Synthesis of 2,5-di(hydroxyalkyl)-1,3-thiazoles

Article abstract of DOI:10.1134/S1070363215080113

A general approach towards synthesis of 2(5)-hydroxyalkyl-substituted 1,3-thiazole derivatives has been proposed. The method includes lithiation of 1,3-thiazole ring followed by reacting the formed thiazole lithium derivatives with electrophiles.

Full text of DOI:10.1134/S1070363215080113

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 8, pp. 1855–1861. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © V.O. Sinenko, S.R. Slivchuk, Ya.G. Bal’on, V.S. Brovarets, 2015, published in Zhurnal Obshchei Khimii, 2015, Vol. 85, No. 8,
pp. 1298–1304.
Synthesis of 2,5-Di(hydroxyalkyl)-1,3-thiazoles
V. O. Sinenkoa, S. R. Slivchuka, Ya. G. Bal’onb, and V. S. Brovaretsa
a Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kiev, 02660 Ukraine
e-mail: brovarets@bpci.kiev.ua
b Komisarenko Institute of Endocrinology and Metabolism, National Academy of Medical Science, Kiev, Ukraine
Received April 23, 2015
Abstract—A general approach towards synthesis of 2(5)-hydroxyalkyl-substituted 1,3-thiazole derivatives has
been proposed. The method includes lithiation of 1,3-thiazole ring followed by reacting the formed thiazole
lithium derivatives with electrophiles.
Keywords: 1,3-thiazole, n-butyllithium, electrophile, diol
DOI: 10.1134/S1070363215080113
Natural and synthetic derivatives of 1,3-thiazole
exhibit a range of biological activities and play
significant part in the processes in living organisms
[1–5]. Compounds possessing psychotropic [6–11] and
nerve blocking [12] effects as well as anticancer drugs
with cytotoxic activity against HT-1080 and MG-22A
cancer cell lines [13] have been found among
representatives of this class. The above-mentioned 1,3-
thiazole derivatives with antitumor activity contain
hydroxyl groups in the molecules; many compounds of
this series are drugs with broad range of the biological
effects [14–20]. Therefore, synthesis of such
compounds is a fairly topical issue.
affords the diols containing primary as well as
secondary alcohol groups.
Commercially available 2-bromo-1,3-thiazole I was
used as the starting reagent. It is known to react with n-
butyllithium to form 2-thiazolyllithium, the latter being
highly reactive towards various electrophiles [24–27]
including aldehydes and N,N-dimethylformamide. For
example, sequential treatment of thiazole 1 with n-
butyllithium and aldehydes as described in [28]
afforded compounds IIa and IIb in high yield. For
further functionalization of 1,3-thiazole ring, the
products IIa and IIb were treated with n-butyllithium,
and then DMF was added. As a result, previously
unknown aldehydes IIIa and IIIb were obtained. Their
reduction with sodium borohydride gave diols IVa and
IVb (Scheme 1).
The earlier reported methods of hydroxyalkyl-1,3-
thiazoles [14–23] are not preparative. Herein, we
propose a suitable approach towards synthesis of the
compounds containing hydroxyalkyl substituents at
positions 2 and 5 of the 1,3-thiazole ring. This method
Isomeric diols IXa and IXb were prepared via a
series of transformations. Initially, 1,3-thiazole-2-
Scheme 1.
(1) n-BuLi
(1) n-BuLi
(2) DMF
(2) R
O
(3) H2O, H+
(3) H2O, H+
N
N
N
N
NaBH4
R
R
R
Br
S
S
S
S
OH
IIa, IIb
OH
IIIa, IIIb
O
OH
IVa, IVb
OH
I
R = Me (a), Ph (b).
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SINENKO et al.
Scheme 2.
(1) n-BuLi
(1) n-BuLi
(2) DMF
(3) H2O, H+
(2) R
O
N
N
OH
N
(3) H2O
R
HO
O
O
R
H
I
S
S
S
OH
O
R
O
O
V
VI
VIIa, VIIb
H2O, H+
N
N
NaBH4
H
S
S
O
OH
OH
VIIIa, VIIIb
OH
IXa, IXb
R = Me (a), Ph (b).
Scheme 3.
(1) n-BuLi
(2) H
O
N
N
S
(3) H2O, H+
NaBH4
H
O
O
N
VI
S
O
OH
O
O
X
XI
N
H2O, H+
NaBH4
H
S
S
O
OH
OH
OH
XII
XIII
Scheme 4.
(1) n-BuLi
(2) H
O
N
S
OH
N
N
(3) H2O, H+
H
HO
O
O
O
H
S
S
O
O
O
XV
XIV
XVI
N
N
H2O, H+
NaBH4
NaBH4
H
O
XIII
S
S
O
O
OH
OH
XVIII
XVII
carbaldehyde V [24] and synthon VI [29] were
prepared; they are capable of selectively reacting with
n-butyllithium to form 5-lithiated 1,3-thiazole [28, 29].
Herein we report for the first time that the lithium
derivative reacted with acetaldehyde or benzaldehyde
to give the secondary alcohols VIIa and VIIb. Hyd-
rolysis of the latter in the presence of p-toluenesulfonic
acid yielded aldehydes VIIIa and VIIIb, structural
isomers of compounds IIIa and IIIb. In turn,
aldehydes VIIIa and VIIIb were reduced into the
corresponding diols IXa and IXd with sodium
borohydride (Scheme 2).
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SYNTHESIS OF 2,5-DI(HYDROXYALKYL)-1,3-THIAZOLES
Table 1. Yields, melting points, and elemental analysis data for compounds III–XVIII
Found, %
Calculated, %
Comp.
no.
Yield,
%
mp, °С
(eluent)
Formula
N
S
N
S
IIIa
58
74
60
80
75
83
42
64
95
79
60
69c
89
85
95
30
78–80 (CH2Cl2–EtOAc, 75 : 25)
68–71 (CH2Cl2–EtOAc, 90 : 10)
Oil (EtOAc)
9.11
6.60
8.95
6.56
7.08
5.61
9.11
6.52
9.02
6.62
9.85
9.79
9.05
7.72
7.69
9.95
20.61
14.83
20.28
14.67
16.04
12.48
20.53
14.72
20.31
14.19
22.56
22.28
20.49
17.38
17.26
22.57
C6H7NO2S
C11H9NO2S
C6H9NO2S
C11H11NO2S
C8H11NO3S
C13H13NO3S
C6H7NO2S
C11H9NO2S
C6H9NO2S
C11H11NO2S
C5H5NO2S
C5H7NO2S
C6H7NO2S
C7H7NO3S
C7H9NO3S
C5H5NO2S
8.91
6.39
8.80
6.33
6.96
5.32
8.91
6.39
8.80
6.33
9.78
9.65
8.91
7.56
7.48
9.78
20.40
14.62
20.14
14.49
15.93
12.18
20.40
14.62
20.14
14.49
22.40
22.09
20.40
17.31
17.13
22.40
IIIb
IVa
IVb
111–113 (CH2Cl2–EtOAc, 50 : 50)
Oil (CH2Cl2–EtOAc, 60 : 40)
Oil (CH2Cl2–EtOAc, 60 : 40)
Oil (CH2Cl2–EtOAc, 90 : 10)
Oil (CH2Cl2–EtOAc, 85 : 15)
Oil (EtOAc–MeOH, 90 : 10)
96–98 (EtOAc)
VIIаа
VIIb
VIIIаb
VIIIb
IXa
IXb
XII
Oil (CH2Cl2–EtOAc, 85 : 15)
XIII
XV
Oil (EtOAc)
d
–
XVI
XVII
XVIII
Oil (CH2Cl2–EtOAc, 90 : 10)
Oil (EtOAc)
105–106 (CH2Cl2–EtOAc, 75 : 25)
a
b
c
The substance was earlier obtained as described in [28]. Compound was earlier with 39% yield as described in [28]. Yield for the
method a. d bp 63°C (0.6 mmHg).
The simplest representative of the diols obtained,
biological properties are currently under study and will
be discussed in the upcoming reports.
2,5-di(hydroxymethyl)-1,3-thiazole XIII, was syn-
thesized as follows. Initially, compound VI was
converted into aldehyde XII and then reduced to diol
XIII with sodium borohydride (Scheme 3).
EXPERIMENTAL
NMR spectra of the solutions in DMSO-d6 were
recorded using
a
Bruker AVANCE DRX-500
Similar reaction starting from the available 1,3-
spectrometer [500 (1H), 125 MHz (13C)] relative to
internal TMS. IR spectra (KBr) were registered with a
Vertex 70 spectrometer. Melting points were
determined using a Fisher Johns instrument. GC–MS
spectra were registered using a liquid chroma-
tography–mass spectrometry system for an Agilent
1100 Series high-performance chromatograph equipped
with a diode array and an Agilent LC\MSD SL mass-
selective detector with rapid ionization mode switching
(positive/negative). Parameters of the GC–MS
analysis: Zorbax SB-C18 column (1.8 μm, 4.6 ×
15 mm, PN 821975-932); solvent A, acetonitrile–water
(95 :5 ) + 0.1% trifluoroacetic acid, solvent B, 0.1%
aqueous solution of trifluoroacetic acid; eluent rate
3 mL min–1; injection volume 1 μL; UV detector at 215,
thiazole-5-carbaldehyde XIV [31] afforded 2-(hyd-
roxymethyl)-1,3-thiazole-5-carbaldehyde XVIII,
a
structural isomer of aldehyde XII. Aldehyde XVIII
was reduced into 2,5-di(hydroxymethyl)-1,3-thiazole
XIII with yield of 83% (Scheme 4).
Composition and structure of the products was
1
confirmed by elemental analysis (Table 1), H, 13C
NMR, and IR spectroscopy data as well as chromato–
mass spectrometry (Table 2).
In summary, we have elaborated a convenient
method to prepare 2,5-di(hydroxyalkyl)-1,3-thiazoles
as well as isomeric pairs III and VIII, X and XVI, XI
and XVII, XII and XVIII, IV and IX, potential
biologically active substances. Their chemical and
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SINENKO et al.
Table 2. Spectral data for compounds IV–XVIII
Comp.
no.
m/z,
ν, cm–1
δН, ppm
δС, ppm
[M + 1]+
IIIa
3204 (O–H), 1.46 d (3H, CH3, JHH 6.3 Hz), 4.98 q (1Н, 187.16 (C2thiazole), 184.3 (С=О), 152.83 158
1672 (C=O) CHOH, JHH 6.3 Hz), 6.38 s (1Н, OH), 8.58 s (C4thiazole), 138.43(C5thiazole), 67.23 (СОН),
(1Н, C4Hthiazole), 10.0 s (1Н, CHO)
23.78 (CH3)
IIIb
3191 (O–H), 6.04 s (1Н, СН ), 7.14 s (1Н, OH), 7.30 t (1Н, 184.9 (C2thiazole), 184.29 (С=О), 152.78 220
1667 (C=O) C6H5, JHH 7.2 Hz), 7.37 t (2Н, C6H5, JHH (C4thiazole), 138.52 (C5thiazole), 141.83, 128.46,
7.2 Hz), 7.49 d (2Н, C6H5, JHH 7.5 Hz), 8.56 s 128.00, 126.74 (С6Н5), 72.9 (CHOH)
(1Н, C4Hthiazole), 10.02 s (1Н, CHO)
IVa
IVb
3248 (O–H) 1.42 d (3H, CH3), 4.62 s (2H, СН2), 4.87 q 177.55 (C2thiazole), 139.69 (C4thiazole), 139.00 160
(1Н, CHOH, JHH 6.6 Hz), 5.45 s (1Н, OH), (C5thiazole), 66.92 (СОН), 55.91 (СОН),
6.01 s (1Н, OH), 7.49 s (1Н, C4Hthiazole
)
24.27 (CH3)
3338 (O–H) 4.66 s (2H, СН2), 5.93 s (1Н, CHOH), 6.74 s 175.68 (C2thiazole), 143.01 (C5thiazole), 139.11 222
(1Н, OH), 7.28 t (1Н, C6H5, JHH 7.4 Hz), 7.36 t (C4thiazole), 140.25, 128.28, 127.56, 126.49
(2Н, C6H5, JHH 7.4 Hz), 7.48 d (2Н, C6H5, JHH (С6Н5), 72.75 (CH2OH), 55.96 (CHOH)
7.1 Hz), 7.53 s (1Н, C4Hthiazole
)
VIIa
VIIb
3258 (O–H) 1.42 d (3H, CH3, JHH 6.3 Hz), 3.93–4.09 m 166.36 (C2thiazole), 147.97 (C5thiazole), 137.88 202
(4H, OCH2CH2O), 4.97–5.04 m (1Н, CHOH), (C4thiazole), 99.68 (OCHO), 65.15 (CH2CH2),
5.72 s (1Н, OH), 7.62 s (1Н, C4Hthiazole
)
62.60 (CHOH), 25.81 (CH3)
3240 (O–H) 3.93–4.06 m (4H, OCH2CH2O), 5.96 s (1Н, 167.35 (C2thiazole), 144.33 (C5thiazole), 138.95 264
OСНO),
(C4thiazole), 146.75, 128.43, 127.55, 125.96
6.04 d (1Н, CHOH, JHH 4.0 Hz), 6.44 d (1Н, (С6Н5), 99.62 (OCHO), 68.56 (CH2CH2),
OH, JHH 4.0 Hz), 7.27 t (1Н, C6H5, JHH 6.9 Hz), 65.18 (CHOH)
7.36 t (2Н, C6H5, JHH 7.9 Hz), 7.44 d (2Н,
C6H5, JHH 7.9 Hz), 7.63 s (1Н, C4Hthiazole
)
VIIIa 3262 (O–H), 1.47 d (3H, CH3, JHH 6.3 Hz), 5.07–5.15 m 184.98 (С=О), 163.91 (C2thiazole), 155.47 158
1679 (C=O) (1Н, CHOH), 6.03 d (1Н, OH, JHH 3.9 Hz), (C5thiazole), 141.30 (C4thiazole), 62.88 (CHOH),
8.07 s (1Н, C4Hthiazole), 9.87 s (1Н, CHO)
25.70 (CH3)
VIIIb 3348 (O–H), 6.15 d (1Н, CHOH, JHH 4.2 Hz), 6.72 d (1Н, 184.94 (С=О), 164.57 (C2thiazole), 153.75 220
1684 (C=O) OH, JHH 4.2 Hz), 7.29 t (1Н, C6H5, JHH 7.4 Hz), (C5thiazole), 142.09 (C4thiazole), 143.7, 128.6,
7.37 t (2Н, C6H5, JHH 7.4 Hz), 7.46 d (2Н, 127.85, 126.09 (С6Н5), 68.69 (CHOH)
C6H5, JHH 7.4 Hz), 8.03 s (1Н, C4Hthiazole), 9.86
s (1Н, CHO)
IXa
IXb
XII
3236 (O–H) 1.41 d (3H, CH3, JHH 6.6 Hz), 4.65 d (2H, СН2, 172.11 (C2thiazole), 145.65 (C5thiazole), 137.26 160
JHH 5.8 Hz), 5.00–4.92 m (1Н, СН), 5.58 d (C4thiazole), 62.62 (СОН), 61.03 (СОН),
(1Н, OH, JHH 4.4 Hz), 5.93 t (1Н, OH, JHH 25.85 (CH3)
5.7 Hz), 7.48 s (1Н, C4Hthiazole
)
3315 (O–H) 4.63 s (2H, СН2), 5.93 s (1Н, OH), 5.99 s (1Н, 173.27 (C2thiazole), 144.43 (C5thiazole), 138.41 222
CHOH), 6.3 s (1Н, OH), 7.26 t (1Н, C6H5, JHH (C4thiazole), 144.64, 128.32, 127.38, 125.95
6.9 Hz), 7.35 t (2Н, C6H5, JHH 6.9 Hz), 7.42 d (С6Н5), 68.67 (CH2OH), 61.04 (CHOH)
(2Н, C6H5, JHH 7.5 Hz), 7.49 s (1Н, C4Hthiazole
)
3211 (O–H), 4.8 s (2H, СН2), 5.9 s (1Н, OH), 8.07 s (1Н, 184.87 (С=О), 164.54 (C2thiazole), 149.97 144
1682 (C=O) C4Hthiazole), 9.88 s (1Н, CHO) (C5thiazole), 142.3 (C4thiazole), 56.21 (СH2ОН)
3227 (O–H) 4.63 s (2H, СН2), 4.67 s (2H, СН2), 5.48 s (1Н, 173.14 (C2thiazole), 140.01 (C5thiazole), 139.00 146
XIII
XV
OH), 5.96 s (1Н, OH), 7.52 s (1Н, C4Hthiazole
)
(C4thiazole), 61.05 (СОН), 55.85 (СОН)
–
3.98–4.13 m (4H, OCH2CH2O), 6.17 s (1Н, 157.17 (C2thiazole), 134.85 (C4thiazole), 134.34 158
СН), 7.93 s (1Н, C4Hthiazole), 8.77 s (1Н, C2Hthiazole) (C5thiazole), 97.30 (OCHO), 68.38 (CH2CH2)
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SYNTHESIS OF 2,5-DI(HYDROXYALKYL)-1,3-THIAZOLES
Table 2. (Contd.)
Comp.
ν, cm–1
no.
m/z,
[M + 1]+
δН, ppm
δС, ppm
XVI
1687 (C=O) 3.96–4.09 m (4H, OCH2CH2O), 6.26 s (1Н, 185.04 (С=О), 166.13 (C2thiazole), 144.43 186
СН), 8.3 s (1Н, C4Hthiazole), 9.92 s (1Н, CHO) (C4thiazole), 144.41 (C5thiazole), 97.3 (OCHO),
65.17 (CH2CH2)
XVII 3236 (O–H) 3.96–4.09 m (4H, OCH2CH2O), 4.83 s (2H, 163.45 (C2thiazole), 145.63 (C5thiazole), 135.95 188
СН2), 5.9 s (1Н, OH), 5.96 s (1Н, OСНO ), (C4thiazole), 98.61 (OCHO), 67.56 (CH2CH2),
7.60 s (1Н, C4Hthiazole
)
67.17 (CHOH)
XVIII 3244 (O–H), 4.79 s (2H, СН2), 6.35 s (1Н, OH), 8.56 s 184.16 (С=О), 183.44 (C2thiazole), 152.85 144
1661 (C=O) (1Н,C4Hthiazole), 10.01 s (1Н, CHO)
(C4thiazole), 138.35 (C5thiazole), 61.36 (СH2ОН)
254, 265 nm; ionization method – chemical ionization
at atmospheric pressure (APCI), scan range m/z 80–
1000. Elemental analysis was performed in the
Institute of Bioorganic Chemistry and Petrochemistry
of National Academy of Sciences of Ukraine. The
reaction progress was monitored by TLC on Silufol
UV-254 plates eluting with CH2Cl2–EtOAc mixture
and detecting with UV light. The obtained compounds
were purified via column chromatography (Silica gel
60, 230–400 mesh).
portionwise to a solution of 0.008 mol of compound
IIIa in 6 mL of tetrahydrofuran and 3 mL of methanol
cooled at 5°C. The mixture was stirred during XII h;
the solvent was removed under reduced pressure. The
residue was purified by chromatography (EtOAc).
[5-(Hydroxymethyl)-1,3-thiazol-2-yl](phenyl)-
methanol (IVb) was prepared similarly to thiazole
IIIb from aldehyde IVa.
1-[2-(1,3-Dioxolan-2-yl)-1,3-thiazol-5-yl]ethan-1-
ol (VIIa). A solution of n-butyllithium in hexane
(70.4 mL, 2.5 mol/L) was added dropwise to a solution
of 0.146 mol of compound VI in 250 mL of tetra-
hydrofuran at –80 to –70°C over 0.5 h. The mixture
was stirred during 1 h, and then 0.22 mol of acetal-
dehyde was added dropwise at –70 to –60°C. The
reaction mixture temperature was adjusted to –20°C
for 0.5 h. Next, 68 mL of water was added dropwise,
and the mixture was stirred during 2 h at 20–25°C. The
organic layer was separated; the aqueous layer was
extracted with ethyl acetate and dried over sodium
sulfate. The solvent was removed under reduced
pressure, and the residue was purified by chromato-
graphy (CH2Cl2–EtOAc, 60 : 40).
1-(1,3-Thiazol-2-yl)ethanol IIa [30], phenyl(1,3-
thiazol-2-yl)methanol IIb [28], 1,3-thiazole-2-car-
baldehyde V [24], 2-(1,3-dioxolan-2-yl)-1,3-thiazole
VI [29], 2-(1,3-dioxolan-2-yl)-1,3-thiazole-5-carbal-
dehyde X, and [2-(1,3-dioxolan-2-yl)-1,3-thiazol-5-yl]-
methanol XI [28] were prepared via the earlier
reported methods.
2-(1-Hydroxyethyl)-1,3-thiazole-5-carbaldehyde
(IIIa). A solution of n-butyllithium in hexane (68 mL,
2.5 mol/L) was added dropwise to a solution of
0.077 mol of compound IIa in 150 mL of tetrahydro-
furan at –80 to –70°C over 0.5 h. The mixture was
stirred during 1 h, and then 0.116 mol of dimethyl-
formamide was added dropwise at –70 to –60°C. The
reaction mixture was stirred during XII h. Then,
170 mL of 15% acetic acid solution was added
dropwise. The mixture was extracted with ethyl
acetate; the organic layer was dried over sodium
sulfate. After the solvent removal, the residue was
purified via chromatography (CH2Cl2–EtOAc, 75 : 25).
[2-(1,3-Dioxolan-2-yl)-1,3-thiazol-5-yl](phenyl)-
methanol (VIIb) was prepared similarly from
0.366 mol of compound VI, 176 mL of 2.5 mol/L n-butyl-
lithium hexane solution, and 0.55 mol of benzaldehyde.
5-(1-Hydroxyethyl)-1,3-thiazole-2-carboxaldehyde
(VIIIa). 0.0006 mol of p-toluenesulfonic acid was
added to a solution of 0.006 mol of compound VIIa in
10 mL of acetonitrile and 4 mL of water. The mixture
was refluxed during 9 h. After cooling to 20°C, 20 mL
of ethyl acetate was added. The organic layer was
separated, the solvent was removed under reduced
2-[Hydroxy(phenyl)methyl]-1,3-thiazole-5-carbal-
dehyde (IIIb) was prepared similarly from phenyl(1,3-
thiazol-2-yl)methanol IIb.
1-[5-(Hydroxymethyl)-1,3-thiazol-2-yl]ethan-1-ol
(IVa). 0.004 mol of sodium borohydride was added
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 8 2015

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SINENKO et al.
2. Metzger, J.V., Comprehensive Heterocyclic Chemistry,
pressure, and the residue was purified by chromato-
graphy (CH2Cl2–EtOAc, 80 : 20).
New York: Pergamon, 1984, vol. 6, p. 235.
3. Wu, Y.-J. and Yang, B.V., Prog. Heterocycl. Chem.,
2007, vol. 18, p. 247. DOI: 10.1016/S0959-6380(07)
80013-4.
5-[Hydroxy(phenyl)methyl]-1,3-thiazole-2-car-
baldehyde (VIIIb) was prepared similarly from [2-
(1,3-dioxolan-2-yl)-1,3-thiazol-5-yl](phenyl)methanol
VIIb.
4. Wu, Y.-J., Top. Heterocycl. Chem., 2012, vol. 29,
p. 307. DOI: 10.1007/7081_2012_78.
1-[2-(Hydroxymethyl)-1,3-thiazol-5-yl]ethan-1-ol
(IXa) and [2-(hydroxymethyl)-1,3-thiazol-5-yl]-
(phenyl)methanol (IXb) were synthesized from
aldehydes VIIIa and VIIIb according to the procedure
described for compound IVa.
5. Gaumont, A.-C., Gulea, M., and Levillain, J., Chem.
Rev., 2009, vol. 109, p. 1371. DOI: 10.1021/cr800189z.
6. Dwivedi, C., Gupta, T.K., and Parmar, S., J. Med.
Chem., 1972, vol. 15, p. 553. DOI: 10.1021/jm00275a031.
7. Chaudhari, S.K., Verma, M., Chaturvedi, A.K., and
Parmar, S.S., J. Pharm. Sci., 1975, vol. 64, p. 614. DOI:
10.1002/jps. 2600640407.
5-(Hydroxymethyl)-1,3-thiazole-2-carbaldehyde
(XII) was prepared similarly to compound VIIIa from
the thiazole XI.
8. El-Feky, S.A.H. and El-Samii, Z.K.A., Arch. Pharm.,
1991, vol. 324, p. 381. DOI: 10.1002/ardp.19913240613.
2,5-Di(hydroxymethyl)-1,3-thiazole (XIII). a.
0.005 mol of sodium borohydride was added
portionwise to a solution of 0.01 mol of compound XII
in 6 mL of tetrahydrofuran and 3 mL of methanol
cooled to 5°C. The mixture was stirred during 9 h, the
solvent was removed under reduced pressure, and the
residue was purified by chromatography (EtOAc).
9. Trapani, G., Carotti, A., Franco, M., Latrofa, A.,
Genchi, G., and Liso, G., Eur. J. Med. Chem., 1993,
vol. 28, p. 13. DOI: 10.1016/0223-5234(93)90074-O.
10. Tsutsumi, S., Okonogi, T., Shibahara, S., Ohuchi, S.,
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11. Ergeneand, N. and Capan, G., Farmaco, 1994, vol. 49,
b. Compound XIII was also prepared from
compound XVIII according to the above procedure in
83% yield.
p. 133.
12. Stenlake, J.B., Dhar, N.C., Henderson, C.F., Machr, R.B.,
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14. Xue, C., Metcalf, B.W., Han, A., Robinson, D.J.,
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2005/192302, 2005.
15. Burgess, G., Pat. WO 2012/114223, 2012.
16. Jacobs, R.T., Klimas, M.T., Ohnmacht, C.J., and
Terpko, M.O., US Patent 5512575, 1996.
17. Kuzmich, D., Disalvo, D., and Razavi, H., WO Patent
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18. Zhang, X., Hufnagel, H., Hou, C., Johnson, D.L., Sui, Z.,
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5-(1,3-Dioxolan-2-yl)-1,3-thiazole (XV). 0.0215 mol
of p-toluenesulfonic acid was added to a solution of
0.43 mol of 1,3-thiazole-5-carbaldehyde XIV [31] and
1.5 mol of ethylene glycol in 500 mL of benzene. The
mixture was heated during 8 h with a Dean–Stark trap,
and then 500 mL of water was added. The mixture was
extracted with ethyl acetate. The extract was dried over
sodium sulfate and evaporated. The residue was
distilled in vacuum.
5-(1,3-Dioxolan-2-yl)-1,3-thiazole-2-carbaldehyde
(XVI) was prepared similarly to compound IIIa from
5-(1,3-dioxolan-2-yl)-1,3-thiazole XV.
[5-(1,3-Dioxolan-2-yl)-1,3-thiazol-2-yl]methanol
(XVII) was obtained from 5-(1,3-dioxolan-2-yl)-1,3-
thiazole-2-carbaldehyde XVI following the procedure
described for compound IVa.
5-(Hydroxymethyl)-1,3-thiazole-2-carbaldehyde
(XVIII) was prepared from compound XVII similarly
to aldehyde VIIIa.
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