Use of a metallation reaction to obtain substituted 2-(5-methyl-2- thiazolyl)ethanols

Article abstract of DOI:10.1007/s10593-005-0242-0

The interaction of anions, obtained by treating 2,4,5-trimethylthiazole and 2,5-dimethyl-4-phenylthiazole with butyllithium, with aliphatic and aromatic aldehydes leads to substituted 2-thiazolyl-1-ethanols. It was established that the metallation reaction occurs at the 2-methyl group of the thiazoles. 2005 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-005-0242-0

Chemistry of Heterocyclic Compounds, Vol. 41, No. 7, 2005
USE OF A METALLATION REACTION
TO OBTAIN SUBSTITUTED 2-(5-METHYL-
2-THIAZOLYL)ETHANOLS
A. Yu. Liakina, A. A. Formanovsky, I. S. Popova, and I. V. Mikhura
The interaction of anions, obtained by treating 2,4,5-trimethylthiazole and 2,5-dimethyl-
4-phenylthiazole with butyllithium, with aliphatic and aromatic aldehydes leads to substituted
2-thiazolyl-1-ethanols. It was established that the metallation reaction occurs at the 2-methyl group of
the thiazoles.
Keywords: butyllithium, 2,5-dimethyl-4-phenylthiazolide anion, 2-thiazolylethanols, metallation.
Metallation of alkyl- and aryl-substituted thiazoles with butyllithium is a key reaction for obtaining
various functional derivatives of these compounds. The interaction of 2-methylbenzothiazole with butyllithium
and the reaction of the resulting anion with acid chlorides and esters of carboxylic acids, aldehydes, and other
electrophiles has been studied in detail [1].
A very small number of studies has been devoted to the metallation of aryl- and alkyl-2,4,5-substituted
thiazoles. It was shown that in the case of 2-methyl-4-phenylthiazole the presence of a stabilizing anion of the
phenyl substituent in position 4 of the thiazole increases the acidity of the hydrogen atom in position 5 and
precisely this position is subject to electrophilic attack. On the other hand, in the case of 2,4-dimethylthiazole the
acidity of the hydrogen atom in position 5 of the thiazole is less than the acidity of the hydrogen atom of the
methyl group in position 2, consequently electrophilic attack is effected at the 2-CH3 group [2].
There are no data in the literature on the metallation of 2,5-dimethyl-4-substituted thiazoles. To establish
the effect of the nature of the substituent at position 4 of the thiazole on the conditions and direction of the
metallation of 2,5-dimethylthiazoles with butyllithium, we have studied the condensation of anions obtained
from 2,5-dimethylthiazoles, containing a methyl or phenyl substituent in position 4 with a fairly representative
selection of aldehydes.
R1
R1
R1
1) R2CHO
2) H+
BuLi
OH
N
N
N
Li
Et2O, THF
from -100 to -70°C
R2
Me
Me
Me
Me
S
S
S
3a–h, 4a–c
1, 2
1, 3 R1 = Me, 3 a R2 = i-Pr, b R2 = i-Bu, c R2 = Ph, d R2 = 2-CF3C6H4, e R2 = 3-CF3C6H4,
f R2 = 4-MeSC6H4, g R2 = 4-F-3-MeOC6H3, h R2 = 2-F-4-MeOC6H3; 2, 4 R1 = Ph;
4 a R2 = Ph, b R2 = 2-FC6H4, c R2 = 3-FC6H4
__________________________________________________________________________________________
M. M. Shemyakin and Yu. A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of
Sciences, Moscow 117997; e-mail: synorg@ibch.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii,
No. 7, pp. 1038-1043, July, 2005. Original article submitted November 25, 2003.
0009-3122/05/4107-0877©2005 Springer Science+Business Media, Inc.
877

We have obtained 2-thiazolyl-1-ethanols 3a-h and 4a-c for the first time (Table 1). Metallation of
thiazole 1 and treatment of the anion with aldehydes was carried out at -70°C. The yields of compounds 3a-h
were 20-60%. Metallation of thiazole 2 and subsequent treatment of the anion with aldehydes was carried out at
-100°C. On increasing the temperature of the reaction of thiazole 2 with butyllithium to -70°C the yields of
compounds 4a-c were reduced.
In the 1H NMR spectra of compounds 3a-h and 4a-c the signals of the protons of the methylene group at
position 2 of the thiazole were not equivalent and were a doublet of doublets with different coupling constants
(Table 2). The signal of the CH group proton for compounds 3c-h and 4a-c, in which R2 is a substituted or
unsubstituted phenyl radical lies at 5.00-5.50 ppm. In the case of compounds 3a and 3b, in which R2 is an
isopropyl or an isobutyl radical respectively, the signal is displaced towards high field and is observed at 3.69
(for compound 3a) and 4.02 ppm (for compound 3b).
To confirm the course of the metallation reaction at the 2-methyl group of the thiazole under the usual
conditions the 2,5-dimethyl-4-phenylthiazolide anion was synthesized and treated with D2O. The obtained
compound 6 was purified chromatographically and its 13C NMR spectrum was recorded. As additional standard
the 13C NMR spectrum of 2-methyl-5,6,7,8-tetrahydro-4H-cyclohepta[d]-1,3-thiazole (5) [3] was used for
reliable identification of the signal of the 2-methyl group of the thiazoles.
1) D2O
2) H+
BuLi
N
N
ТHF, Et2O,
–100 oC
Li
Me
Me
Me
N
S
S
2
D
Me
S
6
In the 13C NMR spectrum of compound 2 a signal was present at 12.05 ppm which was absent from this
region in the spectrum of compound 5. This permits assignment of the signal at 12.38 ppm in the spectrum of
compound 6 to the carbon atom of the methyl group at position 5 of the thiazole. Signals were present in the
13C NMR spectra of compounds 2, 5, and 6 in the region of 18 ppm (18.57 for 2, 18.00 for 5, and 18.56 for 6). In
the case of the undeuterated thiazoles 1, 2, and 5 this signal is a singlet, but in the case of the deuterated thiazole
6, it was a triplet (J = 88.8 Hz). This enables assignment of the signal near 12 ppm to the carbon atom of the
methyl group at position 2 of thiazoles 2 and 5. Since in the spectrum of deuterated compound 6 the signal near
12 ppm is split into a triplet, it may be suggested that in the case of 2,5-dimethyl-substituted thiazoles the
presence of a phenyl substituent at position 4 of the thiazole has no effect on the acidity of the hydrogen of the 5-
methyl group and the metallation reaction occurs at the 2-methyl group.
The mass spectra of the obtained 2-thiazolylethanols were poorly informative due to the instability of
compounds in the electron beam. In the spectrum of compound 4a a low-intensity peak was present with m/z 295
for the molecular ion. The most intense peak with m/z 276 corresponds presumably with the 5-methyl-4-phenyl-
(2-phenylvinyl)thiazolium cation with a conjugated system of double bonds. An intense peak was also present in
the spectrum with m/z 189, which corresponds to the mass of the initial thiazole 2.
878

TABLE 1. Physicochemical Characteristics of Compounds 3a-h, 4a-c
Found, %*
Calculated, %
——————
Com-
pound
Empirical
formula
Rf
Yield,
%
mp, °С
(TLC)*2
C
H
N
S
3a
3b
3c
3d
3e
3f
С10H17NOS
С11H19NOS
С13H15NOS
С14H14F3NOS
С14H14F3NOS
С14H17NOS2
С14H16FNO2S
С14H16FNO2S
С18H17NOS
С18H16FNOS
С18H16FNOS
63.77
60.26
59.51
61.93
65.05
66.92
55.88
55.80
55.39
55.80
59.96
60.18
59.79
59.77
59.93
59.77
6.48
8.60
8.76
8.98
6.48
6.48
4.71
4.68
4.64
4.68
6.19
6.13
5.70
5.73
5.76
5.73
6.94
7.03
6.94
6.57
6.94
6.00
4.71
4.65
4.89
4.65
5.50
5.01
5.02
4.98
5.05
4.98
13.67
16.09
13.50
15.03
13.51
13.74
0.45
0.35
0.35
0.25
0.27
0.24
0.16
0.45
0.45
0.50
0.50
Oil
Oil
60
40
55
50
50
53
51
25
60
55
55
90-92
117-119
98-99
95-97
94-95
68-70
95
21.54
22.95
3g
3h
4a
4b
4c
73.21
73.19
68.81
68.99
68.89
68.99
5.85
5.80
5.28
5.15
5.45
5.15
4.65
4.74
4.56
4.47
4.64
4.47
10.71
10.86
108-110
87-90
_______
* Samples of substances 3a-h and 4a-c for elemental analysis were obtained
by recrystallization from hexane.
*2 Benzene–acetone, 10:1 (compounds 3f,g, 4a-c); 4:1 (compounds 3a-c,h);
19:1 (compounds 3d,e).
The structure of compound 4a was confirmed by data of X-ray structural analysis in [4]. In the crystal
molecules of 4a are linked by intermolecular hydrogen bonds OH···N, and the thiazole ring and the phenyl ring
at position 4 are disposed in one plane due to conjugation (Fig. 1).
It has therefore been shown that metallation of 2,5-dimethylthiazoles containing a methyl or phenyl
group in position 4 leads to the formation of anions at the methyl group in position 2. Subsequent reaction of the
anions with aldehydes leads to the preparation of 2-thiazolyl-1-ethanols.
Fig. 1. Structure of the 2-thiazolyl-1-ethanol 4a molecule and numbering of the atoms.
879

880

EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on a Bruker AMX-400 instrument (400 and 100 MHz
respectively), internal standard was TMS. Melting points were determined on a Boetius hot stage (heating rate
4 deg/min). The mass spectrum of compound 4a was obtained on a Kratos MS-890A, energy of ionizing
electrons was 70 eV, temperature of ionization chamber 200°C. Solvents were used after careful purification and
drying. Thiazoles 1 and 2 were obtained by the method of Hantzsch [5] by the interaction of thioacetamide and
3-bromo-2-butanone [6] and phenyl 1-bromoethyl ketone [7].
2-Thiazolyl-1-ethanols 3a-h and 4a-c (General Procedure). A solution of thiazole 1 (1 g, 7.87 mmol)
in a mixture of ether (20 ml) and THF (4 ml) was cooled to -70°C (toluene, dry ice, liquid nitrogen) with stirring
in a current of argon. A 1.6-fold excess of a solution of BuLi (1.6 M) in hexane (8 ml, 12.6 mmol) was added
during 10 min with a syringe. The mixture was stirred for 30 min, and the colorless solution became red-black. A
1.2-fold excess of aldehyde dissolved in THF (2 ml) was added to the solution during 10 min and maintained for
20-30 min, after which aqueous 1 M citric acid solution (20 ml) was added and the reaction mixture left to heat
to room temperature. The mixture was washed with water (2 × 20 ml) and with saturated NaCl solution (10 ml),
dried over Na2SO4, the solvent evaporated, and the residue dried in the vacuum of an oil pump.
2-Thiazolyl-1-ethanols 4a-c were obtained according to the procedure given above from thiazole 2 (1 g,
5.29 mmol), butyllithium (2.6 ml, 9.5 mmol), the butyllithium was added at -100°C.
2-(2-Hydroxy-3-methylbutyl)-4,5-dimethyl-1,3-thiazole (3a). Yellow oil, yield 1 g.
2-(2-Hydroxy-4-methylpentyl)-4,5-dimethyl-1,3-thiazole (3b) was purified by steam distillation and a
yellow oil (0.7 g, 40%) was obtained.
2-(2-Hydroxy-2-phenylethyl)-4,5-dimethyl-1,3-thiazole (3c). The red oil was rubbed in a mixture of
ether–hexane, 1:1 cooled to +5°C. A yellow powder (1 g) was obtained.
2-[2-Hydroxy-2-(2-trifluoromethylphenyl)ethyl]-4,5-dimethyl-1,3-thiazole (3d). The white powder
was washed with hexane, and dried. Yield 1.2 g.
2-[2-Hydroxy-2-(3-trifluoromethylphenyl)ethyl]-4,5-dimethyl-1,3-thiazole (3e). After rubbing with
hexane a white powder (1.17 g) was obtained.
2-{2-Hydroxy-2-[4-(methylthio)phenyl]ethyl}-4,5-dimethyl-1,3-thiazole (3f). The orange crystals
were washed with hexane and dried. Yield 1.75 g.
2-[2-Hydroxy-2-(4-fluoro-3-methoxyphenyl)ethyl]-4,5-dimethyl-1,3-thiazole (3g). The oil crystallized
spontaneously in a matter of week, the fine yellow crystals were washed with hexane, and dried. Yield 1.2 g.
2-[2-Hydroxy-2-(2-fluoro-4-methoxyphenyl)ethyl]-4,5-dimethyl-1,3-thiazole (3h) was purified by
chromatography on silica gel (eluent CHCl3). The obtained oil crystallized spontaneously during 3 days. The
crystals were separated, and washed with cold hexane. Yield 0.5 g.
2-(2-Hydroxy-2-phenylethyl)-5-methyl-4-phenyl-1,3-thiazole (4a). After recrystallization from
hexane a white powder (0.5 g) was obtained.
2-[2-Hydroxy-2-(2-fluorophenyl)ethyl]-5-methyl-4-phenyl-1,3-thiazole (4b). After rubbing with
hexane a yellowish powder (0.9 g) was obtained.
2-[2-Hydroxy-2-(3-fluorophenyl)ethyl]-5-methyl-4-phenyl-1,3-thiazole (4c). After rubbing with
hexane a yellowish powder (0.9 g) was obtained.
2-Deuteromethyl-5-methyl-4-phenyl-1,3-thiazole (6). The anion of thiazole 2 was generated
analogously to the procedure described above based on initial thiazole 2 (0.1 g, 0.53 mmol). Butyllithium (1 ml,
1.6 mmol) was added at -100°C. After 30 min D2O (0.1 ml, 5.2 mmol) was added, and the mixture was
maintained at -100°C for 30 min. A 1 M aqueous solution of citric acid (20 ml) was then added, and the reaction
mixture allowed to warm to room temperature. The reaction mixture was washed with water (2 × 20 ml), and
with saturated NaCl solution (10 ml), dried over Na2SO4, the solvent evaporated, and the residue dried in an oil
pump vacuum. The yellow oil obtained was purified chromatographically (SiO2, 1% acetone in benzene).
Yield 0.05 g (49%) of a colorless oil.
881

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