Convenient and simple synthesis of 2-aminothiazoles by the reaction of α-halo ketone carbonyls with ammonium thiocyanate in the presence of N-methylimidazole

Article abstract of DOI:10.1016/j.tetlet.2012.07.080

Substituted 2-aminothiazole derivatives were obtained as a result of N-methylimidazole catalyzed cyclization of α-halo ketone carbonyls with ammonium thiocyanate in water-alcoholic media. The generality of the method has been demonstrated by screening a series of aromatic/heteroaromatic/aliphatic α-halo ketones, α-halo β-diketones, and α-halo β-ketoesters. The developed method is simple, mild, and general route for the preparation of diversely functionalized 2-aminothiazoles in good to moderate yields from readily available starting materials.

Full text of DOI:10.1016/j.tetlet.2012.07.080

Tetrahedron Letters 53 (2012) 5265–5269
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Convenient and simple synthesis of 2-aminothiazoles by the reaction of
ketone carbonyls with ammonium thiocyanate in the presence of
N-methylimidazole
a-halo
⇑
H. M. Meshram , Pramod B. Thakur, B. Madhu Babu, Vikas M. Bangade
Organic Chemistry Division–I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Substituted 2-aminothiazole derivatives were obtained as a result of N-methylimidazole catalyzed cycli-
zation of -halo ketone carbonyls with ammonium thiocyanate in water–alcoholic media. The generality
of the method has been demonstrated by screening a series of aromatic/heteroaromatic/aliphatic -halo
ketones, -halo b-diketones, and -halo b-ketoesters. The developed method is simple, mild, and general
Received 21 May 2012
Revised 12 July 2012
Accepted 18 July 2012
Available online 27 July 2012
a
a
a
a
route for the preparation of diversely functionalized 2-aminothiazoles in good to moderate yields from
readily available starting materials.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
2-Aminothiazoles
Ammonium thiocyanate
a-Halo carbonyls
N-Methylimidazole catalysis
Water–alcoholic reaction media
Natural and synthetic molecules containing thiazole structural
motifs are very well known for their broad spectrum of biological
activities.1–5 Particularly, 2-aminothiazoles have been reported to
possess antitumor,6 antiviral,7 antibacterial,8 antiprion,9 and psy-
chotropic activities.10 Beside this, 2-aminothiazole scaffolds were
successfully employed as an adenosine receptor antagonist,11 as
well as heterocyclic bioisosteres of the phenol moiety on dopamine
agonists and anti-Parkinsonian agent, pramipexole.12 Recently, 2-
aminothiazole analogue MB06322 is identified as a prodrug for
the treatment of type 2 diabetes13 and 2-aminothiazole-4-carbox-
ylate derivatives as active compounds against Mycobacterium
tuberculosis H37Rv and the b–ketoacyl–ACP synthase mtFabH14
(Fig. 1). In addition, the conjugated polyaminothiazole films have
been reported to display electrochemical properties with high
thermal stability.15 Along with this, the sulfur-containing aromat-
ics are also attractive candidates for organic semiconductors16 and
can act as unique co-ordination compounds for electronic, mag-
netic, and optical materials.17,18
O
O
P
O
NH
O
S
O
N
NH2
H2N
HN
N
S
O
O
O
methyl 2-amino-5-benzylthiazole-4-carboxylate
MB06322
Figure 1. Representative examples of biologically active 2-aminothiazole
derivative.
ketones with a mixture of N-bromosuccinimide, thiourea, and ben-
zoyl peroxide.21
In continuation of our efforts in the development of novel and
eco-friendly protocols to synthesize biologically active molecules,22
we have discovered a new method for the synthesis of highly
Due to such a prevalence and prominence of 2-aminothiazoles
moiety, many synthetic protocols have been reported which in-
substituted 2-aminothiazoles by the reaction of a-halo ketone car-
bonyls with ammonium thiocyanate. Despite some excellent meth-
ods have been published which are mild and high yielding19f,g, our
method holds a tag of novel route which first time utilizes the
ammonium thiocyanate as both source of ammonia and thiocya-
nate ion in a one pot reaction sequence. To the best of our knowl-
edge, there is no report concerning single step synthesis of 2-
cludes Hantzsch’s cyclocondensation of thiourea with
a-haloke-
tones/ -thiocyanate
a
-tosylketone19 and the reactions of
a
carbonyl compounds with aromatic or aliphatic amine hydrochlo-
rides.20 They are also synthesized by one-pot reaction of enolizable
aminothiazole by the reaction of ammonium thiocyanate with
halo ketone carbonyls. In this Letter, we wish to describe our preli-
a-
⇑
Corresponding author. Fax: +91 40 27193275.
E-mail address: hmmeshram@yahoo.com (H.M. Meshram).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.080

5266
H. M. Meshram et al. / Tetrahedron Letters 53 (2012) 5265–5269
minary result about N-methylimidazole catalyzed direct synthesize
of highly substituted 2-aminothiazoles in water-alcoholic media.
The current observation demonstrates the extended utility of
ammonium thiocyanate salt in the exploratory synthesis of highly
functionalized 2-aminothiazole-4-carboxylate derivatives.
(Rf = 0.85, 20% EtOAc/hexanes in a 3 time run), one compound
was slightly polar (Rf = 0.64, 20% EtOAc/hexanes in a 3 time run)
and another was much polar (Rf = 0.35, 20% EtOAc/hexanes in a 3
time run). From the available authentic sample of previous reac-
tion, slightly polar compound was confirmed as phenacyl thiocya-
nate. The more polar compound was isolated by column
chromatography and taken for spectral characterization. According
to the literature,20 2-aminothiazole ring can be obtained by the
The initial purpose of this research was to develop a method to
synthesize the phenacyl thiocyanates by the reaction of phenacyl
bromide with ammonium thiocyanate in the presence of imidaz-
ole. Our study started with the reaction between phenacyl bromide
(1 mmol) and ammonium thiocyanate (1 mmol) in the presence of
imidazole (0.1 mmol) in 5 ml methanol at rt and the selected re-
sults are summarized in Table 1. The progress of the reaction
was monitored by TLC. After 15 min of stirring we have observed
the complete consumption of phenacyl bromide and appearance
of only one slightly polar compound on TLC (Rf = 0.64, 20%
EtOAc/hexanes in 3 time run). The reaction mixture was subjected
to column chromatography and pure isolated compound was taken
for spectral analysis. 1H NMR spectrum of compound exhibited
characteristic singlet at d 4.75 ppm corresponds to the two hydro-
gens attached to carbon between carbonyl and SCN group, 13C NMR
shows peak at d 111.8 ppm for carbon of SCN group. FT-IR spec-
trum exhibits sharp absorption at 2155 cmÀ1 while mass spectrum
exhibited [M+H] peak at m/z = 178. On the basis of spectral data,
the structure of isolated compound was assigned as phenacyl
thiocyanate.
reaction of a-thiocyanate carbonyl compounds with amines. Hence
we guessed the isolated polar compound as 4-phenyl-2-aminothi-
azole which might have formed by the reaction between in situ
generated ammonia and phenacyl thiocyanate under the influence
of imidazole.
The FT-IR spectra of the isolated polar compound showed the
broad peak at 3432 cmÀ1 which corresponds to the primary amino
group and does not show any absorption in the range of carbonyl
and thiocyanate functionality. The 1H NMR spectrum exhibited a
sharp singlet at d 6.65 ppm and broad singlet at d 5.21 ppm corre-
sponding to the one hydrogen of thiazole ring at C-5 and two
hydrogens of amino group attached to C-2, respectively. Whereas
in the 13C NMR spectrum, the signals, respectively at d 101.8 and
167.6 ppm correspond to C-5 and C-2 of thiazole ring was visible.
The mass spectrum exhibited a molecular ion peak [M+] at m/
z = 176 for C9H8N2S. Based on the analysis of the spectral data,
the structure of compound was assigned as 4-phenyl-2-aminothi-
azole. The assigned structure was also confirmed by comparison
with the spectral data obtained for an authentic sample prepared
by available literature procedure.19a
Unexpectedly, the next reaction between phenacyl bromide and
ammonium thiocyanate in the presence of imidazole in methanol
was performed for a longer time (2 h). TLC showed the complete
consumption of phenacyl bromide and exhibited the formation of
two new compounds on TLC approximately in 1:1 area ratios. In
comparison with the polarity of phenacyl bromide on TLC
The above observations reveal that the 4-phenyl-2-aminothia-
zole can be obtained by the reaction of phenacyl bromide with
ammonium thiocyanate in the presence of imidazole in methanol
Table 1
Optimization of reaction condition for the synthesis of 4-phenyl-2-aminothiazole
a By 1H NMR analysis.
b Except this all reactions were carried out in closed condition.
c With 2 equiv of ammonium thiocyanate.
d At 100 °C.

H. M. Meshram et al. / Tetrahedron Letters 53 (2012) 5265–5269
5267
Table 2
Catalyst
Synthesis of highly substituted 2-aminothiazoles by using optimized reaction
O
S
N
conditiona
O
NH4SCN
N +
NH2
S
Solvent
Br
Entry Reactant
Time
(h)
Product
Yieldb
(%)
Thiocyanted
Product
2a
Cyclised
Product
3a
1a
O
Br
1a
Scheme 1. Optimization of reaction condition for the synthesis of 4-phenyl-2-
3a
1
1.2
1.2
84
79
N
aminothiazole.
NH2
S
O
F
Br
1b
at rt. Previous literature shows the formation of only thiocyanated
product23 2a by the reaction of phenacyl bromide with ammonium
thiocyanate. The literature does not show any report regarding the
sequential use of ammonium thiocyanate as source of both SCN
and NH3 for the synthesis of 2-aminothiazole in one pot reaction.
Encouraged by our observations, next we planned to study the
reaction in detail to establish the optimized reaction condition to
get maximum yield of 4-phenyl-2-aminothiazole 3a (Scheme 1).
To avoid possible loss of ammonia from the reaction media, we
have carried out the reaction in a closed vessel and observed an in-
crease in yield of the desired product. To choose an appropriate
solvent for a particular reaction is not a simple issue.24 Keeping
in mind the solubility of ammonium thiocyanate salt, different po-
lar solvents were screened and the results are included in Table 1.
Water is an attractive option from an environmental point of
view25 and its ability to enhance the rates and affect the selectivity
in various organic transformations due to high hydrogen bonding
ability.26 Hence we also attempted water as solvent for the model
reaction. Result shows overall decrease in the yield of reaction but
showed some increase in the selectivity of the desired product (Ta-
ble 1, entry 7). As the use of an aqueous mixture of solvents was
found to be advantageous in some organic processess,27 we tried
some 1:1 mixture of solvents and results were encouraging. We
observed a noticeable increase in the selectivity of the desired
product with the mixture of solvents. After examining various sol-
vent systems, the best result was obtained with 1:1 mixture of
iPrOH:H2O (Table 1, entry 10). When imidazole was replaced with
N-methylimidazole, the enhancement in selectivity and rate of
reaction was observed (Table 1, entry 11). Other similar bases like
4-dimethylaminopyridine (DMAP), 4-diazabicyclo[2.2.2]octane
(DABCO), triethylamine (TEA), diisopropylethylamine (DIPEA),
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,5-diazabicy-
clo[4.3.0]non-5-ene (DBN) showed adverse effect on the selectivity
of desired product and hence eliminated from further study. Fur-
ther we screened N-methylimidazole with different mol% and de-
lighted to find that the 10 mol % catalyst is sufficient to catalyze
the present reaction effectively. There was not much improvement
observed in the yield of desired product, even if we doubled the
amount of ammonium thiocyanate (Table 1, entry 16). Further to
improve the selectivity of the cyclized product, the model reaction
was also tested at a higher temperature (100 °C), but significant in-
crease in selectivity was not observed (Table 1, entry 17). It was
also found that, the conversion in model reaction was not com-
plete. The exact reason for this is not well understood. But, we as-
sume that, this might be due to the less availability of free NH3
required for cyclization because of the possible formation of
ammonium bromide during the reaction.29 Control reaction with-
out N-methylimidazole in iPrOH:H2O (1:1) was also performed
which gave very trace amount of the desired cyclized product (Ta-
ble 1, entry 24). On the basis of the above study, we have chosen
iPrOH:H2O (1:1) as solvent system and N-methylimidazole
(10 mol %) as catalyst as the set of optimized condition for the syn-
thesis of 4-phenyl, 2-aminothiazole at rt (Table 1, entry 11).
For the general validity of the reaction, the optimized reaction
2
N
3b
F
NH2
S
O
Cl
Cl
Br1c
Cl
3
1.5
84
Cl
3c
N
NH2
S
O
Br
Br1d
N
4
1.5
1
82
88
74
3d
Br
NH2
NH2
S
O
O2N
Br
1e
5
N
O2N
3e
3f
S
O
Br
N
6
7
1.2
1f
NH2
S
O
Br
1g
1.2
81
N
NH
2 3g
S
O
MeO
Br
1h
8
9
1.5
1.5
N
78
78
3h
MeO
NH2
S
O
O
Br
1i
N
3i
3j
NH2
NH2
S
Br
O
1j
N
10
11
12
1.5
1.2
1.2
78
86
82
S
Br
1k
N
3k
NH2
S
Br
O
N
S
1l
NH32l
N
S
S
1m
13
14
1.5
2
73
68
Br
3m
NH2
S
O
O
N
N
Br
1n
N
3n
S
NH2
N
Br1o
15
16
Br
1.5
2
71
74
Br
S
3o
NH2
S
S
O
O
N
Cl
1p
NH2
3p
S
(continued on next page)
was tested on several structurally varied
a-halo ketone carbonyl
components and results are summarized in Table 2 (Scheme 2).

5268
H. M. Meshram et al. / Tetrahedron Letters 53 (2012) 5265–5269
presence of catalytic amount of N-methylimidazole to furnish
Table 2 (continued)
highly substituted 2-aminothiazoles in good to moderate yield. It
is worth to mention that, fused 2-aminothiazole like 3r and 3t
can also be obtained in moderate yield with our method. Similarly,
Entry Reactant
Time
(h)
Product
Yieldb
(%)
O
aromatic and heteroaromatic
a-bromo b-ketoesters also under-
1q
Br
N
17
18
19
2.2
2.5
1.2
73
69
78
went cyclization to give desired product in good yield (Table 2, en-
try 24, 25).
In conclusion, the reactions of a-halo ketone carbonyls with
ammonium thiocyanate in the presence of catalytic N-methylimid-
3q
3r
NH2
NH2
S
O
O
N
Br
O
1r
1s
S
azole result in one-pot synthesis of 2-aminothiazole derivatives via
N
a-thiocyanate carbonyl compounds. The discovery and develop-
NH2
NH2
3s
3t
S
ment of this method30 led to a general route for the preparation
of diversely functionalized 2-aminothiazoles in good to moderate
yields from readily available starting materials. The described
method first time utilizes ammonium thiocyanate as both source
of ammonia and thiocyanate ion for the synthesis of 2-aminothiaz-
oles in one pot reaction sequence in water-alcoholic media. In
addition to its simplicity, mild reaction condition and a wide scope
of substrates are the distinct features of this protocol. Further stud-
ies on the scope and limitations of this reaction are in progress.
Br
Br
O
O
O
N
Br
1t
S
20
2
57
O
O
O
O
N
S
O
21
22
1.2
1.2
69
67
O
NH2 3u
1u
1v
O
O
N
S
O
O
O
NH2
3v
Cl
O
O
Acknowledgments
N
S
O
O
23
24
1.8
2
67
79
Br
O
O
N3wH2
P.B.T, B.M.B and V.M.B thank CSIR New Delhi for the award of a
fellowship and Dr. J.S. Yadav, Director IICT, for his support and
encouragement.
1w
O
O 1x
N
S
Br
O
3x
NH2
NH2
References and notes
O
O
N
O
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O
N
S
25
2
73
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N
Br
1y
3y
O
O
a
Reaction condition: all the reactions were carried out with
bonyls (1 mmol), ammonium thiocyanate (1 mmol) in the presence of N-methyl-
imidazole (0.1 mmol) in PrOH:H2O (1:1).
a-halo ketone car-
i
b
Isolated yields.
Variety of substituted aryl
went smooth cyclization under optimized condition to give the de-
sired product in good yield (Table 2, entries 1–12). Fused ring
halo ketone carbonyls like, 2-bromo-1-(naphthalen-6-yl)ethanone
(1k) and 1-(anthracen-10-yl)-2-bromoethanone (1l) also gave
their respective cyclized product in high yield and within short
time (Table 2, entry 11, 12). It is noteworthy that different hetero-
a-halo ketone carbonyls 1(a–l) under-
a
-
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3408.
aryl a-bromo ketones 1(m–o) also gave desired product in moder-
10. Zablotskaya, A.; Segal, I.; Germane, S.; Shestakova, I.; Domracheva, I.;
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Geterotsiklicheskikh Soedinenii).
ate yields under optimized condition (Table 2, entry 13–15).
Desired 2-aminothiazole product can also be obtained for different
a-substituted,
a-bromo ketones like 1i and 1j. Generality of the
procedure is further strengthened by examining the aliphatic
bromo ketones which gave their respective product in good to
moderate yields (Table 2, entry 16–18).
a
-
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As a logical extension, we investigated the scope and limitations
of this method for the cyclization of
pounds. Different structurally varied
yls 1(s–y) reacted smoothly with ammonium thiocyanate in the
a-halo b-dicarbonyl com-
a
-bromo/chloro b-dicarbon-
R1
R1
R2
O
X
1(a-y)
N-methylimidazole(10 mol%)
N
NH4SCN
R2
NH2
S
iPrOH:H2O (1:1), 1-2.5 hr, rt
3(a-y)
R1 = -Aromatic, -Heteroaromatic, -Aliphatic, X = -Br, -Cl
R2 = -H, -CH3, -Ph, -COCH3, -COOEt, -COOCH2Ph
Scheme 2. Synthesis of highly substituted 2-aminothiazoles by using optimized
reaction condition.

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30. Typical procedure for the synthesis of 2- aminothiazoles: To a stirred solution of
a
-halo carbonyl (1.0 mmol) and N-methylimidazole (0.1 mmol) in 5 ml
iPrOH:H20 (1:1) was added ammonium thiocyanate (1 mmol). The reaction
flask was closed and the reaction mixture was vigorously stirred at room
temperature for the stipulated time (Table 2). After the desired product
formation indicated by TLC, the reaction mixture was poured on 10 mL ice cold
water and extracted with dichloromethane (3 Â 5 mL), washed with brine
(10 mL). The organic layers were combined and dried over anhydrous Na2SO4.
Na2SO4 was filtered off and solvent was evaporated in rotary vacuum
evaporator to obtain the crude products. Crude products were further
purified by silica gel column chromatography (100–200 mesh) using ethyl
acetate:hexane (1:3 to 1:4) as eluent to obtain the corresponding pure
products. All the compounds were characterized by spectral analysis
techniques. 2-Aminothiazole derivatives are well documented in the
literature with their characterization data. The obtained data for all
synthesized compounds were in good agreement with the documented data
in the literature. The characterization data for new compound 4-(anthracen-9-
yl)-thiazol-2-amine (3l, Table 2, Entry 12) are given. The title compound was
prepared according to the typical procedure given above with 82% yield in
1.2 h. Rf(20% EtOAc/hexanes in 3 times run) 0.34; Yellow solid. mp 223–225 °C;
1H NMR (300 MHz, (CD3)2SO): d 8.44 (s, 1H), 7.99–7.93 (m, 4H), 7.45–7.35(m,
4H), 6.62 (br s, 2H), 6.49 (s, 1H) ppm. 13C NMR (75 MHz, (CD3)2SO): d 169.8,
149.2, 138.19, 130.46, 128.59, 127.81, 126.82, 125.80, 125.44, 123.99,
100.98 ppm. IR(KBr): = 3432, 3111, 2923, 2856, 1654, 1596, 1522, 1483,
1335, 1030, 712 cmÀ1. MS (ESI): m/z = 299 [M+Na]+.