A thorough study on the reaction of DMAD with 1-arylaminoimidazole-2-thiones. Expeditious synthesis of imidazo[2,1-b][1,3]thiazoles through a novel arylamino rearrangement

Article abstract of DOI:10.1016/j.tet.2009.11.056

Upon reaction of 1-arylamino-imidazole-2-thiones 1 with dimethyl acetylenedicarboxylate (DMAD) in the presence of 2.2 equiv of sodium hydride, imidazothiazoles 4 were exclusively formed (71-82% yield). However, from the reaction of 1 with DMAD in the absence of base, only the S-substituted products 5 were formed as an E/Z mixture (53-55%), which could also be converted to 4 with 2.0 equiv of sodium hydride (65-68%). Furthermore, 5a-E/Z was converted to arylamino-substituted derivatives 8a upon reaction with 1.1 equiv of sodium hydride in 78% yield. Formation of 8a (75% yield) was also possible by reaction of thione 1a with DMAD in the presence of sodium methoxide in methanol. Substitution on the imidazole 3-NH of thione 1a leading to 6a-Z was observed either by heating 1a with DMAD (91%) or by heating the 5a-E/Z mixture in benzene (90% yield). Finally, when 5a-E reacted with acetic anhydride the acetylated derivative 7a-Z was the only isolated product (58%). Full assignment of all ¹H and ¹³C NMR chemical shifts has been unambiguously achieved.

Full text of DOI:10.1016/j.tet.2009.11.056

Tetrahedron 66 (2010) 709–714
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A thorough study on the reaction of DMAD with 1-arylaminoimidazole-
2-thiones. Expeditious synthesis of imidazo[2,1-b][1,3]thiazoles through
a novel arylamino rearrangement
*
Constantinos Neochoritis, Nicolaos Eleftheriadis, Constantinos A. Tsoleridis ,
*
Julia Stephanidou-Stephanatou
Department of Chemistry, Laboratory of Organic Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Macedonia, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 June 2009
Received in revised form 29 October 2009
Accepted 12 November 2009
Available online 15 November 2009
Upon reaction of 1-arylamino-imidazole-2-thiones 1 with dimethyl acetylenedicarboxylate (DMAD) in
the presence of 2.2 equiv of sodium hydride, imidazothiazoles 4 were exclusively formed (71–82% yield).
However, from the reaction of 1 with DMAD in the absence of base, only the S-substituted products 5
were formed as an E/Z mixture (53–55%), which could also be converted to 4 with 2.0 equiv of sodium
hydride (65–68%). Furthermore, 5a-E/Z was converted to arylamino-substituted derivatives 8a upon
reaction with 1.1 equiv of sodium hydride in 78% yield. Formation of 8a (75% yield) was also possible by
reaction of thione 1a with DMAD in the presence of sodium methoxide in methanol. Substitution on the
imidazole 3-NH of thione 1a leading to 6a-Z was observed either by heating 1a with DMAD (91%) or by
heating the 5a-E/Z mixture in benzene (90% yield). Finally, when 5a-E reacted with acetic anhydride the
acetylated derivative 7a-Z was the only isolated product (58%). Full assignment of all 1H and 13C NMR
chemical shifts has been unambiguously achieved.
Keywords:
Arylamino rearrangement
DMAD addition
Imidazolethiones
Imidazothiazoles
Ó 2009 Published by Elsevier Ltd.
1. Introduction
substituted imidazole-2-thiones with methyl acetylenedicarboxylate
(DMAD, Scheme 1). In order to achieve our goal, 1-arylamino-imid-
Imidazoles are scaffolds in highly significant biomolecules in-
cluding biotin, the essential amino acid histidine, histamine, the
pilocarpine,1 and other terrestrial and marine alkaloids,2 which
have been shown to exhibit interesting biological activities such as
antimicrobial, cytotoxic, and anticryptococcal inhibition of nitric
oxide synthase.3 N-Aminoimidazoles and N-aminoimidazoline
thiones have been found to inhibit retroviral replication.4 Imidazole
derivatives also find important applications in other fields, such as
polymers,5 insecticides,6 antioxidants,7 photonucleases,8 and fluo-
rescent dyes.9 Therefore, considerable interest has been devoted to
the development of methods for their elaboration.10
azole-2-thiones14,15 1 were selected, since the enhanced reactivity of
the sulfur over the 3-NH and 6-NH positions is well documented.13
We anticipated therefore, that by initial thio-Michael-type addition
followed by methanol elimination and cyclization, either 2 or 3 could
be formed. However, we found that from the reaction of thiones 1
R
Me
5
6
COOMe
COOMe
R
4 Me
5
N
N
S 2
O
1
NaH, 2.2 eq
THF, rt, 24 h
6
H
3
+
N
NH
HN
Ar
3
2S7
N
1'
2'
8
3'
MeOOC
6'
4
5'
X
1
R
Ar
2. Results and discussion
NaH, 2.2 eq
THF, rt, 24 h
4a Me
4b Me
C6H5
Due to the great pharmacological interest in fused imidazoles11
and as a continuation of our research on new fused imidazoles12,13
we considered the synthesis of some imidazothiadiazine 2 or imid-
azothiadiazepine 3 derivatives by using the reaction of suitably
C6H4-Cl-4
4c C6H5 C6H5
R
R
Me
R
Me
Me
N
Ar
O
Ar
Ar
N
N
N
N
N
N
N
N
+
or
S
S
S
O
O
H
COOMe
H
COOMe
MeOOC
2A
H
* Corresponding authors. Tel.: þ30 2310 997831; fax: þ30 2310 997679.
E-mail addresses: tsolerid@chem.auth.gr (C.A. Tsoleridis), ioulia@chem.auth.gr
(J. Stephanidou-Stephanatou).
2B
3
Scheme 1. Formation of imidazothiazoles 4.
0040-4020/$ – see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tet.2009.11.056

710
C. Neochoritis et al. / Tetrahedron 66 (2010) 709–714
R
Me
with DMAD in the presence of NaH, imidazothiazoles 4 were ex-
clusively formed.
After this unexpected formation of imidazothiazoles 4, the re-
action between thiones 1 and DMAD was thoroughly investigated
and the results are shown in Schemes 2 and 3.
AcOEt or
CH2Cl2
R
Me
COOMe
COOMe
R
Me
4
5
1N NH
6
N
N
N
N
HN
Ar
MeOOC
+
HN
Ar
+
HN
Ar
rt, 24 h
2S7
3
COOMe
H
H
S
S
MeOOC 8
5-E
9 COOMe
1
5-Z
a
b
c
R=Me, Ar = C6H5
R=Me, Ar = C6H4Cl-4
R=Ar=C6H5
Me Me
Me Me
NaH, 2.2 eq
THF, rt, 24 h
4
5
COOMe
NaH, 2.0 eq
THF, rt, 24 h
6
Ph
N
N
N
N
COMe
HN
9
N
S72
S
8
H
MeOOC
Ph
COOMe
8
R
Me
9
COOMe
H
6
5
6a-Z
N
N
S 2
O
7a-Z 58%
reflux of a
H
3
benzene,
reflux, 48 h
mixture,
benzene,
48 h
N
2'
8
Ac2O
reflux, 3 h
1'
6'
3'
MeOOC
5'
X
4
COOMe
COOMe
Me Me
NH
Me Me
Me Me
AcOEt or
CH2Cl2
Scheme 3. Cyclization to imidazothiazoles 4.
N
N
N
N
N
+
+
HN
Ph
MeOOC
HN
Ph
MeOOC
HN
Ph
rt, 24 h
H
COOMe
S
S
S
8
9
H
COOMe
1a
isolated in lower yield (29%), most probably due to low solubility of
the starting thione in water. The yield was improved to 49% by
using a 10% ethanol/water solution. The configuration of 5 is in
good agreement with previous results according to which addition
is solvent and temperature dependent.16
5a-Z
53% (1:4) 5a-E
NaH, 1.1 eq
THF, rt, 3 h
MeONa, 1.1 eq
MeOH, rt, 4 h
Me Me
Me Me
NH
8a-E 75%
Subsequently, the reaction between 1a and DMAD was repeated
in benzene at reflux for 48 h (Scheme 2), whereupon, instead of the
sulfur substituted derivative 5, the 3-N-substituted compound 6a-Z
(91% yield) was the only reaction product (Scheme 2). The same
product 6a-Z was also formed in 90% yield when 5a (4:1 E/Z) was
heated in benzene for 48 h, proving the intermediacy of 5 in the
formation of 6. On the contrary, when the imidazolethione 1a and
DMAD were stirred in methanol at ambient temperature in the
presence of 1.1 equiv of sodium methoxide for 4 h, reaction on
the arylamino nitrogen was observed leading to the formation of
the arylamino-substituted derivative 8a-E in 75% yield. Analo-
gously, 8a was isolated (78% yield) as a 2:1 Z/E mixture, when
a w4:1 5a-E/5a-Z mixture was stirred with 1.1 equiv of sodium
hydride in dry THF at ambient temperature for 3 h. Finally, in an
attempt to cyclize 5, reaction of 2a-E with acetic anhydride was
studied, whereupon only the 3-acetylated derivative 7a-Z was
formed in 58% yield.
+
N
NH
N
Ph
Ph
N
H
N
S
S
MeOOC
MeOOC
COOMe
H
MeOOC
8a-Z
78% (2:1)
8a-E
Scheme 2. Reaction conditions for the synthesis of compounds 6a, 7a and 8a.
Initially, upon reaction of 1a or 1b with DMAD in ethyl acetate at
room temperature for 24 h a w4:1 mixture of 5-E/5-Z was formed
in good yield (53%, Schemes 2 and 3) through a Michael-type ad-
dition reaction. From the reaction mixture, the major E-isomer
could be isolated upon crystallization. On the contrary, when the
reaction was performed with 1c, 5c-Z containing only traces of 5c-E
was isolated (55%). In order to investigate the reaction stereo-
selectivity, the reaction between 1a and DMAD was repeated while
monitoring the temperature. At ꢀ20 ꢁC for 1 h, a stereoselectivity
change was observed, namely a w1:2 5a-E/5a-Z isomeric mixture
was formed (51% yield). Moreover, the same reaction was attemp-
ted using water as solvent, whereupon a 1:3 5a-E/5a-Z mixture was
Cyclization to imidazothiazoles 4a–c was successful either when
a 5-Z/E mixture was stirred with 2.0 equiv of sodium hydride in dry
THF at ambient temperature for 24 h (65–68% yield), or when
R
Me
R
Me
H
O
N
N H
N
N H
Ar
Ar
N
N
COOMe
COOMe
H
H
H
S
S
5-Z
10
H
H
MeOOC
MeOOC
O
at lower
temperature
11
12
*
NaH or
MeONa
in protic solvent
or water
COOMe
COOMe
R
Me
NH
R
Me
R
Me
-
H
at rt
N
N H
N
N
N
Ar
H
N
N
N
Ar
COOMe
Ar
S
1
S
H
H
S
COOMe
COOMe
H
9
MeOOC8
9
5-E
R
Me
R
N
Me
R
Me
R
N
Me
- MeO
Ar
N
N N
OMe
O
N
N
N
~ H
N
O
Ar
H
N
Ar N
O
S
S
S
S
N
MeOOC
MeOOC
H
MeOOC
MeOOC
Ar
H
MeOOC
H
13
14
15
4
*
For intermediates 9 and 10 see also Figure 1
Scheme 4. Plausible mechanism for the formation of compounds 5 and 4.

C. Neochoritis et al. / Tetrahedron 66 (2010) 709–714
711
Table 1
Electron densities and HOMO coefficients on sulfur in compounds 1a–c (AM1)
Compound
S-7 HOMO Pz coefficient
Charge qnet (electrons)
1a
1b
1c
ꢀ0.6506
ꢀ0.6491
ꢀ0.6213
ꢀ0.2612
ꢀ0.2563
ꢀ0.2555
initial formation of 9 or 10 (Fig. 1), 3-NH hydrogen abstraction is the
most probable pathway and the negatively charged acetylenedi-
carboxylate moiety is supposed to be still linear and the C2–S–C8
angle about 100ꢁ. At room temperature, fast rotation about the C2–
S7 and S7–C8 bonds favors conformation 9 leading to 5-E isomers.
On the contrary, at lower temperatures the favored conformation
10 could be stabilized by secondary electronic interactions of C9-
ester group with nitrogen atoms N1 and N6 leading to 5-Z isomers.
In the case of a C5-phenyl substituent the electron density as well
as the HOMO coefficient of S-7 are decreased (Table 1, AM1)17
leading at ambient temperature almost exclusively to a product
with Z-configuration. Finally, in protic solvents or in water it is
believed that intermediate 11 could be more easily protonated by
abstracting a solvent hydrogen forming intermediate 12 and sub-
sequently 5-Z. Although it is well known that Michael-type amine
and thione addition to acetylenic esters leads to E/Z isomeric
mixtures, no attempt has been made until now to explain this
stereospecificity.16
Concerning the formation of 4, reaction of 5 with sodium hy-
dride furnishes the anion 13. Migration of the carbomethoxy-vinyl
group to the 6-arylamino nitrogen results in formation of 14, from
which subsequent ring closure to 15 can occur. Finally, formation of
the isolated imidazothiazoles 4 is feasible through nitrogen–ni-
trogen bond fission, formation of a new thiazole ring and 1,3-H
migration. Thus, as a result, for the formation of the end products 4,
an arylamino group migration from thione position 1 to the ace-
tylenedicarboxylate moiety of 4 takes place. An alternative plausi-
ble mechanism for the formation of 4 (Scheme 5) involving N1–N6
bond fission and formation of the tautomeric intermediate mixture
18A and 18B through 16 and 17 could also be proposed. However, in
this case the final product would be a 4A, 4B mixture. Since, in the
case of the asymmetrically substituted thione 1c only one isomer of
4c was formed this mechanism should be excluded.
Figure 1. (a) At room temperature fast rotation about C2-S7 and S7-C8 bonds favors
conformation 9 leading to 5a-E isomer. (b) At lower temperatures conformation 10 is
stabilized by electronic interactions of C9-ester group with nitrogen atoms N1 and N6
leading to 5a-Z isomer (AM1).
thiones 1a–c were allowed to react with DMAD in the presence of
2.2 equiv of sodium hydride for 24 h (71–82% yield), proving thus
that cyclization to 4 proceeds through initial formation of 5.
For the formation of 5 and 4 the following mechanistic scheme
can be proposed (Scheme 4). Initially, by the reaction of thiones 1
with DMAD a mixture of Z- and E-substituted derivatives 5 is
formed. In an attempt to explain the regiospecificity of acetylene-
dicarboxylate addition to the thione sulfur, we assume that after
3. Structure assignments of the new compounds
The assigned molecular structures of the new compounds 4, 5, 6,
7 and 8 were based on rigorous spectroscopic analysis including IR,
NMR (1H, 13C, H–H COSY, H–H NOESY, HETCOR and COLOC), MS and
R
Me
R
Me
R
Me
N
N
N
N
N
N
Ar
Ar
Ar
N
N
N
S
S
S
H
H
OMe
H
OMe
MeOOC
MeOOC
MeOOC
OMe
O
O
O
O
14
17
16
R
Me
R
Me
R
Me
R
Me
N
N
N
S
N
N N
S
N
N
Ar
O
Ar
+
NH
H
H
NH
S
S
N
N
MeOOC
COOMe
4A
Ar
Ar
MeOOC
MeOOC
OMe
OMe
O
O
4B
18B
18A
Scheme 5. Alternative plausible mechanism for the formation of compounds 4 leading to an isomeric mixture and therefore excluded.

712
C. Neochoritis et al. / Tetrahedron 66 (2010) 709–714
energy molecular model for 5a-E isomer calculated by AM1 in
accordance with NMR data is represented.
H3C CH3
H3C
CH3
H
N
N
N
N
N
H
H
O
H
H
O
S
H
S
O
4. Conclusion
N
H
H
O
H
C
O
H
O
O
In conclusion, we have achieved the synthesis of new
imidazo[2,1-b][1,3]thiazoles through a novel arylamino rearrange-
ment. Furthermore, the substituent, solvent, and temperature
dependent Michael-type addition reaction of DMAD to 1-
arylaminoimidazole-2-thiones was thoroughly investigated. The
stereospecificity of the reaction between thiones and acetylenedi-
carboxylates leading to formation of E/Z isomeric mixtures was also
studied and it was established that at room temperature formation
of 5-E isomers is favored, whereas at lower temperatures Z-isomers
are the predominated ones.
CH3
H
H3C
5a-E
H3C
4a
Figure 2. COLOC correlations observed in compounds 4a and 5a-E.
elemental analysis data. In Figure 2 the COLOC correlations of
protons with carbons via J and 3J coupling for compounds 4a and
2
5a-E are depicted.
Concerning the identification of the various isolated compounds
of high diagnostic value is the substantial chemical shift difference
5. Experimental
5.1. General
between the 3- and 6-NH protons, which resonate at
w6.9, respectively. The 4- and 5-methyl group carbon chemical
shifts are also of diagnostic value, since in a thione ring they res-
d w11.9 and
onate at
d 9.4 and 8.5, whereas in a thiol at d 13.3 and 8.5, re-
Melting points were measured on a Kofler hot–stage and are
uncorrected. Column chromatography was carried out using
Merck silica gel. TLC was performed using precoated silica gel
glass plates 0.25 mm containing fluorescent indicator UV254 pur-
chased from Macherey–Nagel, using a 3:1 mixture of petroleum
ether/ethyl acetate. Petroleum ether refers to the fraction boiling
between 60 and 80 ꢁC. NMR spectra were recorded at room
temperature on a Bruker AM 300 spectrometer at 300 MHz for 1H
and 75 MHz for 13C, respectively, using CDCl3 as solvent. Chemical
spectively. Furthermore, the carbomethoxy-vinyl proton chemical
shifts for E-isomers are found between 5.0–5.7 ppm, whereas those
for Z-isomers between 6.5–7.0 ppm in agreement with E- and Z-
configurations of dimethyl citraconate and dimethyl mesaconate,
where the vinyl proton resonates at
Another characteristic feature of E-, Z-isomers is the JCH coupling
constant. As depicted in Figure 3, a value of 3JCH of 11.0 Hz is found
d
5.87 and
d
6.68, respectively.18
3
Me
2J = 3.4
O
shifts are expressed in
d values (ppm) relative to TMS as internal
1J = 168.7
S
S
standard for 1H and relative to TMS (0.00 ppm) or to CDCl3
(77.05 ppm) for 13C NMR spectra. Coupling constants nJ are
reported in Hz. Second order 1H spectra in the aromatic region,
where it was possible, were analysed by simulation.20 IR spectra
were recorded on a Perkin–Elmer 1600 series FTIR spectrometer
and are reported in wave numbers (cmꢀ1). Low-resolution elec-
tron impact mass spectra were recorded on a 6890 N LC/MS sys-
tem (Agilent Technology) and elemental analyses performed with
a Perkin–Elmer 2400-II CHN analyzer in the Laboratory of Organic
Chemistry, University of Thessaloniki. Structural assignments of
the derived compounds were established by analysis of their IR,
MS and NMR spectra (1H, 13C, DEPT, H–H COSY, H–H NOESY,
HETCOR and COLOC).
H
O
1J = 169.5
H
2J = 1.5
3J = 11.0
O
O
O
3J = 5.9
O
O
O
Me
Me
All J values in Hz
Me
E-
Z-
1
3
Figure 3. JCH,2JCH and JCH coupling constants measured in 5a-E and 5a-Z.
in 5a-E isomer approximately twice the value of 5.9 Hz found in 5a-
Z isomer, in accordance with the literature.19 Finally, concerning
compounds 4, the proposed E-configuration of the exocyclic vinyl
group was based on the low-field resonance of the NH proton at
10.44–10.58 ppm, due to hydrogen bonding with the adjacent
carbonyl oxygen. This hypothesis is also supported by the fact that
4-E isomer is calculated to be energetically favored by w3.5 kcal/
mol (AM1) over its 4-Z counterpart. In Figure 4 a global lower
5.2. General procedure for the reaction of thiones (1a–c)
with dimethyl acetylenedicarboxylate
A reaction mixture of thione 1 (1.0 mmol) and dimethyl acetyle-
nedicarboxylate (0.22 g, 1.1 mmol) in ethyl acetate (20 mL), was
stirred at ambient temperature until thione 1 was consumed com-
pletely (followed by TLC, approximately 24 h). From the reaction
mixture the solvent was distilled off in vacuo and the resulting res-
idue was either crystallized (5a–b) or subjected to column chroma-
tography on silica gel using petroleum ether/AcOEt (7:1) as eluent,
slowly increasing the polarity up to 4:1 to give the isolated product
(5c):
5.2.1. Dimethyl 2-[(1-anilino-4,5-dimethyl-1H-imidazol-2-yl)thio]-
but-2-enedioate (5a). Yellow solid (0.191 g, 53% yield), as a mixture
of E- and Z-isomers in a w4:1 ratio. From this mixture crystalliza-
tion of the major E-isomer was possible from ether.
Major isomer 5a-E: mp 135–137 ꢁC. IR (Nujol) nmax: 3208, 3182
(br), 3118, 1742, 1718 cmꢀ1 1H NMR (CDCl3)
. d 2.14 (s, 3H, 5-CH3),
2.23 (s, 3H, 4-CH3), 3.67 (s, 3H, 8-OCH3), 3.70 (s, 3H, 9-OCH3), 5.87
(s, 1H, 9-H), 6.48 (ddd, J¼7.7, 2.0, 1.0 Hz, 2H, 20,60-H), 6.93 (tt, J¼6.9,
1.0 Hz, 1H, 40-H), 7.10 (br s, 1H, NH), 7.23 (ddd, J¼7.7, 6.9, 2.0 Hz, 2H,
Figure 4. Global lower energy conformation of 5a-E calculated by AM1 in accordance
with NMR data.

C. Neochoritis et al. / Tetrahedron 66 (2010) 709–714
713
30,50-H).19 13C NMR (CDCl3)
d
8.6 (5-CH3), 13.3 (4-CH3), 52.1 (9-
5.3.1. Dimethyl
(2E)-2-(3-anilino-4,5-dimethyl-2-thioxo-2,3-dihy-
OCH3), 53.3 (8-OCH3), 112.7 (C-20,60), 116.6 (C-9), 121.7 (C-40), 129.5
(C-2)y, 129.5 (C-30,50), 129.7 (C-5), 134.8 (C-4), 146.3 (C-10), 147.1 (C-
8), 163.8 (9-CO), 165.8 (8-CO). MS (LCMS) m/z (%) 360 (100, Mþ).
Anal. calcd for C17H19N3O4S (361.42): C, 56.50; H, 5.30; N, 11.63.
Found: C, 56.37; H, 5.15; N, 11.48.
dro-1H-imidazol-1-yl)but-2-enedioate (6a-Z). Yellowish oil in 91%
yield; IR (neat) nmax: 3161 (br), 1750, 1712 cmꢀ1 1H NMR (CDCl3)
.
d
2.03 (s, 3H, 6-CH3), 2.14 (s, 3H, 5-CH3), 3.75 (s, 3H, 9-OCH3), 3.88
(s, 3H, 8-OCH3), 6.70–6.74 (m, 2H, 20,60-H), 6.92 (br s, 1H, NH), 6.94–
7.01 (m, 1H, 40-H), 7.27 (s, 1H, 9-H), 7.26–7.29 (m, 2H, 30,50-H). 13C
Minor isomer 5a-Z: After isolation of 5a-E some NMR data of the
NMR (CDCl3) d 8.5 (5-CH3), 9.3 (4-CH3), 52.6 (9-OCH3), 53.6 (8-
minor isomer 5a-Z were also deduced: 1H NMR (CDCl3)
d
2.11 (s, 3H,
OCH3), 114.2 (C-20,60), 119.6 (C-4), 122.3 (C-40), 123.3 (C-5), 129.4 (C-
30,50), 129.8 (C-9), 135.8 (C-8), 145.8 (C-10), 162.1 (C-2), 162.4 (8-CO),
162.9 (9-CO). MS (LCMS) m/z (%) 362 (100, Mþþ1). Anal. calcd for
C17H19N3O4S (361.42): C, 56.50; H, 5.30; N,11.63. Found: C, 56.71; H,
5.25; N, 11.78.
5-CH3), 2.17 (s, 3H, 4-CH3), 3.65 (s, 3H, 8-OCH3), 3.72 (s, 3H, 9-
OCH3), 6.53 (s, 1H, 9-H), 6.55 (d, J¼8.9 Hz, 2H, 20,60-H), 6.91–6.93
(m, 1H, 40-H), 7.21–7.23 (m, 2H, 30,50-H), 7.29 (br s, 1H, NH). 13C NMR
(CDCl3)
d 8.4 (5-CH3), 13.2 (4-CH3), 52.0 (9-OCH3), 53.4 (8-OCH3),
112.8 (C-20,60), 116.4 (C-9), 121.5 (C-40), 127.9 (C-5), 129.4 (C-30,50),
129.5 (C-2), 133.7 (C-4), 145.9 (C-10), 146.2 (C-8), 164.8 (9-CO), 165.1
(8-CO).
5.4. Isomerization of 2a (mixture E/Z) in benzene at reflux
A solution of thione 2a (4:1 mixture E/Z) (1.0 mmol) in benzene
(20 mL) was heated at reflux until compound 2a was consumed
completely (followed by TLC, approximately 48 h). The solvent was
distilled off in vacuo and the resulting residue was subjected to
column chromatography on silica gel using petroleum ether/AcOEt
(5:1) as eluent, slowly increasing the polarity up to 1:1 to give only
6a-Z, in 90% yield.
5.2.2. Dimethyl
2-({1-[(4-chlorophenyl)amino]-4,5-dimethyl-1H-
imidazol-2-yl}thio)but-2-enedioate (5b). Yellow solid (0.214 g, 54%),
as a mixture of the E- and Z-isomer in a 4:1 ratio. From this mixture
crystallization of the major E-isomer was possible from ether.
Major isomer (E): mp 139–141 ꢁC; IR (Nujol) nmax: 3172 (br),1740,
1717 cmꢀ1. 1H NMR (CDCl3)
d 2.13 (s, 3H, 5-CH3), 2.22 (s, 3H, 4-CH3),
3.67 (s, 3H, 8-OCH3), 3.71 (s, 3H, 9-OCH3), 5.89 (s, 1H, 9-H), 6.43 (d,
J¼8.9 Hz, 2H, 20,60-H), 7.18 (d, J¼8.9 Hz, 2H, 30,50-H), 7.44 (br s, 1H,
5.5. Reaction of thione 1a with DMAD in the presence
of sodium methoxide
NH). 13C NMR (CDCl3)
d 8.6 (5-CH3), 13.1 (4-CH3), 52.0 (9-OCH3),
53.4 (8-OCH3), 113.9 (C-20,60), 116.8 (C-9), 126.6 (C-40), 129.5 (C-2),
129.5 (C-30,50), 129.6 (C-5), 134.9 (C-4), 144.9 (C-10), 145.2 (C-8),
163.8 (9-CO), 165.1 (8-CO). MS (LCMS) m/z (%) 396/398 (100,
Mþþ1). Anal. calcd for C17H18ClN3O4S (395.86): C, 51.58; H, 4.58; N,
10.61. Found: C, 51.69; H, 4.56; N, 10.39.
To a suspension of compound 1a (1.0 mmol) in dry methanol
(10 mL) at 20 ꢁC, sodium (1.1 mmol) was added, the mixture was
stirred for 10 min, DMAD (1.0 mmol) was then added and the re-
action mixture was stirred for 4 h at 20 ꢁC. Dilution of the reaction
mixture with 40 mL ice resulted to precipitation of the product
which was rinsed with ether to give the dimethyl (2E)-2-[4,5-di-
methyl-2-thioxo-2,3-dihydro-1H-imidazol-1-yl(phenyl)amino]but-2-
enedioate (8a-E).
Minor isomer (Z): After isolation of 5b-E the NMR data of the
minor isomer 5b-Z were also deduced: 1H NMR (CDCl3)
d 2.11 (s, 3H,
5-CH3), 2.17 (s, 3H, 4-CH3), 3.65 (s, 3H, 8-OCH3), 3.72 (s, 3H, 9-
OCH3), 6.51 (d, J¼8.9, 2H, 20,60-H), 6.54 (s, 1H, 9-H), 7.17 (d, J¼8.9 Hz,
2H, 30,50-H), 7.47 (br s, 1H, NH). 13C NMR (CDCl3)
d
8.4 (5-CH3), 13.1
Yield 75%; mp 178–180 ꢁC. IR (Nujol) nmax: 3424 (br), 1746,
(4-CH3), 52.0 (9-OCH3), 53.2 (8-OCH3), 112.8 (C-20,60), 116.4 (C-9),
121.5 (C-40), 127.9 (C-5), 128.5 (C-2), 129.4 (C-30,50), 134.0 (C-4),
145.8 (C-8), 146.6 (C-10), 164.8 (8-CO), 165.1 (9-CO).
1709 cmꢀ1. 1H NMR (CDCl3)
d 2.06 (s, 3H, 5-CH3), 2.10 (s, 3H, 4-CH3),
3.67 (s, 3H, 8-OCH3), 3.78 (s, 3H, 7-OCH3), 5.13 (s, 1H, 9-H), 7.23–
7.25 (m,1H, 40-H), 7.33–7.36 (m, 2H, 30,50-H), 7.48 (d, J¼7.7, 2H, 20,60-
H), 11.9 (br s, 1H, NH). 13C NMR (CDCl3)
d 8.4 (5-CH3), 9.4 (4-CH3),
5.2.3. Dimethyl (2Z)-2-[(1-anilino-4-methyl-5-phenyl-1H-imidazol-
2-yl)thio]but-2-enedioate (5c). Yellow solid (0.233 g, 55%), mp 126–
128 ꢁC, was isolated only as the Z-isomer. IR (Nujol) nmax: 3174 (br),
51.5 (8-OCH3), 53.2 (7-OCH3), 96.6 (C-9), 124.0 (C-20,60), 127.4 (C-40),
129.4 (C-30,500), 141.0 (C-10), 149.5 (C-8), 161.1 (C-2), 166.6 (8-CO),
163.5 (7-CO). MS (LCMS) m/z (%) 362 (100, Mþþ1). Anal. calcd for
C17H19N3O4S (361.42): C, 56.50; H, 5.30; N,11.63. Found: C, 56.38; H,
5.21; N, 11.48.
1732, 1700 cmꢀ1. 1H NMR (CDCl3)
d 2.31 (s, 3H, 4-CH3), 3.67 (s, 3H,
8-OCH3), 3.72 (s, 3H, 9-OCH3), 6.58 (d, J¼7.7 Hz, 2H, 20,60-H), 6.61 (s,
1H, 9-H), 6.90 (t, J¼7.3 Hz, 1H, 40-H), 7.15–7.22 (m, 2H, 30,50-H), 7.24
(br s, 1H, NH), 7.33–7.37 (m, 5H, 4-Ph).13C NMR (CDCl3)
d
14.2 (4-
5.6. Isomerization of 5a in the presence of sodium hydride
CH3), 52.1 (9-OCH3), 53.5 (8-OCH3), 113.1 (C-20,60), 122.7 (C-9), 121.6
(C-40), 128.0 (C-400), 128.3 (C-200,600), 128.4 (C-2), 128.6 (C-5), 129.2
(C-300,500), 129.4 (C-30,50), 132.0 (C-4), 135.7 (C-100), 145.1 (C-10), 147.0
(C-8), 164.8 (9-CO), 165.0 (8-CO). MS (LCMS) m/z (%) 424 (100,
Mþþ1). Anal. calcd for C22H21N3O4S (423.48): C, 62.40; H, 5.00; N,
9.92. Found: C, 62.47; H, 4.95; N, 9.78.
To a suspension of compound 5a (1.0 mmol of E/Z 4:1 mixture)
in dry THF (15 mL) at 20 ꢁC sodium hydride (60% in oil, 1.1 mmol)
was added under argon. The reaction mixture was stirred for 3 h at
room temperature. After dilution of the solution with 40 mL ice–
water the product precipitated. The crude product mixture was
subjected to column chromatography on silica gel using petroleum
ether/EtOAc (3:1) as eluent, to give the dimethyl 2-[4,5-dimethyl-2-
thioxo-2,3-dihydro-1H-imidazol-1-yl(phenyl)amino]but-2-enedioate
(8a) as a 2:1 mixture of isomers E/Z in 78% yield.
5.3. Reaction of thione 1a with DMAD in benzene at reflux
A reaction mixture of thione 1a (1.0 mmol) and DMAD (0.22 g,
1.1 mmol) in benzene (20 mL), was heated at reflux until thione was
consumed completely (followed by TLC, approximately 48 h). The
solvent was distilled off in vacuo and the resulting residue was
subjected to column chromatography on silica gel using petroleum
ether/AcOEt (5:1) as eluent, slowly increasing the polarity up to 1:1
to give only.
5.7. Formation of (2E)-2-[(arylamino)(methoxycarbonyl)-
methylene]-5,6-dimethylimidazo[2,1-b][1,3]thiazol-3(2H)-
one (4)
5.7.1. Method A. From the reaction of thiones 1 with DMAD. General
procedure. To a suspension of compound 1 (1.0 mmol) in dry tet-
rahydrofuran (15 mL) at 20 ꢁC, sodium hydride (60% in oil,
2.2 mmol) was added under argon. Salt formation was allowed to
proceed for 30 min, DMAD (1.0 mmol) was then added and the
y
Revealed after the acquisition of the C–H coupled spectrum.

714
C. Neochoritis et al. / Tetrahedron 66 (2010) 709–714
reaction mixture was stirred at for 24 h at room temperature. Di-
lution of the solution with 40 mL ice–water precipitated the
product. The crude product mixture was subjected to column
chromatography on silica gel using petroleum ether/EtOAc (5:1) as
eluent, to give the purified imidazothiazoles 4.
5.8. Reaction of 5a-E with acetic anhydride
A solution of 5a-E (1.0 mmol) in acetic anhydride (10 mL) was
heated at reflux for 3 h. The reaction mixture was then washed
repeatedly with water; the remainder was dried and subjected to
column chromatography on silica gel using petroleum ether/EtOAc
(3:1 up to 1:1) as eluent, to give the purified product.
5.7.1.1. (2E)-2-[(Anilino)(methoxycarbonyl)methylene-5,6-dime-
thylimidazo[2,1-b][1,3]thiazol-3(2H)-one (4a). Isolated as a white
solid in 74% yield, mp 159–161 ꢁC.IR (Nujol)nmax: 1713, 1661 cmꢀ1
.
5.8.1. Dimethyl 2-[3-acetyl-4,5-dimethyl-2-thioxo-2,3-dihydro-1H-
imidazol-1-yl(phenyl)amino]but-2-enedioate 7-Z. Yellow solid,
0.234 g (58%), mp 160–162 ꢁC; IR (Nujol) nmax: 1740, 1707 cmꢀ1. 1H
1H NMR (CDCl3)
d 2.17 (s, 3H, 6-CH3), 2.44 (s, 3H, 5-CH3), 3.73 (s, 3H,
OCH3), 6.98 (d, J¼7.8 Hz, 2H, 20,60-H), 7.18 (t, J¼7.4 Hz, 1H, 40-H), 7.
31–7.37 (m, 2H, 30,50-H), 10.54 (s, 1H, NH). 13C NMR (CDCl3)
d
8.6 (5-
NMR (CDCl3) d 1.96 (s, 3H, 5-CH3), 2.07 (s, 3H, 4-CH3), 2.18 (s, 3H,
CH3), 12.6 (6-CH3), 53.2 (OCH3), 104.3 (C-2), 120.7 (C-5), 121.4
(C-20,60), 125.4 (C-40), 129.4 (C-30,50), 139.8 (C-10), 141.7 (C-6), 142.6
(C-8), 146.5 (C-7a), 162.6 (C-3), 163.2 (8-CO). MS (LCMS) m/z (%) 368
(100, MþþK). Anal. calcd for C16H15N3O3S (329.37): C, 58.34; H,
4.59; N, 12.76.Found: C, 58.53; H, 4.42; N, 12.88.
COCH3), 3.75 (s, 3H, 8-OCH3), 3.89 (s, 3H, 7-OCH3), 7.21–7.23 (m, 1H,
40-H), 7.30 (s, 1H, 9-H), 7.29–7.35 (m, 2H, 30,50-H), 7.55–7.57 (m, 2H,
20,60-H). 13C NMR (CDCl3)
d 8.7 (4-CH3), 9.3 (5-CH3), 22.5 (3-CH3),
52.6 (8-OCH3), 53.6 (7-OCH3), 121.1 (C-5), 121.4 (C-4), 122.9 (C-
20,60), 126.5 (C-40), 128.9 (C-30,50), 130.0 (C-9), 135.5 (C-8), 139.4 (C-
10), 162.6 (8-CO), 161.9 (7-CO), 164.3 (C-2), 170.9 (3-CO). MS (LCMS)
m/z (%) 404 (100, Mþþ1). Anal. calcd for C19H21N3O5S (403.45): C,
56.56; H, 5.25; N, 10.42.Found: C, 56.66; H, 5.06; N, 10.38.
5.7.1.2. (2E)-2-{[(4-Chlorophenyl)amino](methoxycarbonyl)-
methylene}-5,6-dimethylimidazo[2,1-b][1,3]thiazol-3(2H)-one
(4b). Isolated as a white solid (71% yield), mp 169–171 ꢁC. IR
(Nujol) nmax: 1725, 1679 cmꢀ1 1H NMR (CDCl3)
. d 2.17 (s, 3H, 6-
References and notes
CH3), 2.43 (s, 3H, 5-CH3), 3.76 (s, 3H, OCH3), 6.91 (d, J¼8.7 Hz, 2H,
20,60-H), 7.30 (d, J¼8.7 Hz,, 2H, 30,50-H), 10.44 (br s, 1H, NH). 13C
1. Grimmett, M. R. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.,
Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 3, pp 77–220.
2. (a) Du, H.; He, Y.; Sivappa, R.; Lovely, C. J. Synlett 2006, 965–992; (b) Hoffmann,
H.; Lindel, T. Synthesis 2003, 1753–1783.
3. De Luca, L. Curr. Med. Chem. 2006, 13, 1–23 and references cited therein.
4. Lagoja, I. M.; Pannecouque, C.; Van Aerschot, A.; Witvrouw, M.; Debyser, Z.;
Balzarini, J.; Herdewijn, P.; De Clercq, E. J. Med. Chem. 2003, 46, 1546–1553.
5. Al-Dujaili, A. H.; Atto, A. T.; Al-Kurde, A. M. Eur. Polym. J. 2001, 37, 927–932.
6. Wang, Q.; Li, H.; Li, Y.; Huang, R. J. Agric. Food Chem. 2004, 52, 1918–1922.
7. Yanagimoto, K.; Lee, K.-G.; Ochi, H.; Shibamoto, T. J. Agric. Food Chem. 2002, 50,
5480–5484.
8. Li, Y.; Xu, Y.; Qian, X.; Qu, B. Tetrahedron Lett. 2004, 45, 1247–1251.
9. (a) Timtcheva, I.; Maximova, V.; Deligeorgiev, T.; Zaneva, D.; Ivanov, I. J.
Photochem. Photobiol. A: Chem. 2000, 130, 7–11; (b) Rucker, V. C.; Foister, S.;
Melander, C.; Dervan, P. B. J. Am. Chem. Soc. 2003, 125, 1195–1202.
10. For recent reviews about imidazoles see: (a) Bellina, F.; Cauteruccio, S.; Rossi, R.
Tetrahedron 2007, 63, 4571–4624; (b) Kamijo, S.; Yamamoto, Y. Chem. Asian J.
2007, 2, 568–578.
11. (a) Andreani, A.; Granaiola, M.; Guardigli, M.; Leoni, A.; Locatelli, A.; Morigi, R.;
Rambaldi, M.; Roda, A. Eur. J. Med. Chem. 2005, 40, 1331–1334; (b) Madg El-Din,
A. A.; Roaiah, H. F.; Elsharabasy, S. A.; Hassan, A. Y. Phosphorus, Sulfur and Silicon
2007, 182, 529–536; (c) Blakeney, J. S.; Reid, R. C.; Le, G. T.; Fairlie, D. P. Chem.
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NMR (CDCl3)
d 8.6 (5-CH3), 12.7 (6-CH3), 53.4 (OCH3), 105.9 (C-2),
120.8 (C-5), 122.7 (C-20,60), 129.5 (C-30,50), 130.8 (C-40), 138.6 (C-10),
141.8 (C-6)z, 141.9 (C-8)y, 146.6 (C-7a), 162.7 (3-CO), 163.1 (COOMe).
MS (LCMS) m/z (%) 364/366 (100, Mþþ1). Anal. calcd for
C16H14ClN3O3S (363.82): C, 52.82; H, 3.88; N, 11.55. Found: C,
52.67; H, 3.92; N, 11.68.
5.7.1.3. (2E)-2-[Anilino(methoxycarbonyl)methylene]-5-methyl-6-
phenylimidazo[2,1-b][1,3]thiazol-3(2H)-one(4c). Isolated as a white
solid (82% yield), mp 175–177 ꢁC.IR (Nujol)nmax: 3244, 3025, 2945,
1713, 1679 cmꢀ1. 1H NMR (CDCl3)
d 2.73 (s, 3H, 5-CH3), 3.72 (s, 3H,
OCH3), 6.99 (d, J¼7.8 Hz, 2H, 20,60-H), 7.18 (t, J¼7.5 Hz,1H, 40-H), 7.27–
7.32 (m, 1H, 400-H), 7. 31–7.36 (m, 2H, 30,50-H), 7.39–7.44 (m, 2H,
300,500-H), 7.68 (d, J¼7.5 Hz, 2H, 200,600-H), 10.58 (s, 1H, NH). 13C NMR
(CDCl3)
d 9.9 (5-CH3), 53.2 (OCH3), 104.0 (C-2), 121.4 (C-5), 121.5 (C-
20,60), 125.5 (C-40), 127.4 (C-200,600), 127.5 (C-400), 128.5 (C-300,500), 129.4
(C-30,50), 133.6 (C-100), 139.7 (C-10), 142.9 (C-8), 144.6 (C-6), 147.2 (C-
7a),163.0 (C-3),163.1 (COOMe). MS (LCMS) m/z (%) 392 (100, Mþþ1).
Anal. calcd for C21H17N3O3S (391.44): C, 64.43; H, 4.38; N,
10.73.Found: C, 64.51; H, 4.22; N, 10.75.
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5.7.2. Method B. From Dimethyl 2-[(1-arylamino-4-methyl-5-meth-
yl(or phenyl)-1H-imidazol-2-yl)thio]but-2-enedioate (5-E/Z). To a sus-
pension of 5-E/Z(1.0 mmol) in dry tetrahydrofuran (15 mL) at
20 ꢁC sodium hydride (60% in oil, 2.0 mmol) was added under
argon. The reaction mixture was stirred for 24 h at room tem-
perature. Dilution of the solution with 40 mL ice–water pre-
cipitated the product. The crude product mixture was subjected to
column chromatography on silica gel using petroleum ether/
EtOAc (5:1) as eluent to give the purified imidazothiazoles 4.
Compound 4a was obtained in 68% yield, 4b in 67% yield and 4c in
65% yield.
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z
These assignments may be interchanged.