A Novel and Convenient Approach to 2-Unsubstituted Imidazolium and Thiazolium Salts

Article abstract of DOI:10.1055/s-2003-42100

The selective reductive cleavage of highly functionalized 5-(tert-butylamino)-2-(phenylthio)thiazolium chlorides and mesoionic 2-(phenylthio)thiazolium-5-thiolates has been effected efficiently at room temperature using an excess of PhSH in the presence of Et₃N to give the corresponding 2-unsubstituted imidazolium and thiazolium-5-thiolates. The NaBH₄ reduction of 2-(methylthio)imidazolium chlorides and the H ₂O₂ treatment of a thiazoline-2-thione are also reported.

Full text of DOI:10.1055/s-2003-42100

LETTER
2167
A Novel and Convenient Approach to 2-Unsubstituted Imidazolium and
Thiazolium Salts
U
nsubstituted Imid
e
azolium an
o
d Thiazolium
r
Salts ges Morel*
Synthèse et Electrosynthèse Organiques, UMR 6510, Université de Rennes I, Campus de Beaulieu, 35042 Rennes Cedex, France
Fax +33(223)236738; E-mail: Georges.Morel@univ-rennes1.fr
Received 19 June 2003
results of such investigation are described in the present
paper.
Abstract: The selective reductive cleavage of highly functional-
ized 5-(tert-butylamino)-2-(phenylthio)thiazolium chlorides and
mesoionic 2-(phenylthio)thiazolium-5-thiolates has been effected
efficiently at room temperature using an excess of PhSH in the pres-
ence of Et3N to give the corresponding 2-unsubstituted imidazolium
and thiazolium-5-thiolates. The NaBH4 reduction of 2-(methylth-
io)imidazolium chlorides and the H2O2 treatment of a thiazoline-2-
thione are also reported.
NaBH4 treatment in EtOH solution of thiazolium cations
possessing a piperidino or a thio group at the 2-position
produced either the 2-piperidino-2,3-dihydrothiazoles8 or
the 2-unsubstituted thiazolidines.7,9 An attempt to remove
the phenylthio substituent of 2a (R = Me) under identical
conditions resulted in the ring-opening of the reduced thi-
azolium salt via the a-aminothioamide 4. In contrast to
these observations, NaBH4 induced a selective cleavage
of the C–S bond of the 2-(methylthio)imidazolium chlo-
ride 1 to afford the expected salt 5 in moderate yield.10
Key words: thiazoles, imidazoles, mesoionic compounds, reduc-
tion
Thiazolium cations, which are active moieties of thiamine
(vitamin B1), have attracted great interest in recent years
from both chemical and biological viewpoints. Especial-
ly, the reactivities of the C-2 acidic proton and the nucleo-
philic carbene character of intermediates formed by this
proton abstraction have been discussed for a long time.1
Conjugated bases are now recognized to be of particular
importance for access to dimeric 2,2¢-bithiazolinylidenes
(dithiadiazafulvalenes)1–3 which are excellent p-donor or-
ganic materials. Deprotonation of 2-unsubstituted imida-
zolium salts has also received considerable attention on
account of the possible isolation of corresponding bases.4
Such carbenoid species appear to be more reluctant to pro-
duce 2,2¢-biimidazolinylidenes (tetraazafulvalenes).2
The literature reports that reaction of thiazoline-2-thiones
with H2O2 causes the formation of reduced thiazolium hy-
drogensulfates. To achieve the anion interchange, a bari-
um halide11 or a strong protonic acid3 was included in the
reaction mixture. Conversion of the 2-(phenylthio)thiazo-
lium iodide 3a (R = Me) to the thiazoline-2-thione 6 was
carried out in the presence of sodium hydrosulfide, by
analogy with the procedure employed in the related sele-
none series12 (Scheme 1). However, the H2O2 sequence
was found to be unsatisfactory in the case of 6 owing to a
ready oxidation of the anticipated 5-(methylthio)thiazoli-
um salt 7. A longer reaction time (6 h) promoted the com-
plete formation of the sulfoxide derivative 8.13
A new method is based on our recent discovery14 that the
reaction of the 2-(phenylthio)thiazolium salt 2a with
PhSH/Et3N promotes the formation of the imidazolium-4-
thiolate 9a which is then quantitatively converted into the
methiodide 10a. Such a result was rationalized assuming
a Dimroth type rearrangement with a subsequent reduc-
tion of the transient mesoionic imidazole 11a (Scheme 2).
We previously developed one-pot preparations of highly
substituted imidazolium5 and thiazolium6,7 halides like
1–3 (Figure 1). Considering the remarkable ease with
which our reactions occur, it appeared attractive to exam-
ine the possibilities of generating 2-unsubstituted imida-
zolium and thiazolium salts by the reductive cleavage of
these 2-(methylthio) and 2-(phenylthio) derivatives. The
Y
i-Pr
PhS
PhS
S
N
S
Me2N
S
I
Cl
i-Pr
Cl
NHt-Bu
N
N
N
R
SMe
Me
R
NHt-Bu
Ph
Ph
Ph
Ph
3
1: Y = SMe
5: Y = H
2
4
Figure 1
SYNLETT 2003, No. 14, pp 2167–2170
0
6
.1
1
.2
0
0
3
Advanced online publication: 29.10.2003
DOI: 10.1055/s-2003-42100; Art ID: D14703ST
© Georg Thieme Verlag Stuttgart · New York

2168
G. Morel
LETTER
S
H2O2/HPF6
acetone
NaSH/EtOH
r.t., 2 h
S
S
S
3a
PF6
SMe
PF6
+
Me
N
N
N
SMe
S(O)Me
Me
Me
Ph
Ph
Ph
6 (85%)
7
8
Scheme 1
PhS
t-Bu
t-Bu
t-Bu
N
N
N
PhSH
Et3N
IMe
PhSH
Et3N
I
2
N
N
N
R
S
R
S
SMe
R
Ph
Ph
11
Scheme 2 a: R = Me, b: R = Et, c: R = CH2Ph, d: R = 4-MeOC6H4 e: R = 2,6-Me2C6H3
Ph
9
10
The development of this simple and mild reduction pro-
cess provides further examples of 2-unsubstituted imida-
zolium-4-thiolates 9. In support of the proposal displayed
in Scheme 2, we also describe additional data based on the
action of PhSH/Et3N on the thiazolium-5-thiolates 127
(Scheme 3) that are structurally analogous to intermedi-
ates 11.
Table 1 2-Unsubstituted Imidazolium and Thiazolium-Thiolates
According to Schemes 2 and 3
Substrate
Solvent
PhSH (and Time (h)a
Et3N) mol
Product/yield
(%)b
equiv
2a
2b
THF
3
4
4
4
4
3
4
3
3
23
28
28
28
28
24
48
28
48
9a (72)
9b (71)
9c (86)
THF
PhS
S
S
S
2c
CHCl3
CHCl3
CHCl3
THF
PhSH
Et3N
IMe
I
N
N
N
R
S
R
R
S
SMe
2d
9d (49)
9e (66)
Ph
12a–d
Ph
13a–d
Ph
14a–d
2e
12a
12b
12c
12d
13a (80)
13b (58)
13c (86)
13d (94)
Scheme 3 a: R = Me, b: R = Et, c: R = CH2Ph, d: R = 4-MeOC6H4
THF
Our results are summarized in the Table 1. Reductions
were typically carried out at room temperature in anhy-
drous THF or CHCl3 containing a large excess of ben-
zenethiol and Et3N. It was thus possible to isolate in
moderate to high yields a series of mesoionic imidazoles
9 and thiazoles 13 of very poor solubility in common or-
ganic solvents, which nevertheless displayed an excellent
reactivity towards electrophilic compounds as CH3I. All
the products were characterized by satisfactory elemental
analyses and usual spectroscopic methods.15
CHCl3
CHCl3
a The reactions were run until starting compounds were completely
transformed on the basis of 1H NMR analyses.
b Yields refer to isolated pure mesoionic compounds.
Thiolate ions have already been shown to reduce a range
of compounds.18 In particular, the reduction of a-sulfenyl-
ated carbonyl derivatives19 apparently involves direct nu-
cleophilic attack by thiolates on the sulfur atom. A variety
of studies have also suggested the occurrence of a single
electron transfer pathway from thiolates to organic sub-
strates.20 We did not attempt here to distinguish between
Large amounts of diphenyl disulfide were also recov-
ered as well as the N-tert-butyl-2-phenyl-2-oxo-thio-
acetamide16 in the case of starting material 2. Omission of
Et3N from the PhSH treament of 12a resulted in the
complete recovery of starting thiazole.
On account of its operational ease, it was reasonable to ex- these two mechanisms.
pect that a similar process could occur with N,N¢-bridged
In conclusion, the PhSH/Et3N reduction of 2-(phenyl-
bis(thiazolium) salts to furnish the corresponding 2, 2¢-un-
substituted bis(imidazolium) species. The reaction has
been performed as represented in Scheme 4 by the
conversion of the N, N¢-polymethylene dication 15 to the
bisimidazole 16 in 53% yield.17
thio)thiazolium derivatives provides an efficient synthetic
route to 2-unsubstituted imidazolium and thiazolium
salts. The need to use an excess of malodorous PhSH is
widely compensated by the ready availability of starting
Synlett 2003, No. 14, 2167–2170 © Thieme Stuttgart · New York

LETTER
Unsubstituted Imidazolium and Thiazolium Salts
2169
t-Bu
t-Bu
SPh
PhS
S
N
S
N
PhSH
Et3N
2Cl
N
N
N
N
(CH2)6
(CH2)6
t-BuNH
S
S
NHt-Bu
p-Tol
p-Tol
p-Tol
p-Tol
15
16
Scheme 4
(12) Bellec, N.; Lorcy, D.; Boubekeur, K.; Carlier, R.; Tallec, A.;
Los, S.; Pukacki, W.; Trybula, M.; Piekara-Sady, L.; Robert,
A. Chem. Mater. 1999, 11, 3147; and references therein.
(13) Procedure for Preparation of Thiazolium Hexafluoro-
phosphates 7 and 8: To a solution of 6 (0.5 g, 2 mmol) in
acetone (12 mL) were added HPF6 (3 mmol, from 60%
solution in water) and H2O2 (10 mmol, from 35% solution in
water). The reaction medium was stirred at 0 °C for 30 min
then at r.t. for 45 min and concentrated in vacuo. The
residual syrup was triturated with Et2O to afford a mixture of
salts 7 and 8 as insoluble viscous oil.
materials and the simplicity of the process. Our approach
avoids the classical quaternization of imidazoles and
thiazoles, which sometimes requires prolonged reflux
times21 or drastic conditions.22 Further use of salts 5, 10
and 14 for the preparation of carbenes or dimers is under
consideration.
References
(1) (a) Bordwell, F. G.; Satish, A. V. J. Am. Chem. Soc. 1991,
113, 985. (b) Chen, Y.-T.; Jordan, F. J. Org. Chem. 1991,
56, 5029. (c) López-Calahorra, F.; Castells, J.; Domingo, L.;
Martí, J.; Bofill, J. M. Heterocycles 1994, 37, 1579.
(d) Arduengo, A. J.; Goerlich, J. R.; Marshall, W. J. Liebigs
Ann./Recueil 1997, 365; and references therein.
(2) For a review on the synthesis of DTDAFs and TAFs, see:
Beckert, R. Adv. Heterocycl. Chem. 2000, 77, 115.
(3) For recent examples on the DTDAF series: Guérin, D.;
Carlier, R.; Lorcy, D. J. Org. Chem. 2000, 65, 6069.
(4) Reviews: (a) Herrmann, W. A.; Köcher, C. Angew. Chem.
Int. Ed. Engl. 1997, 36, 2162. (b) Arduengo, A. J. Acc.
Chem. Res. 1999, 32, 913. (c) Bourissou, D.; Guerret, O.;
Gabbaï, F. P.; Bertrand, G. Chem. Rev. 2000, 100, 39.
(5) Malvault, Y.; Marchand, E.; Morel, G. J. Org. Chem. 1992,
57, 2121.
NMR data for salt 7 (in admixture with 8): 1H NMR (200
MHz, CDCl3): d =2.47 (s, 3 H), 3.95 (s, 3 H), 7.50 (m, 5 H),
9.65 (s, 1 H). 13C NMR (75.5 MHz, CDCl3): d = 20.3 (q,
1J = 143 Hz), 42.6 (qd, 1J = 146 Hz, 3J = 2 Hz), 125.9 (m),
130.0, 130.7, 132.0 138.0 (arom C), 147.5 (m), 158.0 (dq,
1J = 216 Hz, 3J = 4 Hz).
A similar treatment for 6 h gave a viscous oil insoluble in
CH2Cl2. 1H NMR spectroscopy analysis confirmed that the
sulfoxide 8 was greatly preponderant ( 95%) in this final
product; (0.54 g, 70% yield). 1H NMR (500 MHz, D2O): d =
2.93 (s, 3 H), 3.94 (s, 3 H), 7.60 (m, 5 H), 10.26 (s, 1 H). 13
C
NMR (125.8 MHz, D2O): d = 41.4 (q, 1J = 142 Hz), 41.7 (qd,
1J = 147 Hz, 3J = 2.3 Hz), 123.7, 129.7, 129.9, 132.4 (arom
C), 144.9, 148.5 (2 × m), 162.3 (dq, 1J = 220 Hz, 3J = 4.7 Hz).
MS (EI): m/z [M – HPF6]+· calcd for C11H11NOS2:
237.02821; found: 237.02835.
(6) Berrée, F.; Malvault, Y.; Marchand, E.; Morel, G. J. Org.
Chem. 1993, 58, 6022.
(14) Touimi Benjelloun, A.; Morel, G.; Marchand, E.
Heteroatom. Chem. 2000, 11, 16.
(7) Touimi Benjelloun, A.; Morel, G. Sulfur Lett. 1996, 20, 107.
(8) (a) Bssaibis, M.; Robert, A.; Lemaguerès, P.; Ouahab, L.;
Carlier, R.; Tallec, A. J. Chem. Soc., Chem. Commun. 1993,
601. (b) Bssaibis, M.; Robert, A.; Souizi, A. A. J. Chem.
Soc., Perkin Trans 1 1994, 1469.
(15) Due to its extremely unpleasant odour, manipulations of
PhSH were carried out in a well-ventilated fume hood.
Typical Experimental Procedure for the Synthesis of
Representative Examples 13a and 14a and Their
Spectroscopic Data: PhSH (0.33 g, 3 mmol) and Et3N (0.3
g, 3 mmol) were added to a solution of mesoionic
(9) Touimi Benjelloun, A.; Morel, G.; Marchand, E.
Phosphorus, Sulfur Silicon Relat. Elem. 1998, 133, 195.
(10) Experimental Procedure: NaBH4 (0.25 g, 6.6 mmol) was
added portionwise over a period of 3 min to a solution of 1-
methyl imidazolium chloride 1 (0.68 g, 2 mmol) in 95%
EtOH (15 mL). After 45 min at r.t., the mixture was poured
into 60 mL of water and washed with Et2O. The aq phase
was saturated with NaCl and extracted with CH2Cl2 (2 × 10
mL). The combined CH2Cl2 layers were dried over Na2SO4
and concentrated to dryness. Trituration of the residue with
CH2Cl2–Et2O gave a crystalline material (5, 0.28 g, 48%);
mp 222 °C. 1H NMR (300 MHz, CDCl3): d = 0.97 (d, J = 6.2
Hz, 6 H), 1.66 (d, J = 6.6 Hz, 6 H), 2.99 (m, 1 H), 3.82 (s, 3
H), 4.58 (d, J = 4 Hz, NH), 5.02 (m, 1 H), 7.50 (m, 5 H),
10.34 (s, 1 H). 13C NMR (75.5 MHz, CDCl3): d = 23.0, 23.1,
34.8 (3 × qd), 47.8, 48.6 (2 dm), 121.5 (m), 125.9, 129.3,
130.1, 130.5 (arom C), 131.7 (dm, 1J = 215 Hz), 134.9 (m).
MS (FAB): m/z [M]+ calcd for C16H24N3: 258.1970; found:
258.1955. Anal. Calcd for C16H24ClN3: C, 65.40; H, 8.23; N,
14.30. Found C, 65.60; H, 8.28; N, 14.17.
heterocycle 3a (0.32 g, 1 mmol) in anhyd THF (5 mL). A
yellowish material precipitated slowly. The mixture was
maintained at r.t. for 1 d. Thiazole 13a was collected by
filtration, washed with Et2O, water and recrystallized from
MeOH (0.17 g, 0.8 mmol); mp 228–230 °C. 1H NMR (200
MHz, CDCl3): d = 3.74 (s, 3 H), 7.49 (m, 5 H), 8.15 (s, 1 H).
MS (EI): m/z [M]+· calcd for C10H9NS2: 207.01764; found:
207.01791. Anal. Calcd C, 57.97; H, 4.35; N, 6.76; S, 30.92.
Found C, 57.83; H, 4.35; N, 6.58; S, 31.31. The 13C NMR
spectrum could not be recorded because of the low solubility
of 13a in CDCl3 and other usual solvents.
A suspension of 13a in CHCl3 was treated with 2 equiv of
CH3I at r.t. for 1 h. The resulting solution was concentrated
in vacuo to give a greyish solid that was recrystallized from
CH2Cl2–Et2O (14a, 94% yield); mp 152–154 °C. 1H NMR
(300 MHz, CDCl3): d = 2.53 (s, 3 H), 4.18 (s, 3 H), 7.60 (s,
5 H), 11.07 (s, 1 H). 13C NMR (75.5 MHz, CDCl3): d = 20.3
(q, 1J = 143 Hz), 43.1 (qd, 1J = 146 Hz, 3J = 2.3 Hz), 125.6
(m), 129.5, 130.6, 131.4, 137.2 (arom C), 147.0 (m), 160.0
(dq, 1J = 219 Hz, 3J = 4.9 Hz). MS (EI): m/z [M – CH3I]+·
calcd for C10H9NS2: 207.01764; found: 207.01791. Anal.
(11) Leeper, F. J.; Smith, D. H. C. Tetrahedron Lett. 1988, 29,
1325.
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2170
G. Morel
LETTER
Calcd for C11H12INS2: C, 37.82; H, 3.44; N, 4.01; S, 18.34.
Found C, 37.84; H, 3.46; N, 4.05; S, 18.67.
(16) Morel, G.; Marchand, E.; Touimi Benjelloun, A.;
Sinbandhit, S.; Guillou, O.; Gall, P. Eur. J. Org. Chem.
1998, 2631.
(19) (a) Aufauvre, Y.; Verny, M.; Vessière, R. Bull. Soc. Chim.
Fr. 1973, 1373. (b) Karavan, V. S.; Simonov, D. A.;
Temnikova, T. I. J. Gen. Chem. USSR 1982, 52, 1757.
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B.; Su, W. Y. J. Org. Chem. 1985, 50, 5184. (b) Meissner,
J. W. G.; van der Laan, A. C.; Pandit, U. K. Tetrahedron
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Tetrahedron Lett. 1980, 21, 2429. (b) Doughty, M. B.;
Risinger, G. E. Bioorg. Chem. 1987, 15, 1. (c) Shi, Z.;
Thummel, R. P. J. Org. Chem. 1995, 60, 5935.
(17) Compound 16; amorphous semi-solid. 1H NMR (200 MHz,
CDCl3): d = 0.97 (m, 2 H), 1.42 (m, 2 H), 1.98 (s, 9 H), 2.36
(s, 3 H), 3.81 (t, J = 7 Hz, 2 H), 7.22 (d, J = 8 Hz, 2 H), 7.38
(d, J = 8 Hz, 2 H), 7.76 (s, 1 H). MS (FAB): m/z [M + H]+
calcd for C34H47N4S2: 575.32422; found: 575.32410.
(18) Fry, A. J. In Comprehensive Organic Synthesis, Vol. 8;
Trost, B. M.; Fleming, I., Eds.; Pergamon: New York, 1991,
983–997.
(22) (a) Singh, H.; Singh, D.; Kumar, S. Tetrahedron 1992, 22,
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Synlett 2003, No. 14, 2167–2170 © Thieme Stuttgart · New York