Synthesis of 2,3-dihydroimidazo[2,1-b]thiazole derivatives via cyclization of N-allylimidazoline-2-thiones

Article abstract of DOI:10.1002/jhet.469

A novel method for the preparation of 2,3-dihydroimidazo[2,1-b]thiazole 9 by iodination and subsequent cyclization of the easily available N-allylimidazoline-2-thiones 5, is described. Selected transformations of the iodomethyl derivatives 9, leading to methylidene compounds 10 or the sulfide 11 (Nu = RS), via elimination with a base or via substitution with an enolizable imidazoline-2-thione (the term "1,3-dihydroimidazole-2-thione" will be used alternatively), respectively, are presented.

Full text of DOI:10.1002/jhet.469

November 2010
Synthesis of 2,3-Dihydroimidazo[2,1-b]thiazole Derivatives via
Cyclization of N-Allylimidazoline-2-thiones
1287
a
Marcin Jasinski, Grzegorz Mloston [1], * and Heinz Heimgartner *
a
b
´
´
a
´ ´
Department of Organic and Applied Chemistry, University of Łodz, Tamka 12,
´ ´
PL-91-403 Łodz, Poland
bInstitute of Organic Chemistry, University of Zu¨rich, Winterthurerstrasse 190,
CH-8057 Zu¨rich, Switzerland
*E-mail: gmloston@uni.lodz.pl or heimgart@oci.uzh.ch
Received January 2, 2010
DOI 10.1002/jhet.469
Published online 20 August 2010 in Wiley Online Library (wileyonlinelibrary.com).
A novel method for the preparation of 2,3-dihydroimidazo[2,1-b]thiazole 9 by iodination and subse-
quent cyclization of the easily available N-allylimidazoline-2-thiones 5, is described. Selected transfor-
mations of the iodomethyl derivatives 9, leading to methylidene compounds 10 or the sulfide 11 (Nu ¼
RS), via elimination with a base or via substitution with an enolizable imidazoline-2-thione (the term
‘‘1,3-dihydroimidazole-2-thione’’ will be used alternatively), respectively, are presented.
J. Heterocyclic Chem., 47, 1287 (2010).
INTRODUCTION
In spite of the fact that N-allyl-1,3-dihydroimidazole-
2-thiones seem to be attractive starting materials for
diverse cyclization reactions involving the allyl group,
there are only few reports on their synthesis available to
date. The first approach, reported already in 1895, was
the condensation of N-allylthiourea with 2-hydroxy-1,2-
diphenylethanone (benzoine) [4]. The second synthesis
described the condensation of isothiocyanic acid and
acetals of N-allyl a-aminoacetaldehyde [5]. In addition,
the reaction of allylisothiocyanate with glucosamine is
reported to yield the desired product [6], and the analo-
gous condensation with 1-amino-3-methylbutan-2-one
gave N-allyl-5-isopropylimidazoline-2-thione [7].
The goal of this study was the preparation of a series
of less known N-allyl-1,3-dihydroimidazole-2-thiones
and their subsequent cyclization to corresponding fused
N,S-heterocycles. Heterocyclic thiones with an allyl-sub-
stituted N-atom attached to the C¼¼S group are known
In a series of recent articles, a convenient approach to
2-unsubstituted imidazole N-oxides 1, including opti-
cally active derivatives, has been reported [2]. In gen-
eral, the applied method is based on the condensation of
a-(hydroxyimino)ketones 2 with a primary aliphatic
amine and formaldehyde. Alternatively, the correspond-
ing hexahydro-1,3,5-triazines 3, being trimers of formal-
dehyde imines, can be used (Scheme 1).
Irrespective of the substitution pattern, the reaction of
1 with 2,2,4,4-tetramethylcyclobutane-1,3-dithione (4)
resulted in the ‘‘sulfur transfer reaction’’ leading to 1,3-
dihydroimidazole-2-thiones 5 in high-yield [2b,2d,3]. In
addition to N-alkyl and N-cycloalkyl substituted imidaz-
ole N-oxides 1, some of the corresponding N-allyl deriv-
atives were also obtained in good yields [2a]. However,
the latter have not been explored for further conversions
yet.
C
V
2010 HeteroCorporation

´ ´
M. Jasinski, G. Mloston, and H. Heimgartner
1288
Vol 47
Scheme 1
to undergo an intramolecular 1,5-cyclization to yield
fused thiazoles. Thus, treatment of the N-allyltriazole-
thione 6 with iodine in ethanol at room temperature
gave the thiazolo[2,3-c][1,2,4]triazole hydroiodide 7 [8]
(Scheme 2). The analogous bromide was obtained from
the reaction with bromine in chloroform.
2,3-dihydroimidazo[2,1-b]thiazoles 9 as crystalline prod-
ucts, with the exception of 9e (Scheme 3, Table 1).
The structure of products 9 was proved by means of
spectroscopic methods. For example, the 13C-NMR
spectrum of 9b showed the signals for three imidazole
C-atoms at 145.3, 141.7, and 133.6 ppm as well as two
triplets for CH2 groups at 49.3 and 7.3 ppm (assigned to
CH2N and CH2I, resp.), and a doublet for a CH group at
52.2 ppm.
To the best of our knowledge, there are no analogous
reactions with imidazoline thiones, described so far.
However, in the case of benzimidazoline-2-thiones, a
similar cyclization has been observed [9].
The presence of the iodomethyl group in compounds
9 enables further transformation with basic and nucleo-
philic agents. In fact, treatment of 9a with triethylamine
in ethanol afforded, after elimination of HI, the exo-
methylidene derivative 10a. Furthermore, the attempted
substitution of iodide with potassium cyanide, carried
out either in acetone or in ethanol, led to the same elim-
ination product 10a. On the other hand, the reaction of
9f with the enolizable 1,4,5-trimethylimidazoline-2-thi-
one (5g) in ethanol, led successfully to the sulfide 11 in
good yield (Scheme 4).
RESULTS AND DISCUSSION
In accordance with the known procedure [2], heating
of 1,3,5-triallylhexahydro-1,3,5-triazine (3a, R3 ¼ allyl)
and 3-(hydroxyimino)butan-2-one (2a, R1 ¼ R2 ¼ Me)
in ethanol gave the expected 1-allyl-4,5-dimethylimida-
zole N-oxide (1a) in 78% yield (Scheme 1, Table 1).
The imidazoline-2-thione 5a was prepared from 1a by
treatment with 0.5 mol equivalents of 4 in dichlorome-
thane at room temperature. The same procedures were
applied for the synthesis of 5b–5f.
Table 1
Solutions of the purified imidazoline-2-thiones 5 in
ethanol were treated with iodine at room temperature,
Synthesis of 1-allylimidazole N-oxides 1,1-allyl-1,3-dihydroimidazole-
2-thiones 5, and 2,3-dihydro-2-(iodomethyl)imidazo[2,1-b]thiazoles 9.
and the corresponding hydroiodides
8 precipitated
directly from the reaction mixture. The subsequent neu-
tralization with aqueous sodium acetate solution gave
Yield [%]
R1
R2
R3
1
5
9
Scheme 2
a
b
c
d
e
f
Me
MeCO
EtO2C
PhNHCO
Me
Me
Me
Me
Me
Ph
Alla
All
All
All
All
All
78
54
36
84
71
52
89
39c
76
36
65
61
74
39
52
77
b
Ph
Ph
73 [2a]
a All ¼ allyl.
b Not isolated in pure form.
c Overall yield starting from 3a via 1e.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010
Synthesis of 2,3-Dihydroimidazo[2,1-b]thiazole Derivatives via Cyclization
of N-Allylimidazoline-2-thiones
1289
Scheme 3
CONCLUSIONS
alkylation of 2-amino-1,3-thiazole with propargyl bro-
mide and subsequent cyclization are the key steps [11c].
In the light of the already reported approaches, our
method, presented in this article, enlarges the number of
synthetic tools for the preparation of new, diversely sub-
stituted imidazo[2,1-b]thiazoles. Of special importance
is the availability of differently substituted a-(hydroxy-
imino)ketones 2, which are key starting materials for the
presented multi-step procedure.
The presented study shows that treatment of the easily
available N-allyl-1,3-dihydroimidazole-2-thiones 5 with
iodine results in the cyclization leading to imidazo[2,1-
b]thiazole derivatives 9, bearing an iodomethyl group as
an additional reaction center. As selected transforma-
tions of these products, the elimination of HI and the
substitution with 1,4,5-trimethylimidazoline-2-thione, as
an example of an S-nucleophile, are presented.
The importance of imidazo[2,1-b]thiazoles is well
documented, as many derivatives of them display
diverse biological activities [10] (see also [11]). The
presented synthetic approach supplements the already
reported methods for the preparation of 2,3-dihydroimi-
dazo[2,1-b]thiazoles, which are based on reactions either
of appropriate imidazole or thiazole derivatives. In the
case of imidazole derivatives, the bis-alkylation of imid-
azoline-2-thiones with 1,2-dibromoethane was most fre-
quently applied [12]. Another approach is the thermal
cyclization of N-vinylimidazoline-2-thiones, which leads
to the aromatized fused system [13]. The non-aromat-
ized parent system was obtained via a formal vinyl
transfer reaction of the parent imidazoline-2-thione with
S-vinyl-S-(4-methylphenyl)-N-tosylimine [14]. The reac-
tions starting with 1,3-thiazole derivatives are described
to a comparable extent. As a typical example, the cyclo-
condensation of an a-bromoacetophenone with 2-amino-
1,3-thiazoles can be mentioned [11a]. A very recent
report deals with a multistep procedure, in which the
EXPERIMENTAL
Melting points were determined in capillaries using a Melt-
Temp II apparatus (Aldrich) and are uncorrected. IR Spectra
were recorded on a NEXUS FT-IR spectrophotometer as KBr
pellets; absorptions in cm–1. 1H- and 13C-NMR spectra were
measured on a Tesla BS567A (80 MHz) or Varian Gemini 200
(200 and 50 MHz, resp.) instrument or a Bruker AC 400
instrument (400 and 100 MHz, resp.) in a suitable solvent
(CDCl3, CD3OD or DMSO-d6); chemical shifts (d) were given
in ppm (TMS ¼ 0 ppm), coupling constants J in Hz. The mul-
tiplicity of the 13C signals was deduced from DEPT spectra.
The HRMS spectra were registered on a Finnigan MAT-95
instrument.
Synthesis of 4,5-disubstituted 1-allyl-1H-imidazole 3-
oxides (1a–f). In the cases of 1a, 1d, 1e, and 1f, the solution
of 1,3,5-triallylhexahydro-1,3,5-triazine (3a, 0.69g, 3.3 mmol)
and the corresponding a-(hydroxyimino)ketone of type 2 (10
mmol) in ethanol (15 mL) was refluxed for the required time
(ca. 3 h, TLC monitoring, silica gel, MeOH). The solvent was
removed under reduced pressure and the crude product was
Scheme 4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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M. Jasinski, G. Mloston, and H. Heimgartner
1290
Vol 47
washed several times with Et2O and purified thereby. In the
cases of 1b and 1c, a solution of 3a (0.94g, 4.5 mmol) in Et2O
(2 mL) was added to the magnetically stirred and cooled solu-
tion (water/ice external bath) of the corresponding a-(hydrox-
yimino)ketone 2 (10 mmol) in 5 mL Et2O. When the addition
was complete, the cooling bath was removed and the stirring
was continued for 24 h at room temperature. Then, the color-
less precipitate was filtered off and purified by flash chroma-
tography (SiO2). Acetone was used first as an eluent to remove
the remaining 2, followed by a mixture of ethyl acetate and
MeOH (1:1). Next, the same reaction was repeated using
recovered 2. The combined fractions of the crude product 1
were purified by recrystallization from an appropriate solvent.
The 1-allyl-4-methyl-5-phenyl-1H-imidazole 3-oxide (1e)
could not be obtained in pure form and, therefore, the crude
product was converted immediately into the corresponding im-
idazole-2-thione 5e. The protocol for the synthesis of thiones
of type 5, as well as spectroscopic and analytical data for 1-
allyl-4,5-diphenyl-1H-imidazole 3-oxide (1f), were already
reported [2a].
1-Allyl-4,5-dimethyl-1H-imidazole 3-oxide (1a). The crude
product was purified by flash chromatography on silica using
AcOEt with increasing amounts of MeOH (up to 1:1 ratio) to
give 1a in 78% yield (1.19 g). Light yellow semi-solid, hygro-
scopic. IR (KBr): m 3100–2900vs (br.), 1627m, 1443m, 1393s,
1378s, 1335s, 1187m, 1148m, 1004m, 926m. 1H-NMR (200
MHz, CDCl3): d 8.18 (s, 1H, HAC(2)); 5.91–5.72 (m, 1H,
ACH¼¼); 5.26–4.95 (m, 2H, ¼¼CH2); 4.37–4.34 (m, 2H,
ACH2A); 2.13, 2.06 (2s, 6H, 2Me). 13C-NMR (50 MHz,
CDCl3): d 131.3 (d, ACH¼¼); 126.3, 125.2 (2s, C(4), C(5));
121.3 (d, C(2)); 118,5 (t, ¼¼CH2); 47.8 (t, ACH2A); 8.3, 7.0
(2q, 2 Me). EI-HRMS: 152.0975 (Mþ, C8H12N2Oþ; calcd.
152.0950).
1565s, 1498m, 1447m, 1418m, 1309m, 1277m, 759m. 1H-
NMR (80 MHz, CDCl3): d 12.90 (s, 1H, NH); 7.88 (s, 1H,
HAC(2)); 7.77–7.61 (m, 2 arom. H); 7.44–6.99 (m, 3 arom.
H); 6.07–5.67 (m, 1H, ACH¼¼); 5.46–5.03 (m, 2H, ¼¼CH2);
4.52–4.42 (m, 2H, ACH2A); 2.63 (s, 3H, Me). 13C-NMR (50
MHz, CDCl3): d 157.2 (s, C¼¼O); 138.0, 131.7, 121.9 (3s, 1
C(Ph), C(4), C(5)); 130.2 (d, ACH¼¼); 128.9, 125.2, 124.1,
120.5 (4d, 5 CH(Ph), C(2)); 119.9 (t, ¼¼CH2); 47.8 (t,
ACH2A); 9.55 (q, Me). EI-HRMS: 257.1173 (Mþ,
C14H15N3O2þ; calcd. 257.1164).
Synthesis of 1,3,5-triallylhexahydro-1,3,5-triazine (3a). The
allylamine (50 mL, 38 g, 0.67 mol) was carefully dissolved in
methanol (80 mL) and cooled to 0ꢀC. Then, solid paraformal-
dehyde (21 g, 0.7 mol) was added in small portions, the
obtained suspension was allowed to reach r.t. and was stirred
overnight. Next day, the solvent was removed in vacuo and
the oil was short-path distilled at 95–100ꢀC/2 mm Hg to give
3a in 84% yield. All spectra of 3a corresponded with literature
data [15].
Synthesis of 4,5-disubstituted 1-allyl-2,3-dihydroimida-
zole-2-thiones (5a–f). To the magnetically stirred solution of
N-oxide 1 (10 mmol) in CH2Cl2 (30 mL), the solution of
2,2,4,4-tetramethylcyclobutane-1,3-dithione (4, 0.95 g, 5.5
mmol) in dichloromethane (8 mL) was added at 0ꢀC. After the
ice-bath was removed, stirring was continued overnight. The
solvent was removed to dryness, the residue was washed with
two portions of ether (10 mL each), and the crude product was
recrystallized from an appropriate solvent.
1-Allyl-2,3-dihydro-4,5-dimethylimidazole-2-thione (5a). Yield
1.40 g (84%). Light yellow crystals, mp 147–149ꢀC (CHCl3/
Et2O). IR (KBr): m 3166m, 3088s, 2949m, 2923m, 1661w,
1497m, 1431m, 1412m, 1397m, 1236m. 1H-NMR (200 MHz,
CDCl3): d 12.17 (br. s, 1H, NH); 6.16–5.69 (m, 1H, ACH¼¼);
5.30–4.92 (m, 2H, ¼¼CH2); 4.71–4.61 (m, 2H, ACH2A); 2.08,
2.04 (2s, 6H, 2 Me). 13C-NMR (50 MHz, CDCl3): d 157.5 (s,
C¼¼S); 131.7 (d, ACH¼¼); 121.3, 119.9 (2s, C(4), C(5)); 116.7
(t, ¼¼CH2); 46.3 (t, ACH2A); 8.7, 8.6 (2q, 2Me). EI-HRMS:
168.0726 (Mþ, C8H12N2Sþ; calcd. 168.0721).
4-Acetyl-1-allyl-5-methyl-1H-imidazole 3-oxide (1b). Yield
0.97 g (54%). Colorless crystals, mp 39–40ꢀC (CH2Cl2/Et2O).
IR (KBr): m 3117s, 1660vs, 1557s, 1420m, 1407m, 1333m,
1
1274m, 1145m, 950m, 731m. H-NMR (200 MHz, CDCl3): d
7.93 (s, 1H, HAC(2)); 6.15–5.68 (m, 1H, ACH¼¼); 5.46–5.04
(m, 2H, ¼¼CH2); 4.54–4.44 (m, 2H, ACH2A); 2.82 (s, 3H,
MeCO); 2.48 (s, 3H, Me). 13C-NMR (50 MHz, CDCl3): d
191.3 (s, C¼¼O); 132.0, 129.6 (2s, C(4), C(5)); 130.2 (d,
ACH¼¼); 125.6 (d, C(2)); 119.6 (t, ¼¼CH2); 47.6 (t, ACH2A);
30.6 (q, MeCO); 9.9 (q, Me). EI-HRMS: 180.0905 (Mþ,
C9H12N2O2þ; calcd. 180.0899).
4-Acetyl-1-allyl-2,3-dihydro-5-methylimidazole-2-thione
(5b). Yield 1.39 g (71%). Pale yellow crystals, mp 145–148ꢀC
(MeOH). IR (KBr): m 3150–2900vs, 1641vs, 1596m, 1492m,
1
1414s, 1385m, 1375m, 1353m, 1262m, 1177m. H-NMR (200
MHz, CDCl3): d 11.74 (br. s, 1H, NH); 5.90–5.71 (m, 1H,
ACH¼¼); 5.18–4.94 (m, 2H, ¼¼CH2); 4.79–4.29 (m, 2H,
ACH2A); 2.42, 2.40 (2s, 6H, 2 Me). 13C-NMR (50 MHz,
CDCl3): d 186.1 (s, C¼¼O); 162.2 (s, C¼¼S); 134.2, 124.2 (2s,
C(4), C(5)); 130.4 (d, ACH¼¼); 117.6 (t, ¼¼CH2); 46.3 (t,
ACH2A); 28.5 (q, MeCO); 10.9 (q, Me). EI-HRMS: 196.0681
(Mþ, C9H12N2OSþ; calcd. 196.0670).
Ethyl 1-allyl-2,3-dihydro-5-methyl-2-thioxoimidazole-4-car-
boxylate (5c). The crude product was purified by flash chro-
matography on silica using AcOEt to give 5c in 52% yield
(1.17 g). Colorless crystals, mp 146–148ꢀC (CHCl3/petroleum
ether). IR (KBr): m 3150–2900s (br.), 1698 vs, 1497m, 1462m,
1417s, 1372m, 1359m, 1267m, 1173m, 1158m, 1088m. 1H-
NMR (200 MHz, CDCl3): d 11.10 (br. s, 1H, NH); 6.01–5.82
(m, 1H, ACH¼¼); 5.28–5.04 (m, 2H, ¼¼CH2); 4.81–4.74 (m,
2H, ACH2A); 4.34 (q, J ¼ 7.1, 2H, MeCH2O); 2.47 (s, 3H,
Me); 1.38 (t, J ¼ 7.1, 3H, MeCH2O). 13C-NMR (50 MHz,
CDCl3): d 162.4 (s, C¼¼S); 158.6 (s, C¼¼O); 134.8, 115.5 (2s,
C(4), C(5)); 130.7 (d, ACH¼¼); 117.4 (t, ¼¼CH2); 60.8 (t,
Ethyl 1-allyl-5-methyl-3-oxido-1H-imidazole-4-carboxylate
(1c). The crude product was purified by flash chromatography
on silica using AcOEt with increasing amounts of MeOH (up
to 1:1 ratio) to give 1c in 36% yield (0.76 g). Colorless semi-
solid. IR (KBr): m 3150–2950s, 1706vs, 1458m, 1326m,
1
1285m, 1180m, 1091m, 742m. H-NMR (200 MHz, CDCl3): d
8.27 (s, 1H, HAC(2)); 6.03–5.84 (m, 1H, ACH¼¼); 5.36–5.06
(m, 2H, ¼¼CH2); 4.61–4.58 (m, 2H, ACH2A); 4.40 (q, J ¼
7.1, 2H, MeCH2O); 2.46 (s, 3H, Me); 1.39 (t, J ¼ 7.1, 3H,
MeCH2O). 13C-NMR (50 MHz, CDCl3): d 158.8 (s, C¼¼O);
131.8, 121.6 (2s, C(4), C(5)); 130.4 (d, ACH¼¼); 126.8 (d,
C(2)); 118.7 (t, ¼¼CH2); 60.5 (t, MeCH2O); 47.6 (t, CH2N);
13.8 (q, MeCH2O); 9.5 (q, Me). EI-HRMS: 210.1017 (Mþ,
C10H14N2O3þ; calcd. 210.1004).
1-Allyl-5-methyl-3-oxido-N-phenyl-1H-imidazole-4-carbox-
amide (1d). Yield 1.98 g (77%). Yellow solid, mp 115–117ꢀC
(CH2Cl2/Et2O). IR (KBr): m 3119m, 1664m, 1621s, 1598s,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Synthesis of 2,3-Dihydroimidazo[2,1-b]thiazole Derivatives via Cyclization
of N-Allylimidazoline-2-thiones
1291
MeCH2O); 46.3 (t, CH2N); 13.9 (q, MeCH2O); 9.9 (q, Me).
EI-HRMS: 226.0777 (Mþ, C10H14N2O2Sþ; calcd. 226.0776).
1-Allyl-2,3-dihydro-5-methyl-N-phenyl-2-thioxoimidazole-4-
carboxamide (5d). Yield 2.43 g (89%). Colorless solid, mp
259–262ꢀC (decomp.) (EtOH). IR (KBr): m 3252m, 3200–
2900s (br.), 1640vs, 1599m, 1533m, 1497m, 1447s, 1403m,
(ca. 5 mL), an aqueous solution (5%) of AcONa (20 mmol)
was added, and the solution was stirred for 30 min at room
temperature. The mixture was extracted with chloroform, the
combined organic phases were washed with an aqueous solu-
tion (10%) of Na2S2O3, dried (CaCl2), and after filtration the
solvent was evaporated. The crude product was purified by
flash chromatography on silica (CHCl3) to give 1.06 g (36%)
of 9a as a colorless solid; mp 83–86ꢀC (decomp., CHCl3). IR
(KBr): m 3010–2870vs (br.), 1585m, 1483s, 1452m, 1421m,
1
1362m, 761m. H-NMR (200 MHz, DMSO-d6): d 12.53, 9.56
(2br.s, 2H, 2 NH); 7.60–7.56 (m, 2 arom. H); 7.32–7.24 (m, 2
arom. H); 7.07–6.99 (m, 1 arom. H); 5.92–5.76 (m, 1H,
ACH¼¼); 5.12 (dd, J ¼ 10.4, 1.2, 1H); 4.92 (dd, J ¼ 17.2, 1.4,
1H); 4.66–4.64 (m, 2H, ACH2A); 2.38 (s, 3H, Me). 13C-NMR
(50 MHz, DMSO-d6): d 161.6, 156.5 (2s, C¼¼O, C¼¼S); 138.4,
133.4, 117.7 (3s, 1 C(Ph), C(4), C(5)); 131.9 (d, ACH¼¼);
128.8, 123.8, 119.7 (3d, 5 CH(Ph)); 116.8 (t, ¼¼CH2); 45.6 (t,
ACH2A); 9.9 (q, Me). EI-HRMS: 273.0940 (Mþ,
C14H15N3OSþ; calcd. 273.0936).
1-Allyl-2,3-dihydro-4-methyl-5-phenylimidazole-2-thione
(5e). The crude N-oxide 1e prepared according to the general
protocol was subsequently transformed into 5e by treatment
with 4 in CH2Cl2 solution [3]. Pure product was obtained by
flash chromatography on silica using acetone, then MeOH, in
39% overall yield (0.83 g). Colorless needles, mp 164–165ꢀC
1
1382m, 1367m, 1314m, 1227m, 1187m, 807m. H-NMR (200
MHz, CDCl3): d 4.42–4.29 (m, 1H); 4.00–3.85 (m, 2H); 3.45
(dd, J ¼ 10.2, 4.7, 1H); 3.31 (t, J ¼ 10.5, 1H); 2.02, 1.99 (2s,
6H, 2 Me). 13C-NMR (50 MHz, CDCl3): d 143.2, 137.8, 121.3
(3s, 3 C(imidazole)); 51.9 (d, CH); 49.4 (t, CH2N); 12.8, 8.8
(2q,
2
Me); 8.1 (t, CH2I). EI-HRMS: 293.9689 (Mþ,
C8H11IN2Sþ; calcd. 293.9688).
Selected Data for 8a. Yellow crystals. mp 146–149ꢀC
(decomp., EtOH). IR (KBr): 3054vs (br.), 2960–2870vs,
1
1646m, 1498m, 1442m, 1176m. H-NMR (80 MHz, CD3OD):
d 5.18–4.93 (m, 1H); 4.54 (dd, J ¼ 12.0, 7.7, 1H); 4.35 (dd, J
¼ 12.0, 4.0, 1H); 3.78 (s, 1H); 3.74 (d, J ¼ 5.8, 1H); 2.25 (s,
6H, 2 Me).
(EtOH). IR (KBr):
m
3150–2900vs (br.), 1599m, 1506s,
6-Acetyl-2,3-dihydro-2-iodomethyl-5-methylimidazo[2,1-b]thia-
zole (9b). Yield 2.09 g (65%). Yellow crystals, mp 152–153ꢀC
(EtOH). IR (KBr): m 1655vs, 1547s, 1492m, 1464m, 1411w,
1370s (br.), 1282m, 1212m, 1178m, 1158s, 951m, 548m. 1H-
NMR (400 MHz, CDCl3): d 4.52–4.45 (m, 1H); 4.13–4.04 (m,
2H); 3.54 (dd, J ¼ 10.4, J ¼ 4.0, 1H); 3.36 (t, J ¼ 10.8, 1H);
2.48, 2.42 (2s, 6H, 2 Me). 13C-NMR (100 MHz, CDCl3): d
195.0 (s, C¼¼O); 145.3, 141.7, 133.6 (3s, 3 C(imidazole)); 52.2
(d, CH); 49.3 (t, CH2N); 27.3 (q, MeCO); 11.2 (q, Me); 7.3 (t,
CH2I). EI-HRMS: 321.9648 (Mþ, C9H11IN2OSþ; calcd.
321.9637).
Selected data for 8b. Yellow needles, mp 178–180ꢀC
(EtOH). IR (KBr): m 3040–2750vs (br.), 1664vs, 1590m,
1525m, 1483m, 1412s, 1340m, 1303m, 1239m, 1179m. 1H-
NMR (400 MHz, DMSO-d6): d 5.01–4.94 (m, 1H); 4.50 (dd, J
¼ 12.0, 7.6, 1H); 4.25 (dd, J ¼ 12.0, 4.0, 1H); 3.79–3.71 (m,
2H); 2.53, 2.44 (2s, 6H, 2 Me).
Ethyl 2,3-dihydro-2-iodomethyl-5-methylimidazo[2,1-b]thia-
zole-6-carboxylate (9c). The crude 8c was suspended in etha-
nol (5 mL), an aqueous solution (5%) of AcONa (20 mmol)
was added, and the solution was stirred for 30 min at room
temperature. The mixture was extracted with few portions of
chloroform, the combined organic phases were washed with an
aqueous solution (10%) of Na2S2O3 and dried (CaCl2), and the
solvent was evaporated to give 9c in 61% overall yield (2.14
g). Colorless solid, mp 130–134ꢀC (decomp., CHCl3). IR
(KBr): m 1694vs, 1497s, 1459m, 1396m, 1376m, 1345m,
1195m, 1173s, 1157s, 1089m, 782m. 1H-NMR (400 MHz,
CDCl3): d 4.53–4.48 (m, 1H); 4.27 (q, J ¼ 7.2; MeCH2O);
4.15 (dd, J ¼ 11.6, 7.2, 1H); 4.05 (dd, J ¼ 11.6, 4.0, 1H);
3.53 (dd, J ¼ 10.4, 4.8, 1H); 3.38 (t, J ¼ 10.4, 1H); 2.46 (s,
3H, Me); 1.31 (t, J ¼ 7.0, MeCH2O). 13C-NMR (100 MHz,
CDCl3): d 163.1 (s, C¼¼O); 146.6, 135.0, 132.8 (3s, 3 C(imid-
azole)); 60.4 (t, MeCH2O); 52.2 (d, CH); 49.7 (t, CH2N); 14.4,
10.9 (2q, 2 Me); 7.8 (t, CH2I). EI-HRMS: 351.9779 (Mþ,
C10H13IN2O2Sþ; calcd. 351.9742).
1485m, 1424m, 1388m, 1243m, 1198m, 763m, 700m. 1H-
NMR (200 MHz, CDCl3): d 12.39 (br. s, 1H, NH); 7.46–7.40
(m, 3 arom. H); 7.32–7.27 (m, 2 arom. H); 5.95–5.76 (m, 1H,
ACH¼¼); 5.20–4.88 (m, 2H, ¼¼CH2); 4.62–4.58 (m, 2H,
ACH2A); 2.16 (s, 3H, Me). 13C-NMR (50 MHz, CDCl3): d
158.8 (s, C¼¼S); 132.1 (d, ACH¼¼); 130.2, 128.8, 128.7 (3d, 5
CH(Ph)); 128.3, 127.4, 122.2 (3s, 1 C(Ph), C(4), C(5)); 117.3
(t, ¼¼CH2); 46.9 (t, ACH2A); 9.3 (q, Me). EI-HRMS:
230.0882 (Mþ, C13H14N2Sþ; calcd. 230.0878).
1-Allyl-2,3-dihydro-4,5-diphenylimidazole-2-thione (5f). Yield
2.22 g (76%). Colorless crystals, mp 293–296ꢀC (EtOH). IR
(KBr): m 3100–2900vs (br.), 1508m, 1493s, 1482s, 1425m,
1397m, 1388m, 1238m, 1199m, 918m, 773s, 702s. 1H-NMR
(200 MHz, CDCl3): d 11.36 (br. s, 1H, NH); 7.48–7.43 (m, 3
arom. H); 7.35–7.31 (m, 2 arom. H); 7.24 (s, 5 arom. H);
5.93–5.77 (m, 1H, ACH¼¼); 5.18–4.89 (m, 2H, ¼¼CH2); 4.62–
4.57 (m, 2H, ACH2A). 13C-NMR (50 MHz, CDCl3): d 160.7
(s, C¼¼S); 131.9 (d, ACH¼¼); 134.2, 128.5, 127.4, 125.4 (4s, 2
C(Ph), C(4), C(5)); 131.1, 129.6, 129.1, 128.8, 128.0, 126.4
(6d, 10 CH(Ph)); 117.8 (t, ¼¼CH2); 47.1 (t, ACH2A). EI-
HRMS: 292.1047 (Mþ, C18H16N2Sþ; calcd. 292.1034).
Synthesis of 5,6-disubstituted 2,3-dihydro-2-(iodomethyl)-
imidazo[2,1-b]thiazoles (9a–f). To a solution (or suspension)
of the corresponding imidazoline-2-thione 5 (10 mmol) in dry
ethanol (ca. 20 mL), an equimolar amount of nicely powdered
iodine (2.54 g) was added in small portions, and vigorous stir-
ring was continued for 24 h at room temperature. The resulting
mixture was cooled and the yellow precipitate of crude 8 was
filtered off. After evaporation of the solvent, the residue was
washed with few portions of ether, filtered off and combined.
If necessary, the crude hydroiodide 8 was recrystallized from
hot EtOH. The obtained salt was suspended in ethanol (ca. 10
mL), an aqueous solution (5%) of AcONa (1.64 g, 20 mmol)
was added, and stirring was continued for 1 h at room temper-
ature. The resulting product 9 was filtered off and crystallized
from an appropriate solvent.
2,3-Dihydro-2-iodomethyl-5-methyl-N-phenylimidazo[2,1-b]
thiazole-6-carboxamide (9d). Yield 2.97 g (74%). Colorless
crystals, mp 195–203ꢀC (decomp., EtOH). IR (KBr): m 3281m,
2,3-Dihydro-2-iodomethyl-5,6-dimethylimidazo[2,1-b]thiazole
(9a). The isolated hydroiodide 8a was dissolved in ethanol
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

´ ´
M. Jasinski, G. Mloston, and H. Heimgartner
1292
Vol 47
1656s, 1593s, 1569m, 1523s, 1490s, 1440s, 1385m, 1301m,
1235m, 1189m, 1173m, 756m. 1H-NMR (200 MHz, DMSO-
d6): d 9.68 (br s, 1H, NH); 7.84–7.80 (m, 2 arom. H); 7.34–
7.26 (m, 2 arom. H); 7.07–7.00 (m, 1 arom. H); 4.86–4.80 (m,
1H); 4.36 (dd, J ¼ 11.6, 7.6, 1H); 4.05 (dd, J ¼ 11.6, 4.8,
1H); 3.75–3.65 (m, 2H); 2.53 (s, 3H, Me). 13C-NMR (50
MHz, CDCl3): d 161.1 (s, C¼¼O); 144.5, 139.0, 134.3, 132.6
(4s, 1 C(Ph), 3 C(imidazole)); 128.5, 122.9, 119.7 (3d, 5
CH(Ph)); 53.2 (d, CH); 49.1 (t, CH2N); 10.4 (t, CH2I); 10.2
(q, Me). EI-HRMS: 398.9917 (Mþ, C14H14IN3OSþ; calcd.
398.9902).
142.5, 137.3, 121.4 (4s, 4 C); 107.9 (t, ¼¼CH2); 49.8 (t, CH2);
12.9, 8.9 (2q, 2 Me).
6-Acetyl-2,3-dihydro-5-methyl-2-methylidenimidazo[2,1-b]
thiazole (10b). Yield 0.12 g (62%). Mp 82–85ꢀC (CH2Cl2/
hexane). IR (KBr): m 1656vs, 1631m, 1550s, 1499m, 1460m,
1379s, 1356m, 1187m, 1166m, 951m, 891m. 1H-NMR (400
MHz, CDCl3): d 5.40 (q-like, J ꢁ 2.3, 1H); 5.31 (q-like, J ꢁ
2.7, 1H); 4.70 (t, J ¼ 2.4, 2H); 2.44, 2.41 (2s, 6H, 2 Me). 13C-
NMR (100 MHz, CDCl3): d 195.0 (s, C¼¼O); 144.9, 141.0,
140.5, 137.2 (4s, 4 C); 109.5 (t, ¼¼CH2); 49.2 (t, CH2); 27.3
(q, MeCO); 11.0 (q, Me). EI-HRMS: 194.0529 (Mþ,
C9H10IN2OSþ; calcd. 194.0515).
2,3-Dihydro-2-iodomethyl-6-methyl-5-phenylimidazo[2,1-b]
thiazole (9e). Workup analogous to that described for 9a gave
1.39 g (39%) of 9e as a colorless semi-solid after column
Synthesis of 2,3-dihydro-5,6-diphenyl-2-{[(1,4,5-trimethyl-1H-
imidazol-2-yl)sulfanyl]methyl}imidazo[2,1-b]thiazole
(11). A
chromatography (silica, CHCl3/AcOEt 9:1). IR (KBr):
m
mixture of equimolar amounts of 9f (0.8 g, 1.9 mmol) and
1,4,5-trimethyl-2,3-dihydroimidazole-2-thione (5g, 0.27 g, 1.9
mmol) in ethanol (10 mL) was heated to reflux for 48 h. Then,
half of the solvent was evaporated, the resulting solution
treated with AcONa (0.35g, 5% aqueous solution), vigorously
stirred, and extracted with CHCl3 (3 ꢂ 10 mL). The combined
organic phases were dried (CaCl2), filtered, and the solvent
was evaporated to dryness. The resulting solid was purified by
column chromatography (silica, CHCl3/AcOEt 1:1) to give
0.26 g (32%) of 11 as a colorless solid. Mp 155–157ꢀC (ace-
tone). IR (KBr): m 2920m, 1602m, 1504m, 1477m, 1458s,
1441s, 1394m, 1335m, 1123m, 769m, 697s. 1H-NMR (400
MHz, CDCl3): d 7.41–7.07 (m, 10 arom. H); 4.55–4.50 (m,
1H); 4.22 (dd, J ¼ 11.6, 6.8, 1H); 4.07 (dd, J ¼ 11.6, 4.8,
1H); 3.70–3.62 (m, 1H); 3.45 (s, 3H, MeN); 3.36 (dd, J ¼
14.0, 7.2, 1H); 2.13, 2.07 (2s, 6H, 2 Me). 13C-NMR (100
MHz, CDCl3): d 147.4, 142.4, 136.1, 134.4, 132.3, 130.4,
127.6, 126.4 (8s, 8 C); 129.1, 129.0, 128.3, 128.2, 126.9,
126.7 (6d, 10 CH(Ph)); 52.0 (d, CH); 49.9, 39.4 (2t, 2 CH2);
1603m, 1492m, 1474m, 1457s, 1423m, 1376m, 764m, 700m.
1H-NMR (200 MHz, CDCl3): d 7.49–7.42 (m, 2 arom. H);
7.36–7.29 (m, 3 arom. H); 4.54–4.41 (m, 1H); 4.18 (d, J ¼
5.2, 2H); 3.61–3.41 (m, 2H); 2.28 (s, 3H, Me). 13C-NMR (50
MHz, CDCl3): d 146.2, 140.1, 130.7, 129.7 (4s, C(Ph), 3
C(imidazole)); 128.8, 127.7, 127.3 (3d, 5 CH(Ph)); 52.2 (d,
CH); 51.2 (t, CH2N); 14.0 (q, Me); 7.7 (t, CH2I). EI-HRMS:
355.9851 (Mþ, C13H13IN2Sþ; calcd. 355.9844).
Selected data for 8e. Pale yellow solid, mp 108–109ꢀC
(decomp., CHCl3). IR (KBr): m 3000–2450vs (br.), 1624m,
1598m, 1504m, 1515m, 1200m, 766m, 749m, 701m. H-NMR
1
(80 MHz, CDCl3): d 7.51 (s, 5 arom. H); 5.37–5.04 (m, 1H);
4.69 (dd, J ¼ 12.0, 7.2, 1H); 4.28 (dd, J ¼ 12.0, 4.0, 1H);
4.01–3.75 (m, 2H); 2.43 (s, 3H, Me).
2,3-Dihydro-2-iodomethyl-5,6-diphenylimidazo[2,1-b]thiazole
(9f). Yield 2.17 g (52%). Colorless solid, mp 173–176ꢀC
(decomp., EtOH). IR (KBr): m 1600m, 1504m, 1475s, 1456m,
1441m, 1336m, 1123w, 965w, 772s, 700s. 1H-NMR (400
MHz, CDCl3): d 7.52–7.33 (m, 7 arom. H); 7.28–7.17 (m, 3
arom. H); 4.57–4.50 (m, 1H); 4.20 (dd, J ¼ 11.6, 6.8, 1H);
4.13 (dd, J ¼ 11.6, 4.0, 1H); 3.61 (dd, J ¼ 10.4, 4.8, 1H);
3.53 (t, J ¼ 10.6, 1H). 13C-NMR (100 MHz, CDCl3): d 147.2,
142.2, 134.0, 130.2, 127.0 (5s, 2 C(Ph), 3 C(imidazole));
130.8, 129.2, 129.1, 128.5, 128.3, 126.9 (6d, 10 CH(Ph)); 52.4
(d, CH); 51.2 (t, CH2N); 7.7 (t, CH2I). EI-HRMS: 418.0009
(Mþ, C18H11IN2OSþ; calcd. 418.0002).
31.6, 11.5, 9.1 (3q,
C24H24N4S2þ; calcd. 432.1442).
3
Me). EI-HRMS: 432.1453 (Mþ,
Acknowledgments. The authors thank the Rector of the Univer-
´ ´
sity of Łodz for generous support (University Grant # 505/0712)
and Dr. E. Rocker (JLU Giessen) for his help in registration of the
¨
HRMS spectra. Financial support by F. Hoffmann-La Roche AG,
Basel, is gratefully acknowledged.
Selected data for 8f. Pale yellow solid, mp 212–218ꢀC
(decomp., EtOH). IR (KBr): m 3050–2700vs (br.), 1514s,
1443m, 1173m, 1100m, 769s, 733m, 698s. H-NMR (80 MHz,
1
REFERENCES AND NOTES
CDCl3): d 7.52, 7.38 (2s, 10 arom. H); 5.19–4.94 (m, 1H);
4.65 (dd, J ¼ 12.0, 7.4, 1H); 4.32 (dd, J ¼ 12.0, 4.5, 1H);
3.83 (d, J ¼ 6.4, 2H).
[1] Presented these results at the 22nd International Congress
on Heterocyclic Chemistry, St. John’s, Canada, August 2-7, 2009.
´ ´
[2] (a) Mloston, G.; Jasinski, M.; Linden, A.; Heimgartner, H.
Synthesis of 5,6-disubstituted 2,3-dihydro-2-methyliden-
imidazo[2,1-b]thiazoles (10). To a solution of 9 (1.0 mmol) in
ethanol (5 mL), freshly distilled Et3N (3.0 mmol, 0.30 g) was
added and the resulting solution was refluxed for 3 h. The
mixture was cooled to room temperature, filtered through a
Celite plug, and the solvents were evaporated. Purification by
flash chromatography (silica, CHCl3) gave pure substance.
2,3-Dihydro-5,6-dimethyl-2-methylidenimidazo[2,1-b]thiazole
(10a). Yield 53 mg (32%). Mp 107–110ꢀC (CHCl3). Decom-
poses during the storage at room temperature. IR (KBr): m
2922s (br.), 1624m, 1482s, 1443s, 1374m, 1304m, 1266m,
´
Helv Chim Acta 2006, 89, 1304; (b) Mloston, G.; Mucha, P.; Urba-
niak, K.; Broda, K.; Heimgartner, H. Helv Chim Acta 2008, 91, 232;
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(c) Mucha, P.; Mloston, G.; Jasinski, M.; Linden, A.; Heimgartner, H.
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Tetrahedron: Asymmetry 2008, 19, 1600; (d) Jasinski, M.; Mloston,
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(e) Mloston, G.; Mucha, P.; Tarka, R.; Urbaniak, K.; Linden, A.;
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Heimgartner, H. Pol J Chem 2009, 83, 1105; (f) Mloston, G.; Roman-
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[3] Mloston, G.; Gendek, T.; Heimgartner, H. Helv Chim Acta
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1
1170m, 862m. H-NMR (200 MHz, CDCl3): d 5.39 (q-like, J
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2.11 (s, 6H, 2 Me). 13C-NMR (50 MHz, CDCl3): d 142.9,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010
Synthesis of 2,3-Dihydroimidazo[2,1-b]thiazole Derivatives via Cyclization
of N-Allylimidazoline-2-thiones
1293
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DOI 10.1002/jhet