One-pot multicomponent synthesis of novel thiazol-2-imines via microwave irradiation and their antifungal evaluation

Article abstract of DOI:10.1080/00397911.2018.1482348

Microwave-assisted green approach is developed for an efficient synthesis of thiazol-2-imines under catalyst-free conditions. The desired products are formed by one-pot three-component reaction which is an improvised method for Hantzsch thiazole synthesis

Full text of DOI:10.1080/00397911.2018.1482348

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
One-pot multicomponent synthesis of novel
thiazol-2-imines via microwave irradiation and
their antifungal evaluation
Saba Kauser Jaweed Shaikh, Ravindra Ramappa Kamble, Shilpa M.
Somagond, Atulkumar A. Kamble & Mahadev N. Kumbar
To cite this article: Saba Kauser Jaweed Shaikh, Ravindra Ramappa Kamble, Shilpa M.
Somagond, Atulkumar A. Kamble & Mahadev N. Kumbar (2018): One-pot multicomponent
synthesis of novel thiazol-2-imines via microwave irradiation and their antifungal evaluation,
Synthetic Communications, DOI: 10.1080/00397911.2018.1482348
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2018.1482348
One-pot multicomponent synthesis of novel thiazol-2-
imines via microwave irradiation and their
antifungal evaluation
Saba Kauser Jaweed Shaikh, Ravindra Ramappa Kamble, Shilpa M. Somagond,
Atulkumar A. Kamble, and Mahadev N. Kumbar
Department of Studies in Chemistry, Karnatak University, Dharwad, Karnataka, India
ABSTRACT
ARTICLE HISTORY
Received 1 January 2018
Microwave-assisted green approach is developed for an efficient syn-
thesis of thiazol-2-imines under catalyst-free conditions. The desired
products are formed by one-pot three-component reaction which is
an improvised method for Hantzsch thiazole synthesis. The micro-
wave-assisted protocol gives excellent yields with high purity in just
10–15 min. All the synthesized compounds have been screened for
antifungal activity and some of the derivatives show a broad spec-
trum against fungal pathogens.
KEYWORDS
1,2,4-Triazolone; antifungal
activity; green synthesis;
multicomponent reaction;
thiazol-2-imines
GRAPHICAL ABSTRACT
Introduction
Green synthesis is one of the trending and effective forms of artwork which has revolu-
tionized the research perspective for a synthetic organic chemist. In quest of these,
microwave-assisted organic synthesis (MAOS) has successfully accomplished the synthe-
sis of a structurally diverse collection of complex molecules as well as a small library of
compounds under short intervals of time. This method is also known for its spectacular
accelerations in most of the reactions with improved yields, reduced cost, reduced
CONTACT Ravindra Ramappa Kamble
kamchem9@gmail.com
Department of Studies in Chemistry, Karnatak
University, Dharwad, Pavate Nagar, Dharwad 580 003, Karnataka, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2018 Taylor & Francis

2
S. K. J. SHAIKH ET AL.
O
NH2
S
H
N
O
OH
S
S
N
R
N
HO
O
S
N
O
N
H
OH
N
O
O
O
O
OH OH
Penicillin
Tiazofurin
Meloxicam
Figure 1. Clinically available drugs with thiazole moieties.
F
NH
S
O
O
S
O
N
N
F
N
N
H
(b) Pꢀ-a
Figure 2. Examples of biological active thiazol-2-imine derivatives.
(a) KHG22394
energy, higher atom economy, low-waste, short reaction time, and use of environmen-
tally greener solvents which implies to be labeled as one of the pioneers in “green chem-
istry”.[1] The MAOS has been found to be an effective synthetic strategy which increases
the reaction rates of multicomponent reactions.[2]
Heterocycles are chemically flexible framework as they respond to various demands of
biological systems which invariably make them demonstrate interesting biological activ-
ities.[3] In particular, thiazole and their derivatives have found to be a core unit in drug
designing and development of various therapeutic agents (Fig. 1).[4] Thiazole ring has
been found to play a crucial role in the lead identification and optimization, as pharma-
cophoric and bioisosteric elements, and also as a spacer.[5] Organic compounds contain-
ing the thiazole ring are used as antitumor, cytotoxic,[6] antifungal,[7] antibacterial,[8]
antiparasitic,[9] antitubercular,[10] anticancer,[11] and anti-inflammatory agents.[12]
Then comes into action is the thiazol-2-imine ring system which is present in several
drug motifs, which is found to be of considerable interest due to its significant biological
activities[13]. The structural fragment thiazol-2-imine is found in muscarinic agonists as
well as in anti-inflammatory, analgesic, and kinase (CDK1, CDK5, and GSK3) inhib-
ition,[14] antifungal,[15] melanin-reducing activity (skin whitening agent) KHG22394
(Fig. 2),[16] and as platelet GPIIb/IIIa receptor antagonist.[17] Also, the scaffold of thia-
zol-2-imine, Pifithrin (Pft-a) (Fig. 2) has been predicted as a possible lead for the diag-
nosis of neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease,
stroke, cancer therapy.[18]
The synthesis of 2-aminothiazole was first reported by Hantzsch basically employing
the thiourea and a-haloketones.[19] Many of the reaction conditions also unveiled that
could possibly synthesize thiazol-2-imines in basic medium or neutral medium or with
ammonium thiocyanate and also in aqueous media catalyzed by diammonium hydrogen
phosphate or DABCO.[20] Also, the condensation reaction of a-haloketones with

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3
thiourea under acidic conditions gave rise to various quantity of aminothiazoles as side
products. The same method was embraced for the synthesis of the N-alkylated imino-
thiazolines that could be obtained by replacing thioureas with mono and N, N-disubsti-
tuted thioureas under different reaction conditions.[21] Various other strategies include
potassium thiocyanate treatment of a-bromoketimines,[22] reaction of N-monoalkylated
thioureas with 3-bromomethyl-2-cyanocinnamonitrile,[23] cycloadditions followed by
elimination of 5-imino-1,2,4-thiazolidin-3-ones with enamines and ester enolate,[24] ring
transformation of 1-arylmethyl-2-(thiocyanomethyl)aziridines in the presence of TiCl4
and acylchloride,[25] reaction of N-propargylaniline with acylisothiocyanates,[26] and phe-
nylamino acetonitrile with alkyl isothiocyanates.[27] In addition to this, the synthesis
of thiazol-2-imines was also carried out by the reaction of substituted amines with iso-
thiocyanates.[28] Lately, the three component reaction of phenacyl bromide or 2-chloro-
1,3-dicarbonyl compound, amine and phenyl isothiocyanate has been developed to give
subsequent thiazol-2-imines.[29] The one-pot reaction of 1,1-(ethane-1,2-diyl) dipyridi-
nium bistribromide (EDPBT), as a brominating agent, enolizable ketones and disubsti-
tuted thioureas was reported by Murru et al.[30]
Although there are reports of the one-pot three-component[31] reaction of thiazol-2-
imines in basic alumina under MW irradiation[32] or the trypsin-catalyzed reactions[33]
which are effective, but the drawbacks associated with many reported methods are
unavoidable and hazardous with malicious workups. Therefore, there is an urgent need
to develop efficient, easily available and green approach which can be easily pursued for
the synthesis of thiazol-2-imines. Our attempt to synthesize thiazol-2-imines without the
use of catalyst or reagent of that sort, towards directing a greener approach instigated us
to explore the microwave irradiation method. We could overcome many drawbacks with
respect to the existing methodologies such as easy workup, higher yields, atom economy,
short reaction time, and low wastage during the course of the reaction.
Experimental
General procedure for the synthesis of (5Z)-N-(3-(aryl)-4-phenylthiazol-2(3H)-
ylidene)benzenamine 4(a–l) and 5-methyl-2-aryl-4-((2Z)-4-phenyl-2-
(arylimino)thiazol-3(2H)-yl)-2H-1,2,4-triazol-3(4H)-one 4(o–t)
The reaction was performed in a single mode Discover SP (CEM Corporation,
Matthews, North Carolina, United States) microwave synthesizer with controlled irradi-
ation up to 300 W having a magnetic stirrer. An equimolar ratio of compounds 1, 2a,
and 3(a–l) were taken in a sealed glass tube vial (30.0 mL) in ethanol (10.0 mL). The
sealed vessel with reaction mixture was pre-stirred for 60 s at room temperatuꢀre.
Further, the reaction mixture was irradiated by 100 W microwave radiation at 120 C
for 10–15 min at medium stirring. The reaction temperatures were monitored with an
IR sensor equipped outside of the reactor. After completion of the reaction (TLC), the
reaction mixture was cooled and quenched in ice. The resulting precipitate was filtered
and recyrstallized from ethanol (Scheme 1). Similarly, compounds 4(o–t) were prepared
by employing equimolar ratio of compounds 1, 2(a–-c), and 3(m–n) in a sealed glass
tube vial (30.0 mL) in ethanol (10.0 mL), which was further irradiated by 100 W micro-
wave radiation at 120 ꢀC for 10–15 min, followed by similar workup (Scheme 2).

4
S. K. J. SHAIKH ET AL.
Ph
N
C
S
2
R
N
Ph
EtOH
N
O
S
Br
Ph
MW, 120°C, 10 min
NH2
R
Ph
1
3(a-l)
4(a-l)
a) R = -C6H5, b) R = -C6H4-2-Cl, c) R = -C6H4-3-Cl, d) R = -C6H4-4-Cl, e) R = -C6H4-4-Br, f) R = -C6H4-4-F, g) R
= -C6H4-4-OCH3, h) R = -C6H4-4-CH3, i) R = -C6H4-4-CF3, j) R = -C6H4-3-NO2, k) R = -NH-C6H5, l) R = -(CH2)2
Scheme 1. One-pot three-component synthesis of thiazol-2-imines 4(a–l).
Scheme 2. One-pot three-component synthesis of thiazol-2-imines 4(o–t).
(5Z)-N-(3,4-Diphenylthiazol-2(3H)-ylidene)benzenamine (4a)
Yield: 94%; chrome yellow solid, m.p.: 189–192 ꢀC; IR (KBr, cmꢁ1): 3443, 1617, 1578.
1H NMR (400 MHz, CDCl3, d ppm): 5.98 (1H, s, CH), 7.05 (2H, dd, J ¼ 8 Hz, Ar-H),
7.13 (2H, dd, J ¼ 8 Hz, Ar-H), 7.18–7.21 (4H, m, Ar-H), 7.27–7.30 (3H, m, Ar-H),
7.31–7.36 (4H, m, Ar-H). 13C NMR (100 MHz, CDCl3, d ppm): 97.2, 121.57, 123.16,
127.47, 128.15, 128.23, 128.79, 129.10, 129.35, 131.62, 137.40, 137.94, 139.90, 151.84,
160.08. GC-MS m/z Calcd Mass: 328.43; Found: 328. CHN analysis for C21H16N2S
Calcd: C, 76.80; H, 4.91; N, 8.53. Found: C, 76.82; H, 4.90; N, 8.55.
Results and discussion
The present methodology proposes the multicomponent strategy for the synthesis of
substituted thiazol-2-imines through a green approach (Schemes 1 and 2). Our investi-
gation started when 2-bromoacetophenone 1, phenylisothiocyanate 2a and aniline 3a
were taken in a one-pot three-component (3CR’s) condition in absolute ethanol under
microwave (MW) irradiation at 100 W maximum power for 10 min at the temperature
of 120 ꢀC. To our surprise, the neat reaction occurred affording the desired product 4a
in 89% in just 10 min. To understand the efficiency of the above methodology, the reac-
tion was also performed under conventional heating at 150 ꢀC for about 1.5–2 h and
yield of the reaction was 65% (Table 1, entry 2).

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Table 1. Optimization of the reaction conditions for the synthesis of 4a.a
Ph
N
S
Ph
O
N
Solvent
Br
Ph
Ph NH2
N
C S
Ph
Ph
MW, 120°C, 100W,
3a
2a
10 min
4a
1
Entry No.
Solvent
EtOH
EtOH
MeOH
AcOH
Time (min)
Yield (%)b
1
2
3
4
10
1.5–2 h
10
89
68c
75
72
10
5
6
1:1(H2O:EtOH)
DMF
10
10
68
72
7
8
9
10
CH3CN
THF
PEG
Ethyl-L-lactate
10
10
1–2 h
1–2 h
1 h
67
65d
55
53
11
Neat
No reaction
aReaction conditions:
a mixture of 2-bromoacetophenone 1 (1.0 mmol), phenylisothiocyanate 2a
(1.0 mmol) and aniline 3a (1.0 mmol) in EtOH (5 mL) was irradiated at 100 W maximum power, at the
c
temperature of 120 ꢀC; bisolated yield; reaction was performed under conventional heating at 150 ꢀC;
dincomplete reaction even after the 30–45 min of microwave irradiation.
By earlier literature reports it was observed that the synthesis of substituted thiazol-2-
imines occurs with the use of enzyme-catalyzed reactions and also under basic condi-
tions.[32,33] But we could isolate the desired product in good yields without the use of
any catalyst but just by performing the protocol under microwave irradiation.
Encouraged by these results we thought to optimize the reaction conditions by varying
the solvent systems and also to accord their resulting yields. We screened various sol-
vents like methanol, acetic acid, dimethylformamide, acetonitrile, tetrahydrofuran, and
aqueous EtOH (1:1) under microwave conditions. Through the investigation, we could
observe that the polar protic solvents yielded better than aprotic solvents. Also the sol-
vents such as PEG and ethyl-L-lactate were investigated under microwave conditions but
the yields were observed to be moderate percentage with an incomplete reaction. Out of
these screened solvents, an equimolar ratio of water and ethanol yielded the product in
68% (Table 1, entry 5). All the other solvents yielded the desired product 4a in moder-
ate to excellent yields. It was also observed that the reaction was incomplete when it
was irradiated in THF for about 30–45 min (Table 1, entry 8). The model reaction was
also carried out under neat condition and through our investigation, we found out that
the reaction gave a mixture of products (no trace of desired product) along with
unreacted starting materials even after 48 h (Table 1, entry 11).
The substrate scope of this methodology was explored by a wide range of aromatic and
heterocyclic amines with aryl isothiocyanate and 2-bromoacetophenone. All the substi-
tuted amines readily reacted with aryl isothiocyanate and 2-bromoacetophenone to fur-
nish the products in excellent yields (Table 2). The percentage yield of the desired
product was affected by the electronic nature as well as the positions of the substituents
on the aromatic ring of the amines, respectively. Higher yield was observed when elec-
tron-donating groups were present at the para position of the amine analogs (Table 2,
entries 7 and 8). The significant decrease in the yields was observed when electron-with-
drawing groups were present at the para position (Table 2, entries 4–6) compared to the

6
S. K. J. SHAIKH ET AL.
Table 2. Optimization of substrate scope of amines.a
(continued)

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7
(continued)

8
S. K. J. SHAIKH ET AL.
aReaction conditions: a mixture of 2-bromoacetophenone 1 (1.0 mmol), 2(a–c) (1.0 mmol), and 3(a–n) (1.0 mmol) in
EtOH (5 mL) was irradiated at 100 W maximum power, at the temperature of 120 ꢀC; bisolated yield.
ortho and meta positions (Table 2, entries 2 and 3). Subsequently, lower yields were
observed in case of ꢁNO2 group at the meta positions due to its electron withdrawing
nature (Table 2, entry 10). In case of trifluoromethyl group at the para position (Table 2,
entry 9), the observed yield was moderate as compared to the unsubstituted aromatic
amine (Table 2, entry 1). When phenyl hydrazine was taken into account, moderate yield
was observed (Table 2, entry 11). Aliphatic amine also showed increase in the yields with
good atom economy (Table 2, entry 12). Substrate scope was further explored using 2-
aryl-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-oxo-4-yl amines 3(m–n). To our delight all
the substituted amines resulted into good yields (Table 2, entries 13–18).
An attempt on synthesizing thiazol-2-imine with various aliphatic, aromatic, and het-
erocyclic amines under microwave condition at short interval of reaction time, with no
catalysts, no acidic/basic reaction conditions and excellent yields proves to be a well-per-
formed one. This methodology shows that there is more scope of exploration for the
synthesis of various amines linked to thiazol-2-imine substrate which possesses potent
pharmacological activities.
The plausible mechanism (multicomponent) for the formation of title compounds
4(a–l), 4(o–t) has been outlined in Scheme 3. Initially, the addition of amine (s) to phe-
nylisothiocyanate affords in situ thiourea intermediate, which undergoes thia-Michael
addition of sulphur to the carbon of bromomethyl group of 1. Further, it facilitates the
abstraction of NH proton which undergoes cyclization by the loss of water to yield the
product. The reaction proceeds to give the syn product because of the higher acidity of
NH proton flanked by a phenyl group.

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9
Ar
Ar
Ar
NH2
O
3(a-n)
N
NH
OH
Ph
N
N
Br
R‘
Ph
O
R‘
-Br
S
S
1
Ph
H
N
C
S
R‘
2(a-c)
-H2O
Ar = Aryl or 4-amino-2-aryl-5-methyl-
1,2,4-triazolin-3-one
N
R‘
Ar
N
S
Ph
4(a-l), 4(o-t)
Scheme 3. Plausible mechanism for the formation of 4(a–l) and 4(o–t) under microwave conditions.
Steric hinderance between
aryl groups prefers S-cis product
Ar
Ar'
N
Ar'
N
N
N
Ar
Ph
Ph
S
S
S-cis
Figure 3. Schematic representation to show S-cis geometry of thiazol-2-imine 4(a–l), 4(o–t).
N-cis
The synthesized compounds 4(a–l) and 4(o–t) were characterized by IR, 1H, 13C
NMR, and GC-MS. The IR spectrum of all compounds showed a medium intense band
appeared in the range of 1641–1685 cmꢁ1 which corresponds to the C ¼ N stretching. A
strong adsorption band appears around 1708–1702 cmꢁ1 due to the C ¼ O stretching of
the 1,2,4-triazolin-3-one group. In case of 1H NMR, the C5-H of the thiazole ring
appeared as a singlet around 6.14–5.95 ppm. The signals which appeared around
6.96–8.01 ppm were attributed to the aromatic protons in all the compounds. In the
case of 13C NMR spectral analyses, the C5 carbon of the thiazole ring and the imine car-
bon resonated around 97.16–98.87 ppm and 160.08–174.51 ppm, respectively. The other
magnetically non-equivalent carbon atoms appeared as signals at their respective chem-
ical shift values. The mass spectral analyses of titled compounds have shown the
molecular ion peak corresponding to their molecular mass. The X-ray crystal structure
of thiazol-2-imine by previously reported method also confirmed that they have syn
(S-cis) stereochemistry due to the steric hindrance between the substituted phenyl and
N-Phenyl groups (Fig. 3).[34]

10
S. K. J. SHAIKH ET AL.
Table 3. In vitro antifungal activities of 4(a–l) and 4(o–t) expressed in ZOI (mm) and MIC (lg/mL).
ZOI
C. albicans
ZOI
A. fumigatus
ZOI
niger
Entry No.
(mm)
MIC (lg/mL)
(mm)
MIC (lg/mL)
(mm)
MIC (lg/mL)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4o
4p
4q
4r
16
12
18
15
16
10
10
14
15
16
12
18
10
16
10
12
14
18
24
25
50
50
25
25
10
10
50
25
50
10
25
5
18
14
18
12
14
10
13
16
12
12
12
12
16
15
12
14
10
10
26
10
25
25
10
10
10
10
25
5
25
10
25
25
10
25
10
5
10
16
14
12
10
10
12
14
12
16
14
16
15
14
12
10
16
12
24
10
25
25
5
10
2.5
25
25
2.5
25
25
25
5
5
25
5
2.5
10
30
5
10
10
5
25
30
4s
4t
10
30
Fluconazole
Antifungal activity
All the newly synthesized compounds were screened for their antifungal activity by the
Disc Diffusion method. The antifungal activity of synthesized compounds 4(a–l) and
4(o–t) was screened against three (03) fungal strains Candida albicans, Aspergillus fumi-
gatus, and Aspergillus niger using Fluconazole as a standard. All determinations were
done in triplicate and the zones of inhibitions were recorded in mm. The preliminary
investigations were conducted for all the compounds at a concentration of 100 lg/mL in
DMSO, for the above-mentioned microorganisms. Series of dilutions of compounds
were prepared (2.5, 5, 10, 25, 50, 75, 100 lg/mL) to determine the Minimum Inhibitory
Concentrations (MIC) value. The Zone of Inhibition (ZOI) and MIC are summarized in
Table 3. Antifungal activity with MICꢂ 50 lg/mL was observed for all the synthesized
derivatives. According to Table 3, the compounds 4(a–l) and 4(o–t) displayed moderate
to excellent activity against three fungal strains.
Amongst compounds 4(a–l), 4f (containing p-fluro substituent) and 4i (containing p-
trifluoromethyl substituent) exhibited highest activity against A. niger evidenced by
the MIC of 2.5 lg/mL. Compound 4i has also shown excellent activity against A. fumi-
gatus with MIC of 5 lg/mL. All the other compounds have displayed good activity
against A. fumigatus and A. niger in the MIC range of 5–25 lg/mL compared to the
standard Fluconazole. Whereas, these compounds displayed moderate activity against
C. albicans.
Among the series 4(o–t), the compound 4s (containing p-chloro substituent) displayed
remarkable activity against A. niger with MIC of 2.5 lg/mL whereas, compounds 4o, 4p,
and 4r have shown MIC of 5 lg/mL against fungal strain A. niger. Compounds 4o, 4p,
and 4s were found to be active against C. albicans with MIC of 5 lg/mL. All other com-
pounds displayed good activity against all three fungal strains with the MIC range of
10–25 lg/mL when compared to the standard Fluconazole.

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11
Conclusions
Microwave-assisted organic synthesis (MAOS) has become a remarkable tool that has
initiated the need to explore the “chemistry space” and the diversity of the com-
pounds,[35] which can also ease the drug discovery in the coming years.[36] In view of
this, we have reported the synthesis of novel thiazol-2-imine by one-pot three-compo-
nent method,[37] which is a greener approach under mild, catalyst-free conditions and to
increase the atom economy starting from a-haloketones, isothiocyanates, and substituted
amines. This methodology was found to execute the reaction into good to excellent yield
when the electronic nature of the substituent came into action and thus, a wide variety
of differently substituted derivatives could be synthesized. The synthesized compounds
were screened for their in vitro antifungal activity against three fungal strains C. albi-
cans, A. fumigatus, and A.niger. Amongst them compounds 4f, 4i, and 4s displayed
highest activity against A. niger whereas, most of the compounds have shown promis-
ing results.
Acknowledgments
The authors are grateful to the University Scientific Instrumentation Centre (USIC), Karnatak
University, Dharwad and Indian Institute of Science (IISc), Bengaluru, India for providing the
spectral data and facility to conduct the experiments. The authors acknowledge the NGH College
of Dental Sciences Belgaum, Karnataka, India for antifungal activity.
Funding
The authors are thankful to UGC, New Delhi for providing financial assistance under UGC-UPE
thrust area ‘‘Antitumor activity: An Integrated Approach’’ vide [F. No. 14-3/2012(NS/PE) Dated:
14-03-2012]. One of the authors Saba Kauser J. Shaikh acknowledges UGC, New Delhi, India for
awarding RFSMS Fellowship vide No. F.25-1/2013-14(BSR)/7-100/2007(BSR), Dated 30/05/2014.
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