Efficient synthesis of 2,4-disubstituted thiazoles under grinding

Article abstract of DOI:10.1080/00397911003629440

A simple and convenient protocol is described for the preparation of 2,4-disubstituted thiazoles via a condensation reaction of -halo carbonyl compounds with thiourea or thioacetamide at room temperature, under grinding, in good yields.

Full text of DOI:10.1080/00397911003629440

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Efficient Synthesis of 2,4-Disubstituted
Thiazoles Under Grinding
a
a
a
Majid M. Heravi , Nargess Poormohammad , Yahia S. Beheshtiha
a
&
a
Bita Baghernejad
Department of Chemistry, School of Science, Azzahra University,
Vanak, Tehran, Iran
Version of record first published: 02 Feb 2011.
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2011): Efficient Synthesis of 2,4-Disubstituted Thiazoles Under Grinding, Synthetic Communications:
(
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 41:4, 579-582
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Synthetic Communications , 41: 579–582, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911003629440
EFFICIENT SYNTHESIS OF 2,4-DISUBSTITUTED
THIAZOLES UNDER GRINDING
Majid M. Heravi, Nargess Poormohammad,
Yahia S. Beheshtiha, and Bita Baghernejad
Department of Chemistry, School of Science, Azzahra University, Vanak,
Tehran, Iran
Abstract A simple and convenient protocol is described for the preparation of 2,4-disubsti-
tuted thiazoles via a condensation reaction of a -halo carbonyl compounds with thiourea or
thioacetamide at room temperature, under grinding, in good yields.
Keywords Grinding; phenacyl bromide; solvent-free; thiazoles
INTRODUCTION
Thiazoles and their derivatives are found to be associated with various biologi-
[
1,2]
cal activities such as antibacterial, antifungal, and anti-inflammatory activities.
[
3]
Different thiazole-bearing compounds possess anti-inflammatory activities,
and some are known to be used as pharmaceutical as well as agrochemical pro-
[
4–6]
ducts.
were reported to exhibit antiviral, analgesic, antitumor, and cytotoxic activities.
A survey of literature reveals that a number of 2,4-disubstituted thiazoles
7,8]
[
The aminothiazole ring system is a useful structural element in medicinal chemistry
and has found broad application in drug development for the treatment of
[
allergies, hypertension,
9]
[10]
[11]
[12]
[13]
inflammation,
bacterial infection,
and HIV.
In
addition, thiazoles are also synthetic intermediates and common substructures in
numerous biologically active compounds. Thus, the thiazole nucleus has been much
studied in the fields of organic and medicinal chemistry.
The solvent-free approach to the synthesis of molecules is attractive because
the majority of solvents are either toxic or flammable and add considerably to the
Received November 4, 2009.
Address correspondence to Majid M. Heravi, Department of Chemistry, School of Science,
Azzahra University, Vanak, Tehran, Iran. E-mail: mmh1331@yahoo.com
5
79

580
M. M. HERAVI ET AL.
Scheme 1.
overall cost of synthesis. In many instances, the solvent-free approach allows shorter
reaction times, improved selectivities, and easier separations and purifications than
[
14]
conventional solvents.
solvent-free reactions, and it provides an up-to-date account of the range of synthetic
A monograph has recently appeared on the subject of
[
15]
reactions that have been investigated under solvent-free conditions. Therefore, in
this article, we describe a highly efficient synthesis of thiazoles by the solvent-free
mixing of a -halo carbonyl compounds with thioureas at room temperature in good
yields (Scheme 1).
RESULTS AND DISCUSSION
In a typical procedure, phenacyl bromide reacts with thioureas to provide
excellent yields of 2,4-disubstituted thiazoles after just a few minutes of grinding.
After optimizing the conditions, we next examined the scope and generality of this
method to other substrates using different substituted phenacyl bromides and substi-
tuted thioureas. The phenacyl bromide with electron-rich functionality (entries 5 and
6
, Table 1) as well as electron-poor functionality (entries 2 and 4, Table 1) underwent
a condensation reaction with thiourea=substituted thiourea equally well to afford the
corresponding 2-aminothiazoles in excellent isolated yields. The results are summar-
ized in Table 1.
It can be observed that all reactions were complete in 15–20 min under grinding
without the need for any added catalyst or solvent at ambient temperature. Highly
efficient grinding is required for the success of these reactions. The good results
obtained following our simple procedure are a pleasant surprise in view of the numer-
ous catalysts employed in organic solvents to synthesize this class of compounds.
Table 1. Synthesis of 2,4-disubstituted thiazoles under grinding
ꢀ
Mp ( C)
a
Entry
Ar
R
Time (min)
Product
Observed
Reported
Yield (%)
[16]
150
1
2
3
4
5
6
C
6
H
5
NH
NH
2
15
15
20
20
15
20
3a
3b
3c
3d
3e
3f
151
69
95
94
92
91
93
91
[16]
4-MeOC
6
H
4
4
2
67
200–203
[
16]
C
6
H
5
CH
CH
3
203
69
[16]
67–68
4-MeOC
6
H
3
[16]
163–164
4-ClC
4-ClC
6
H
H
4
NH
CH
2
165
113
[16]
111
6
4
3
a
Isolated yields.

SYNTHESIS OF 2,4-DISUBSTITUTED THIAZOLES
581
In conclusion, we have described a novel and efficient method for the synthesis
of 2,4-disubstituted thiazoles under grinding. The important features of this procedure
are green aspects, such as avoidance of hazardous organic solvents, toxic catalysts,
and waste; easy workup; mildness; excellent yield; and environmental friendliness.
EXPERIMENTAL
Chemicals and Apparatus
Chemical were purchased from the Fluka, Merck, and Aldrich chemical
companies. Melting points were measured with a Bamstead Electrothermal 9200
apparatus and are uncorrected. Gas chromatography–mass spectrometry (GC-MS)
spectra were recorded on an Agilent Technologies 6890 network GC system and
an Agilent 5973 network mass selective detector. Thin-layer chromatography
(
TLC) on commercial aluminum-backed plates of silica gel 60 F254 was used to
1
monitor the progress of reactions. H NMR spectra were recorded on a Bruker
AQS Avance300-MHz spectrometer using tetramethylsiliane (TMS) as an internal
standard (CDCl3 solution). Yields refer to isolated pure products. Products
were identified by GC-MS and H NMR, and the data were compared to those of
authentic samples purchased from commercial sources.
1
2,4-Disubstituted Thiazoles
Grinding of phenacyl bromide (1 mmol), thiourea, or thioacetamide (1 mmol)
in a solvent-free environment at room temperature after 15–20 min provided the
corresponding product. The progress of the reaction was monitored by TLC. After
completion of the reaction, the product was extracted using ethyl acetate. The
solvent was removed under reduced pressure to obtain the crude solid product.
The crude product was recrystallized from the ethanol to give the pure product.
2-Amino-4-phenylthiazole (3a)
ꢀ
[16]
ꢀ
1
Mp 151 C (lit. : 150 C); GC-MS: 177 (M); H NMR (300 MHz, CDCl ) d
3
5
7
.09 (s, 2H), 6.54 (s, 1H), 7.29–7.84 (m, 5H, arom), 5.09 (2H, s), 6.54 (1H, s),
.29–7.84 (5H, arom, m).
ACKNOWLEDGMENT
The authors are thankful to Alzahra Research Council for partial financial
support.
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