Visible light triggered, catalyst free approach for the synthesis of thiazoles and imidazo[2,1-: B] thiazoles in EtOH:H2O green medium

Article abstract of DOI:10.1039/c6ra05385h

The development of a visible light promoted, mild and greener approach for the synthesis of highly functionalized thiazoles and imidazo[2,1-b]thiazoles under photochemical activation in EtOH:H₂O green medium is demonstrated. The characteristic feature of the present protocol is the utilization of visible light (an omnipresent, nontoxic, environmentally benign and inexpensive reagent) to form C-S and C-N bonds and circumvent the use of catalysts or photosensitizers. The reported protocol is the first example of visible light promoted synthesis of thiazoles and imidazo[2,1-b]thiazoles with various attractive features like being catalyst free, eco-efficient and possessing cost effectiveness, short reaction time, excellent yields and sustainability to fulfill the parameters of green chemistry.

Full text of DOI:10.1039/c6ra05385h

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Visible light triggered, catalyst free approach for the synthesis of thiazoles
and imidazo[2,1-b]thiazoles in EtOH : H2O green medium
Anu Mishra,a Madhulika Srivastava,a Pratibha Rai,a Snehlata Yadav,a Bhartendu Pati Tripathi,a
Jaya Singhb and Jagdamba Singha*
aEnvironmentally Benign Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad-211002
(India); Tel: +919415218507; E-mail: dr.jdsau@gmail.com
bDepartment of Chemistry, LRPG College, Sahibabad, Uttar Pradesh, India.E-mail: nimesh.singh@in.abb.com
Abstract :
The development of a visible light promoted, mild and greener approach for the synthesis of
highly functionalized thiazoles and imidazo[2, 1-b]thiazoles under photochemical activation in
EtOH:H2O green medium is demonstrated. The characteristic feature of the present protocol is
the utilization of visible light (an omnipresent, nontoxic, environmentally benign and
inexpensive reagent) to form C-S, C-N bond and circumlocute the use of catalysts or
photosensitizers. The reported protocol is the first example of visible light promoted synthesis of
thiazoles and imidazo[2, 1-b]thiazoles with various attractive features like being catalyst free,
eco-efficient and possessing cost effectiveness, short reaction time, excellent yields and the
sustainability to fulfill the parameters of green chemistry.
Introduction
Increasing needs are the key to new inventions which lead to new thoughts and new creations.
The frequent use of hazardous solvents and metal catalysts in the laboratory pollutes our
environment severely. Researchers and scientists are thus shifting their focus towards maximum
environmentally benign and sustainable utilization of resources which is capable of being
maintained at a steady level without causing ecological damage or exhausting natural resources.1
The development of visible light mediated synthesis has been recognised as a prominent route
for a number of organic transformations2 because of its ability to provide activation energy to the
reactant in the chemical reactions. Light is an abundant, easily handled, renewable energy source
as well as a valuable tool for a myriad of green chemical reactions and thus has attracted much
attention.3 Chemists have successfully performed a variety of visible light induced reactions and
1

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achieved their goals. Several research groups have used compact fluorescent light (CFL) and
light emmiting diodes (LEDs) as a visible light source for the formation of the target compound.
Easy availability, simple handling, cost effectiveness and safe approach, places this method
under the heading of green chemistry.4
There are several organic molecules which are unable to absorb visible light.5 To
overcome this barrier chemists use photo sensitizers and photo catalysts. In literature different
methods have been reported which incorporate the transition metals, certain organic dyes and
nanoparticles as a photocatalyst.6 However a number of disadvantages associated with trasition
metal photocatalyst as it shows adverse inherent malignancy, short durability and
8c
expensiveness.7 At present, many nanoparticles like ZnO/γ-Mn2O3,8a ZnO/CdO,8b ZnO/V2O5,
8d
ZnO/Ag/Mn2O3 and electrospun nanomaterials8e which also act as photocatalytic substances
and fruitful for degradation of several textile elluent, organic dyes and organic pollutants. But
still nanoparticles exhibit drawbacks as large band gap,8f depletion of crystallinity8g which
consequence less efficiency. Within this context a catalyst free synthesis using green solvent
medium in various synthetic processes has emerged as an important tool.9
Thiazole and its derivatives are present in innumerable natural compounds such as in
epithilone, thiostrepton, TPP (a coenzyme of Krebs cycle), carboxylase vitamin B1 and
antibiotics (penicillin),10 with significant medicinal and biological importance. Thiazoles are
largely associated with medicinal chemistry exhibiting vast applications in drug development for
the treatment of allergies,11 inflammation,12 HIV infections,13 hypertension,14 bacterial
infections,15 hypnotics,16 schizophrenia17 and treatment of pain,18 as new inhibitors of bacterial
DNA gyrase B19 and as fibrinogen receptor antagonists with antithrombotic activity.20 They
express tremendous biological activities such as being antitumor,21 antifungal,22 antimicrobial,23
anti-inflammatory,24 antitubercular,25 anticonvulsant,26 diuretic,27 neuroprotective and having
antioxidant activity.28
2

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Br
Cl
N
O
O
OH
O
H
N
O
N
S
Br
N
N
S
N
N
N
H
NH
Cl
S
O
S
HN
Antimycobacterial agenta
DNA Gyrase inhibitorc
Antifungal agentb
O
S
S
NH
S
N
N.HCl
N
NH
N
S
O
R
NEt2.HCl
N
N
H
CH3
H3C
Anti HIV agentd
Anticancer agente
Antitumor agentf
S
N
O
O
N
R
N
O
S
O
O
N
N
N
O
N
H3C
CH3
O
O
N
Cl
S
H3C
N
CH3
H
Anti-Hepatitis C virusj
Antihypertensive agentg,h
Nonsedative anxiolytici
Figure29a-j Some medicinally important derivatives of thiazole and imidazothiazole
Numerous protocols for the synthesis of thiazoles30 and imidazothiazoles31 using various types of
catalysts and different reaction conditions have been developed. Though the reported methods
have several advantages, there are certain drawbacks associated with these methods example
long reaction time, use of costly catalyst, difficulty in the recovery of high boiling solvent, low
yield of the product, limited availability of starting material, non-reusability of catalyst and
solvent. Thus there was a need to design a more eco-efficient method for the synthesis of
thiazoles. In continuation of our previous work,32 we were encouraged to develop a more
sustainable process for the synthesis of the target scaffold which involved a visible light induced
reaction without the use of a catalyst for the completion of the reaction. Mild reaction conditions
make it a more relevant, efficient and a cleaner methodology for the synthesis of the target
scaffold. (Scheme 1)
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Previous works :
S
H2N
NHR1
2
S
N
NHR1
3
Hazardous solvent/
Metal catalyst/
High Temprature/
Base
O
R
Br
R
S
N
R
1
N
R2
5
S
NH2
R2
N
4
Present work :
S
N
S
NH2
S
R2
O
NHR1
N
R
S
N
H2N
NHR1
Br
2
4
N
CFL (24W)
Ethanol: Water
4:1
CFL (24W)
Ethanol: Water
4:1
R2
3
R
1
5
R
Scheme 1 Synthesis of thiazole (3a) & (5a) derivatives
For optimization studies of visible light mediated two component synthesis of thiazoles and
imidazothiazoles, we carried out two different sets of reactions by the use of phenacyl bromide
(1), N-phenylthiourea (2) and 2-aminothiazole (4) as reactants. Condensation of phenacyl
bromide (1, 1mmol) and N-phenylthiourea (2, 1mmol) and condensation of phenacyl bromide (1,
1mmol) and 2-aminothiazole (4, 1mmol) have been taken as model reactions for the synthesis of
different types of thiazoles. During optimization we examined the effect of different solvents,
different intensities of light sources and varied catalysts under different experimental conditions
to obtain the best condition for the above transformation (Table 1). In our initial endeavour, we
took two reaction mixtures with 1.0 mmol of each reactant in ethanol using CFL (24W)
4

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irradiation as a source of visible light. Under this condition, the condensation of phenacyl
bromide (1) and N-phenyl thiourea (2) gave the product ( 3a) with 85% yield within 10 minutes
and condensation of phenacyl bromide (1) and 2-aminothiazole (4) afforded the product (5a)
with 55% yield within 5 h (Table 1, entry 8). An interesting result was obtained by the
condensation of (1) and (2). Immediate formation of product (3) took place on addition of
second reactant, confirmed by TLC analysis but pure product was formed after 10 minutes.
When the same model reactions were performed under catalyst free conditions in a variety of
other non-polar traditional organic solvents at rt, they resulted in lower yield of the product. In
case of DCM and THF the reaction mixture showed the non-consumption of the starting
reactant materials on TLC and resulted in moderate yield of the product (3a). However, product
(5a) was not formed in case of DCM within 5h (Table 1, entry 4) and took almost 24 h of CFL
irradiation and resulted in trace amount of product (5a); in case of THF product (5a) afforded
very poor yield of the product (Table 1, entry 2). In case of toluene there was a solubility
concern of reactant (2) and that’s why it afforded a very low, 15% yield of product (3a).
However product (5a) was not formed within 5h and took almost 24 h of CFL irradiation to get
the trace amount of the product (5a). In order to increase the yield of the product we next
performed our synthesis in polar solvents like methanol and ethanol. Interestingly there occurred
an increase in yield of the product (3a) and (5a). Now our complete focus on further
improvement of the reaction with respect to time. When we used methanol a small amount of
phenacyl bromide (1) and N-phenyl thiourea (2) remained unutilized after 10 minutes resulted
80% yield of the product (Table 1, entries 7), moreover the pure product (3a) was formed after 1
h with 90% yield; while in case of ethanol, a considerable decrease in reaction time was
observed and pure product was formed with 85% yield (Table 1, entries 8) within 10 minutes.
After that we tried mixed solvent system of EtOH : H2O to carry out the above transformation
and found that EtOH : H2O solvent system proved successful in increasing the yield of the
product (Table 1, entries 9,10,11,12). The utility of ethanol and water is to increase the
solubility of reactants and in turn, the yield of the product. It is also hypothesized that the
transition states of the above reaction would be stabilized by water because of its high static
permittivity.33 The increased yield of product in EtOH:H2O solvent system may be due to the
hydrophobic nature of reactant (1) and (4) in water. This leads to an increase in the number of
collisions between reactants and results in increasing their ground state energy as well as the
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reaction rates. In order to further increase the efficiency of the reaction we used different ratio of
EtOH : H2O solvent system and discovered that (4:1) combination gives the best result (Table 1,
entries 12). At this stage, in quest of eco-friendlier conditions, both the test reactions were
carried out in neat condition without the use of a catalyst.34 No reaction was observed (Table 1,
entries 13). A catalyst free synthesis using EtOH : H2O (4:1) as a solvent is a considerably cost
effective, safer and environmentally benign method for the above transformation.
Table 1 optimization table of solventa
S
S
NH2
O
S
N
H2N
N
NH
N
2 H
Br
S
N
4
CFL (24W)
Solvent
CFL (24W)
Solvent
N
1
5
3
Entry
1
Solvent
Toluene
THF
Time (min)
Yieldb (3a)
Time (h)
Yieldb (5a)
c
10
10
10
10
10
10
10
10
15
65
50
73
75
77
80
85
86
86
93
95
5
5
5
5
5
5
5
5
5
5
5
5
5
-
2
15
c
3
Benzene
DCM
-
c
4
-
5
DMSO
CH3CN
Methanol
EtOH
28
6
Trace
45
7
8
55
9
EtOH:H2O(1:1) 10
EtOH:H2O(2:1) 10
EtOH:H2O(3:1) 10
EtOH:H2O(4:1) 10
55
10
11
12
13
57
59
60
c
c
Neat
10
-
-
aReaction conditions: 1a (1.0 mmol), 2a (1.0 mmol) in solvent were irradiated under open air at
b
room temperature using CFL (24W). Isolated yield of the product (%). cnot detected.
After the realisation of the best solvent system for the synthesis of thiazoles, we investigated
different sources and intensities of visible light irradiation by performing a series of reactions
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using CFL light (18W and 20W) and LEDs (white 7W). It was found that when we performed
the reaction in compact fluorescent lamp (CFL, 24W) in place of LEDs, the product formed
readily (Table 2, entry 1,8). However in the absence of visible light, the rate of formation of
product significantly decreases (Table 2, entry 2, 3). We further performed our test reaction with
photoredox catalyst, eosin Y which is activated by irradiating visible light. It was seen that
although the reaction initially completed a bit faster with 0.5mol% and 1mol% of eosin Y, but
the difference in final yield of the product was marginal (Table 2, entries 1, 9 and 10). Therefore
we selected a catalyst free condition for the required transformation. The presence of oxygen as
an oxidant was important for the formation of the desired product since the product was formed
in traces in the absence of oxygen (Table 2, entries 4, 5). Moreover, the reaction was inhibited
with benzoquinone (2 mmol) (Table 2, entry 11) in optimized state, which indicates that there
may be radical intermediates involved in the reaction.35
Table 2 optimization table of reaction conditionsa
S
S
NH2
O
S
N
H2N
N
NH
N
2 H
Br
S
N
4
Reaction conditions
Ethanol: Water
(4:1)
Reaction conditions
Ethanol: Water
(4:1)
N
1
5
3
Entry
Reaction Condition
Time
(min)
10
Yieldb (3a) Time (h) Yieldb (5a)
1
2
3
4
5
6
7
8
9
24W, CFL, air, no catalyst
Daylight, air, no catalyst
No light, air, no catalyst
CFL , degassed
95
43
34
54
36
87
80
76
96
5
5
5
5
5
5
5
5
5
60
18
10
10
10
c
10
-
c
CFL , N2
10
-
20W, CFL, air, no catalyst
18 W, CFL, air, no catalyst
White LED (7W), no catalyst
CFL, air, eosinY (0.5 mol%)
10
52
40
23
60
10
10
10
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10
11
CFL , air, eosin Y(1mol%)
CFL. Air, Benzoquinoned
10
10
96
52
5
5
60
16
aReaction condition: 1a (1.0 mmol), 2a (1.0 mmol) ) in ethanol: water irradiated using CFL
under open air at room temperature. bIsolated yield of the product (%).cnot detected. d2 mmol.
Once the optimal conditions had been finalised the scope and limitations of the developed
synthetic strategy was explored by the use of a series of different derivatives of phenacyl
bromides (1), thiourea (2) and thiazoles (4). It was observed that the use of phenacyl bromide
(1) bearing an electron withdrawing group showed a significant effect on the yield of the
product. Similarly, use of thiourea with or without phenyl ring affected the yield of the product;
thiourea bearing phenyl ring as a substituent increases the yield of the product, the product being
free from the need of purification. In case of thiourea purification is necessary to obtain the pure
product and the yield of the product also is less as compared to that in the case of N-phenyl
thiourea.
Different types of phenacyl bromide used (1)
O
O
O
O
O
O
Br
Br
Cl
Br
Br
Br
Br
O2N
H3CO
Br
H3C
a
b
c
e
d
f
O
Br
N
g
Different types of thiourea used (2)-
S
S
S
S
S
HN NH
2
HN NH
2
HN NH
2
HN NH
2
HN NH
2
2
CH
2 5
CH
Cl
c
3
e
a
b
d
Different types of thiazoles used (4)-
Cl
S
S
S
NH
NH
NH
2
2
2
N
b
N
N
a
c
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Table 3 Substrate scopea (3)
S
O
S
N
H2N
NHR1
Br
2
NHR1
CFL (24W)
Ethanol: Water
4:1
1
R
3
R
Entry
Phenacyl
Thiourea (2)
Product (3) Time (min)
Yieldb (%)
bromide (1)
1
2
3
4
5
6
7
8
a
a
b
b
b
c
c
d
d
e
e
e
f
a
b
a
d
b
a
b
a
b
a
c
b
a
b
c
e
3aa
3ab
3ba
3bd
3bb
3ca
3cb
3da
3db
3ea
3ec
3eb
3fa
08
10
10
10
10
09
09
05
05
07
07
09
09
10
08
10
95
88
85
82
82
87
85
96
94
94
94
90
89
87
89
81
9
10
11
12
13
14
15
16
f
f
a
3fb
3fc
3ae
aAll reactions were carried out in EtOH: H2O (4:1) in the prescence of visible light irradiation
using a 24W CFL at room temperature under air. bIsolated yield of the product (%).
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Table 4 Substrate scopea (5)
S
NH2
R2
O
R
N
N
S
4
Br
N
R2
CFL (24W)
Ethanol: Water
4:1
R
1
5
Entry Phenacyl bromide (1) 2-aminothiazole
(4)
Product (5) Time (h)
Yieldb (%)
1
2
3
4
5
6
7
a
f
a
b
b
b
c
c
c
5aa
5fb
5db
5gb
5ac
5cc
5ec
5.0
5.5
5.0
6.5
6.5
6.5
6.5
60
59
61
50
53
55
53
d
g
a
c
e
aAll reactions were carried out in EtOH: H2O (4:1) in the prescence of visible light irradiation
using a 24W CFL at room temperature under air. bIsolated yield of the product (%).
Mechanism
On the basis of literature surey,36, 37, 38 a plausible mechanistic pathway for the synthesis of
different types of thiazoles has been proposed. The reaction was initiated by [1,3]tautomerism in
reactants (2) and (4). Then visible light promoted homolytic fission of the C-Br bond of phenacyl
bromide, S-H bond of N-phenyl thiourea (Scheme 2) and N-H bond of 2-amino thiazole (Scheme
3) takes place resulting to free radicals (A), (B), (C) respectively. After that radical (A) combines
with (B) (Scheme 2) and radical (A) combines with (C) (Scheme 3) to give (D) and (E),
respectively as mentioned in the mechanism. A homolytic cleavage of carbonyl carbon supported
by hydrogen free radical and similar cleavage of N-H bond supported by bromine free radical
takes place. Finally the newly formed free radicals (F) and (G) coalesce to form the desired
product (3) and (5) via cyclization followed by removal of H2O molecule.
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Scheme 2 Plausible mechanism for the synthesis of thiazole derivatives
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Scheme 3 Plausible mechanism for the synthesis of imidazo[2,1-b]thiazole derivatives
Conclusion
In summary, we have disclosed a visible-light-induced synthetic strategy to attain a facile
synthesis of biologically and medicinally important thiazoles (3) and imidazo-thiazoles (5) via
oxidative coupling of phenacyl bromide (1) with N-phenyl thiourea (2) and 2-amino thiazole (4)
without the use of heat, base, ligands or an additional oxidant. The present protocol has been
applied to the rapid synthesis of products (3) and (5) using commercially available substrates,
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without the use of hazardous chemicals, catalysts or harsh reaction conditions. The extension of
methodology can be examined with a variety of phenacyl bromide derivatives as well as with
thiourea and 2-amino thiazole derivatives. Utilization of visible light, eco-efficiency, cost-
effectiveness, use of greener reagent, no requirement of bases and catalysts, use of mixed
solvent system of EtOH:H2O, experimental feasibility, short reaction time, easy workup and
high yields of the product makes this protocol attractive and superior to the proposed other
methods.
Acknowledgements:
We sincerely thank SAIF, Punjab University, Chandigarh, for providing micro-analyses and
spectra. The author A. Mishra is thankful to UGC, New Delhi, for the award of Junior Research
Fellowship (JRF), authors M. Srivastava and P. Rai are thankful to UGC, New Delhi, for the
award of Senior Research Fellowship (SRF). B.P. Tripathi and S. Yadav are also thankful to
UGC, New Delhi for Resarch fellowship.
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DOI: 10.1039/C6RA05385H
Abstract
The development of a visible light promoted, mild and greener approach for the synthesis of
highly functionalized thiazoles and imidazo[2, 1-b]thiazoles under photochemical activation in
EtOH:H2O green medium is demonstrated. The characteristic feature of the present protocol is
the utilization of visible light (an omnipresent, nontoxic, environmentally benign and
inexpensive reagent) to form C-S, C-N bond and circumlocute the use of catalysts or photo
sensitizers. The reported protocol is the first example of visible light promoted synthesis of
thiazoles and imidazo[2, 1-b]thiazoles with various attractive features like being catalyst free,
eco-efficient and possessing cost effectiveness, short reaction time, excellent yields and the
sustainability to fulfill the parameters of green chemistry.
R
N
S
S
N
NH2
R2
Br
N
R2
5
4
O
or
S
S
NHR1
1
N
R
H2N
NHR1
2
3
R
EtOH:H2O
Eco-friendly
Easy work up
Ethanol-Water solvent system
Catalyst free
Operational simplicity
C-S and C-N new
bond formed
Visible light assisted
free radical pathway