Novel one-pot expeditious synthesis of 2,4-disubstituted thiazoles through a three-component reaction under solvent free conditions

Article abstract of DOI:10.1080/00397911.2017.1399422

An expeditious one pot method has been developed for the synthesis of 2,4-disubstituted thiazoles under solvent free conditions via a multicomponent approach. Substituted thiazoles were synthesized with high yields by the reaction of cyclic ketones, thios

Full text of DOI:10.1080/00397911.2017.1399422

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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Novel one-pot expeditious synthesis of 2,4-
disubstituted thiazoles through a three-
component reaction under solvent free conditions
Kodam Sujatha & Rajeswar Rao Vedula
To cite this article: Kodam Sujatha & Rajeswar Rao Vedula (2018): Novel one-pot expeditious
synthesis of 2,4-disubstituted thiazoles through a three-component reaction under solvent free
conditions, Synthetic Communications, DOI: 10.1080/00397911.2017.1399422
To link to this article: https://doi.org/10.1080/00397911.2017.1399422
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Date: 08 January 2018, At: 09:57

SYNTHETIC COMMUNICATIONS®
https://doi.org/10.1080/00397911.2017.1399422
Novel one-pot expeditious synthesis of 2,4-disubstituted
thiazoles through a three-component reaction under solvent
free conditions
Kodam Sujatha and Rajeswar Rao Vedula
Department of Chemistry, National Institute of Technology, Warangal, India
ABSTRACT
ARTICLE HISTORY
An expeditious one pot method has been developed for the synthesis
of 2,4-disubstituted thiazoles under solvent free conditions via a
multicomponent approach. Substituted thiazoles were synthesized
with high yields by the reaction of cyclic ketones, thiosemicarbazide,
and phenacyl bromides or 3-(2-bromoacetyl)-2H-chromen-2-ones in a
shorter reaction time with high purity via simple purification
technique.
Received 6 September 2017
KEYWORDS
2
,4-Disubstituted thiazoles;
cyclic ketones;
cyclocondensation;
multicomponent reactions;
phenacyl bromides;
thiosemicarbazone
GRAPHICAL ABSTRACT
Introduction
[
1]
Multicomponent reactions are simple efficient,
convergent, diversity oriented
[
2,3]
reactions,
in which three are more reactants come together in a single reaction
operation to form a desired novel product in which all the reactants are incorporated into
the product. One-pot multicomponent approach is the best method of synthesis of
[
4,5]
complex heterocyclic molecules,
it involves minimum number of steps, there is no
isolation of intermediate, without use of noxious solvents, shorter reaction time, easy work
up procedure to give good to excellent yields.
Coumarins are important pharmacophores in medicinal chemistry and have biological
[
6]
[7]
[8]
[9]
activities, such as cytotoxic, anti-inflammatory, antituberculosis, antibacterial,
[
10]
[11]
[12]
[13]
antiviral,
herbicidal,
anti-HIV agent,
and antioxidant.
Significantly coumarin
CONTACT Rajeswar Rao Vedula
rajeswarnitw@gmail.com
Department of Chemistry, National Institute of
Technology, Warangal-506004, Telangana, 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.
Copyright © NIT, WARANGAL

2
K. SUJATHA AND R. R. VEDULA
Figure 1. Some of the representative examples of biologically potent compounds bearing thiazole
scaffold.
[
14]
[15]
derivatives are used as luminescent materials,
inhibition of platelet aggregation,
[
16]
[17]
allosteric MEK1 inhibitor
and also acts as free radical scavengers.
In the recent years, thiazole[18,19] and its derivatives attained considerable interest
[
20]
due to their wide variety of biological and pharmacological activities, , such as
[
21]
[22]
[23]
[24]
[25]
antiproliferative,
anticancer,
antimalarial,
anti-HIV,
antimicobacterial,
anti-inflammatory[26] and antihypertensive agents. Moreover thiazole and its derivatives
being a structural framework in variety of biologically important natural, semi-synthetic,
[
27]
and synthetic drugs
(Fig. 1). Besides, actinomycete member’s producing complex
naturally occurring antibiotics which are thiazole embedding secondary metabolites.
[
28]
In view of various physiological activities associated with coumarins and thiazoles,
our current studies are focused on the development of new routes for the synthesis of
thiazoles incorporating both aryl and coumarin moieties. We have developed a one-pot
multicomponent reaction for the synthesis of title compounds assuming that the resulting
compounds may possess good biological activities.
2
,4-Disubstituted thiazoles were generally synthesized by various methods. The most
common method involves the Hantzsch thiazole synthesis. This involves condens[3a1t–io33n]
of α -halogeno ketones with thiourea or thioamides.[29,30] King and co-workers
synthesized 2,4-disubstituted thiazoles by replacing α -halogenoketones with ketone and
halogen. Despite of this modification, the method of King and co-workers is cumbersome
and time taking process (24–25 h).
Results and discussion
By considering the importance of the heterocyclic moieties and in continuation of
our earlier work on the development of biologically important heterocyclic
compounds containing nitrogen and sulfur atoms,[34,35] we designed synthesis of novel
2
,4-disubstituted thiazoles, using a multicomponent approach involving modified
Hantzsch thiazole synthesis at room temperature. An equimolar mixture of phenacyl
bromide or 3-(2-bromoacetyl)-2H-chromen-2-one, thiosemicarbazide and cyclic ketone

SYNTHETIC COMMUNICATIONS®
3
was stirred for 5 min at room temperature to afford the corresponding 2,4-disubstituted
thiazoles (4, 5, and 6a–m) with good to excellent yields (85–95%) (Table 1).
In the one step solvent free synthesis (Scheme 1, method 1), it is believed that the phe-
nacyl bromides or 3-(2-bromoacetyl) coumarins react with thiosemicarbazide to give the
corresponding intermediate 2-hydrazino-4-substituted thiazoles followed by the reaction
with cyclic ketones to afford the target compounds (4, 5, and 6).
We have synthesized compounds 4, 5, and 6 by a one pot condensation of three reac-
tants in ethanol at 60 °C (method 2) and also we have performed the synthesis of 4, 5, and 6
by unambiguous method (Scheme 2, method 3). In the method 3, condensation of various
phenacyl bromides or 3-(2-bromoacetyl) coumarins with thiosemicarbazide to give corre-
sponding 2-hydrazino-4-substituted thiazoles (8). These on treatment with cyclic ketones
resulted in the formation of 4, 5, and 6 through a two-step process. The products obtained
by all the three methods were found to be identical by their mixed melting point measure-
ments, co-TLC, and IR spectra. In the present investigation, method 1 was used as it has
more advantages, such as higher yields, shorter reaction times, milder reaction conditions,
one pot, solvent free and easy reaction workup. In method 2 the overall yields were 75–85%
and this method was not used for the synthesis of title compounds. The intermediates
2
-hydrazino-4-aryl thiazoles and 2-hydrazino-4-coumarinyl thiazoles were synthesized
[
36,37]
by following the literature procedures.
Method 3
Reaction between phenacyl bromide or 3-(2-bromoacetyl) coumarin, thiosemicarbazide
and cyclic ketone is expected to give the compound 4/5/6 or corresponding N-cyclopenty-
lidine (9), cyclohexylidene (10), and 3,4-dihydronaphthalene-1(2H)-ylidene-5-substituted-
6
H-1,3,4-thiadiazines (11) or both depending on the mode of cyclization and reaction
conditions used. In the present investigation the reaction between 1 and 2 proceeds
selectively in such a way that the thioamide of 2 undergoes cyclization to give only
2
,4-disubstituted thiazoles. The reaction conditions played a crucial role in the selective
hetero cyclization. The alternate products 9, 10, and 11 can be rejected on the basis of
1
3
spectral studies (IR, NMR, C, and Mass).
Table 1. Synthesis of compounds (4, 5, and 6a–m) and their corresponding yields.
Entry
R
R1
Yields (%) (method 1)
4
5
Phenacyl
6,8-Dibromo-3-coumarinyl
Phenacyl
4-Bromo phenacyl
4-Chloro phenacyl
2,4-Dichloro phenacyl
4-Nitro phenacyl
6-Bromo-3-coumarinyl
6,8-Dibromo-3-coumarinyl
8-Methoxy-3-coumarinyl
Phenacyl
4-Chloro phenacyl
4-Nitro phenacyl
—
95
95
96
91
90
96
95
96
93
92
97
93
95
92
85
—
6
6
6
6
6
6
6
6
6
6
6
6
6
a
b
c
d
e
f
g
h
i
H
H
H
H
H
H
H
H
6-OCH
6-OCH
6-OCH
6-OCH
6-OCH
3
3
3
3
3
j
k
l
6,8-Dibromo-3-coumarinyl
6-Bromo-8-methoxy-3-coumarinyl
m

4
K. SUJATHA AND R. R. VEDULA
Scheme 1. Synthesis of 2,4-disubstituted thiazoles via multicomponent approach.
Scheme 2. Unambiguous synthesis of 2,4-disubstituted thiazoles.
The formation of the products (4, 5, and 6) can be explained (Scheme 3), by the intra
molecular cyclization of α-thioketone (7) to give 2-hydrazino-4-substituted thiazole (8).
This intermediate undergoes intermolecular condensation reaction with cyclic ketone to
give final compounds (4, 5, and 6).
Scheme 3. Plausible mechanism for the synthesis of 2,4-disubstituted thiazoles.

SYNTHETIC COMMUNICATIONS®
5
All the structures of newly synthesized compounds have been confirmed by their
spectral data. The IR spectrum of compound 6c shows prominent peaks at 3450–
030 cm− (b, m to different NH stretchings), 1609 cm (C=N–) stretching vibrations,
1
−1
3
1
respectively. The H-NMR spectrum of compound 6c gave prominent peaks for three
CH protons of tetralone at δ 2.04 (t, J ¼ 5.2 Hz, 2H), 2.82 (s, 2H) and 2.91 (t, J ¼ 6.0 Hz,
2
2
H), respectively. Thiazole proton appeared as singlet at δ 6.77. The NH proton appeared
at δ 12.34. The peaks of the remaining aromatic protons were observed in the usual region.
1
3
C NMR spectrum of 6c shows three non-equivalent methylene carbons of tetralone ring
at δ 21.74, 26.51, and 29.32 ppm respectively and thiazole carbon appeared at δ
1
05.37 ppm. Whereas the remaining aromatic carbons were observed in the usual region.
þ
The mass spectrum of 6c exhibited [MþH] peak at m/z 354 as base peak.
Experimental section
All the chemicals which were used in the present study were purchased from commercial
sources and used further without any purification. Melting points were determined in open
capillaries with a Stuart melting point apparatus (Mumbai, India) and were uncorrected.
1
IR spectra were recorded on Perkin Elmer Spectrum 100S spectrophotometer. H-NMR
spectra were recorded on Bruker WM-400 spectrometer in δ ppm using TMS as the
standard, ESI-MS spectra were recorded on JEOL JMSD-300 spectrometer. Elemental
analyses were performed on a Carlo Erba EA 1108 automatic elemental analyzer,
compounds purity was checked by TLC plates (E Merck, Mumbai, India). The supplemental
1
13
materials contain H and C NMR spectra of products 4, 5, and 6.
General procedure for the synthesis of 2,4-disubstituted thiazoles (method 1)
An equimolar amount of phenacyl bromide or 3-(2-bromoacetyl)-2H-chromen-2-one,
thiosemicarbazide and cyclopentanone/cyclohexanone/tetralone were taken in a round
bottom flask and stirred at room temperature for about 5 min. The progress of the reaction
was monitored through TLC using ethyl acetate and n-hexane (40%). After completion of
the reaction, the separated solid was filtered, washed with ether to remove unreacted cyclic
ketone and dried. The product was purified by recrystallization from methanol.
2
-(2-Cyclopentylidenehydrazinyl)-4-phenylthiazole (4)
Phenacyl bromide (199 mg, 1 mmol), thiosemicarbazide (91 mg, 1 mmol), and
cyclopentanone (0.5 mL, 4 mmol) were stirred at room temperature for 5 min. The
solid separated was filtered and washed with ether to remove unreacted cyclic ketone.
The product was recrystallized from methanol. Black solid; mp 142–143 °C; yield (95%);
−
1
1
IR (KBr, νmax, cm ): 3437–3053 (b, m to different NH stretching), 1628 (–C=N–); H
NMR (400 MHz, CDCl ): δ 1.80–1.87 (m, 2H), 1.90–1.96 (m, 2H), 2.5–2.57 (m, 4H),
3
6
.74 (s, 1H), 7.38–7.42 (m, 1H), 7.44–7.48 (m, 2H, ArH), 7.74 (d, J ¼ 7.6 Hz, 2H);
1
3
C NMR (100 MHz, CDCl ): δ 24.83, 24.95, 29.91, 33.28, 101.67, 125.60, 129.13, 129.33,
3
þ
1
29.79, 143.69, 168.90, 169.27. ESI-MS, m/z (%): 258 (MþH) ; anal. calcd for
C H N S, C, 65.34; H, 5.87; N, 16.33; S, 12.46%. Found: C, 65.30, H, 5.84; N, 16.39; S,
1
4
15 3
1
2.42.

6
K. SUJATHA AND R. R. VEDULA
6
2
,8-Dibromo-3-(2-(2-cyclohexylidenehydrazinyl) thiazol-4-yl)-2h-chromen-
-one (5)
6
,8-Dibromo-3-(2-bromoacetyl)-2H-chromen-2-one (425 mg, 1 mmol), thiosemicarbazide
(
91 mg, 1 mmol) and cyclohexanone (0.5 mL, 4 mmol) were stirred at room temperature
for 5 min. The solid separated was filtered and washed with ether to remove unreacted
cyclic ketone. The product was recrystallized from methanol. Yellow solid; mp 172–
−
1
1
73 °C; yield (95%); IR (KBr, ν , cm ): 3448–3061 (b, m to different NH stretching
max
1
vib.), 1733 (C=O of lactone), 1609 (C=N); H NMR (400 MHz, DMSO-d ): δ 1.59–1.64
6
(
m, 6H), 2.26 (s, 2H), 2.45 (s, 2H), 7.74 (s, 1H), 8.11 (s, 2H), 8.40 (s, 1H), 10.98 (s, 1H);
1
3
C NMR (100 MHz, DMSO-d ): δ 22.19, 25.33, 26.91, 34.86, 110.42, 116.96, 121.98,
6
1
22.50, 123.63, 131.29, 136.86, 138.63, 144.95, 147.07, 148.92, 158.23, 175.30. ESI- MS,
þ
m/z (%): 498 (MþH) ; anal. calcd for C H Br N O S, C, 43.48; H, 3.04; Br, 32.14; N,
1
8
15
2 3 2
8
.45; S, 6.45%. Found: C, 43.53; H, 3.12; Br, 32.19; N, 8.49; S, 6.41.
-(2-(3,4-Dihydronaphthalen-1(2h)-ylidene)hydrazinyl)-4-phenylthiazole (6a)
Phenacyl bromide (199 mg, 1 mmol), thiosemicarbazide (91 mg, 1 mmol) and tetralone
2
(
0.5 mL, 4 mmol) were stirred at room temperature for 5 min. The solid separated was
filtered and washed with ether to remove unreacted cyclic ketone. The product was
1
recrystallized from methanol. Black solid; mp 157–159 °C; yield (96%); H NMR (400 MHz,
CDCl ): δ 1.89–1.95 (m, 2H), 2.57 (t, J ¼ 6.8 Hz, 2H), 2.76 (t, J ¼ 6.0 Hz, 2H), 6.92 (s, 1H),
3
7
2
.15 (d, J ¼ 4.4 Hz, 1H), 7.27–7.29 (m, 3H), 7.33 (d, J ¼ 7.2 Hz, 1H), 7.41 (t, J ¼ 7.6 Hz,
13
H), 7.82 (d, J ¼ 7.6 Hz, 2H), 8.16 (t, J ¼ 4.8 Hz, 1H); C NMR (100 MHz, CDCl ):
3
δ 21.41, 25.68, 29.41, 103.58, 124.62, 125.96, 126.57, 127.96, 128.44, 128.76, 128.92,
1
5
32.12, 134.34, 139.32, 147.23, 150.58, 170.17. Anal. calcd for C H N S, C, 71.44; H,
19 17 3
.36; N, 13.15; S, 10.04%. Found: C, 71.49; H, 5.31; N, 13.19; S, 10.14.
Conclusion
In conclusion, we have successfully synthesized a novel 2,4-disubstituted thiazole
derivatives through a multi component approach under solvent free reaction conditions.
The method had the advantages of mild reaction conditions, better to excellent yields,
one pot operational simplicity.
Acknowledgments
The authors are thankful to the Director, National Institute of Technology, Warangal, Telangana,
India for providing the facilities. K. S. thanks to the MHRD, India for fellowship.
References
[
[
[
1] D’Souza, D. M.; Muller, T. J. J. Chem. Soc. Rev. 2007, 36(7), 1095–1108.
2] Haji, M. Beilstein J. Org. Chem. 2016, 12, 1269–1301.
3] Jain, V.; Bijani, S.; Ambasana, P.; Mehariya, K.; Bhoya, U.; Pandey, B.; Shah, A. Synth.
Commun. 2016, 46, 63–72.
[4] Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168–3210.
[5] Ruijter, E.; Scheffelaar, R.; Orru, R. V. A. Angew. Chem. Int. Ed. 2011, 50, 6234–6246.
[6] Borges, F.; Roleira, F.; Milhazes, N.; Santana, L.; Uriarte, E. Curr. Med. Chem. 2005, 12(8),
8
87–916.

SYNTHETIC COMMUNICATIONS®
7
[
7] Mohareb, R. M.; Abdo, N. Y. M. Molecules 2015, 20, 11535–11553.
8] Bhila, V. G.; Patel, C. V.; Patel, N. H.; Brahmbhatt, D. I. Med. Chem. Res. 2013, 22(9),
338–4346.
[
4
[
9] de Souza, S. M.; Monache, F. D.; Smania Jr, A. Z. Naturforsch. 2005, 60c, 693–700.
[
[
[
[
10] Hassan, M. Z.; Osman, H.; Ali, M. A.; Ahsan, M. J. Eur. J. Med. Chem. 2016, 123, 236–255.
11] Purohit, N. V. Indian J. Chem. 2001, 40B, 222–227.
12] Garro, H. A.; Pungitore, C. R. Curr. Drug Discov. Technol. 2015, 12(2), 66–79.
13] Fylaktakidou, K. C.; Hadjipavlou-Litina, D. J.; Litinas, K. E.; Nicolaides, D. N. Curr. Pharm.
Des. 2004, 10(30), 3813–3833.
[
[
[
[
14] Bullock, S. J.; Felton, C. E.; Fennessy, R. V.; Harding, L. P.; Andrews, M.; Pope, S. J. A.; Rice,
C. R.; Riis-Johannessen, T. Dalton Trans. 2009, 47, 10570–10573
15] Di Braccio, M.; Grossi, G.; Roma, G.; Signorello, M. G.; Leoncini, G. Eur. J. Med. Chem. 2004,
39, 397–409.
16] Han, S.; Zhou, V.; Pan, S.; Liu, Y.; Hornsby, M.; McMullan, D.; Klock, H. E.; Haugen, J.; Lesley,
S. A.; Gray, N.; Bioorg. Med. Chem. Lett. 2005, 15, 5467–5473.
17] Kancheva, V. D.; Boranova, P. V.; Nechev, J. T.; Manolov, I. I. Biochimie 2010, 92(9),
1
138–1146.
[
[
18] Rouf, A.; Tanyeli, C. Eur. J. Med. Chem. 2015, 97, 911–927.
19] Chhabria, M. T.; Patel, S.; Modi, P.; Brahmkshatriya, P. S. Curr. Top. Med. Chem. 2016, 16,
2
841–2862.
[
[
[
[
[
[
[
20] Ayati, A.; Emami, S.; Asadipour, A.; Shafiee, A.; Foroumadi, A. Eur. J. Med. Chem. 2015, 97,
99–718.
6
21] Laczkowski, K. Z.; Misiura, K.; Switalska, M.; Wietrzyk, J.; Laczkowska, A. B.; Fernandez, B.;
Paneth, A.; Plech, T. Anticancer Agents Med. Chem. 2014, 14(9), 1271–1281.
22] Turan-Zitouni, G.; Altintop, M. D.; Ozdemir, A.; Kaplancikli, Z. A.; Ciftci, G. A.; Temel, H. E.
Eur. J. Med. Chem. 2016, 107, 288–294.
23] Cabrera, D. G.; Douelle, F.; Feng, T. S.; Nchinda, A. T.; Younis, Y.; White, K. L.; Wu, Q.; Ryan,
E.; Burrows, J. N.; Waterson, D.; J. Med. Chem. 2011, 54(21), 7713–7719.
24] Curreli, F.; Kwon, Y. D.; Zhang, H.; Scacalossi, D.; Belov, S. D. S.; Tikhonov, A. A.; Andreev,
I. A.; Altieri, A.; Kurkin, A. V.; Kwong, P. D.; J. Med. Chem. 2015, 58(17), 6909–6927.
25] Hampannavar, G. A.; Karpoormath, R.; Palkar, M. B.; Shaikh, M. S.; Chandrasekaran, B. ACS
Med. Chem. Lett. 2016, 7(7), 686–691.
26] Helal, M. H. M.; Salem, M. A.; El-Gaby, M. S. A.; Aljahdali, M. Eur. J. Med. Chem. 2013, 65,
5
17–526.
[
[
[
[
[
[
[
[
27] Xinjiang, W.; Fekadu, K.; Volker, M. S. Mutat. Res. 2005, 589, 81–102.
28] Newman, D. J.; Cragg, G. M.; Snader, K. M. J. Nat. Prod. 2003, 66, 1022–1037.
29] Hantzsch, A.; Weber, H. J. Ber. Dtsch. Chem. Ges. 1887, 20, 3118.
30] Hantzsch, A. Justus Leibigs Ann. Chem. 1988, 249, 1.
31] Dodson, R. M.; King, L. C. J. Am. Chem. Soc. 1945, 67(12), 2242–2243.
32] King, L. C.; Hlavacek, R. J. J. Am. Chem. Soc. 1950, 72, 3722–3725.
33] Koelsch, C. F. J. Am. Chem. Soc. 1950, 72(7), 2993–2995.
34] Santhosh, P.; Kranthi Kumar, G.; Srinivas, B.; Rajeswar Rao, V. Tetrahedron Lett. 2013, 54,
5
663–5666.
[
[
[
35] Krishnaiah, V.; Rajesh Kumar, K.; Santosh, K.; Rajeswar Rao, V.; Srigiridhar, K.; Murali
Krishna, T. Bioorg. Med. Chem. Lett. 2015, 25, 5797–5803.
36] Subrahmanya Bhat, K.; Shivarama Holla, B. Phosphorus, Sulfur Silicon Relat. Elem. 2004, 179,
1
019–1026.
37] Santhosh, P.; Rajeswar Rao, V. Indian J. Chem. 2014, 53B, 115–119.