1-Arylaminoimidazole-2-thiones as intermediates in the synthesis of imidazo[2,1-b][1,3,4]thiadiazines

Article abstract of DOI:10.1016/j.tet.2008.01.136

The synthesis of the hitherto unknown imidazo[2,1-b][1,3,4]thiadiazines 7 in good to very good yields (up to 77%) by using suitable imidazole-2-thione precursors 1 has been described, while S-vinylimidazoles 8 and 9 were isolated as by-products. Moreover, the reactivity of the three possible reaction sites of the starting thiones 1 was initially examined by methylation experiments, whereupon the enhanced reactivity of sulfur was proven by the isolation of the methylated derivatives 3 and 4. By prolonged methylation the imidazolinone 6 is finally formed. Theoretical calculations support the experimental results of alkylation products.

Full text of DOI:10.1016/j.tet.2008.01.136

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3527e3533
www.elsevier.com/locate/tet
1-Arylaminoimidazole-2-thiones as intermediates in the synthesis of
imidazo[2,1-b][1,3,4]thiadiazines
*
Constantinos Neochoritis, Constantinos A. Tsoleridis , Julia Stephanidou-Stephanatou
Department of Chemistry, Laboratory of Organic Chemistry, Aristotle University of Thessaloniki, 54124, Macedonia, Greece
Received 14 November 2007; received in revised form 11 January 2008; accepted 31 January 2008
Available online 6 February 2008
Abstract
The synthesis of the hitherto unknown imidazo[2,1-b][1,3,4]thiadiazines 7 in good to very good yields (up to 77%) by using suitable imidazole-
2-thione precursors 1 has been described, while S-vinylimidazoles 8 and 9 were isolated as by-products. Moreover, the reactivity of the three
possible reaction sites of the starting thiones 1 was initially examined by methylation experiments, whereupon the enhanced reactivity of sulfur
was proven by the isolation of the methylated derivatives 3 and 4. By prolonged methylation the imidazolinone 6 is finally formed. Theoretical
calculations support the experimental results of alkylation products.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Imidazolethiadiazines; Imidazolone; Methylation; Selectivity; S-Vinylimidazoles
1. Introduction
tris(imidazoline) benzene,10 preparation of triple-stranded
helices and zigzag chains by coordination with copper(I),11
synthesis of palladium complexes with pyridine/imidazoline
ligands that react readily with carbon monoxide,12 prepara-
tion of supramolecular structures by self assembly using
pep stacking and hydrogen bonding interactions.13 Re-
cently, it has been reported that N-aminoimidazoles and
N-aminoimidazoline thiones inhibit retroviral replication.14
In addition, the regioselective synthesis of a series of pyri-
dinyl imidazoles, inhibitors of p38 MAP (mitogen activated
protein) kinase, from suitable imidazole-2-thione precursors
has been studied.15,16 Moreover, it is long known that 2,3-
dihydroimidazo[2,1-b]thiazoles exhibit anti-inflammatory
activity,17 whereas the synthesis of some imidazo[2,1-b]thi-
azolones has been recently reported.18
Heterocyclic compounds are rich sources of diverse
physical, chemical, and biological properties.1 In medicinal
chemistry they are commonly used as templates to design bi-
ologically active agents.2 Moreover, in the past 20 years the
drug-discovery process has undergone extraordinary changes
and high-throughput biological screening of potential drug
candidates has led to an ever increasing demand for novel
drug-like compounds.3 Imidazole is a common structural unit
found in many biologically active compounds.4 Substituted
imidazoles have been synthesized by combinatorial fashion
on solid supports5 as well as in the solution phase6 and are
promising scaffolds for drug design.7 2-Substituted imidazol-
ines and imidazoles are of increasing interest because of their
applications8 as disinfectants, pharmaceuticals and also be-
cause of their applications in supramolecular chemistryd
preparation of molecular tectonics through formation of
intermolecular hydrogen bonds,9 formation of helical assem-
bly through triple hydrogen bonds in tris(oxazoline)e
2. Results and discussion
As long as the preparation of new fused imidazole deriva-
tives is of great pharmacological interest, we have considered
the synthesis of some imidazo[2,1-b][1,3,4]thiadiazines as
possible anti-inflammatory drugs by using suitable imidazole-
2-thione precursors replacing thus the thiazoline by a thiadi-
azine ring.
* Corresponding author. Fax: þ30 2310 997679.
E-mail address: tsolerid@chem.auth.gr (C.A. Tsoleridis).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.136

3528
C. Neochoritis et al. / Tetrahedron 64 (2008) 3527e3533
Table 1
Energy properties of compounds 1ae3a, 5a as well as of anionic forms 10e13
calculated at the DFT level (B3LYP/6-31G*)
Our synthetic approach is depicted in Scheme 1. 1-Aryl-
amino-4,5-dimethylimidazole-2-thiones were prepared
1
according to a known procedure14,19 by the reaction of
3-chloro-2-butanone with potassium thiocyanate and arylhy-
drazines. However, as reported earlier by us20 a closer inspec-
tion of the 1H NMR spectra of compounds 1 indicated a
tautomerization between the thione 1 and the thiol 2 (2:1 ratio,
CDCl3, ambient temperature). This observation is also sup-
ported by theoretical calculations (DFT B3LYP/6-31G*) on
the tautomers 1a and 2a according to which 1a is predicted
to be more stable than 2a by 13.47 kcal/mol. Moreover, calcu-
lations were carried out for the isomers 3a and 5a, whereupon
5a is favored over its isomer by 10.39 kcal/mol (Table 1).
Next, the reactivity of the three possible reaction sites of
the molecule, namely the 3-NH, 6-NH, and 7-SH positions
was investigated and therefore, theoretical calculations were
carried out, according to which the 3-NH or the SH proton ab-
straction is favored over that of the 6-NH proton, as depicted
in Figure 1 and in Table 1. The anions 10 and 11, which re-
sulted after the proton abstraction from 3-NH or 7-SH are
mesomeric forms and therefore they have the same geometry
Compound
Etotal (au)
DEa
1a
2a
ꢀ989.4327159
ꢀ989.4112437
ꢀ1028.7455122
ꢀ1028.7289525
ꢀ988.8707755
ꢀ988.8540585
ꢀ988.8435396
0
13.47b
0
5a
3a
10.39c
0
10.49d
17.09e
10, 11
12
13
a
In kcal/mol.
b
c
d
e
DE¼Etotal (2a)ꢀEtotal (1a)
DE¼Etotal (3a)ꢀEtotal (5a)
DE¼Etotal (12)ꢀEtotal (10)
DE¼Etotal (13)ꢀEtotal (10)
.
.
.
.
between anions 12 and 10 (or 13 and 11) is 10.49 (or
17.09) kcal/mol, anion 12 being more stable than 13. Using
the atomic charge distribution over 1a and 2a as reference,
the calculated new atomic charges on the anions reveal that
in 10 (or 11) the negative charge of 3-N atom is decreased
by 0.1002 electrons, whereas a small increase is calculated
for the anion 11. For the anion 12 a small decrease, whereas
and energy. So, the difference in total energies (DEtotal
)
H3C
CH3
H3C
CH3
H3C
CH3
ArNHNH2
KSCN
+
H3C
N
N
N
N
N
N
1. NaH, 30 min
2. CH3I, 1.5 h
HN
Ph
N
HN
CH3COCHClCH3
SH
SCH3
SCH3
55%
Ph
Ar
THF, rt
2
3a 85%
4a
a
b
c
Ar = C6H5
Ar = C6H4Cl-4
Ar = C6H4NO2-4
H3C
CH3
N
N
CH3
HN
AcOH
CH3I, Me2CO
reflux, 5 h
S
Ph
5a
H3C
CH3
NH
1. NaH, 30 min
2. CH3I, 1.5 h
4a
60%
H3C
N
THF, rt
HN
Ar
CH3
S
1. NaH, 30 min
2. CH3I, 7 days
H3C
N
N
CH3
N
1
Ph
O
THF, rt
Method A
Method B
6a 40%
1. NaH 1.2 eq, 30 min
2. BrCH2CH2Br 1.4 eq
1. NaH 2.2 eq, rt, 30 min
2. BrCH2CH2Br 1.4 eq
rt, 2 h
1.5 h
3. NaH 1.2 eq, 1.5 h
DMF, -10 °C
H3C
6
CH3
7
H3C
CH3
4
N
H3C
CH3
N
5
6
HN
N
N
N
N
Ar
+
+
N
N
8a
Ar
11
2
S
8
3
S
Ar
9
9
S
10
1
2
8
Br
7a 62% (77%)a
7b 60% (74%)
7c 56% (71%)
a
8a 31% (14%)
8b 29% (15%)
8c 21% (10%)
9a 5% (1%)
-
-
The yields in parentheses refer to method B
Scheme 1. Reaction scheme and conditions for the synthesis of compounds 4e9.

C. Neochoritis et al. / Tetrahedron 64 (2008) 3527e3533
3529
H3C
5
CH3 H3C
3
CH3 H3C
CH3
H3C
CH3 H3C
CH3 H3C
CH3
4
H
N
NH
H
N
N
H
N
N
H
N
N
N
NH
N
N
N
1
2
N
N
N
N
N
C
C
C
C
C
C
6
Ph
Ph
Ph
Ph
Ph
Ph
S
1a
SH
2a
S
10
S
11
S
12
SH
13
7
0
13.47
0
0
10.49
17.09
Figure 1. Relative energies (kcal/mol) for the tautomers 1a and 2a as well as for their anions 10e13 after the abstraction of one proton from the position 3 or 6 or 7
calculated at the DFT level (B3LYP/6-31G*).
for 13 a small increase in electronic charge of 6-N atom is cal-
culated. For the 7-S atom a substantial increase in electronic
charge is calculated for all anions, especially for 10 (or 11)
(Table 2). This charge increase can be attributed mainly on
charge delocalization on the sulfur atomic orbitals and the
stabilization induced by the aromatization of the imidazole
ring. Therefore, sulfur alkylation should predominate under
mild reaction conditions.
However, the use of an excess of sodium hydride and
methyl iodide in combination with prolonged reaction times
leads to the formation of the hydrolysis product, the imidazol-
one 6a, which was isolated in 40% yield. Most probably, the
reaction proceeds through initial formation of 4a, from which
upon further methylation 14 could be formed. By subsequent
hydrolysis during the workup procedure compound 6a is
formed, as depicted in Scheme 2.
In order to confirm the above results we started studying the
methylation reaction on compounds 1. Upon refluxing 1a with
excess of methyl iodide in acetone for 5 h only the S-alkyl
product 3a was isolated in 85% yield, which could be con-
verted to the exocyclic N-methyl derivative 4a by further
methylation with sodium hydride and methyl iodide in 55%
yield (Scheme 1). Imidazole 4a was also formed in 60% yield
in a one step reaction by methylation of 1a with sodium hy-
dride and methyl iodide. These experimental results confirm
the theoretical predictions.
Having in hand the above methylation results it could be
rather safely predicted that the target imidazo[2,1-b]-
[1,3,4]thiadiazines could be synthesized from thiazolones 1
by using 1,2-dibromoethane. Indeed, compounds 7ae7c were
synthesized in good yield (56e62%) by the cyclization of thio-
nes 1ae1c with sodium hydride and 1,2-dibromoethane
(Method A, Scheme 1), along with the S-vinyl derivatives
8ae8c (21e31% yield) and the N-2-bromoethyl-S-vinyl
compound 9a (5% yield), increasing thus the overall reaction
yield to 77e96%. However, the yield of the thiadiazines 7
Table 2
Net charge distribution over some atoms of compounds 1a and 2a in neutral as well as for their anions 10e13 calculated at the DFT level (B3LYP/6-31G*)
Compound
Atomic net charge qnet (ꢁ104 electrons)
1
2
3
Dqa
4
5
6
Dqb
7
Dqc
1a
2a
10
11
12
13
a
ꢀ3680
ꢀ3620
ꢀ3680
ꢀ3680
ꢀ3474
ꢀ3223
3429
2545
2879
2879
3645
2547
ꢀ6365
ꢀ4814
ꢀ5363
ꢀ5363
ꢀ6408
ꢀ5340
2758
1750
1865
1865
2723
1753
2892
3005
2836
2836
2858
2875
ꢀ5116
ꢀ5228
ꢀ5154
ꢀ5154
ꢀ5044
ꢀ5297
ꢀ3306
ꢀ243
ꢀ1002
ꢀ5545
ꢀ5545
ꢀ4659
ꢀ687
2239
5302
1353
444
549
ꢀ72
69
Dq(10)¼q(1a)ꢀq(10), Dq(11)¼q(2a)ꢀq(11)
.
.
b
c
Dq(12)¼q(1a)ꢀq(12), Dq(13)¼q(2a)ꢀq(13)
Dq(10)¼q(1a)ꢀq(10), Dq(11)¼q(2a)ꢀq(11), Dq(12)¼q(1a)ꢀq(12), Dq(13)¼q(2a)ꢀq(13)
.
CH3
NH
H3C
CH3
CH3
H3C
CH3
H3C
CH3
CH3
H3C
H3C
H
H
H
H3C
N
H
N
N
N
N
N
N
N
N
CH3I
NaH
CH3I
-HI
N
N
N
N
N
S
S
CH3
S
S
CH3
S
CH3
Ph
Ph
Ph
Ph
Ph
I
1a
3a
4a
H3C
CH3
CH3
CH3
OH2
CH3
CH3
CH3
CH3
H3C
H3C
H3C
I
I
H3C
H3C
H3C
H3C
N
N
CH3
N
N
O
CH3
H
N
N
N
N
- CH3SH
- HI
CH3I
N
N
N
N
O
S
S
S
CH3
Ph
Ph
Ph
Ph
CH3
6a
14
Scheme 2. Plausible mechanism for the synthesis of compounds 3a and 4a and for the formation of compound 6a.

3530
C. Neochoritis et al. / Tetrahedron 64 (2008) 3527e3533
was considerably increased (71e77%) at the expense of the
by-products by initial addition of 2.2 equiv of sodium hy-
dride followed after 30 min by dropwise addition of the
1,2-dibromoethane (Method B).
and d 3.98 (br s) with their carbons resonating at 20.6 and
51.7 ppm, respectively. The methylene group at d 3.98 being
in the vicinity of the phenyl group appears as a broad signal,
whereas the second methylene protons show COLOC correla-
tion spot with the quaternary carbon at 130.5 ppm (C-8a), con-
firming thus their position (Fig. 2).
3. Structure assignments
For the vinyl substituted compounds 8, 8a will be analyzed.
The mass spectrum (m/z¼245) and elemental analysis were in
accord with the molecular formula C13H15N3S. The proton
NMR spectrum showed the presence of two methyl groups
at d 2.07 (on C-5, 126.9 ppm) and d 2.21 (on C-4,
132.7 ppm). Concerning the vinyl group, the H-8 proton ap-
pears as doublet of doublets at d 6.53 (Jcis¼9.5 Hz,
Jtrans¼16.7 Hz, on C-8, 128.6 ppm), whereas the two H-9 pro-
tons appear as doublet of doublets at d 5.75 (Jtrans¼16.7 Hz,
Jgem¼0.4 Hz) and d 5.79 (Jcis¼9.5 Hz, Jgem¼0.4 Hz) with their
carbon resonating at 116.4 ppm.
The assigned molecular structures of all new compounds
are based on rigorous spectroscopic analysis including IR,
NMR (1H, 13C, DEPT, COSY HeH, NOESY HeH, HETCOR
CeH and COLOC CeH), MS, and elemental analysis data.
Concerning compound 3a the methyl protons resonating at
d 2.87 have long range CeH (COLOC) correlation with the
quaternary carbon at 144.5 ppm (C-2) via 3JCH, whereas
both methyl protons at d 2.15 and at d 2.44 have COLOC cor-
relation with the quaternary carbons at 125.4 and 128.4 ppm,
2
3
via JCH and JCH, being the C-5 and C-4, respectively. The
NHPh proton resonating at d 8.31 shows COLOC correlations
with C-10 and C-20, and also NOESY correlation spot with the
methyl protons at d 2.15 proving thus that methyl is set on C-5.
The intensities of the COLOC correlation spots are higher
between C(5)eCH3(5) and C(4)eCH3(4) than the correlations
between C(5)eCH3(4) and C(4)eCH3(5) proving thus that
2
3
In Figure 2 the COLOC (long range via JCH and JCH
couplings) CeH correlations for compounds 3a, 6a, 7b, and
8a are depicted.
4. Conclusion
3
2JCH is closer to the optimized value of 10 Hz than the JCH
In summary, the methylation of 1-phenylamino-4,5-dime-
thylimidazole-2-thiones has been studied and the results are
in agreement with the results of theoretical calculations ac-
cording to which the 3-position proton is more acidic than
the NHAr proton. Furthermore, by prolonged methylation an
imidazolinone is formed as the only reaction product. More
important, the target synthesis of the hitherto unknown phar-
macologically interesting imidazo[2,1-b][1,3,4]thiadiazines
in very good yields by using suitable imidazole-2-thione
precursors has been achieved.
(Fig. 2). This observation can be used as evidence for the
assignment of the methyl signals of 4,5-dimethylimidazoles.
The structure of compound 6a was deduced from the spec-
tral data presented in Section 5, as well from the COLOC cor-
relations depicted in Figure 2. The mass spectrum (m/z¼231)
and elemental analysis are in accord with the molecular
formula C13H17N3O. The more downfield carbon signal at
151.6 ppm is assigned to the ureido carbonyl group that gives
in IR a strong double absorption at 1702 and 1690 cmꢀ1
.
Concerning the imidazothiadiazines 7, the structure of
compound 7b will be analyzed. The mass spectrum (m/z¼
279/281) and elemental analysis are in accord with the mole-
cular formula C13H14ClN3S. The proton NMR spectrum
showed the presence of two methyl groups at d 1.90 (C-6)
and d 2.15 (C-7) having COLOC correlation spots with both
quaternary carbons at 122.5 ppm (C-6) and 130.9 ppm (C-7).
There are also two methylene groups at d 2.99 (t, J¼5.3 Hz)
5. Experimental
5.1. General procedure
Melting points were measured on a Kofler hot-stage and are
uncorrected. Column chromatography was carried out using
Merck silica gel (70e230 mesh). Petroleum ether refers to
the fraction boiling between 60 and 80 ꢂC. IR Spectra: Perkine
Elmer 1600 series FTIR spectrophotometer, n in cmꢀ1. NMR
spectra were recorded on a Bruker AM 300 spectrometer at
300 MHz for 1H and 75 MHz for 13C, respectively, using
CDCl3 as solvent. The chemical shifts are expressed in d values
H3C
H3C
CH3
CH3
H3C
H
N
N
N
N
N
N
CH3
H
H
S
O
H
H
CH3
H
H
3a
6a
1
(ppm) relative to TMS as internal standard for H (0.00 ppm)
or to CDCl3 (77.05 ppm) for 13C NMR spectra. Coupling con-
stants nJ are reported in hertz. Low-resolution electron impact
mass spectra (EIMS) were obtained on a 6890N GC/MS
instrument (Agilent Technology), m/z (rel intensity in %);
ionization energy 70 eV. Elemental analyses performed with
a PerkineElmer 2400-II CHN analyzer. Geometries were
optimized and Mulliken net atomic charges were computed
at the Density Functional Theory (DFT, B3LYP/6-31G level)
in vacuo as implemented in the Gaussian 03 package.21
H
H
H3C
CH3
H3C
CH3
Cl
H
N
N
N
N
N
N
H
H
S
H
S
H
H
H
H
H
8a
7b
Figure 2. Long range correlations (COLOC) between protons and carbons via
3
2JCH and JCH in compounds 3a, 6a, 7b, and 8a.

C. Neochoritis et al. / Tetrahedron 64 (2008) 3527e3533
3531
5.2. Synthesis of compounds 1 and 3
for 30 min, methyl iodide (0.285 g, 2.0 mmol) was then added
and the solution was stirred for 1.5 h. Water was added, the
organic layer was washed with water, dried (Na2SO4), and
concentrated. The methylated product was crystallized, by
the addition of petroleum ether, as a yellow solid in 55% yield.
5.2.1. 1,3-Dihydro-4,5-dimethyl-1-phenylamino-2H-
imidazole-2-thione (1a)
The compound was synthesized in 70% yield according to a
known procedure.19,20 Mp 229e231 ꢂC (lit.19 230e232 ꢂC).
1
Mp 78e80 ꢂC (CH2Cl2epet. ether). H NMR (CDCl3) d 1.94
(s, 3H, 5-CH3), 2.18 (s, 3H, 4-CH3), 2.47 (s, 3H, S-CH3), 3.35
(s, 3H, N-CH3), 6.46 (d, J¼9.0, 2H, H-20,60), 6.86e6.91 (m,
1H, H-40), 7.21e7.27 (m, 2H, H-30,50). 13C NMR (CDCl3)
d 8.4 (5-CH3), 13.1 (4-CH3), 15.0 (S-CH3), 39.8 (N-CH3),
112.1 (C-20,60), 120.1 (C-40), 124.5 (C-5), 129.4 (C-30,5þ0),
132.7 (C-4), 141.5 (C-2), 147.7 (C-10). EIMS: 247 (M ,
100), 232 (7), 200 (35), 191 (25), 141 (100). Anal. Calcd for
C13H17N3S (247.36): C, 63.12; H, 6.93; N, 16.99. Found: C,
63.34; H, 6.89; N, 16.83.
5.2.2. 1-[(4-Chlorophenyl)amino]-1,3-dihydro-4,5-
dimethyl-2H-imidazole-2-thione (1b)
The compound was synthesized in 70% yield according to
a known procedure.19 Mp 226e228 ꢂC. IR (cmꢀ1) 3208, 3190
(NH), 3092, 2920, 2726, 1670, 1596. 1H NMR (CDCl3þ
DMSO-d6) d 1.98 (s, 3H, 4-CH3), 2.08 (s, 3H, 5-CH3), 3.12
(br s, 0.41H, 2-SH), 6.58 (d, J¼12.0, 2H, H-20,60), 7.14 (d,
J¼12.0, 2H, H-30,50), 8.15 (br s, 1H, NH), 11.9 (br s, 0.59H,
3-NH). 13C NMR (CDCl3þDMSO-d6) d 8.0 (4-CH3), 9.4
(5-CH3), 114.7 (C-20,60), 117.8 (C-5), 122.5 (C-4), 125.2
(C-400), 128.9 (C-30,50), 145.7 (C-10), 159.8 (C-2). EIMS:
5.3.1.2. Method B from 1a. To a suspension of compound 1a
(0.110 g, 0.5 mmol) in dry tetrahydrofuran (10 mL) at 0 ꢂC
sodium hydride (0.036 g of 60% in oil, 1.5 mmol) was added.
Salt formation was allowed to proceed at ambient temperature
for 30 min, methyl iodide (0.43 g, 3.0 mmol) was then added
and the solution was stirred for 1.5 h. The reaction mixture
was worked up as above and compound 4a was obtained in
60% yield.
ꢃ
253/255 (Mþ , 100), 237/239 (20), 220/22 (20), 211/213
(12), 185 (30), 170 (15), 127 (25). Anal. Calcd for
C11H12ClN3S (253.75): C, 52.07; H, 4.77; N, 16.56. Found:
C, 51.99; H, 4.67; N, 16.33.
5.2.3. 1,3-Dihydro-4,5-dimethyl-1-[(4-nitrophenyl)amino]-
2H-imidazole-2-thione (1c)
The compound was synthesized in 71% yield according to
a known procedure.19 Mp 262e264 ꢂC (lit.19 275e280 ꢂC).
1H NMR (CDCl3þDMSO-d6) d 1.98 (s, 3H, 4-CH3), 2.10 (s,
3H, 5-CH3), 6.66 (d, J¼8.8, 2H, H-20,60), 8.08 (d, J¼8.8,
2H, H-30,50), 9.53 (s, 1H, NH), 12.03 (br s, 1H, 3-NH). 13C
NMR (CDCl3þDMSO-d6) d 8.0 (4-CH3), 9.4 (5-CH3), 111.8
(C-20,60), 118.2 (C-5), 122.3 (C-4), 125.7 (C-30,50), 140.4
5.4. Synthesis of compound 6a
5.4.1. 1,3-Dihydro-1-(methyl(phenyl)amino)-3,4,5-tri-
methyl-2H-imidazole-2-one (6a)
To a suspension of compound 1a (0.116 g, 0.5 mmol) in dry
tetrahydrofuran (20 mL) at 0 ꢂC sodium hydride (0.048 g of
60% in oil, 2.0 mmol) was added. Salt formation was allowed
to proceed at ambient temperature for 30 min, methyl iodide
(0.57 g, 4.0 mmol) was then added and the solution was stirred
for seven days. Water was added, the organic layer was
washed with water, dried (Na2SO4), and concentrated. The
imidazolone was crystallized, by the addition of methylene
chloride and petroleum ether, as a white solid in 40% yield.
Mp 200e202 ꢂC (CH2Cl2epet. ether). IR (cmꢀ1) 1702, 1690
(C]O). 1H NMR (CDCl3) d 1.89 (q, J¼0.9, 3H, 5-CH3),
2.02 (q, J¼0.9, 3H, 4-CH3), 3.19 (s, 3H, 3-CH3), 3.34 (s,
3H, PhN-CH3), 6.57e6.62 (m, 2H, H-20,60), 6.81e6.87 (m,
1H, H-40), 7.20e7.25 (m, 2H, H-30,50). 13C NMR (CDCl3)
d 7.7 (5-CH3), 8.9 (4-CH3), 27.3 (3-CH3), 39.7 (PhN-CH3),
112.1 (C-4), 112.3 (C-20,60), 114.2 (C-5), 119.6 (C-40þ), 129.2
(C-30,50), 149.0 (C-10), 151.6 (C]O). EIMS: 231 (M , 100),
189(50), 173 (39), 159 (40). Anal. Calcd for C13H17N3O
(231.29): C, 67.51; H, 7.41; N, 18.17. Found: C, 67.59; H,
7.47; N, 18.13.
ꢃ
(C-40), 152.9 (C-10), 160.8 (C-2). EIMS: 264 (Mþ , 100),
248 (15), 234 (15), 217 (18), 207 (50), 185 (30), 128 (27).
Anal. Calcd for C11H12N4 O2S (264.31): C, 49.99; H, 4.58;
N, 21.20. Found: C, 49.94; H, 4.79; N, 21.43.
5.2.4. 1-Anilino-4,5-dimethyl-2-methylthio-1H-imidazole (3a)
The compound was synthesized in 80% yield according to a
known procedure.19 Mp 197e199 ꢂC (lit.19 198 ꢂC). 1H NMR
(CDCl3) d 2.15 (s, 3H, 5-CH3), 2.44 (s, 3H, 4-CH3), 2.87 (s,
3H, SCH3), 6.59 (d, J¼9.0, 2H, H-20,60), 6.90e6.96 (m, 1H,
H-40), 7.20e7.26 (m, 2H, H-30,50), 8.31 (br s, 1H, NH). 13C
NMR (CDCl3þDMSO-d6) d 7.6 (5-CH3), 9.6 (4-CH3), 15.2
(SCH3), 112.5 (C-20,60), 121.8 (C-40), 125.4 (C-5), 128.4
(C-4), 129.1 (C-30,50), 143.9 (C-10), 144.5 (C-2). EIMS: 233
ꢃ
(Mþ , 100), 141 (73).
5.3. Synthesis of compound 4
5.3.1. 2-Methylthio-N-phenyl-N,4,5-trimethyl-1H-
imidazole-1-amine (4a)
5.5. General procedure for the reaction of thiones (1ae1c)
with 1,2-dibromoethane (method A)
5.3.1.1. Method A from 3a. To a suspension of compound 3a
(0.116 g, 0.5 mmol) in dry tetrahydrofuran (20 mL) at 0 ꢂC
sodium hydride (0.030 g of 60% in oil, 1.2 mmol) was added.
Salt formation was allowed to proceed at ambient temperature
To a suspension of compound 1a (0.5 mmol) in dry dime-
thylformamide (5 mL) at ꢀ10 ꢂC sodium hydride (0.015 g of
60% in oil, 0.62 mmol) was added. Salt formation was allowed
to proceed for 30 min, 1,2-dibromoethane (0.14 g, 0.7 mmol)

3532
C. Neochoritis et al. / Tetrahedron 64 (2008) 3527e3533
was then added and the reaction mixture was stirred for 1.5 h
at ꢀ10 ꢂC. Sodium hydride (0.015 g of 60% in oil, 0.62 mmol)
was again added to this solution at ꢀ10 ꢂC and the reaction
mixture was stirred for another 1.5 h. Dilution of the solution
with 40 mL ice-water precipitated the products. The crude
product mixture was subjected to column chromatography
on silica gel using petroleum ether/EtOAc (3:1) as eluent, to
give in order of elution.
1H, H-9), 6.44 (d, J¼8.8, 2H, H-20,60), 6.48 (dd, Jcis¼9.6,
Jtrans¼16.7, 1H, H-8), 6.63 (br s, 1H, NH), 7.19 (d, J¼8.8,
2H, H-30,50). 13C NMR (CDCl3) d 8.4 (5-CH3), 13.3 (4-CH3),
114.0 (C-20,60), 116.0 (C-9), 126.4 (C-40), 126.7 (C-5), 128.9
(C-8), 129.5 (C-30,50), 133.6 (C-4), 136.6 (C-2), 144.90 (C-10).
EIMS: 279/281 (Mþ, 70), 153 (100), 126/128 (15), 94 (40).
Anal. Calcd for C13H14ClN3S (279.79): C, 55.81; H, 5.04;
N, 15.02. Found: C, 55.99; H, 5.12; N, 14.93.
5.5.1. From compound 1a
5.5.2.2. 6,7-Dimethyl-4-(4-chlorophenyl)-3,4-dihydro-2H-imid-
azo[2,1-b][1,3,4]thiadiazine (7b). White solid in 60% yield.
1
5.5.1.1. 1-[(N-2-Bromoethyl)-(N-phenyl)]amino-4,5-dimethyl-
2-(vinylthio)-1H-imidazole (9a). Colorless crystals, yield
0.018 g, 5%. Mp 77e79 ꢂC. 1H NMR (CDCl3) d 2.00 (s,
3H, 5-CH3), 2.21 (s, 3H, 4-CH3), 3.57 (t, J¼8.3, 2H, H-10),
3.97e4.21 (m, 2H, H-11), 5.36 (d, Jcis¼9.5, 1H, H-9), 5.38
(d, Jtrans¼16.6, 1H, H-9), 6.41 (d, J¼9.0, 2H, H-20,60), 6.62
(dd, Jcis¼9.5, Jtrans¼16.6, 1H, H-8), 6.90e6.95 (m, 1H,
H-40), 7.22e7.28 (m, 2H, H-30,50). 13C NMR (CDCl3) d 8.7
(5-CH3), 13.3 (4-CH3), 27.5 (C-11), 55.3 (C-11), 116.4
(C-9), 116.6 (C-20,60), 121.0 (C-40), 125.4 (C-5), 128.6
(C-8), 129.7 (C-30,50), 134.1 (C-4), 137.8 (C-2), 146.5
(C-10). Anal. Calcd for C15H18BrN3S (352.29): C, 51.14; H,
5.15; N, 11.93. Found: C, 51.01; H, 5.22; N, 11.78.
Mp 141e143 ꢂC. H NMR (CDCl3) d 1.90 (s, 3H, 6-CH3),
2.15 (s, 3H, 7-CH3), 2.99 (t, J¼5.3, 2H, H-2), 3.98 (br s,
2H, H-3), 6.62 (d, J¼8.9, 2H, H-20,60), 7.26 (d, J¼8.9, 2H,
H-30,50). 13C NMR (CDCl3) d 7.5 (6-CH3), 12.8 (7-CH3),
20.6 (C-2), 51.7 (C-3), 119.0 (C-20,60), 122.5 (C-6), 128.7
(C-40), 129.6 (C-30,50), 130.5 (C-8a), 130.9 (C-7), 146.1
(C-10). EIMS: 279/281 (Mþ, 85), 237/239 (50), 223/225
(45), 184/186 (15), 169/171 (100), 137/139 (30). Anal. Calcd
for C13H14ClN3S (279.79): C, 55.81; H, 5.04; N, 15.02.
Found: C, 55.72; H, 5.07; N, 15.13.
5.5.3. From compound 1c
5.5.3.1. 4,5-Dimethyl-1-N-(4-nitrophenyl)amino-2-(vinylthio)-
5.5.1.2. 4,5-Dimethyl-1-N-phenylamino-2-(vinylthio)-1H-imid-
1H-imidazole (8c). White solid in 21% yield. Mp 86e88 ꢂC.
1
azole (8a). White solid in 31% yield. Mp 140e142 ꢂC. IR
IR (cmꢀ1) 3470 (NH), 1504 (NO2 as), 1330 (NO2 sym). H
1
(cmꢀ1) 3470 (NH). H NMR (CDCl3) d 2.07 (s, 3H, 5-CH3),
NMR (CDCl3) d 2.05 (s, 3H, 5-CH3), 2.21 (s, 3H, 4-CH3),
5.27 (d, Jtrans¼17.1, 1H, H-9), 5.32 (d, Jcis¼9.4, 1H, 9-H),
6.47 (dd, Jcis¼9.4, 1H, 8-H), 6.55 (d, J¼9.2, 2H, H-20,60),
7.4 (br s, 1H, NH), 8.15 (d, J¼9.2, 2H, H-30,50). 13C NMR
(CDCl3) d 8.3 (5-CH3), 13.2 (4-CH3), 111.8 (C-20,60), 116.5
(C-9), 126.1 (C-30,50), 126.9 (C-5), 128.5 (C-8), 134.1 (C-4),
136.9 (C-2), 142.1 (C-40), 151.4 (C-10). EIMS: 290 (Mþ,
78), 153 (100). Anal. Calcd for C13H14N4O2S (290.34): C,
53.78; H, 4.86; N, 19.30. Found: C, 53.62; H, 4.75; N, 19.41.
2.21 (s, 3H, 4-CH3), 5.75 (dd, J¼16.7, 0.4, 1H, Htrans-9),
5.79 (dd, J¼9.5, 0.4, 1H, Hcis-9), 6.53 (dd, J¼16.7, 9.5, 1H,
H-8), 6.50e6.54 (m, 2H, H-20,60), 6.90e6.96 (m, 1H, H-40),
7.10 (br s, 1H, NH), 7.19e7.25 (m, 2H, H-30,50). 13C NMR
(CDCl3) d 8.3 (5-CH3), 12.9 (4-CH3), 112.8 (C-20,60), 116.4
(C-9), 121.8 (C-40), 126.9 (C-5), 128.6 (C-8), 129.5 (Cþ-30,50),
132.7 (C-4), 137.2 (C-2), 146.2 (C-10). EIMS: 245 (M , 70),
153 (100). Anal. Calcd for C13H15N3S (245.34): C, 63.64;
H, 6.16; N, 17.13. Found: C, 63.48; H, 6.27; N, 17.00.
5.5.3.2. 6,7-Dimethyl-4-(4-nitrophenyl)-3,4-dihydro-2H-imid-
5.5.1.3. 6,7-Dimethyl-4-phenyl-3,4-dihydro-2H-imidazo[2,1-b]-
azo[2,1-b][1,3,4]thiadiazine (7c). White solid in 56% yield.
1
[1,3,4]thiadiazine (7a). White solid in 62% yield. Mp 135e
Mp 228e230 ꢂC. H NMR (CDCl3) d 1.97 (s, 3H, 6-CH3),
1
137 ꢂC. H NMR (CDCl3) d 1.90 (s, 3H, 6-CH3), 2.17 (s,
2.18 (s, 3H, 7-CH3), 3.15 (br s, 2H, H-2), 4.20 (br s, 2H,
H-3), 6.80 (d, J¼9.0, 2H, H-20,60), 8.20 (d, J¼9.0, 2H,
H-30,50). 13C NMR (CDCl3) d 7.6 (6-CH3), 12.9 (7-CH3),
22.4 (C-2), 50.9 (C-3), 116.4 (C-20,60), 122.7 (C-6), 125.8
(C-30,50), 131.2 (C-8aþ), 131.7 (C-7), 143.0 (C-40), 152.7
(C-10). EIMS: 290 (M , 78), 258 (30), 248 (31), 234 (30),
180 (100). Anal. Calcd for C13H14N4O2S (290.34): C, 53.78;
H, 4.86; N, 19.30. Found: C, 53.91; H, 4.62; N, 19.41.
3H, 7-CH3), 2.99 (t, J¼5.5, 2H, H-2), 4.00 (br s, 2H, H-3),
6.65e6.70 (m, 2H, H-20,60), 7.00e7.07 (m, 1H, H-40), 7.26e
7.33 (m, 2H, H-30,50). 13C NMR (CDCl3) d 7.5 (6-CH3),
12.7 (7-CH3), 20.5 (C-2), 51.6 (C-3), 117.7 (C-20,60), 122.6
(C-6), 123.5 (C-40), 129.5 (C-30,50)þ, 130.5 (C-7), 130.6
(C-8a), 147.5 (C-10). EIMS: 245 (M , 23), 211 (90), 210
(100), 200 (20), 187 (60), 128 (40). Anal. Calcd for
C13H15N3S (245.34): C, 63.64; H, 6.16; N, 17.13. Found: C,
63.78; H, 6.25; N, 17.30.
5.6. General procedure for the reaction of thiones (1ae1c)
with 1,2-dibromoethane (method B)
5.5.2. From compound 1b
To a suspension of compound 1 (0.5 mmol) in dry dime-
thylformamide (50 mL) sodium hydride (0.27 g of 60% in
oil, 1.13 mmol) was added. Salt formation was allowed to pro-
ceed for 30 min at rt, 1,2-dibromoethane (0.132 g, 0.7 mmol)
in dry dimethylformamide (5 mL) was then added dropwise
5.5.2.1. 4,5-Dimethyl-1-N-(4-chlorophenyl)amino-2-(vinylthio)-
1H-imidazole (8b). White solid in 29% yield. Mp 135e
1
137 ꢂC. H NMR (CDCl3) d 2.07 (s, 3H, 5-CH3), 2.21 (s,
3H, 4-CH3), 5.26 (d, Jtrans¼16.7, 1H, H-9), 5.31 (d, Jcis¼9.6,

C. Neochoritis et al. / Tetrahedron 64 (2008) 3527e3533
3533
S. K.; Murthy, K. H. M.; Zhao, B.; Winborne, E.; Green, D. W.; Fisher,
S. M.; Desjarlais, R. L.; Tomaszek, T. A.; Meek, T. D.; Gleason, J. G.;
Abdelmeguid, S. S. J. Med. Chem. 1994, 37, 3100e3107.
8. Testard, A.; Picot, L.; Fruitier-Arnaudin, I.; Piot, J.-M.; Chabane, H.;
Domon, L.; Thiery, V.; Besson, T. J. Enzyme Inhib. Med. Chem. 2004,
19, 467e473.
and the reaction mixture was stirred at ambient temperature
for 2 h. Dilution of the solution with 40 mL ice-water precip-
itated the products. The crude product mixture was subjected
to column chromatography on silica gel using petroleum
ether/EtOAc (3:1) as eluent, to give in order of elution.
9. (a) Mann, S. Nature 1993, 365, 499e505; (b) Hosseini, M. W. Coord.
Chem. Rev. 2003, 240, 157e166; (c) Hosseini, M. W. Acc. Chem.
Res. 2005, 38, 313e323; (d) Wuest, J. D. Chem. Commun. 2005,
5830e5837.
5.6.1. From compound 1a
Compound 9a in 1% yield; compound 8a in 14% yield and
compound 7a in 77% yield.
10. Nam, S. R.; Kim, H.-J.; Sakamoto, S.; Yamaguchi, K.; Hong, J.-I.
Tetrahedron Lett. 2004, 45, 1339e1342.
11. Huang, X.-C.; Zhang, J.-P.; Lin, Y.-Y.; Chen, X.-M. Chem. Commun.
2005, 2232e2234.
5.6.2. From compound 1b
Compound 8b in 15% yield and compound 7b in 74%
yield.
12. Bastero, A.; Ruiz, A.; Claver, C.; Milani, B.; Zangrando, E. Organometal-
lics 2002, 5820e5829.
13. Cheruzel, L. E.; Mashuta, M. S.; Buchanan, R. M. Chem. Commun. 2005,
2223e2225.
5.6.3. From compound 1c
Compound 8c in 10% yield and compound 7c in 71% yield.
14. Lagoja, I. M.; Pannecouque, C.; Van Aerschot, A.; Witvrouw, M.;
Debyser, Z.; Balzarini, J.; Herdewijn, P.; De Clercq, E. J. Med. Chem.
2003, 46, 1546e1553.
References and notes
15. Laufer, S. A.; Kotschenreuther, D.; Wagner, G. K. J. Org. Chem. 2003, 68,
4527e4530.
1. Balaban, A. T.; Oniciu, D. C.; Katritzky, A. R. Chem. Rev. 2004, 104,
2777e2812.
16. Laufer, S. A.; Wagner, G. K.; Kotschenreuther, D. A.; Albrecht, W.
J. Med. Chem. 2003, 46, 3230e3244.
2. Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R. Heterocycles in Life
and Society; John Wiley-VCH: New York, NY, 1997.
17. Lantos, I.; Bender, P. E.; Razgaitis, K. A.; Sutton, B. M.; DiMartino, M. J.;
Griswold, D. E.; Walz, D. T. J. Med. Chem. 1984, 27, 72e75.
18. El Ashry, E. S. H.; Rashed, N.; Awad, L. F.; Ramadan, E.;
Abdel-Maggeed, S. M.; Rezki, N. ARKIVOC 2007, vii, 30e40.
19. Schantl, J. G.; Lagoja, I. M. Heterocycles 1997, 4, 691e700.
20. Neochoritis, C.; Tsoleridis, C. A.; Stephanidou-Stephanatou, J. ARKIVOC
2007, xv, 101e111.
3. Coleman, C. M.; MacElroy, J. M. D.; Gallagher, J. F.; O’Shea, D. F.
J. Comb. Chem. 2002, 4, 87e93.
4. Blakeney, J. S.; Reid, R. C.; Le, G. T.; Fairlie, D. P. Chem. Rev. 2007, 107,
2960e3041.
5. (a) Tortolani, D. R.; Biller, S. A. Tetrahedron Lett. 1996, 37, 5687e5690;
(b) Gelens, E.; Koot, W. J.; Menge, W. M.; Ottenheijm, H. C.;
Timmerman, H. Bioorg. Med. Chem. Lett. 2000, 10, 1935e1938; (c)
Kondo, Y.; Komine, T.; Sakamoto, T. Org. Lett. 2000, 2, 3111e3113;
(d) Lee, H. B.; Balasubramanian, S. Org. Lett. 2000, 2, 323e326.
6. (a) Blass, B. E.; Huang, C. T.; Kawamoto, R. M.; Li, M.; Liu, S.; Portlock,
D. E.; Rennells, W. M.; Simmons, M. Bioorg. Med. Chem. Lett. 2000, 10,
1543e1545; (b) Boger, D. L.; Dechantsreiter, M. A.; Ishii, T.; Fink, B. E.;
Hedrick, M. P. Bioorg. Med. Chem. 2000, 8, 2049e2057; (c) Boger, D. L.;
Fink, B. E.; Hedrick, M. P. J. Am. Chem. Soc. 2000, 122, 6382e6394; (d)
Hamper, B. C.; Jerome, K. D.; Yalamanchili, G.; Walker, D. M.; Chott,
R. C.; Mischke, D. A. Biotechnol. Bioeng. 2000, 71, 28e37.
7. (a) Xu, J.; Yang, Z.; Dammermann, W.; Zhang, L.; Guse, A. H.; Zhang,
L.-H. J. Med. Chem. 2006, 49, 5501e5512; (b) Abdel-Meguid, S. S.;
Metcalf, B. W.; Carr, T. J.; Demarsh, P.; Desjarlais, R. L.; Fisher, S.;
Green, D. W.; Ivanoff, L.; Lambert, D. M.; Murthy, K. H. M.; Petteway,
S. R.; Pitts, W. J.; Tomaszek, T. A.; Winborne, E.; Zhao, B. G.; Dreyer,
G. B.; Meek, T. D. Biochemistry 1994, 33, 11671e11677; (c) Thompson,
21. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin,
K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone,
V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Peterson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa,
J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene,
M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck,
A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul,
A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko,
A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.;
Al-Laham, M. A.; Peng, Y. C.; Nanayakkara, A.; Challacombe, M.;
Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople,
J. A. Gaussian 03, Rev. B.02; Gaussian: Pittsburgh, PA, 2003.