Metal-Free One-Pot Chemoselective Thiocyanation of Imidazothiazoles and 2-Aminothiazoles with in situ Generated N-Thiocyanatosuccinimide

Article abstract of DOI:10.1055/s-0037-1609553

A chemoselective thiocyanation of imidazothiazoles and 2-aminothiazoles with use of in situ generated N-thiocyanatosuccinimide (NTS) at room temperature is described. The protocol offers mild reaction conditions and high chemoselectivity for electrophilic substitution in imidazothiazoles over nucleophilic substitution. This method provides metal-free and easy conversion of imidazothiazoles and 2-aminothiazoles into their corresponding C-3 and C-5 thiocyanates, respectively, in good to excellent yield. The present protocol also offers the effective thiocyanation of bifunctional imidazothiazoles containing aliphatic -OH and C(sp ²)-H bond functionalities.

Full text of DOI:10.1055/s-0037-1609553

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–G
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S. N. Kadam et al.
Letter
Synlett
Metal-Free One-Pot Chemoselective Thiocyanation of
Imidazothiazoles and 2-Aminothiazoles with in situ Generated
N-Thiocyanatosuccinimide
SCN
Shuddhodan N. Kadam
R1
N
R1
N
N
R1
Ajay N. Ambhore
Madhav J. Hebade
Rahul D. Kamble
Shrikant V. Hese
Milind V. Gaikwad
Priya D. Gavhane
Bhaskar S. Dawane*
N
N
S
N
S
S
NCS
OH
OH
5 examples
alcoholic thiocyanate
not obsered
up to 93% yield
colum cromatography
not required
O
N
NCS
R2
R1
R2
R1
O
N
R2
NCS
N
R1
NH2
School of Chemical Sciences, Swami Ramanand Teerth
Marathwada University, Nanded (MS), 431606, India
bhaskardawane@rediffmail.com
S
NCS
NH2
S
9 examples
up to 90% yield
without cromatography
N
S
nuclear thiocyanate
not obsered
NH2
R1/R1 = H, Cl, Br, F, I, CH3, NO2
R2 = H, NO2
80 to 93% yield for 5 examples
30 to 92% yield for 9 examples
Received: 01.04.2018
Accepted after revision: 09.06.2018
Published online: 23.07.2018
several approaches have been encountered (i.e. use of
iodinated reagents,13 oxidants,14 and brominating agents15)
in combination with readily available, low-cost thiocyanate
salts as thiocyanating agents. But these strategies are mainly
focused on imidazopyridines and indoles.16 Furthermore,
the selectivity of direct electrophilic thiocyanation of
C(sp2)–H bonds over nucleophilic substitution by alcoholic
–OH, when both groups are present in same compound, by
using N-thiocyanatosuccinimide (NTS) as a reagent, has not
been studied previously.
Imidazothiazoles are considered a significant class of
heterocyclic compounds. For example, levamisol and tetra-
misole, known for their antihelminthic and immunomodu-
latory properties, respectively, display an imidazothiazole
core (Figure 1). The majority of imidazothiazoles exhibit a
wide range of biological activities.17 Thiazoles are structur-
ally very close to imidazoles, with the only difference of sul-
fur replaced by nitrogen. Vitamin B (thiamin) (Figure 1) is
an important naturally occurring vitamin which contains
the thiazole ring as an active center involved in various bio-
logical processes. Thiazoles are considered to be one of the
most compelling heterocyclic compounds because of their
broad spectrum of biological activities.18 Considering these
consequential advantages, immense efforts have been
made for the synthesis of imidazothiazoles and thiazoles.19
Introduction of new functional groups into these moieties
may modify their biological profile or may imbed new bio-
logical activities. For this purpose, direct C-3 and C-5 func-
tionalization of imidazothiazoles and thiazoles, respective-
ly, provides an acceptable strategy.
DOI: 10.1055/s-0037-1609553; Art ID: st-2018-k0194-l
Abstract A chemoselective thiocyanation of imidazothiazoles and 2-
aminothiazoles with use of in situ generated N-thiocyanatosuccinimide
(NTS) at room temperature is described. The protocol offers mild reac-
tion conditions and high chemoselectivity for electrophilic substitution
in imidazothiazoles over nucleophilic substitution. This method pro-
vides metal-free and easy conversion of imidazothiazoles and 2-amino-
thiazoles into their corresponding C-3 and C-5 thiocyanates, respective-
ly, in good to excellent yield. The present protocol also offers the
effective thiocyanation of bifunctional imidazothiazoles containing
aliphatic –OH and C(sp2)–H bond functionalities.
Keywords N-thiocyanatosuccinimide, thiocyanation, imidazothiazoles,
2-aminothiazoles, PEG-400
Thiocyanates are considered as one of the most versatile
synthons in the field of organic chemistry. They have
proved their potency as crucial synthetic intermediates in
the synthesis of various sulfur-containing heterocycles such
as sulfides,1 thiocarbamates,2 sulfanyl pyridines,3 and thio-
tetrazoles.4 The intriguing properties of thiocyanate have
been utilized for the synthetic transformation of useful
functionalities such as aryl nitriles,5 sulfonyl cyanides,6
thiazoles,7 thioesters,8 imidazoles,9 and so on. The thiocya-
nation reaction is one of the most significant protocols for
direct C–S bond formation.10 Consequently, enormous
efforts have been made in order to achieve thiocyanation of
various heterocyclic compounds.11 In the midst of various
proceedings for thiocyanation of aryl and heteroaryl com-
pounds, incorporating thiocyanate (SCN) particularly into
C–H functionalities has always been a center of interest be-
cause of its own advantages.12 For accomplishing this goal
Conversion of alcohols to their corresponding alkyl thio-
cyanates or alkyl isothiocyanates has been extensively
studied.20 Recently, Mokhtari et al. reported one-pot thio-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

B
S. N. Kadam et al.
Letter
Synlett
cyanation or isothiocyanation of alcohols by using in situ
generated NTS. Thus, existing methods were focused on ei-
ther thiocyanation of C(sp2)–H bonds or thiocyanation of
alcohols to alkyl thiocyanates or alkyl isothiocyanates.
However, chemoselectivity for C-3 electrophilic thiocyana-
tion over nucleophilic substitution at the alcoholic –OH
group in imidazothiazoles, when both the possibilities are
present in one motif, would be an important synthetic
route for medicinal chemistry research. Encouraged by our
previous work on the thiocyanation of 2-aminothiazoles,21
we herein report an efficient, practical, and metal-free
approach for the one-pot conversion of functionalized
imidazothiazoles and 2-aminothiazoles into their corre-
sponding C-3 and C-5 thiocyanates, respectively. Use of easily
accessible NH4SCN, in situ generated NTS as the reagent,
and PEG-400 as the solvent makes the protocol more acces-
sible and efficient (Scheme 1).
R
OH
O
N
H
S
N
NH2
levamisol
N
O
O
N
N
OH
S
S
O
H2N
N
epothilon
(anticancer agent)
OH
vitamin B
O
H
N
S
N
NEt2⋅HCl
O
N⋅HCl
S
O
N
O
N
N
S
YM-201627, 1
(anticancer agent)
Amg-1 IDO1 inhibitor
O
We initiated our study on the synthesis of the target
compounds by taking 1-(6-(4-chlorophenyl)-3-methyl-
imidazo[2,1-b]thiazol-2-yl)ethanol 1a (Table 1) as the mod-
el substrate. In order to investigate the ideal reaction condi-
tions (Table 1), initially, NBS (1.0 mmol) and NH4SCN (2.0
mmol) were stirred at room temperature (r.t.) in CH3CN (3
mL) for 15 minutes to induce in situ generation of NTS. De-
liberate addition of reactant 1a (1 mmol) to this reagent led
to formation of product 2a in 80% yield after three hours
(Table 1, entry 1). Remarkably, thiocyanation or isothiocya-
nation of the alcoholic –OH group was not obtained for any
derivative X, Z (Scheme 1) by the nucleophilic substitution
route. Enthused by these results, the effect of other solvents
such as DMSO, DMF, H2O, CH2Cl2, THF, CH3OH, and CHCl3
was tested (Table 1, entries 3–9). In search of a “green” sol-
vent for the reaction22 we preferred to test PEG-400 as a
solvent. Interestingly, the best results (93%) were obtained
in PEG-400 (Table 1, entry 2). When NCS was employed for
the in situ generation of NTS, the formation of the product
resulted in a slight decrease in yield with increasing reac-
NH
N
N
NCS
S
F
N
O
N
H
N-thiocyanatosuccinimide (NTS)
antimycrobial agent
Figure 1 Some important compounds containing imidazothiazole and
thiazole as a core structure
tion time (Table 1, entry 3). This observation may be related
with the fact that Br is a better leaving group than Cl. Thus,
formation of NTS may take place faster with NBS rather
than with NCS. Other reagent and solvents, such as HIO3 in
methanol and HIO3 in PEG-400 as solvent were also exam-
ined (Table 1, entries 17 and 18); both of these combina-
tions resulted in poor yields. Product formation of was not
observed without the use of reagent (Table 1, entry 11).
When NBS was used as a reagent for bromination at the C-3
position of imidazothiazole followed by thiocyanation with
NH4SCN, this approach was shown to take more time (24
R1
R1
R1
NCS
r.t., 3 h
r.t., 3 h
N
S
N
S
PEG-400
X
N
PEG-400
N
S
N
N
NTS
NTS
1a–e
X
OH
SCN
OH
2a–e
r.t., 3 h
PEG-400
X
NTS
R1
N
S
N
Z
NCS
Scheme 1 Thiocyanation of imidazothiazole
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

C
S. N. Kadam et al.
Letter
Synlett
hours) with decreased yield of product (75%) (see below
Scheme 5, c and Table 1, entry 12). Furthermore, the yield
of the reaction decreased when (4.0 mmol) of NH4SCN was
used (Table 1, entry 13). The decrease in the quantity of
NH4SCN also decreased the yield of the product (Table 1,
entry 14). We also tested K2S2O8 for the same reaction with
PEG-400 as the solvent; the reaction took a longer time of
20 hours and resulted in a nonseparable trace amount of
product (Table 1, entry 19). The formation of product also
decreased when NH4SCN was replaced by KSCN or NaSCN
(Table 1, entries 15 and 16). Finally, the optimized reaction
conditions were achieved when NBS (1.0 mmol) and
NH4SCN (2.0 mmol) were stirred at room temperature in
PEG-400 (3 mL) for 15 minutes to initiate the in situ genera-
tion of N-thiocyanatosuccinimide. Following slow addition
of 1a (1.0 mmol) (Table 1, entry 2) led to formation of the
product in optimal yield of (93%) by stirring at room tem-
perature for three hours. The product could be obtained in
analytically pure form upon washing with cold aqueous
ethanol, thus avoiding the use of tedious purification by
column chromatography. A gram-scale reaction was also
performed by using NBS (0.01 mol), NH4SCN (0.02 mol),
and reactant 1a (0.01 mol). In this case, the product yield
observed was 75%. Having the optimized reaction condi-
tions in our hand, we further investigated the scope of sub-
strates (Scheme 2). The method was compatible with the
tested substrates, and most of the substrates afforded the
product in good yields. It is clear from Scheme 2 that halo-
gen substituents at R1 lead to good yields. Compound 2a
(Scheme 2) with a chloro substituent was obtained in excel-
lent (93%) yield, the highest amongst all derivatives. Prod-
uct 2d (Scheme 2) with an electron-donating group at R1
was isolated in moderate yield.
It is notable that no derivative gave alkyl thiocyanate or
alkyl isothiocyanate by nucleophilic attack of the alcohol on
in situ generated NTS20a (Scheme 1). Furthermore, deriva-
tives with hydroxy and methoxy substituents at R1 were
not able to provide the desired product. The probable
reason for the deleterious behavior of these derivatives may
be positive mesomeric effect of the electron-donating sub-
stituents, due to which they were unable to furnish the
product.
Table 1 Optimization of the Reaction Conditionsa
Cl
Cl
NCS
reagent
N
N
N
N
solvent, stirred
at r.t.
S
S
OH
OH
2a
1a
Entry
Reagent
Solvent
Yield (%)
1
2
NTS
NTS
NTS
NTS
NTS
NTS
NTS
NTS
NTS
NTS
–
CH3CN
PEG-400
PEG-400
DMSO
80
R1
93
R1
NCS
N
3b
4
80
NTS
N
N
78
PEG-400
r.t., 3 h
N
S
S
5
DMF
50
HO
HO
1a–g
2a–g
6
H2O
trace
75
NCS
H
Cl
7
CH2Cl2
THF
NCS
NCS
N
Br
8
50
N
S
N
N
9
MeOH
70
N
N
S
S
HO
10
11
12
13c
14d
15e
16f
17
18
19
CHCl3
80
HO
HO
2a, 93%
2b, 80%
2c, 90%
CH3CN
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
MeOH
n.r.
75
NCS
N
F
NBS
NTS
NTS
NTS
NTS
HIO3
HIO3
K2S2O8
NCS
N
CH3
70
N
N
69
S
S
HO
60
HO
2d, 85%
2e, 91%
60
NCS
OCH3
NCS
OH
50
N
N
PEG-400
PEG-400
40
N
N
S
S
trace
HO
HO
2f, not obtained
2g, not obtained
a Reaction conditions (unless otherwise specified): 1a (1.0 mmol), NH4SCN
(2.0 mmol), solvent (3mL), 3 h, r.t.; n.r. = no reaction.
b NCS was employed for in situ generation of NTS.
c NH4SCN (4.0 mmol) was used.
Scheme 2 Scope of substrates: Variation of substituents on imidazo-
thiazole. Reaction conditions: NBS (1.0 mmol) NH4SCN (2.0 mmol), sub-
stituted imidazothiazole 1a–g (1 mmol), PEG-400 (3 mL), 3 h. Isolated
yields are given.
d NH4SCN (1.0 mmol) was used
e KSCN (2.0 mmol) was used.
f NaSCN (2.0 mmol) was used.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

D
S. N. Kadam et al.
Letter
Synlett
a)
b)
NTS
H/Ar
H/Ar
NCS
N
S
N
S
NH2
PEG-400
r.t., 3 h
NH2
3
4
R2
R2
R2
R1
R1
R1
NTS, NH4SCN
NTS, NH4SCN
NH4SCN
+
N
N
X
NCS
N
NH2
PEG-400
r.t., 3 h
NH2
PEG-400
r.t., 3 h
NH2
S
S
NCS
S
3a–g
4a–g
4x
Scheme 3 Thiocyanation of 2-aminothiazoles
A similar type of thiocyanation reaction was also tried
on 2-aminothiazole and, in accordance to other methods
reported in literature (Scheme 3),24 the obtained product
yield was poor (30%) (Scheme 4, compound 4h). When we
tried the present protocol with aryl-substituted thiazoles,
the yield of the corresponding products was satisfactory.
This indicates that the aryl group present on the 2-amino-
thiazole ring is activating the substrate for the electrophilic
substitution. To prove the generality of the present meth-
odology, we tried C-5 thiocyanation of 2-aminothiazoles
(Scheme 3). Electron-withdrawing substituents such as hal-
ogens, proved to facilitate the reaction leading to formation
of the products in good yield, amongst which compound 4a
(Scheme 4) was obtained with a maximum yield of 92%.
Derivatives with electron-donating groups (Scheme 4)
furnished the products (such as 4f) with moderate yield.
Furthermore, methyl substitution at R1 (product 4f)
(Scheme 4) did not lead to nuclear thiocyanation in ortho
position to the donating group (4x) (Scheme 3)21. Substitu-
tion at meta position, R2, (Scheme 4) delivered the product
in poor yield (product 4e). Reactions for substrates with
hydroxy and methoxy substituents were unable to provide
the products; this behavior may be justified by the pres-
ence of a strong positive mesomeric effect, which may re-
sult in inability to form product. The method was further
explored for its generality on a new substrate containing an
alcoholic group, which led to moderate yield (product 4i)
(Scheme 4).
A probable mechanistic path was further studied by
taking few other methods into account for control experi-
ments by using the reactions depicted in Scheme 5. It
comes to our notice that the reaction did not proceed in the
absence of any reagent even after 28 hours (Scheme 5, a).
We also tried to use K2S2O8 for thiocyanation of these sub-
R2
R2
R1
R1
NTS
N
N
PEG-400
r.t., 3 h
NH2
NH2
S
S
NCS
3a–g
4a–g
NO2
Cl
O2N
Br
F
N
N
N
S
N
N
NH2
NH2
NH2
NH2
NH2
S
S
S
S
NCS
NCS
NCS
NCS
NCS
4c, 90%
4a, 92%
4e, 65%
4b, 89%
4d, 80%
from different starting materials:
Cl
H3C
N
S
HO
N
N
NH2
N
S
NH2
NH2
N
H
NCS
S
S
NCS
NCS
NCS
4f, 78%
4g, 75%
4i, 40%
4h, 30%
Scheme 4 Scope of substrates for 2-aminothiazoles. Reaction conditions: NBS (1.0 mmol) NH4SCN (2.0 mmol), substituted 2-aminothiazole
3a–i (1 mmol), PEG-400 (3 mL), 3 h. Isolated yields are given.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

E
S. N. Kadam et al.
Letter
Synlett
strates using PEG-400 as the solvent; however, only a non-
separable trace amount of product was formed after a pro-
longed period of 20 hours (Scheme 5, b). When the reaction
was performed with use of NBS as a reagent it required a
prolonged period of 24 hours for the formation of product
in 75% of yield indicating that bromination was followed by
the thiocyanation approach (Scheme 5, c). It was also ob-
served that some amount of reactant was converted into
the corresponding ketone as NBS was supposed to act as an
oxidant. The time for completion of the reaction was dra-
matically reduced to three hours when the present ap-
proach with in situ generated (NTS) was employed, and the
product was obtained in higher yield of 93% (Scheme 5, d).
When NTS was employed as a reagent in the reaction we
tested (Scheme 5, d) the progress of reaction by mixing it
with the radical quencher butylated hydroxytoluene (BHT)
in 1:1 molar ratio of reactant which revealed that the reac-
tion progress was not altered. This indicates that the mech-
anism does not follow a free-radical pathway.
First, ammonium thiocyanate reacts with NBS to initiate
the formation of electrophilic NTS. Afterwards, substituted
imidazothiazole reacts with NTS at the C-3 position. The
formed intermediate finally releases the proton for aroma-
tization to furnish the final product (Scheme 6). This proto-
col ruled out the possibility of nucleophilic attack of alco-
holic –OH on the sulfur atom of NTS to produce alkylox-
ygenyl thiocyanate (ROSCN), which can further react with
NH4SCN to furnish alkyl thiocyanate X (Scheme 1) or iso-
thiocyanate Z (Scheme 1). In spite of all these possibilities,
the reaction has been observed to promote C-3 thiocyana-
tion in imidazothiazole compounds 2a–e (Scheme 1).
O
O
N
Br
+
NH4SCN
N
Br–SCN
+
NH4
O
O
–NH4Br
On the basis of these observations made in control ex-
periments and the previous literature,14,20a,23 it may be pos-
sible that the reaction for C-3 thiocyanation of imidazothi-
azole proceeds through the mechanism shown in Scheme 6.
O
O
N
SCN
N
S
N
Cl
HO
N
NH2
S
PEG-400
N
n.r.
N
+
NTS
a)
b)
stirred r.t.,
28 h
S
OH
Cl
1a
H
NCS
N
N
S
PEG-400
K2S2O8
NH2
N
S
trace
+
NH4SCN
Cl
N
S
N
HO
NCS
H
stirred r.t.,
20 h
OH
1a
Br
Cl
SCN
PEG-400
rt, 12 h
N
N
c)
N
NBS
+
N
N
NH2
N
S
S
HO
S
N
S
NCS
HO
B
OH
1a
Scheme 6 Plausible reaction mechanism for imidazothiazole and 2-
NCS
N
aminothiazole
Cl
NH4SCN
r.t., 12 h
N
The reaction for C-5 thiocyanation of 2-aminothiazole
may proceed through the plausible mechanism shown in
Scheme 6. Ammonium thiocyanate reacts with NBS to pro-
duce electrophilic N-thiocyanatosuccinimide, followed by
reaction at C-5 position of 2-aminothiazole. Finally, the
formed intermediate releases the proton for aromatization,
which results in the final product.
In summary, we have developed a one-pot chemoselec-
tive synthetic route for C-3 and C-5 thiocyanation of imid-
azothiazole and 2-aminothiazole at room temperature.25
The present protocol provides useful information regarding
S
HO
2a, 75%
Cl
NCS
N
Cl
d)
N
S
NTS
N
N
S
PEG-400
r.t., 3 h
HO
OH
1a
2a, 93%
Scheme 5 Control experiments
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

F
S. N. Kadam et al.
Letter
Synlett
the reactivity of in situ generated NTS for thiocyanation of
imidazothiazoles comprising an alcoholic hydroxy group.
The method provides easy and metal-free chemoselective
access for thiocyanation at C-3 position in imidazothiazole
through electrophilic substitution, ruling out the possibility
of forming alkyl thiocyanate or alkyl isothiocyanate
through nucleophilic substitution by alcoholic –OH in the
same substrate. This method provides high yields of C-3 and
C-5 thiocyanates of imidazothiozole and 2-aminothiazole,
respectively, under very mild conditions. The transforma-
tion provides a new opportunity for the synthesis of bio-
active imidazothiazoles and 2-aminothiazoles, which may
gain much attention in the field of synthetic and medicinal
chemistry.
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Funding Information
S.N.K. (F.No. 38/07/14), M.J.H. (F.No 31/21/14), and A.N.A. (F.No.
36/33/14) are grateful to the University Grants Commission for
providing
a teacher fellowship under the Faculty Development
Programme scheme.
)(
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609553.
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(25) Procedure for the Synthesis of 1-(6-(4-Chlorophenyl)-3-
methyl-5-thiocyanatoimidazo[2,1-b]thiazol-2-yl)ethanol
(2a) (Table 1)
A dried 50 mL round-bottomed flask was charged with NBS
(177.98 mg, 1 mmol), NH4SCN (152.24 mg, 2.0 mmol) in PEG-
400 (3 mL) and the reaction mixture was stirred at r.t. for 15
min. The reaction mixture turned milky indicating generation
of NTS (shown by TLC). Next, reactant 1a (292.78 mg, 1 mmol)
was added slowly, and the reaction mixture was further stirred
for 3 h. After completion of the reaction as indicated by TLC,
cold water (20 mL) was added to separate the solid product. The
white solid was filtered, dried, and washed with cold aqueous
ethanol (0.93 mmol, 93% yield).
Compound 2a: Mp 111–113 °C. FT-IR: 3195, 2966, 2154, 1893,
1644 cm–1. 1H NMR (400 MHz, DMSO-d6): δ = 7.94 (d, 2 H, J = 8.0
Hz), 7.62 (s, 2 H), 5.96 (s, 1 H), 5.17 (s, 1 H), 2.73 (s, 3 H), 1.41 (s,
3 H) ppm. 13C{1H} NMR (100 MHZ, DMSO-d6): δ = 152.62,
152.11, 134.68, 134.20, 131.36, 129.84, 128.87, 124.27, 111.02,
97.97, 62.25, 25.24, 12.39 ppm. HRMS (ESI-TOF): m/z [M + H]+
calcd for C15H12ClN3OS2: 349.0110; found: 350.0174.
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Procedure for the Synthesis of 5-thiocyanato-4-(p-tolyl)thi-
azol-2-amine (4f) (Scheme 4)
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Derbin, G. M.; Fargnoli, J.; Hunt, J. T.; Jeyaseena, R.; Kamath, A.;
Kukral, D. W.; Marathe, P.; Mortillo, S.; Qian, L.; Tokarski, J. S.;
Wautlet, B. S.; Zheng, X.; Lombordo, L. J. J. Med. Chem. 2006, 49,
3766. (b) Misra, R. N.; Xiao, H. Y.; Kim, K. S.; Han, W. C.; Barbosa,
S. A.; Hunt, J. T.; Rawlins, D. B.; Shan, W.; Ahmad, S. Z.; Qian, L.;
Chen, B. S.; Zhao, R.; Bendnarz, M. S.; Kellar, K. A.; Mulheron, J.
G.; Batorsky, R.; Roongta, U.; Kamath, A.; Marathe, P.; Ranadive,
S. A.; Sack, J. S.; Tokrski, J. S.; Paletich, N. P.; Lee, F. Y. F.; Webster,
K. R.; Kimball, S. D. J. Med. Chem. 2004, 47, 1719.
A dried round-bottomed flask was charged with NBS (177.98
mg, 1.0 mmol) and NH4SCN (152.24 mg, 2.0 mmol). PEG-400
(3 mL) was added and reaction mixture was stirred at r.t. for
15 min. Formation of a milky color indicated the generation of
NTS (shown by TLC). Then, 4-(p-tolyl)thiazol-2-amine (190.26
mg, 1 mmol) was added slowly, and the reaction mixture was
further stirred for 3 h. When completion of the reaction was
indicated by TLC, the product was separated by addition of cold
water (20 mL). The white solid product was filtered, dried, and
washed with cold aqueous ethanol (0.78 mmol, 78% yield).
Compound 4f: Mp 134–136 °C. FT-IR: 3372, 3269, 3045, 2100,
1612 cm–1 1H NMR (400 MHz, DMSO-d6): δ = 7.88 (s, 2 H),
.
7.69–7.31 (m, 4 H), 2.52 (s, 3 H) ppm. 13C{1H} NMR (100 MHZ,
DMSO-d6): δ = 171.25, 259.25, 139.14, 130.64, 129.39, 129.18,
129.01, 112.57, 21.39 ppm. HRMS (ESI-TOF): m/z [M + H]+ calcd
for C11H9N3S2: 247.0238; found: 248.0305.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G