Reaction of carbon disulfide with 2-bromoimidazolium salts. Novel bicyclic mesoionic thiazolo[3,2-a]imidazoles

Article abstract of DOI:10.1016/j.tetlet.2013.08.006

A new class of thiazolo[3,2-a]imidazole derivatives is obtained in good yields, by reacting 1-methyl-2-bromoimidazolium salts bearing N ⁺-CH₂COAr, N⁺-CH₂COMe, N ⁺-CH₂COOMe, or N⁺-CH₂CN fragments, with carbon disulfide in the presence of Et₃N at room temperature. The mesoionic structures of these compounds are established by NMR spectroscopy and by single-crystal X-ray analysis.

Full text of DOI:10.1016/j.tetlet.2013.08.006

Tetrahedron Letters 54 (2013) 5605–5607
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reaction of carbon disulfide with 2-bromoimidazolium salts. Novel
bicyclic mesoionic thiazolo[3,2-a]imidazoles
Sana Zama a, Abdelmalek Bouraiou a, Sofiane Bouacida b, Thierry Roisnel c, Ali Belfaitah a,
⇑
a Laboratoire des Produits Naturels d’Origine Végétale et de Synthèse Organique, Faculté des Sciences Exactes, Campus de Chaabat Ersas, Université Constantine 1, 25000,
Constantine, Algeria.
b Unité de Recherche de Chimie de l’Environnement et Moléculaire Structurale, Université Constantine 1, 25000, Constantine, Algeria
c Centre de Diffractométrie X, Sciences Chimiques de Rennes, UMR 6226 CNRS, Université de Rennes I, 35042 Rennes CEDEX, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A new class of thiazolo[3,2-a]imidazole derivatives is obtained in good yields, by reacting 1-methyl-2-
bromoimidazolium salts bearing N+-CH2COAr, N+-CH2COMe, N+-CH2COOMe, or N+-CH2CN fragments,
with carbon disulfide in the presence of Et3N at room temperature. The mesoionic structures of these
compounds are established by NMR spectroscopy and by single-crystal X-ray analysis.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 5 May 2013
Revised 22 July 2013
Accepted 1 August 2013
Available online 9 August 2013
Keywords:
2-Bromoimidazole
Bicyclic heterocycle
Thiazolo[3,2-a]imidazolium salts
Mesoionic heterocycles
Crystal structure
N-Phenacyl-2-halogenopyridinium salts I are useful intermedi-
ates for the synthesis of bicyclic heterocycles with a bridgehead
nitrogen atom,1 in particular imidazo[1,2-a]pyridinium salts II,2
oxazolo[3,2-a]pyridinium salts III,3 and thiazolo[3,2-a]pyridines
IV (Fig. 1).4
The use of heteroanalogs of salts I, with a different heterocyclic
ring (thiazolium or isoquinolinium) and/or heteroatoms instead of
halogen was successful.5 However, the reactivity of N-phenacyl-2-
halogenoimidazolium salts 1 has not been studied.
Note that no purification was needed and compounds 1a–g
were isolated in moderate to good yields (47–95%) by simple filtra-
tion after reducing the solvent volume.
Next, inspired by the work of Babaev et al.,7 the action of carbon
disulfide, in the presence of triethylamine, was evaluated on
N-phenacyl-2-bromoimidazolium bromide (1a) (EWG = COC6H5)
as a model reaction.8 The results showed that the starting material
had been consumed (TLC) (Table 1, entry 1) after 30 min.
In continuation of our ongoing program related to the synthesis
of imidazolium salts,6 we report herein the reaction of N-phenacyl-
2-bromoimidazolium bromide (1) with carbon disulfide in the
presence of triethylamine. In addition, this work was extended to
analogs with N+-CH2COMe, N+-CH2COOMe, and N+-CH2CN
fragments.
II (X=N)
Ar III (X=O)
IV (X=S)
Hal
X
Ar
N
N
O
I
Following the standard methodology,6a compounds 1a–d were
obtained in good yields by reacting 1-methyl-2-bromoimidazole
with 1.5 equiv of different 2-bromoacetophenones at reflux in
acetonitrile (Scheme 1). In a similar manner, when 1.2 equiv of
bromoacetone, methyl bromoacetate, or bromoacetonitrile was
used as quaternization agents, the imidazolium compounds 1e–g
were obtained.
Figure 1. Bicyclic heterocycles with a bridgehead nitrogen atom.
Br
N
S
Me
Br
N
S
Me
Me
Br
EWG
N
ii
i
N
N
N
EWG
EWG= COAr, COMe, CO2Me, CN
1a-g
2a-g
⇑
Scheme 1. Reagents and conditions: (i) BrCH2EWG (1.2–1.5 equiv), MeCN, reflux,
12 h; (ii) CS2, Et3N, MeCN, 3 h (Ar is defined in Table 1).
Corresponding author. Tel/fax: +213 (0) 31 81 88 62.
E-mail address: abelbelfaitah@yahoo.fr (A. Belfaitah).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.006

5606
S. Zama et al. / Tetrahedron Letters 54 (2013) 5605–5607
Table 1
The mesoionic thiazolo[3,2-a]imidazoles prepared
Product
Structure
Yielda (%)
64
Me
N
S
S
S
S
S
S
2a
N
O
O
O
O
Me
Me
Me
N
N
N
Me
Cl
2b
2c
2d
2e
79
N
Figure 2. ORTEP plot of the X-ray crystal structure of 1a and the atomic numbering
scheme (thermal ellipsoids are drawn at the 50% probability level).10
S
55
81
55
N
S
N
Me
S
Me
Me
Me
S
S
N
N
N
N
O
O
S
Figure 3. ORTEP plot of the X-ray crystal structure of 2a and the atomic numbering
scheme (thermal ellipsoids are drawn at the 50% probability level).10
2f
46
82
N
OMe
Table 2
S
S
Selected bond lengths for characterized compounds 1a and 2a
2g
N
Bonds length (Å)
1a
2a
CN
C1–N1
N1–C2
C2–N2
N2–C4
C4–C5
C5–N1
N2–C6
C6–C7
C7–O1
C7–C9
C2–Br1
C6–C8
C8–S1
C2–S1
C8–S2
1.460(5)
1.330(5)
1.332(5)
1.376(5)
1.344(6)
1.383(5)
1.457(5)
1.511(5)
1.217(4)
1.477(5)
1.851(4)
—
1.467(3)
1.346(3)
1.342(3)
1.391(3)
1.349(3)
1.378(3)
1.434(3)
1.440(3)
1.243(3)
1.494(3)
—
a
Yields of isolated pure products.
7-Methyl-3-benzoylthiazolo[3,2-a]imidazolium-2-thiolate
was obtained in 64% yield.
(2a)
To demonstrate the efficiency and the scope of the present
method, we performed the cyclocondensation reaction using
substrates with different electron-withdrawing groups. As shown
in Table 1, substrates containing a substituted benzoyl (1a–d),
acetyl (1e), ester (1f), or nitrile (1g), gave the corresponding prod-
ucts 2a–g in moderate to high yields under the same reaction
conditions.
1.405(3)
1.804(2)
1.710(3)
1.673(3)
—
—
—
By analogy to the previously reported mechanism,7 the CH2
group bearing the electron-withdrawing group in imidazolium
salts 1 reacts as a nucleophile with carbon disulfide to give an
enethiol betaine that, via intermolecular heterocyclization, re-
places the halogen atom at position 2 in the imidazole ring, afford-
ing this new class of thiazolo[3,2-a]imidazolium-2-thiolates.
The structure of compound 2a, as a representative example, was
elucidated by detailed NMR studies.8 Unlike the 1H NMR spectrum
of starting imidazolium salt 1a,9 no signal for the methylene group
protons (–CH2COAr) was detected for 2a. At the same time, no sig-
nificant differences were observed in the chemical shifts of the aro-
matic protons. However, comparison of the 13C NMR spectra of
compounds 1a and 2a showed a significant difference at C6. Thus
for the imidazolium salt 1a, the signal for C6 was detected at
56.6 ppm, while for compound 2a, it appeared in the region of
139.3 ppm.
The molecular structures of 1a and the bicyclic heterocycle with
a bridgehead nitrogen atom 2a, were established by single crystal
X-ray diffraction analyses.
Suitable crystals of 1a and 2a for X-ray experiments were ob-
tained by slow evaporation from, respectively, methanol/CHCl3
and ethanol/CH2Cl2 solutions at room temperature. The structures
of compounds 1a and 2a are shown in Figures 2 and 3, and selected
bond lengths for 1a and 2a are presented in Table 2.
The crystal structure of mesoionic compound 2a was compared
with the precursor 1a. Examination showed that the bond lengths
of C1–N1, N1–C2, C2–N2, and N2–C4 in 2a were longer than in
compound 1a. However, the two C–N bond lengths, N2–C6
(1.434(3) Å) and C5–N1 (1.378(3) Å) in 2a were shorter than the
corresponding bonds in 1a (N2–C6 (1.457(5) Å) and C5–N1
(1.383(5) Å). It is interesting to note that the C6–C7 bond length
in compound 2a (1.440(3) Å) was shorter than the corresponding
The structures of products 2b–g were established by analogy
and by comparison of their 1H NMR and 13C spectra with those
of compound 2a.

S. Zama et al. / Tetrahedron Letters 54 (2013) 5605–5607
5607
spectroscopy and X-ray crystallographic analysis confirmed the
structures. A key feature of the reactivity of 1 is the ability to easily
replace the halogen atom at C2 via nucleophilic substitution. The
simplicity of the present procedure makes it an interesting alterna-
tive to other approaches.
Me
S
S
N
N
O
2
Acknowledgments
S
Me
S
S
Me
S
N
N
We thank MESRS (Ministère de l’Enseignement Supérieur et de
la Recherche Scientifique) and ATRST (Agence Thématique de
Recherche en sciences et technologie), Algeria, for financial
support.
N
N
O
O
B
A
References and notes
S
Me
S
N
1. (a) Babaev, E. V. Rev. J. Chem. 2011, 1, 161. and references cited therein; (b)
Khoroshilov, G. E. Chem. Heterocycl. Compd. 2001, 37, 1141.
N
2. (a) Bradsher, C. K.; Brandau, R. D.; Boilek, J. E.; Hough, T. L. J. Org. Chem. 1969,
34, 2129; (b) Hand, E. S.; Paudler, W. W. J. Org. Chem. 1978, 43, 658; (c)
Demchenko, A. M.; Chumakov, V. A.; Nazarenko, K. G.; Krasovskii, A. N.;
Pirozhenko, V. V.; Lozinskii, M. O. Khim. Geterotsikl. Soedin. 1995, 5, 644.
3. Bradsher, C. K.; Zinn, M. J. Heterocycl. Chem. 1967, 4, 66.
4. Blank, B.; DiTullio, N. W.; Krog, A. J.; Saunders, H. L. J. Med. Chem. 1978, 21, 489.
5. (a) Duchardt, K. H.; Kröhnke, F. Liebigs Ann. Chem. 1977, 1692; (b) Babaev, E. V.;
Nasonov, A. F. ARKIVOC 2001, ii, 139; (c) Liebscher, J.; Hassoun, A. Synthesis
1988, 816.
6. (a) Bahnous, M.; Bouraiou, A.; Chelghoum, M.; Bouacida, S.; Roisnel, T.; Smati,
F.; Bentchouala, C.; Gros, P. C.; Belfaitah, A. Bioorg. Med. Chem. Lett. 2013, 23,
1274; (b) Bahnous, M.; Bouraiou, A.; Bouacida, S.; Roisnel, T.; Belfaitah, A. Acta
Crystallogr. 2012, E68, o1391; (c) Chelghoum, M.; Bahnous, M.; Bouacida, S.;
Roisnel, T.; Belfaitah, A. Acta Crystallogr. 2011, E67, o1890.
O
C
Figure 4. Resonance structures A and B, and ylide character C of compound 2.
bond in compound 1a (1.511(5) Å). The bond lengths of the phenyl
ring and C4–C5 in the imidazole ring were almost unchanged.
The distribution of single and double bonds in the bicyclic
7-methyl-3-(benzoyl)thiazolo[3,2-a]imidazolium-2-
thiolate (2a) was established by analogy with other similar
compound,
7. Babaev, E. V.; Rybakov, V. B.; Orlova, I. A.; Bush, A. A.; Maerle, K. V.; Nasonov, A.
F. Russ. Chem. Bull. Int. Ed. 2004, 53, 176.
structures.7,11
8. General procedure for the synthesis of thiazolo[3,2-a]imidazoles 2: Et3N (2 mL)
was added, under vigorous stirring to a suspension of imidazolium salt 1
(1.0 mmol) and CS2 (1 mL) in CH3CN (5 mL). The mixture was kept at room
temperature for 30 min (monitored by TLC). The product formed was isolated
as a yellow solid by simple filtration using a Büchner funnel and was washed
with 5 mL THF/H2O (1:1) mixture. The filtrate was concentrated under reduced
pressure, H2O (5 mL) was added and the residue was extracted with CHCl3
(3 Â 10 mL). The extracts were collected, washed with H2O (15 mL) and brine
(15 mL), dried over anhydrous Na2SO4, and the solvent evaporated under
vacuum. Purification by silica gel flash column chromatography (EtOAc),
afforded an additional 5–10% of the product. (yield: 64% for 2a), mp = 192 °C.
Selected data for 2a: 1H NMR (250 MHz, DMSO-d6) d 8.20 (d, J = 2.1 Hz, 1H),
7.89 (d, J = 2.1 Hz, 1H), 7.73–7.69 (m, 2H, Ar), 7.51–7.34 (m, 3H, Ar), (3.96, 3H,
N–CH3); 13C NMR (62.9 MHz, DMSO-d6) d 184.6 (C@O), 173.4 (C), 139.3 (C),
138.9 (C), 131.5 (CH), 129.3 (2 Â CH), 128.0 (2 Â CH), 126.2 (CH) 119.6 (C),
116.8 (CH), 35.7 (N–CH3).
The crystallographic structure of compound 2a shows that the
new heterocyclic compound possesses a bicyclic skeleton with
fused thiazole-imidazolium rings. The bicyclic thiazolo[3,2-a]imid-
azole fragment is approximately planar and forms a dihedral angle
of a 59.16(5)° with the phenyl ring. The carbonyl group is twisted
by 53.11(9)° with respect to the benzene ring. Consequently, the
carbonyl group is not conjugated with the phenyl fragment.
In the thiazole fragment, the C2–S1 bond (1.710(3) Å) is shorter
than the C8–S1 bond (1.804(2) Å), which indicates the electron
delocalization in the thiazole ring. The C2–S1 bond is conjugated
with the lone electron pair of the bridging nitrogen atom N2,
whereas the C8–S1 bond is not affected by any conjugation.
Therefore, it is more correct to view the structure of 2 as a
combination of the two resonance contributors A and B with
alternating single and double bonds. Thus, the delocalization takes
place between N2+@C2–S1 and N2–C2@S1+fragments of the five-
membered ring (Fig. 4).
The exocyclic C8–S2 bond has the shortest length (1.673(3) Å)
and has, in fact, pronounced double bond character (Table 2). Thus,
it is incorrect to represent the mesoionic system as a structure with
a single C8–S2 bond and the negative charge on the S2 atom.
Consequently, the ylide character C of compound 2 (Fig. 4) and
the localization of the negative charge on the C6 atom is a more
adequate representation (Fig. 4).
9. Selected data for 1a: 1H NMR (250 MHz, DMSO-d6) d 8.12–8.07 (m, 3H, Ar), 7.96
(s, 1H, Ar), 7.79 (t, J = 7.2 Hz, 1H, Ar), 7.65 (t, J = 7.3 Hz, 2H, Ar), 6.18 (s, 2H, N–
CH2), 3.92 (s, 3H, N–CH3); 13C NMR (62.9 MHz, DMSO-d6) d 190.8 (C@O), 135.3
(C), 133.7 (CH), 129.6 (2 Â CH), 128.0 (2 Â CH), 125.5 (CH), 125.4 (CH), 125.2
(C), 56.6 (N–CH2), 37.6 (N–CH3).
10. Crystal structure analysis for 1a: C12H12Br2N2O, Mr = 360.06 g molÀ1
,
monoclinic, space group
P
21/a, a = 10.1113(7) Å, b = 13.8160(11) Å,
c = 10.4189(8) Å, b = 114.006(4)°, V = 1329.60(17) Å3, Z = 4,
q
c = 1.799 g cmÀ3
,
F(000) = 704, crystal size: 0.54 Â 0.42 Â 0.36 mm. Crystal structure analysis
for 2a: C13H10N2OS2, Mr = 274.35 g molÀ1, monoclinic, space group P 21/a,
a = 7.8709(8) Å,
b = 13.3757(12) Å,
c = 12.0879(13) Å,
b = 106.270(4)°,
V = 1221.6(2) Å3, Z = 4,
q
c = 1.492 g cmÀ3
,
F(000) = 568, crystal size:
0.24 Â 0.07 Â 0.06 mm. Crystallographic data (excluding structure factors) for
these compounds have been deposited at the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC 923502 for 1a and CCDC
923503 for 2a. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif./cif.
11. (a) Newton, C. G.; Ramsden, C. A. Tetrahedron 1982, 38, 2965; (b) Babaev, E. V.;
Bush, A. A.; Orlova, I. A.; Rybakov, V. B.; Zhukov, S. G. Tetrahedron Lett. 1999, 40,
7553.
In conclusion, we have found that 1-methyl-2-bromoimidazoli-
um salts bearing a –CH2COAr, –CH2COMe, –CH2COOMe, or –CH2CN
fragment at the quaternary nitrogen, react with carbon disulfide in
the presence of Et3N at room temperature to form a previously
unknown class of thiazolo[3,2-a]imidazoles. 1H and 13C NMR