3-Hydroxythiazole and 1-hydroxyimidazole as products of a mutual ring closure reaction: Extension to selenium derivatives

Article abstract of DOI:10.1080/104265090885129

A thiazole derivative can be easily prepared, e.g., from an α-thiocyanatoketone and a nitrogen nucleophile. In this work, α-bromopropiophenone was chosen as a starting compound. Since the carbonyl group facilitates nucleophilic substitution, bromine can b

Full text of DOI:10.1080/104265090885129

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Phosphorus, Sulfur, and Silicon
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3-Hydroxythiazole and 1-
Hydroxyimidazole as Products
of a Mutual Ring Closure
Reaction: Extension to
Selenium Derivatives
Dagmar Fajkusova a & Pavel Pazdera a
a Department of Organic Chemistry, Masaryk
University , Brno, Czech Republic
Published online: 01 Feb 2007.
To cite this article: Dagmar Fajkusova & Pavel Pazdera (2005) 3-Hydroxythiazole
and 1-Hydroxyimidazole as Products of a Mutual Ring Closure Reaction: Extension
to Selenium Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements,
180:7, 1683-1689, DOI: 10.1080/104265090885129
To link to this article: http://dx.doi.org/10.1080/104265090885129
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Phosphorus, Sulfur, and Silicon, 180:1683–1689, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090885129
3-Hydroxythiazole and 1-Hydroxyimidazole as Products
of a Mutual Ring Closure Reaction: Extension to
Selenium Derivatives
Dagmar Fajkusova
Pavel Pazdera
Department of Organic Chemistry, Masaryk University, Brno,
Czech Republic
A thiazole derivative can be easily prepared, e.g., from an α-thiocyanatoketone
and a nitrogen nucleophile. In this work, α-bromopropiophenone was chosen as a
starting compound. Since the carbonyl group facilitates nucleophilic substitution,
bromine can be simply replaced with the thiocyanato group. The following reaction
with hydroxylamine hydrochloride provides an intermediate, which undergoes a
ring closure reaction. Finally, 3-hydroxy-5-methyl-4-phenylthiazol-2(3H)-iminium
chloride 4a or 1-hydroxy-4-methyl-5-phenyl-1,3-dihydro-2H-imidazole-2-thione 5a
arises depending on the presence of a base. In the next part, this interesting phe-
nomenon was successfully investigated on selenium derivatives as well. All prepared
substances have not been described in the literature yet.
Keywords Cyclization; imidazole; selenium; thiazole
INTRODUCTION
A thiazole derivative can be easily prepared, e.g., from an α-
thiocyanatoketone and a nitrogen nucleophile. However, a compound
containing both nitrogen atoms in the ring arises under certain
conditions.
In 1956, Bayer and Ruhlig1 investigated a series of transformations
of α-thiocyanatoketones by various nitrogen nucleophiles. First, they
studied a reaction of thiocyanatoacetone with hydrazine hydrate under
acid catalysis. This reaction provided different products depending on
Received August 2, 2004; accepted August 12, 2004.
This work was supported by Ministry of Education, Youth and Sports of the Czech
Republic (grant No. MSMT 143 1000 111) and by Grant Agency of the Czech Republic
(grant No. 203/01/1333).
Address correspondence to Dagmar Fajkusova, Department of Organic Chemistry,
Masaryk University, Kotlarska 2, 611 37 Brno, Czech Republic. E-mail: dagmar@chemi.
muni.cz
1683

1684
D. Fajkusova and P. Pazdera
SCHEME 1 The reaction of thiocyanatoacetone with hydrazine hydrate pro-
vided various products depending on the concentration of hydrochloric acid.
the acid concentration. When the acid concentration was 0.02 mol/L,
thiocyanatoacetonazine was isolated; a further addition of hydrochlo-
ric acid led to the formation of an insoluble amorphous product A,
structure of which was not defined. Finally, 3-amino-2-imino-4-methyl-
2,3-dihydrothiazole was obtained; the reactants were used in the 1:1:1
ratio in this case (Scheme 1). When the concentration of hydrochloric
acid raised over 3 mol/L, no reaction was observed.
A reaction of phenacylthiocyanate with hydrazine dihydrochloride1
did not afford any corresponding thiazole derivative. In addition, a re-
action with phenyl hydrazine or 1,1-diphenylhydrazine provided only
phenyl hydrazone or diphenyl hydrazone.
On the other hand, the transformations using thiourea and aniline1
proceeded in the desired way and (4-phenylthiazolyl-2-)isothiourea
and 2-imino-4-methyl-3-phenyl-2,3-dihydrothiazole, respectively, were
obtained.
In the case of hydroxylamine hydrochloride application, the re-
actants were converted into 2-imino-3-hydroxy-2,3-dihydrothiazoles.
The authors have carried out this reaction with thiocyanatoacetone,
phenacylthiocyanate, and 3-thiocyanatobutan-2-one; all the products
were stable only as hydrochlorides.1
RESULTS AND DISCUSSION
In our work, we have chosen α-bromopropiophenone 1 as a starting
compound. Since the carbonyl group facilitates nucleophilic substi-
tution of bromine, thiocyanato group introduction is simply feasible

Thiazole and Imidazole
1685
SCHEME 2 The reaction of α-bromopropiophenone 1 with potassium thio-
cyanate or selenocyanate and hydroxylamine hydrochloride proceeds via inter-
mediates 2 and 3 and provides various products depending on the presence of
a base.
and results in a substrate on which this transformation has not
been examined yet. Therefore, we have carried out a reaction of α-
bromopropiophenone 1 with potassium thiocyanate in the first step.
α-Thiocyanatopropiophenone 2a was obtained and, together with hy-
droxylamine hydrochloride, in situ subjected to reflux according to the
original procedure1 (Scheme 2).
Indeed, 3-hydroxy-5-methyl-4-phenylthiazol-2(3H)-iminium chlo-
ride 4a was isolated. Its structure was confirmed by the X-ray ana-
lysis.* Additionally, it was shown that the iminium form 4 (C2-N3 bond
*CCDC 242563 contains the supplementary crystallographic data for this article.
These data can be obtained free of charge via www.ccdc.cam.ac.uk/data request/cif, by
emailing data request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic
Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK.

1686
D. Fajkusova and P. Pazdera
FIGURE 1 A successful monocrystal preparation enabled X-ray analysis
of 3-hydroxy-5-methyl-4-phenylthiazol-2(3H)-iminium chloride 4a. Crystallo-
graphic data for 4a: C10H11ClN2OS, M = 242.72, monoclinic crystal system,
◦
˚
˚
˚
S. G. P-2(1)/c, a = 9.5303(10) A, b = 13.7937(12) A, c = 8.9540(10) A, α = 90 ,
β = 106.433(11) , γ = 90 , V = 1129.0(2) A , Z = 4, Dcalc = 1.428 Mg/m3. Number
of collected/independent reflections was 4778/1909; Rint = 0.0344. The final R
indices [l > 2σ(l)]: R1 = 0.0315, wR2 = 0.0985, the largest diff. peak and hole
◦
◦
3
˚
3
˚
were 0.315 and −0.312 e/A .
ꢀ
˚
˚
length = 1,332(2) A, C2-N7 = 1,317(3) A) is preferred over the form 4
(Figure 1).
The reaction of α-thiocyanatopropiophenone 2a with hydroxylamine
hydrochloride proceeds presumably via an intermediate 3a, which
undergoes a ring closure reaction. We have found that this cycliza-
tion provides a different product 5a under the presence of a base
(Scheme 2). Its structure was determined as 1-hydroxy-4-methyl-5-
phenyl-1,3-dihydro-2 H-imidazole-2-thione 5a.
We have carried out this reaction in ethanol/water mixture using
sodium carbonate. The 2:1 ratio proved to be very convenient in respect
to the solubility of all reaction components. Moreover, the whole proce-
dure could be performed in one step without separation of potassium
bromide. However, the solid obtained after a partial evaporation of the
solvent had to be subjected to an extraction in dichloromethane.
In the next part, we have investigated such a mutual ring
closure reaction on selenium derivatives. 3-Hydroxy-5-methyl-4-
phenylselenazol-2(3 H)-iminium chloride 4b was prepared in the same
way as the thioanalogue using potassium selenocyanate. The procedure
leading to 1-hydroxy-4-methyl-5-phenyl-1,3-dihydro-2H-imidazole-2-
selenone 5b was modified; we have replaced the mixture of solvents
with ethanol under ultrasound activation. Unfortunately, both cycliza-
tion reactions were accompanied by an efficient elimination process
of elementary selenium. The identity of degradation products was not
examined.

Thiazole and Imidazole
1687
In conclusion, we have studied the mutual ring closure reaction of the
intermediate arising from the reaction of α-thiocyanatopropiophenone
2a with hydroxylamine hydrochloride. Depending on the presence of
sodium carbonate, the thiazole derivative 4a or the imidazole deriva-
tive 5a was obtained. This interesting phenomenon was successfully
investigated on selenium analogues as well.
While the procedure leading to product 4 was known,1 we have deve-
loped other methods leading to the product 5. All prepared substances
have not been described in the literature yet.
We currently study the transformations of the imidazole derivatives,
in respect to their possible applications in the field of ligand chemistry.
EXPERIMENTAL
IR spectra were recorded on an ATI Mattson Genesis spectrometer,
NMR spectra at 200 MHz on a Varian Inova spectrometer (4a and
5a) and at 300 MHz on a Bruker Avance 300 spectrometer (4b and
5b). Melting points were determined on a Kofler hot stage and are
uncorrected. Reaction courses were monitored by thin-layer chromato-
graphy on Silufol UV 254 in diethyl ether. X-ray intensity data were
collected at 120(2) K on a KUMA KM-4 kappa four-circle diffractome-
˚
ter with MoK\a radiation (λ = 0.71073 A). The structure was solved by
direct methods (SHELXS-97) and refined by weighted full-matrix least-
squares on F2 (SHELXL-97). All nonhydrogens were refined anisotropi-
cally; hydrogens were localized from difference Fourier map and refined
isotropically.
3-Hydroxy-5-methyl-4-phenylthiazol-2(3H)-iminium
Chloride 4a
A mixture of α-bromopropiophenone (4.26 g, 18.8 mmol) and potassium
thiocyanate (2.14 g, 22.1 mmol) in ethanol (10 mL) was stirred at the
room temperature for 4 h. Precipitated potassium bromide was filtered
off and washed with ethanol. Hydroxylamine hydrochloride (1.54 g,
22.1 mmol) was added to the filtrate and this mixture was refluxed
for 20 h. After cooling, colorless crystals were separated and washed
1
with ethanol. Yield 70%, m.p. 194–196◦C. H NMR (DMSO-d6): 2.19
(s, 3H, CH3); 7.48–7.59 (m, 5H, C6H5); 9.63 (s, 2H, NH2); 13.01 (s, br,
1H, OH). 13C NMR (DMSO-d6): 12.30 (CH3); 111.59 (5-C); 126.66 (1-C
C6H5); 128.65 (2,6-C C6H5); 129.81 (4-C C6H5); 130.46 (3,5-C C6H5);
134.20 (4-C); 161.09 (2-C). ν˜ (KBr): 3230 (OH), 3181, 3071, 2728, 2669,
2586, 1632 (C N), 1618, 1567, 1489, 1441, 1213.

1688
D. Fajkusova and P. Pazdera
1-Hydroxy-4-methyl-5-phenyl-1,3-dihydro-2H-imidazole-
2-thione 5a
α-Bromopropiophenone (1.00 g, 4.4 mmol) and ammonium thiocyanate
(1.10 g, 14.3 mmol) were dissolved in ethanol/water (2:1). The reac-
tion mixture was stirred at the room temperature until no more α-
bromopropiophenone could be detected (TLC). After that, sodium car-
bonate (1.40 g, 13.2 mmol) and hydroxylamine hydrochloride (0.90 g,
13.2 mmol) were added and the stirring continued until only one com-
pound was present (TLC). The solvent was partially evaporated; a solid
was filtered off and subjected to an extraction by dichloromethane. The
solution was dried and evaporated and a crystalline product was ob-
1
tained. Yield 33%, m.p. 211–213◦C. H NMR (DMSO-d6): 2.24 (s, 3H,
CH3); 7.30–7.52 (m, 5H, C6H5). 13C NMR (DMSO-d6): 8.66 (CH3); 119.56
(5-C); 121.29 (4-C); 126.11 (2,6-C C6H5); 127.16 (4-C C6H5); 128.74 (3,5-
C C6H5); 128.89 (1-C C6H5); 156.34 (2-C). ν˜ (KBr): 3133 (NH), 3091,
2941, 2809 (CH3), 1633 (C N), 1443, 1404, 1269.
3-Hydroxy-5-methyl-4-phenylselenazol-2(3H)-iminium
Chloride 4b
A solution of α-bromopropiophenone (2.00 g, 8.8 mmol) and potassium
selenocyanate (1.52 g, 10.6 mmol) in ethanol (30 mL) was stirred at the
room temperature. Precipitated potassium bromide was filtered off and
washed with ethanol; hydroxylamine hydrochloride (0.73 g, 10.6 mmol)
was added to the filtrate. The reaction then proceeded under reflux; a
selenium exclusion accompanied by a color change was observed. After
filtration, the solvent was partially evaporated; a crystalline product
was filtered off and washed with ethanol. Yield 14%. 1H NMR (MeOD):
2.31 (s, 3H, CH3); 7.44–7.49 (m, 2H, C6H5); 7.52–7.56 (m, 3H, C6H5). 13
C
NMR (MeOD): 14.37 (CH3); 117.38 (5-C); 129.37 (1-C C6H5); 129.94 (2,6-
C C6H5); 131.18 (4-C C6H5); 131.87 (3,5-C C6H5); 136.60 (4-C); 167.02
(2-C). ν˜ (KBr): 3436 (OH), 3243 (NH), 3092, 2706, 2666, 1615, 1563,
1441, 1401, 1261.
1-Hydroxy-4-methyl-5-phenyl-1,3-dihydro-2H-imidazole-
2-selenone 5b
Potassium selenocyanate (4.13 g, 28.6 mmol) was added to a solution
of α-bromopropiophenone (2.00 g, 8.8 mmol) in ethanol (30 mL). The
reaction mixture was stirred at the room temperature. Precipitated
potassium bromide was filtered off and washed with ethanol. The fil-
trate together with hydroxylamine hydrochloride (1.84 g, 26.4 mmol)

Thiazole and Imidazole
1689
and sodium carbonate (2.80 g, 26.4 mmol) was subjected to ultrasound.
A selenium exclusion accompanied by a color change was observed. The
solid was filtered off and the solution was treated with charcoal. The
solvent was removed under reduced pressure and a residue crystallized
by chloroform addition. According an infrared spectrum, remaining se-
lenocyanate was present in the crystalline phase. A pure product was
obtained by dissolving in acetone followed by addition of water. Ace-
tone was then evaporated and the solid was filtered off and dried in
vacuum. Yield 11%. 1H NMR (MeOD): 2.19 (s, 3H, CH3); 7.27–7.34 (m,
2H, C6H5); 7.36–7.43 (m, 3H, C6H5). 13C NMR (MeOD): 10.40 (CH3);
128.58 (2,6-C C6H5); 129.10 (4-C C6H5); 129.95 (1-C C6H5); 130.48 (3,5-
C C6H5); 133.73 (4-C); 156.25 (5-C); 164.43 (2-C). ν˜ (KBr): 3432 (OH),
3273 (NH), 2926, 2854 (CH3), 1636 (C N), 1419, 1293.
REFERENCE
[1] H. Beyer and G. Ruhlig, Chem. Ber., 89, 107 (1956).