Hz), 113.9, 113.2, 111.6 (dd, JCF ¼ 21.0, 4.0 Hz), 110.4 (d, JCF ¼ 15
Hz), 109.4, 103.9 (t, JCF ¼ 26 Hz), 64.3, 14.8. HRMS (ESI, m/z):
calcd for C17H12F2N2OSH [M + H]+: 331.0717. Found: 331.0712.
IR (KBr, cmꢀ1): 2986, 1577, 1497, 1481, 1259, 1061, 1041, 845.
4-(Benzo[d]imidazo[2,1-b]thiazol-2-yl)benzonitrile (3e)33
Yield: 96%; white solid; mp: 210–212 ꢁC, Rf: 0.5% (40% EtOAc/n-
hexane); 1H NMR (400 MHz, DMSO-d6) d 8.97 (s, 1H), 8.04–8.00
(m, 3H), 7.97 (d, J ¼ 8.0 Hz, 1H), 7.86 (d, J ¼ 8.0 Hz, 2H), 7.57 (t, J
¼ 8.0 Hz, 1H), 7.44 (t, J ¼ 8.0 Hz, 1H), 13C NMR (100 MHz,
DMSO-d6) d 148.2, 144.8, 138.7, 133.3, 132.0, 129.8, 127.7, 126.0,
125.6, 123.2, 119.5, 114.0, 118.8, 109.7; MS (GC-MS): 275; IR
(KBr, cmꢀ1): 3053, 2220, 1605, 1493, 1408, 837.
2-(4-(Triuoromethyl)phenyl)benzo[d]imidazo[2,1-b]thiazole
7-Nitro-2-phenylbenzo[d]imidazo[2,1-b]thiazole (3k)32
(3f)28
Yield: 90%; white solid; mp: 218–220, Rf: 0.6 (30% EtOAc/n-
Yield: 92% light-brown solid; mp: 136–138 ꢁC; Rf: 0.6 (40% hexane); 1H NMR (400 MHz, DMSO-d6) d 9.12 (d, J ¼ 2 Hz, 1H),
1
EtOAc/n-hexane) H NMR (400 MHz, DMSO-d6) d 8.30 (s, 1H), 8.91 (s, 1H), 8.47 (dd, J ¼ 2.0, 8.8 Hz, 1H), 8.17 (d, J ¼ 8.8 Hz,
7.93 (d, J ¼ 7.6 Hz, 2H), 7.74–7.69 (m, 2H), 7.57 (d, J ¼ 7.6 Hz, 1H), 7.88 (d, J ¼ 7.6 Hz, 2H), 7.46 (t, J ¼ 7.6 Hz, 2H), 7.33 (t, J ¼
2H), 7.47–7.42 (m, 1H), 7.34–7.31 (t, J ¼ 7.2 Hz, 1H). 13C NMR 7.6 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) d 149.3, 147.7, 144.6,
(100 MHz, DMSO-d6) d 148.2, 144.8, 136.7, 131.8, 129.9, 129.2, 136.4, 133.8, 131.1, 129.3, 128.7, 125.3, 123.1, 122.1, 114.0,
126.7, 125.7, 125.6, 125.2, 124.5, 113.3, 109.1. MS (GC-MS): 318; 110.1. MS (GC-MS): 295; IR (KBr, cmꢀ1): 3068, 1580, 1500, 1332,
IR (KBr, cmꢀ1): 1616, 1496, 1321, 1101, 1068, 746.
814.
776 | RSC Adv., 2020, 10, 770–778
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7-Nitro-2-(4-(triuoromethyl)phenyl)benzo[d]imidazo[2,1-b]
2-Amino-3-(2-(2,4-diuorophenyl)-2-oxoethyl)benzo[d]oxazol-
thiazole (3l)
3-ium bromide (5e)
ꢁ
Yield: 92%; brown solid; mp: 225–227 ꢁC; Rf: 0.5 (60% EtOAc/n- Yield: 92%; white solid; mp: 125–127 C; Rf: 0.6 (40% EtOAc/n-
1
hexane); H NMR (400 MHz, CDCl3) d 8.62 (d, J ¼ 2.0 Hz, 1H), hexane) 1H NMR (400 MHz, CDCl3) d 8.06 (q, J ¼ 8.4 Hz, 1H), 7.26
8.35 (dd, J ¼ 8.8, 2.2 Hz, 1H), 8.06 (s, 1H), 7.96 (d, J ¼ 8.0 Hz, (d, J ¼ 8.4 Hz, 1H), 7.17–7.12 (m, 2H), 7.07–6.97 (m, 2H), 6.81 (t, J
1H), 7.92 (d, J ¼ 8.0 Hz, 1H), 7.71 (d, J ¼ 8.0 Hz, 1H), 7.63 (d, J ¼ ¼ 3.8 Hz, 1H) 5.15 (d, J ¼ 3.8 Hz, 2H). 13C NMR (100 MHz, DMSO-
8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3) d 135.7, 128.1, 126.1, d6) d 187.6 (d, JCF ¼ 5.8 Hz), 168.2, 165.5 (d, JCF ¼ 12.5 Hz), 164.7
126.0, 125.9, 125.8, 125.6, 122.5, 120.8, 112.6, 108.3. MS (GC- (d, JCF ¼ 12.5 Hz), 162.0 (d, JCF ¼ 12.5 Hz), 154.7, 142.8, 133.2 (q,
MS): 363, HRMS (ESI, m/z): calcd for C16H8F3N3O2SH [M + JCF ¼ 4.6 Hz), 131.1, 123.9, 122.8, 113.2 (d, JCF ¼ 3.0 Hz), 110.3,
H]+: 364.0368. Found: 364.0369, IR (KBr, cmꢀ1): 3421, 3377, 108.4, 51.4 (d, JCF ¼ 13.8 Hz), MS (GC-MS): 289; IR (KBr, cmꢀ1):
1681, 1321, 1107, 1064.
3051, 1749, 1697, 1612, 1485, 1238, 1201, 1109, 1022.
2-Amino-5-chloro-3-(2-(4-methoxyphenyl)-2-oxoethyl)benzo[d]
oxazol-3-ium bromide (5f)
2-Amino-3-(2-oxo-2-phenylethyl)benzo[d]oxazol-3-ium
bromide (5a)
ꢁ
Yield: 93%; white solid; mp: 160–162 C; Rf: 0.6 (40% EtOAc/n-
ꢁ
Yield: 94%; white solid; mp: 140–142 C; Rf: 0.6 (40% EtOAc/n-
hexane).1H NMR (400 MHz, CDCl3) d 8.00 (d, J ¼ 8.4 Hz, 2H),
7.16 (d, J ¼ 8.4 Hz, 1H), 7.10 (d, J ¼ 8.4 Hz, 1H), 7.14 (d, J ¼
8.4 Hz, 1H), 7.00 (d, J ¼ 8.8 Hz, 2H), 6.84 (s, 1H), 5.17 (s, 2H),
3.90 (s, 3H). 13C NMR (100 Hz, CDCl3) d 183.9, 159.9, 136.5,
127.5, 125.8, 124.8, 122.2, 117.9, 109.6, 106.3, 104.6, 50.9, 43.1.
MS (GC-MS): 317; IR (KBr, cmꢀ1): 2933, 1766, 1674, 1486, 1240.
hexane).1H NMR (400 MHz, CDCl3) d 8.11 (d, J ¼ 8.0 Hz, 2H),
7.76 (t, J ¼ 7.6 Hz, 1H), 7.63 (t, J ¼ 7.6 Hz, 2H), 7.41 (d, J ¼ 7.2 Hz,
1H), 7.29 (d, J ¼ 7.6 Hz, 1H), 7.20–7.13 (m, 2H), 5.60 (s, 2H). 13
C
NMR (100 Hz, CDCl3) d 192.7, 154.6, 142.5, 134.8, 134.6, 132.0,
129.4, 128.8, 124.5, 122.9, 110.2, 110.1, 48.8. MS (GC-MS): 253;
IR (KBr, cmꢀ1): 2924, 1766, 1689, 1487, 1224.
Conflicts of interest
2-Amino-3-(2-(4-methoxyphenyl)-2-oxoethyl)benzo[d]oxazol-3-
ium bromide (5b)
Authors have no conict of interest to declare.
ꢁ
Yield: 93%; white solid; mp: 160–162 C; Rf: 0.6 (40% EtOAc/n-
hexane).1H NMR (400 MHz, CDCl3) d 8.01 (d, J ¼ 8.8 Hz, 2H),
7.25–7.23 (m, 1H), 7.16–7.10 (m, 2H), 7.00 (d, J ¼ 8.8 Hz, 2H),
6.85–6.83 (m, 1H), 5.19 (s, 2H), 3.90 (s, 3H). 13C NMR (100 Hz,
CDCl3) d 189.2, 164.5, 154.7, 142.7, 130.5, 127.1, 123.9, 122.7,
114.3, 110.2, 108.7, 55.6, 47.8. MS (GC-MS): 283; IR (KBr, cmꢀ1):
2972, 1765, 1670, 1601, 1572, 1485, 1240, 1174, 1103, 1016.
Acknowledgements
The authors thank DST-Govt of India for funding through DST-
SERB-YSS/2015/00450. The authors also thank the Chancellor
and Vice Chancellor of VIT for providing an opportunity to carry
out this study, and VIT for providing ‘VIT SEED GRANT’ for
carrying out this research work.
2-Amino-3-(2-(4-chlorophenyl)-2-oxoethyl)benzo[d]oxazol-3-
ium bromide (5c)
References
Yield: 94%; pale yellow solid; mp: 176–178 ꢁC; Rf: 0.4 (40%
EtOAc/n-hexane); 1H NMR (400 MHz, CDCl3) d 7.90 (d, J ¼
8.3 Hz, 2H), 7.45 (d, J ¼ 8.3 Hz, 2H), 7.17–7.17 (m, 1H), 7.09–7.07
(m, 2H), 6.78–6.74 (m, 1H), 5.13 (s, 2H). 13C NMR (100 MHz,
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124.0, 122.9, 110.3, 108.6, 48.0. MS (GC-MS): 287; IR
(KBr, cmꢀ1): 2966, 1759, 1689, 1587, 1485, 1400, 1088, 1020.
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