One-pot PEG-mediated syntheses of 2-(2-hydrazinyl) thiazole derivatives: novel route

Article abstract of DOI:10.1080/17415993.2017.1371175

Thiazoles are important sulfur-containing molecules that are widely used in diverse fields such as pharmaceuticals, agrochemicals, and material sciences. This is the first report on the PEG-300-mediated one-pot synthesis of 2-(2-hydrazinyl) thiazole deriv

Full text of DOI:10.1080/17415993.2017.1371175

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: http://www.tandfonline.com/loi/gsrp20
One-pot PEG-mediated syntheses of 2-(2-
hydrazinyl) thiazole derivatives: novel route
Dattatraya G. Raut & Raghunath B. Bhosale
To cite this article: Dattatraya G. Raut & Raghunath B. Bhosale (2017): One-pot PEG-mediated
syntheses of 2-(2-hydrazinyl) thiazole derivatives: novel route, Journal of Sulfur Chemistry, DOI:
10.1080/17415993.2017.1371175
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Date: 15 September 2017, At: 01:27

JOURNAL OF SULFUR CHEMISTRY, 2017
https://doi.org/10.1080/17415993.2017.1371175
SHORT COMMUNICATION
One-pot PEG-mediated syntheses of 2-(2-hydrazinyl) thiazole
derivatives: novel route
Dattatraya G. Raut and Raghunath B. Bhosale
Organic Chemistry Research Laboratory, School of Chemical Sciences, Solapur University, Solapur, India
ABSTRACT
ARTICLE HISTORY
Received 10 August 2017
Accepted 20 August 2017
Thiazoles are important sulfur-containing molecules that are widely
used in diverse fields such as pharmaceuticals, agrochemicals,
and material sciences. This is the first report on the PEG-300-
mediated one-pot synthesis of 2-(2-hydrazinyl) thiazole derivatives
from ketones, thiosemicarbazide, and α-halo ketones. Here PEG-300
acts as a solvent as well as supporting catalyst. Formation of com-
pounds was confirmed by IR, 1H NMR, 13C NMR, and mass spectro-
scopic studies.
KEYWORDS
Hydrazinylthiazoles;
PEG-300; ketones;
thiosemicarbazide; α-halo
ketones; multicomponent
syntheses
A series of 2-(2-hydrazinyl) Thiazole derivatives have been synthe-
sized from substituted ketones, thiosemicarbazide & α-halo ketones
using PEG-300 as a reaction medium via one-pot approach.
Highlights
• One-pot method and rapid reaction
• Ambient reaction condition
• PEG-300 as a green solvent
• PEG-300 acts as a non-toxic solvent and supportive catalyst
CONTACT Raghunath B. Bhosale
bhosale62@yahoo.com
Supplemental data for this article can be accessed here. https://doi.org/10.1080/17415993.2017.1371175
© 2017 Informa UK Limited, trading as Taylor & Francis Group

2
D. G. RAUT AND R. B. BHOSALE
• PEG-300 acts as a good cyclizing agent
• Reaction takes place without any rearranged products
• Product obtained in excellent yields
1. Introduction
Multicomponent reactions are also called as one-pot reactions. It is evident that sulfur-
containing heterocyclic compounds are a key structural requirement for biological activ-
ities. Organosulfur compounds constitute a significant class of biologically active drug
molecules that has attracted the attention of researchers and medicinal chemists due
to their wide range of biochemical and pharmacological properties. Organosulfur com-
pounds are being synthesized as drugs by many researchers in order to resist diseases
with minimum toxicity and maximum effects. These predictions have provided a curative
pathway to design new, effective, biologically active sulfur-containing heterocyclic com-
pounds. A number of sulfur derivatives have been reported to exert notable biological
activities. Hydrazinylthiazoles are an important class of compounds of profound interest
to medicinal and industrial chemists because compounds bearing the hydrazinylthiazolyl
nucleus exhibit diverse biological properties such as antioxidant [1], antitubercular [2–5],
adenosine receptor antagonist [6], xanthine oxidase inhibitors [7], anti-microbial [8–13],
anti-inflammatory [14,15], and antiplasmodial [16] activity. Thus, it seems highly desirable
to develop various practical routes to synthesize 2-(2-hydrazinyl) thiazole derivatives.
On the other hand, PEG solvents are known to be inexpensive, easily available, recy-
clable, thermally stable, biologically compatible, non-toxic, and water-soluble compounds
[17,18]. Nowadays, researchers’ attention are focused on the development of new, selective
eco-friendly methods using polyethylene glycol as a green solvent for the preparation of
biologically active compounds [19,20].
2. Results and discussion
Based on these facts, we have synthesized a series of 2-(2-hydrazinyl) thiazole derivatives
4a–s, which are summarized in Table 1 [21,22]. The synthesis involves the condensation
reaction between substituted acetophenones 1 and thiosemicarbazide 2 in the presence of
catalytic amount of glacial acetic acid using PEG-300 as reaction medium to give thiosemi-
carbazone derivatives as reactive intermediates, which then react with the appropriate
α-halo ketones 3 in the presence of PEG-300 as a reaction medium as well as a supportive
catalyst to yield 2-(2-hydrazinyl) thiazole derivatives. The mechanism for the formation
of 2-(2-hydrazinyl) thiazole derivatives 4a–s occurs first by a nucleophilic sulfur attack on
the electron-deficient carbon of the α-haloketone to displace the halogen leaving group
followed by an attack of the imine lone pair on the carbonyl carbon, which, upon cyclo-
condensation, gives the targeted molecules in impressive yields (Scheme 1). The reaction
proceeds smoothly without the formation of any rearranged products. The catalyst PEG-
1
300 can be easily recovered and reused. All the products were characterized by IR, H
NMR, 13C NMR, and mass spectroscopy. These reactions can also take place with other
solvents; however, PEG-300 was chosen as the reaction medium as well as supportive cata-
lyst because it is inexpensive and easily accessible. 1H NMR spectroscopy is one of the most
important techniques used for the characterization of these compounds, which show a

JOURNAL OF SULFUR CHEMISTRY
3
Table 1. Syntheses of 2-(2-hydrazinyl) thiazole derivatives in the presence of PEG-300 [21,22].
Substituentsa
Entry
R1
R2
R3
R4
R5
R6
Time (h)
Yieldsb
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OH
H
H
H
H
H
H
H
H
H
NO2
NO2
NO2
NO2
NO2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
Cl
H
Cl
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
OCH3
CH3
Cl
H
Cl
CH3
OCH3
H
CH3
OCH3
Cl
Cl
H
H
CH3
Cl
NO2
H
F
1.4
1.3
1.3
1.2
1.4
1.4
1.4
1.3
1.2
1.2
1.3
1.2
1.2
1.3
1.3
1.3
1.2
1.4
1.3
87
86
88
87
88
89
87
86
91
90
93
90
89
86
85
90
89
88
90
H
OH
OH
OH
OH
H
H
H
H
H
CH3
CH3
CH3
CH3
H
4s
H
H
aAll the products were charaterized by 1H NMR, IR, and mass spectroscopy.
bIsolated yields after purification.
Scheme 1. The proposed one- pot pathway for 2-(2-Hydrazinyl) thiazole derivatives.
characteristic singlet for the H-5 proton of 1,3-thiazole ring at δ ∼6.75–7.49 ppm. The 13
C
NMR spectra of 2-(2-hydrazinyl) thiazole derivatives show the C-5 carbon of the thiazole
ring resonating at δ ∼100–110 ppm.
3. Conclusions
In conclusion, we have shown that these reactions with PEG-300 as solvent are not only
economical but also environmentally friendly [17–20]. Significant improvements offered
by this procedure are: (i) simple operation under mild conditions, (ii) excellent yields

4
D. G. RAUT AND R. B. BHOSALE
with high purity, (iii) shorter reaction time than reported methods, (iv) cost-efficiency, (v)
environmental friendliness (i.e. avoidance of hazardous organic solvents), (vi) dual role of
PEG-300 (as supporting catalyst and solvent), (vii) easy work up and isolation, (viii) adher-
ence to various principles of green chemistry, (ix) convenient precipitation of the product,
and (x) one-pot synthesis.
4. Experimental
4.1. Materials
1H NMR and 13C NMR spectra were recorded on a Bruker AV-400 spectrometer in CDCl3
using TMS as internal standard. Infrared (IR) spectra were recorded on Thermo scientific
spectrometer. Elemental analyses were obtained using a Thermo Finnigan Flash EA 1112
as an instrument. Mass spectra recorded with an Advion mass spectrometer of Micromax
Company. TLC was performed on glass-backed silica gel sheets (Silica Gel-60 GF254) and
visualized in UV light (254 nm). All melting points (in °C un-corrected) were determined
using an open capillary melting point apparatus. All solvents and chemicals were obtained
from either Merck, Spectrochem or Aldrich and are of analytical grade, and were used
immediately after opening.
4.2. General procedure
Aequimolar mixture of substituted acetophenone (3 mmol), thiosemicarbazide (3 mmol),
and glacial acetic acid 2–3 drops in PEG-300 (20 mL) was heated at 70–75°C for 1.0–1.5 h.
Then the substituted α-haloketones (3 mmol) were added slowly, and the product was pre-
cipitated within 5–10 min. The reaction mass was heated for 15 min more. The progress
of reaction is monitored by TLC. The reaction mass was then cooled and poured into
ice water, and the crude product was recrystallized from ethanol to give title compounds
(4a–s).
4.2.1. N-(1-Phenyl-ethylidene)-Nꢀ-(4-phenyl-thiazol-2-yl)-hydrazine (4d)
Yield: 87%, MF: C17H15N3S/ 293.1; yellow solid; MP. 242–243°C. IR: 3205.3, 3057.0,
1615.5, 1600.5, 1515.7, 1496.4 cm−1. 1H NMR: (400 MHz, CDCl3): δ: 2.62 (s, –CH3, 3H),
6.79 (s, thiazole –CH, 1H), 7.47–7.55 (m, Ar-H, 6H), 7.76–7.84 (m, Ar-H, 4H), 12.73 (s,
–NH, 1H)13C NMR: (400 MHz, CDCl3) δ: 15.0, 101.8, 125.6, 126.5, 128.6, 129.4, 130.0,
130.4, 169.9. MS: m/z 294.1.
4.2.2. 4-(1-(4-(2,4-Dichloro-phenyl)-thiazol-2-yl]-hydrazono)-ethyl)-phenol (4e)
1
Yield: 88%, MF: C17H13Cl2N3OS/ 377.02; pale yellow solid; MP. 280–281°C. H NMR:
(400 MHz, CDCl3) δ 2.33 (s, –CH3, 3H), 6.76–6.80 (m, Ar-H, 2H), 7.13–7.14 (m, Ar-H,
1H), 7.32–7.35 (m, thiazole –CH, 1H), 7.46–7.48 (m, Ar-H, 1H), 7.59–7.61 (m, Ar-H, 2H),
7.66–7.68 (m, Ar-H, 1H), 7.72–7.73 (m, Ar-H, 1H).
4.2.3. N-[4-(2,4-Dichloro-phenyl)-thiazol-2-yl]-Nꢀ-[1-3-nitro phenyl)-ethylidine]-
hydrazine (4k)
Yield: 93%; MF: C17H12Cl2N4O2S/ 406.01; yellow solid; MP.191–192°C. IR: 3211.9, 3065.1,
1600.0, 1563.5, 1526.0, 1463.7, 1344.9 cm−1. 1H NMR: (400 MHz, CDCl3) δ: 2.26 (s, –CH3,

JOURNAL OF SULFUR CHEMISTRY
5
3H,), 7.28–7.30 (m, Ar-H, 3H), 7.48 (s, thiazole –CH, 1H), 7.59–7.63 (t, J = 8 Hz, Ar-H,
1H), 7.78–7.80 (d, J = 8 Hz, Ar-H, 1H), 8.14–8.16 (d, J = 8 Hz, Ar-H, 1H,), 8.23–8.25
(d, J = 8 Hz, Ar-H, 1H,), 8.58 (s, Ar-H, 1H). 13C NMR: (400 MHz, CDCl3) δ: 12.9, 110.0,
120.7, 123.5, 127.2, 129.4, 130.2, 131.5, 131.6, 131.7, 132.5, 133.9, 139.2, 143.8, 146.2, 148.6,
167.9.
4.2.4. N-[4-(4-Chloro-phenyl)-thiazol-2-yl]-Nꢀ-[1-(3-nitro phenyl)-ethylidene]-
hydrazine (4l)
Yield: 90%, MF:C17H13ClN4O2S/ 372.6; yellow solid; MP.270–271°C. IR: 3220.5, 3070.0,
2972.9, 1617.0, 1597.1, 1506.5, 1237.9 cm−1. 1HNMR: (CDCl3, 400 MHz) δ: 2.45 (s, -CH3,
3H), 7.02 (s, thiazole–H, 1H), 7.39–7.41 (d, Ar-H, 2H), 7.61–7.67 (m, Ar-H, 2H), 7.82–7.85
(m, Ar-H, 2H), 8.19–8.23 (m, Ar-H, 1H), 8.63–8.64 (t, Ar-H, 1H), 10.95 (broad s, –NH,
1H) 13C NMR: (CDCl3, 400 MHz) δ: 15.1, 101.7, 118.8, 120.7, 123.7, 125.7, 127.4, 129.0,
129.0, 130.9, 145.8, 154.8, 156.5, 168.5.
4.2.5. N-[1-(3-Nitro phenyl)-ethylidene]-Nꢀ-(4-phenyl-thiazol-2-yl)-hydrazine (4m)
Yield: 89%, MF: C17H14N4O2S/ 338.08; yellow solid; MP. 278–279°C. IR: 3120.2, 2973.6,
2922.1, 1608.0, 1526.2, 1480.6, 1348.6 cm−1 1H NMR: (400 MHz, CDCl3) δ: 2.23
.
(s, -CH3, 3H), 6.97 (s, thiazole –CH, 1H), 2.23 7.30–7.33 (m, Ar-H, 1H), 7.39–7.42 (m,
Ar-H, 2H), 7.57–7.61(t, Ar-H, 1H), 7.80–7.82 (d, J = 8 Hz, Ar-H, 2H), 8.14–8.16 (d, Ar-H,
1H), 8.21–8.24 (d, Ar-H, 1H), 8.57 (s, Ar-H, 1H,), 9.49 (s, NH, 1H,). 13C NMR: (400 MHz,
CDCl3) δ: 12.8, 104.3, 120.6, 123.3, 125.9, 127.9, 128.7, 129.3, 131.4, 134.6, 139.4, 143.3,
148.5, 151.5, 169.1. MS: m/z 339.2.
4.2.6. N-(4-Phenyl-thiazol-2-yl)-Nꢀ-(1-p-tolyl-ethylidene)-hydrazine (4n)
Yield: 86%, MF: C18H17N3S/ 307.11; yellow solid; MP. 272–273°C. IR: 3240.0, 3041.8,
1617.7, 1565.8, 1366.8, 1111.7 cm−1.1H NMR: (400 MHz, CDCl3) δ: 2.42 (s, –CH3,
3H), 2.59 (s, –CH3, 3H), 6.78 (s, thiazole –CH, 1H), 7.25–7.27 (d, J = 8 Hz, Ar-H,
2H,) 7.47–7.54 (m, Ar-H, 3H) 7.71–7.77 (m, Ar-H, 4H), 12.71 (s, NH, 1H). 13C NMR:
(400 MHz, CDCl3) δ: 16.1, 21.3, 100.91, 125.6, 126.6, 127.3, 129.4, 129.6, 130.4, 133.2,
140.9, 141.1, 156.6, 169.9.MS: m/z 308.
4.2.7. 4-Chloro-2-[1-[(4-phenyl-thiazol-2-yl)-hydrazono]-ethyl]-phenol (4r)
Yield: 88%, MF: C17H14ClN3OS/ 343.05; yellow solid; MP. 227–228°C. IR: 3436.6, 3189.6,
3058.3, 2919.5, 1597.2, 1562.7, 1478.6 cm−1. 1H NMR: (400 MHz, CDCl3) δ: 2.58 (s, –CH3,
3H), 4.76 (s, –OH, 1H), 6.86 (s, thiazole –CH, 1H), 6.99–7.01 (d, J = 8 Hz, Ar-H, 1H),
7.30–7.33 (m, Ar-H, 1H), 7.45–7.52 (m, Ar-H, 4H), 7.76–7.78 (d, J = 8 Hz, Ar-H, 2H),
11.04 (s, NH, 1H). MS: m/z 344.2.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
The author D.G.R. is thankful to the Solapur University, Solapur for the award of Departmental
Research Fellowship.

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D. G. RAUT AND R. B. BHOSALE
References
[1] Karatepe M, Karatas F. Antioxidant, pro-oxidant effect of the thiosemicarbazone derivative
Schiff base (4-(1-phenylmethylcyclobutane-3-yl)-2-(2-hydroxybenzylidenehydrazino) thia-
zole) and its metal complexes on rats. Cell Biochem Funct. 2006;24:547–554.
[2] Turan-Zitouni G, Ozdemir A, Kaplancikli ZA, et al. Synthesis and antituberculosis activity of
new thiazolylhydrazone derivatives. Eur J Med Chem. 2008;43:981–985.
[3] Makam P, Kankanala R, Prakash A, et al. 2-(2-Hydrazinyl)thiazole derivatives: design, synthe-
sis and in vitro antimycobacterial studies. Eur J Med Chem. 2013;69:564–576.
[4] Roy KK, Singh S, Sharma SK, et al. Synthesis and biological evaluation of substituted 4-
arylthiazol-2-amino derivatives as potent growth inhibitors of replicating Mycobacterium
tuberculosis H37RV. Bioorg Med Chem Lett. 2011;21:5589–5593.
[5] Shiradkar M, Venkata G, Kumar S, et al. Clubbed triazoles: a novel approach to antitubercular
drugs. Eur J Med Chem. 2007;42:807–816.
[6] Pandya DH, Sharma JA, Jalani HB, et al. Novel thiazole–thiophene conjugates as adenosine
receptor antagonists: synthesis, biological evaluation and docking studies. Bioorg Med Chem
Lett. 2015;25(6):1306–1309.
[7] Song JU, Choi SP, Kim TH, et al. Design and synthesis of novel 2-(indol-5-yl)thiazole deriva-
tives as xanthine oxidase inhibitors. Bioorg Med Chem Lett. 2015;25(6):1254–1258.
[8] Bharti SK, Nath G, Tilak R, et al. Synthesis, anti-bacterial and anti-fungal activities of
some novel Schiff bases containing 2,4-disubstituted thiazole ring. Eur J Med Chem.
2010;45:651–660.
[9] Vijesh AM, Isloor AM, Prabhu V, et al. Synthesis, characterization and anti-microbial studies
of some novel 2,4-disubstituted thiazoles. Eur J Med Chem. 2010;45:5460–5464.
[10] Chimenti F, Bizzarri B, Bolasco A, et al. Synthesis and biological evaluation of novel 2,4-
disubstituted-1,3-thiazoles as anti-Candida spp. Agents. Eur J Med Chem. 2011;46:378–382.
[11] Yilmaz ACI, Gur S, Kazaz C. Synthesis, antibacterial and antifungal activity of some new
thiazolylhydrazone derivatives containing 3-substituted cyclobutane ring. Eur J Med Chem.
2006;41:201–207.
[12] Balladka KS, Bettadapura GK, Chenna GD, et al. Synthesis, characterization, in vitro and
molecular docking studies of new 2,5-dichloro thienyl substituted thiazole derivatives for
antimicrobial properties. Eur J Med Chem. 2010;45:3490–3496.
[13] Bondock S, Khalifa W, Fadda AA. Synthesis and antimicrobial evaluation of some new thiazole,
thiazolidinone and thiazoline derivatives starting from 1-chloro-3,4-dihydronaphthalene-2-
carboxaldehyde. Eur J Med Chem. 2007;42(7):948–954.
[14] Moldovan CM, Oniga O, Parvu A, et al. Synthesis and anti-inflammatory evaluation of some
new acyl-hydrazones bearing 2-aryl-thiazole. Eur J Med Chem. 2011;46(2):526–534.
[15] Giri RS, Thaker HM, Giordano T, et al. Design, synthesis and characterization of novel 2-(2,4-
disubstituted-thiazole-5-yl)-3-aryl-3H-quinazoline-4-one derivatives as inhibitors of NF-κB
and AP-1 mediated transcription activation and as potential anti-inflammatory agents. Eur J
Med Chem. 2009;44(5):2184–2189.
[16] Chopra R, De Kock C, Smith P, et al. Ferrocene-pyrimidine conjugates: synthesis, elec-
trochemistry, physicochemical properties and antiplasmodial activities. Eur J Med Chem.
2015;100:1–9.
[17] Suryakiran N, Ramesh D, Vemkateswarulu Y. Synthesis of 3-amino 1H- pyrazolescatalyzed by
p-toluenesulphonic acid using polyethylene glycol-400 as an efficient and recyclable reaction
medium. Green Chem Lett. 2007;1:73–78.
[18] Kamal A, Reddy DR, Rajender S. A simple and green procedure for the conjugate addition
of thiols to conjugated alkenes employing polyethylene glycol (PEG) as an efficient recyclable
medium. Tetrahedron Lett. 2005;46:7951–7953.
[19] Jadhav SY, Shirame SP, Kulkarni SD, et al. PEG mediated synthesis and pharmacological eval-
uation of some fluoro substituted pyrazolines derivatives as anti-inflammatory and analgesic
agents. Bioorg Med Chem Lett. 2013;23:2575–2578.

JOURNAL OF SULFUR CHEMISTRY
7
[20] Jadhav SY, Bhosale RB, Shirame SP, et al. Synthesis and biological evaluation of fluoro-hydroxy
substituted pyrazolechalcones as anti-inflammatory, antioxidant and antibacterial agents. Int J
Pharm Bio Sci. 2013;4:390–397.
[21] Rahim F, Ullah H, Javid MT, et al. Synthesis, in vitro evaluation and molecular docking studies
of thiazole derivatives as new inhibitors of a-glucosidase. Bioorg Chem. 2015;62:15–21.
[22] Pundeer R, Kiran V, Sushma OP, et al. An efficient synthesis of N-(1-arylethylidene)-N-
(4-arylthiazol-2-yl)hydrazones from α,α-dibromoacetophenones and N-(1-arylethylidene)
thiosemicarbazones. Der Pharma Chemica. 2011;3(3):109–114.