Synthesis and properties of pyrazole carbaldehyde bis(2-hydroxyethyl)- dithioacetal hydrochlorides

Article abstract of DOI:10.1007/s10593-012-0927-0

A simple method has been developed for the synthesis of water-soluble pyrazole derivatives, namely 4-[bis(2-hydroxyethylsulfanyl)methyl]pyrazoles hydrochlorides, by the reaction of a series of pyrazole carbaldehydes with 2-mercaptoethanol in the presence

Full text of DOI:10.1007/s10593-012-0927-0

Chemistry of Heterocyclic Compounds, Vol. 47, No. 11, February, 2012 (Russian Original Vol. 47, No. 11, November, 2011)
SYNTHESIS AND PROPERTIES OF PYRAZOLE
CARBALDEHYDE BIS(2-HYDROXYETHYL)-
DITHIOACETAL HYDROCHLORIDES*
L. K. Papernaya1**, A. A. Shatrova1, A. I. Albanov1,
E. V. Rudyakova1, and G. G. Levkovskaya1
A simple method has been developed for the synthesis of water-soluble pyrazole derivatives, namely
4-[bis(2-hydroxyethylsulfanyl)methyl]pyrazoles hydrochlorides, by the reaction of a series of pyrazole
carbaldehydes with 2-mercaptoethanol in the presence of trimethylchlorosilane. When treated with
aqueous ammonia solution the pyrazole-4-carbaldehydes bis(2-hydroxyethyl)dithioacetal hydro-
chlorides are converted to the 4-[bis(2-hydroxyethylsulfanyl)methyl]pyrazole free bases.
Keywords: bis(2-hydroxyethyl)dithioacetals, 2-mercaptoethanol, 1,3-oxathiolane, pyrazole carbaldehydes,
trimethylchlorosilane, acetalization.
Protection of carbonyl compounds by conversion to acetals, thioacetals, and oxathioacetals is a generally
used method for the synthesis of important natural and polyfunctional compounds [1-4]. Oxathioacetals and
dithioacetals are widely used in synthetic practice in reactions involving ring expansion [5, 6] or opening [7], as
generators of an acyl anion [8-11], or in reactions to lengthen a carbon chain [12-14]. Functionalized thioacetals
are synthons for preparation of benzofuran and indole classes of compounds which are widely used in medicinal
practice [15]. Cyclic thioacetals (oxathiolanes) are efficiently converted to acetals [16] or monosulfoxides [17]
and chiral 1,3-oxathiolanes are valuable structural fragments for the enantioselective synthesis of -hydroxy-
aldehydes and -hydroxyacids [8-11].
At the same time many dithiolanes and oxathiolanes are a constituent part of a lipoic acid with
characteristic pharmacological properties close to that of the group B vitamins. A five-membered oxathiolane
ring appears in the composition of nucleoside analogs having powerful antiviral activity [18-20], in particular in
Lamivudine which is primarily used in the treatment of hepatitis B and HIV infections.
Syntheses of open-chain and cyclic oxathioacetals and dithioacetals are based on condensation of
carbonyl compounds with thiols, dithiols, and mercaptoalkanols and are catalyzed by protonic acids [21, 22],
Lewis acids [23-26], Bu4NBr3 [27], SO2 [28], and Amberlyst-15 ion exchange resin [29]. At the same time
_______
*Dedicated to Academician M. G. Voronkov on his 90th birthday.
**To whom correspondence should be addressed, e-mail: irk_inst_chem@irioch.irk.ru, papern@irioch.irk.ru.
1A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky St.,
Irkutsk 664033, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1680-1690, November, 2011.
Original article submitted June 28, 2011.
0009-3122/12/4711-1395©2012 Springer Science+Business Media, Inc.
1395

many of existing methods are of low chemoselectivity [21, 22], demand rigorous reaction conditions [21, 22],
use of expensive toxic or poorly available catalysts [27], an inert atmosphere, and are characterized by lengthy
processing [21] or additional work up of the reaction mixture in a course of the product separation [24, 25].
Therefore, search for novel and efficient alternative synthetic routes to oxathioacetals and dithioacetals
occurring under mild conditions is of current importance.
Along with this there are only isolated evidences for the synthesis of bis(2-hydroxyethyl)dithioacetals
from aldehydes and mercaptoethanol. In the study [30] a chemoselective method of synthesis of
bis(2-hydroxyethyl)dithioacetal 2,2'-((4-chlorophenyl)methylene)bis(sulfanediyl)diethanol from 4-chlorobenz-
aldehyde and mercaptoethanol using cerium triflate catalyst has been proposed. In another study [31]
acetalyzation of 3-nitrobenzaldehyde by mercaptoethanol to form the corresponding bis(2-hydroxyethyl)-
dithioacetal was performed using NaHSO4-SiO2.
Open-chain or cyclic acetals and thioacetals of the pyrazole series are little known or studied. Pyrazole
is an important structural component in the synthesis of current pharmaceutical preparations which possess
analgesic, anti-inflammatory, antibacterial, or antidepressant activity [32] and also of insectoacaricides [33],
dyes, luminophors, and ligands [34]. It is evident that introduction of acetal function into its structure opens up
still more possibilities for preparation of novel, promising pyrazole derivatives. Hence the development of
water-soluble pyrazole derivatives is of particular practical value.
We have recently shown that pyrazole carbaldehydes and mercaptoethanol react in the presence of
trimethylchlorosilane (Me3SiCl) to give bis(2-hydroxyethyl)dithioacetals hydrochlorides [35].
Within the scope of these investigations we have examined in detail the acetalyzation reaction of
formyl-substituted pyrazoles by mercaptoethanol showing that its course depends on the reaction conditions and
the ratio of starting reagents. We have synthesized several pyrazole bis(2-hydroxyethyl)dithioacetals and their
hydrochlorides. Condensation of pyrazole carbaldehydes with 2-mercaptoethanol was carried out in the presence
of Me3SiCl which was used as both medium and as catalyst, similarly to previously reported work [35].
For the first time we have found that acetalyzation of the pyrazole carbaldehydes 1a-f with a twofold
excess of 2-mercaptoethanol readily takes place to form the pyrazole series bis(2-hydroxyethyl)dithioacetal
hydrochlorides 2a-f (Scheme 1).
Scheme 1
OH
OH
OH
OH
S
S
S
S
Me
Me
O
Me
Me3SiCl
20–22°C
5% NH3
20–22°C
OH
N
.
N
HCl
+ 2 HS
N
Me
N
R
Me
N
R
Me
N
R
4a–f
2a–f (87–96%)
a R = Me, b R = Pr, c R = All, d R = Bn, e R = p-NO2C6H4, f R = i-Pr
1a–f
Reaction of equimolar amounts of the pyrazole carbaldehyde 1d with 2-mercaptoethanol under the
optimal conditions for synthesis of aryloxathiolanes from nitrobenzaldehydes [36] gave a mixture of the bis(2-
hydroxyethyl)dithioacetal hydrochloride 2d and 4-(1,3-oxathiolan-2-yl)pyrazole hydrochloride 3d in the ratio
1
5:1 as judged by H NMR data (Scheme 2). Moreover, unreacted starting aldehyde remained in the reaction
mixture (conversion about 60%).
Hence, in contrast to the nitrobenzaldehydes which formed the aryl-(1,3-oxathiolanes) with good
selectivity using an equimolar amount of 2-mercaptoethanol without heating, the reaction of pyrazole
carbaldehyde 1d under analogous conditions occurred with primary formation of dithioacetal 2d, similarly to its
reaction with a twofold amount of mercaptoethanol. This observation indicates a major tendency of the
carbaldehyde group of 4-formylpyrazoles to react with the thiol fragment of mercapto alcohol according to
1396

principles of hard and soft acids and bases (HSAB) in the presence of the trimethylchlorosilane and this needs
further detailed study.
Scheme 2
O
S
Me
OH
Me3SiCl
20–22°C
.
N
HCl
2d
+
+
Me
1d
N
HS
Bn
3d
The 2-(pyrazol-4-yl)-1,3-oxathiolane hydrochloride 3f was prepared in quantitative yield by heating the
pyrazole carbaldehyde 1f with an equimolar amount of mercaptoethanol (Scheme 3).
Scheme 3
O
S
Me
OH
Me3SiCl
1f
+
.
HCl
N
Me
HS
CH2Cl2, 40°C
N
Me
Me
3f
A possible route for formation of the products 2 and 3 is given in Scheme 4. Depending on the reaction
conditions, a condensation of one or two of the thiol groups of the mercaptoethanol with the aldehyde function
occurs.
The synthesis method (mercapto alcohol being added in small portions to a solution of the aldehyde in
excess of Me3SiCl) allows us to deduce that the Me3SiCl demonstrates the properties of a Lewis acid [37] rather
than a silylating agent in this process. Further, the complex formed is subsequently converted to the addition
product of the mercapto alcohol as shown in Scheme 4.
Finally, we do not exclude the possibility of forming the -chlorothioether HOCH2CH2SCHRCl,
similarly to [38], previously noted for the reaction of formaldehyde with thiols which subsequently react in
accordance with the HSAB principle to give the target dithioacetals.
Continuation of our work will be directed to identifying methods of acetals formation in these processes.
The advantage of using Me3SiCl in the aldehydes acetalyzation reaction includes a possibility of
performing the reaction in mild reaction conditions. A further useful attribute of Me3SiCl is that no any
hygroscopic agents are needed since the water evolved in the synthetic process binds with the Me3SiCl to give
hexamethyldisiloxane and hydrogen halide which promotes formation of the products 2 and 3. The hydrogen
halide formed in the hydrolysis of Me3SiCl then increases the catalytic activity of the system. In turn, the
hexamethyldisiloxane and excess of Me3SiCl are readily removed from the reaction products after its
completion.
It should be particularly noted that all of the studied reactions of the 4-formylpyrazoles with
mercaptoethanol in the presence of Me3SiCl lead to formation of the pyrazole carbaldehyde dithioacetal
hydrochlorides 2a-f or to 4-(1,3-oxathiolan-2-yl)pyrazoles 3d,f. The ability of the pyrazoles to form
hydrohalides is determined by the presence in their structures of "pyridine" type nitrogen atoms with increased
nucleophilicity [39].
1397

Scheme 4
Cl
SiMe3
OH
H
O
OH
R
HS(CH ) OH
R
RCH=O + Me3SiCl
+
2 2
S
H
– Me3SiCl
Cl
SiMe3
HS(CH2)2OH
2a–f
– Me3SiCl,
– H2O
Me3SiCl
O
H
H
S
OH
R
3d,f
2a–f
3d,f
– Me3SiCl,
– H2O
HS(CH2)2OH
– H2O, – H+
+
H
H
S
O
H+
OH
R
H
+
–H O,
– H
2
2Me3SiCl + H2O
Me3SiOSiMe3 + 2HCl
It is known that pyrazole hydrochlorides are unstable but, with the presence of another nucleophilic
center in the pyrazole structure (e.g. a double bond), the reaction can occur by two routes. Thus, for example,
hydrochlorination of alkenyl- or allyl pyrazoles with hydrogen chloride occurs at the N-2 atom only upon
cooling (-70ºC). At room temperature the process takes place with participation of the alkenyl substituent [40].
For the studied pyrazole with allyl substituent at position 1 of the pyrazole ring (as for other pyrazole
carbaldehydes) we have obtained a stable hydrochloride by quaternization at the N-2 atom and this was
identified by 1H, 13C, and 15N NMR methods.
The synthesized pyrazole hydrochlorides 2a-f are oily substances which are stable to storage for several
months at 5-6ºC. They are readily soluble in water.
We have prepared the free bases of the 4-[bis(2-hydroxyethylsulfanyl)methyl]pyrazoles 4a-f (Scheme 1)
by treating the hydrochlorides 2a-f with a diluted aqueous ammonia solution. The bis(2-hydroxyethyl)-
dithioacetals 4a-f can also be prepared by a one-pot method from the starting compounds 1a-f by treatment of
the products 2a-f with 5-7% aqueous ammonia solution without isolation from the reaction mixture.
1
Structures of the synthesized compounds 2a-f, 4a-f were determined by IR, H, 13C, and 15N NMR
spectroscopy and confirmed by elemental analysis and mass spectrometric data.
Hydrochlorides of all of the studied compounds 2a-f are characterized by a low-field shift of the
resonance for the methyl groups protons in positions 3 and 5 of the ring (0.16-0.27 ppm) relative to the free
1
bases 4a-f. In addition, the H NMR spectra of compounds 2a-f show a low-field shift of the resonance for the
SCHS group proton (0.17-0.23 ppm). The shift of the -carbon atom protons signals of the alkyl substituent at
position N-1 when going to the hydrochlorides 2a-f depends on the R substituent. Hence, for compound 2a
(R = Me) the value of the low-field shift is 0.27 ppm while for the hydrochloride 2f (R = i–Pr) this value is
0.43 ppm.
1398

The 13C NMR spectra of compounds 2a-f show deshielding of the carbon atom at the position 4 of the
ring (~ 3-4.4 ppm) and at ring position 3 (~ 5-6.5 ppm). There are also observed shielding of the C-5 atom
(1.5-2.2 ppm) and shielding of the carbon atom of the methyl group on C-5. These changes in chemical shifts of
the ring carbons do not correspond to those observed by Grant and Pugmire for symmetrically unsubstituted
pyrazole [41]. With protonation the chemical shifts of the C-3 and C-5 carbon atoms are shifted by 0.5 ppm to
low field and the chemical shift of the C-4 atom by 3.6 ppm. This conflict can be explained both by a greater
degree of localization of the positive charge on the pyridine N-2 atom and by the electronic effect of methyl
substituents on the ring carbon atoms.
Protonation at the "pyridine" nitrogen atom (N-2) is unambiguously indicated by 2D 15N–1H HMBC
correlation spectra for the N-propyl-substituted pyrazole 4b and its hydrochloride 2b. In the neutral molecule
chemical shifts in the 15N NMR spectrum are -177.5 (N-1) and -110.7 ppm (N-2). Protonation leads to a
substantial high-field shift for atom N-2 of 70 ppm but a relatively small shielding of the N-1 atom by 10 ppm.
Such changes in chemical shifts are also characteristic for other N-1-substituted pyrazoles [42]. The presence of
a broad NH+ stretching band at 2500-2800 cm-1 in the IR spectra also points to protonation of the N atom of the
heterocycle.
Thus for the first time we have found mild and convenient conditions for preparation of water-soluble
pyrazole derivatives which are stable under usual conditions. Reaction of pyrazole carbaldehydes with a twofold
excess of 2-mercaptoethanol in the presence of trimethylchlorosilane leads to a chemoselective formation of the
water-soluble pyrazole bis(2-hydroxyethyl)dithioacetals hydrochlorides. For an equimolar ratio of reagents at
room temperature the process is also principally directed to formation of the dithioacetal hydrochlorides. When
treated with aqueous ammonia solution (5-7%) the quaternized pyrazole derivatives form the corresponding
pyrazolylbis(2-hydroxyethyl)dithioacetal free bases.
EXPERIMENTAL
1
IR spectra were recorded on a Bruker Vertex 70 spectrometer and H, 13C, and 15N NMR spectra on a
Bruker DPX-400 (400, 100, and 40 MHz respectively) with TMS as internal standard. Electron impact mass
spectra (70 eV) were recorded on a Shimadzu GCMS-QP5050A quadrupole mass analyzer (mass detection
range 34-650 Da) using direct introduction of the sample into the ion source. The output temperature was varied
from 30 to 200ºC depending on the volatility of the sample. Melting points were determined on a Boetius block.
Monitoring of a reaction course and obtained compounds purity was carried out on Merck Silica Gel 60 F254
plates in the system chloromethylene–methanol (95:5) and revealed using 0.5-1.0% aqueous KMnO4 solution.
The aldehydes 1a-f were prepared by Vilsmeier-Haack formylation [43] of the corresponding 1,3,5-tri-
substituted pyrazoles synthesized from 3,5-dimethylpyrazole, alkyl halides, allyl bromide, or 4-fluoronitro-
benzene under indole alkylation conditions [44] and characterized in the report [45].
Commercial 1,2-mercaptoethanol and Me3SiCl from the Aldrich company were used without additional
purification.
Pyrazole Series Dithioacetal Hydrochlorides 2a-f (General Method). 2-Mercaptoethanol (0.156 g,
2 mmol) was added dropwise with stirring to a mixture of the aldehyde 1a-f (1 mmol) and Me3SiCl (0.77 ml,
6 mmol). The reaction is accompanied by spontaneous heating and the reaction mixture separated into two
layers. After 15-20 min stirring at room temperature the upper layer was separated and the viscous residue was
washed with hexane, then with ether, and dried in vacuo.
2,2'-{[(1,3,5-Trimethyl-1H-pyrazol-4-yl)methanediyl]disulfanediyl}diethanol Hydrochloride (2a).
1
Yield 0.304 g (97%). H NMR spectrum (CD3OD), , ppm (J, Hz): 2.50 (3H, s, CH3); 2.51 (3H, s, CH3); 2.69
2
3
2
3
(2H, dt, J = 13.7, J = 6.3) and 2.81 (2H, dt, J = 13.7, J = 6.3, 2 CH2S); 3.78 (4H, m, 2CH2O); 3.95 (3H, s,
NCH3); 5.42 (1H, s, SCHS). 13C NMR spectrum, , ppm: 10.3 (CH3); 10.6 (CH3); 35.8 (NCH3); 36.2 (CH2S);
43.5 (SCHS); 62.8 (CH2O); 119.8 (C-4); 144.2 (C-3); 145.8 (C-5). Found, %: C 42.08; H 6.74; Cl 11.29;
N 8.91; S 20.43. C11H20N2O2S2·HCl. Calculated, %: C 42.23; H 6.77; Cl 11.33; N 8.95; S 20.50.
1399

2,2'-{[(3,5-Dimethyl-1-propyl-1H-pyrazol-4-yl)methanediyl]disulfanediyl}diethanol Hydrochloride
1
(2b). Yield 0.315 g (92%). IR spectrum (thin film), , cm-1: 3334 (OH), 2850-2300 (NH+). H NMR spectrum
(CD3OD), , ppm (J, Hz): 0.90 (3H, t, CH2CH3); 1.85 (2H, m, CH2CH3); 2.48 (3H, s, CH3); 2.50 (3H, s, CH3);
2.64 (2H, m) and 2.79 (2H, m, 2CH2S); 3.69 (4H, m, 2CH2O); 4.25 (2H, s, NCH2); 5.39 (1H, s, SCHS). 13C
NMR spectrum, , ppm: 10.3 (CH3); 10.6 (CH3); 10.8 (CH2CH3); 23.6 (CH2CH3); 36.0 (CH2S); 43.4 (SCHS);
51.2 (NCH2); 62.6 (CH2O); 119.6 (C-4); 144.6 (C-5); 145.0 (C-3). 15N NMR spectrum, , ppm: -167.5 (N-1);
-40.7 (N-2). Found, %: C 45.64; H 7.37; Cl 10.44; N 8.19; S 18.74. C13H24N2O2S2·HCl. Calculated, %: C 45.80;
H 7.39; Cl 10.40; N 8.22; S 18.81.
2,2'-{[(3,5-Dimethyl-1-(prop-2-en-1-yl)-1H-pyrazol-4-yl)methanediyl]disulfanediyl}diethanol Hydro-
1
chloride (2c). Yield 0.350 g (95%). IR spectrum (thin film), , cm-1: 3341 (OH), 2840-2500 (NH+). H NMR
spectrum (CD3OD), , ppm (J, Hz): 2.52 (3H, s, CH3); 2.53 (3H, s, CH3); 2.69 (2H, dt, 2J = 14.2, 3J = 6.1) and
2.82 (2H, dt, 2J = 14.2, 3J = 6.1, 2CH2S); 3.71 (2H, dt, 2J = 11.1, 3J = 6.3) and 3.76 (2H, dt, 2J = 11.1, 3J = 6.3,
2CH2O); 4.96 (2H, d, 3J = 5.6, NCH2); 5.12 (1H, d, Jtrans = 17.4) and 5.38 (1H, d, Jcis = 10.4, CH2=); 5.45 (1H, s,
SCHS); 6.00 (1H, d, CH=). 13C NMR spectrum, , ppm: 10.2 (CH3); 10.7 (CH3); 36.2 (CH2S); 43.5 (SCHS);
51.7 (NCH2); 62.8 (OCH2); 120.2 (C-4, CH2=); 131.0 (CH=); 145.2 (C-3); 145.6 (C-5); Found, %: C 46.01;
H 6.88; Cl 10.45; N 8.25. S 18.89. C13H22N2O2S2·HCl. Calculated, %: C 46.07; H 6.84; Cl 10.46; N 8.27;
S 18.92.
2,2'-{[(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)methanediyl]disulfanediyl}diethanol Hydrochloride
1
(2d). Yield 0.373 g (96%). IR spectrum (thin film), , cm-1: 3351 (OH), 2826-2507 (NH+). H NMR spectrum
2
3
2
(CD3OD), , ppm (J, Hz): 2.52 (6H, s, 2CH3); 2.70 (2H, dt, J = 13.8, J = 6.3) and 2.83 (2H, dt, J = 13.8,
3J = 6.3, 2CH2S); 3.71 (2H, dt, J = 11.0, J = 6.3) and 3.76 (2H, dt, J = 11.0, J = 6.3, 2CH2O); 5.45 (1H, s,
SCHS); 5.54 (2H, s, NCH2); 7.23 (2H, m, H-2',6'); 7.38 (1H, m, H-4'); 7.42 (2H, m, H-3',5'). 13C NMR spectrum,
, ppm: 10.6 (CH3); 11.0 (CH3); 36.2 (CH2S); 43.7 (SCHS); 53.1 (NCH2); 62.7 (OCH2); 120.1 (C-4); 128.1
(C-2',6'); 129.9 (C-4'); 130.4 (C-3',5'); 134.9 (C-1'); 145.0 (C-5); 145.7 (C-3). Found, %: C 52.45; H 6.46;
Cl 9.10; N 7.19; S 16.50. C17H24N2O2S2·HCl. Calculated, %: C 52.49; H 6.48; Cl 9.11; N 7.20; S 16.49.
2,2'-{[(3,5-Dimethyl-1-(4-nitrophenyl)-1H-pyrazol-4-yl)methanediyl]disulfanediyl}diethanol Hydro-
2
3
2
3
chloride (2e). Yield 0.378 g (90%). IR spectrum (thin film), , cm-1: 3346 (OH), 2750-2300 (NH+). H NMR
1
spectrum (CD3OD), , ppm (J, Hz): 2.41 (3H, s, CH3); 2.47 (3H, s, CH3) 2.69 (2H, dt, 2J = 13.7, 3J = 6.4) and
2.82 (2H, dt, 2J = 13.7, 3J = 6.4, 2CH2S); 3.69 (2H, dt, 2J = 11.0, 3J = 6.4) and 3.74 (2H, dt, 2J = 11.0, 3J = 6.4,
2CH2O); 5.35 (1H, s, SCHS); 7.75 (2H, d, 3J = 9.0, H-2',6'); 8.39 (2H, d, J = 9.0, H-3',5'). 13C NMR spectrum,
, ppm: 11.8 (CH3); 12.7 (CH3); 36.1 (CH2S); 44.8 (SCHS); 62.7 (CH2O); 119.8 (C-4); 125.8; 126.6
(C-2',3',5',6'); 143.0 (C-1' Ar); 144.6 (C-5); 144.7 (C-3); 150.5 (C-4'). Found, %: C 45.62; H 5.31; Cl 8.48;
N 9.98; S 15.34. C16H21N3O4S2·HCl. Calculated, %: C 45.76; H 5.28; Cl 8.44; N 10.01; S 15.27.
2,2'-{[(3,5-Dimethyl-1-(1-methylethyl-1H-pyrazol-4-yl)methanediyl]disulfanediyl}diethanol Hydro-
1
chloride (2f). Yield 0.315 g (93%). IR spectrum (thin film), , cm-1: 3339 (OH), 2715-2450 (NH+). H NMR
spectrum (CD3OD), , ppm (J, Hz): 1.57 (6H, d, 3J = 6.7 CH(CH3)2); 2.55 (3H, s, CH3); 2.56 (2H, s, CH3); 2.69
2
(2H, dt, J = 14.1, 3J = 6.3) and 2.82 (2H, dt, 2J = 14.1, 3J = 6.3, 2CH2S); 3.70 (2H, dt, 2J = 11.3, 3J = 6.3) and
3.76 (2H, dt, 2J = 11.3, 3J = 6.3, 2CH2O); 4.91 (1H, m, NCH); 5.44 (1H, s, SCHS). 13C NMR spectrum, , ppm:
10.4 (CH3); 10.6 (CH3); 21.5 (CH(CH3)2); 36.2 (CH2S); 43.5 (SCHS); 53.7 (NCH); 62.8 (CH2O); 120.0 (C-4);
144.7 (C-3); 145.6 (C-5). Found, %: C 45.76; H 7.38; Cl 10.38; N 8.21; S 18.85. C13H24N2O2S2·HCl.
Calculated, %: C 45.80; H 7.39; Cl 10.40; N 8.22. S 18.81.
3,5-Dimethyl-1-(1-methylethyl)-4-(1,3-oxathiolan-2-yl)-1H-pyrazole Hydrochloride (3f). A syringe
was used to introduce 2-methylmercaptoethanol (0.156 g, 2 mmol) and then Me3SiCl (1.54 ml, 12 mmol) to a
stirred solution of aldehyde 1f (0.332 g, 2 mmol) in dichloromethane (2 ml) with heating to 35-40ºC. After
stirring for 0.5 h at 40ºC the reaction mixture was evacuated in vacuum without heating, the residue was dried
over P2O5. Yield 0.505 g (96%). White crystals, mp 94-96ºC (hexane). IR spectrum (oil), , cm-1: 2719-1871 br.
1
3
3
(NH+). H NMR spectrum (DMSO-d6), , ppm (J, Hz): 1.75 (3H, d, J = 6.4) and 1.76 (3H, d, J = 6.4,
1400

2
3
(CH3)2CH); 2.44 (3H, s, 3-CH3); 2.59 (3H, s, 5-CH3); 3.27 (2H, m, SCH2); 3.82 (1H, ddd, J = 9.4, J = 9.0,
2
3
3
3
3J = 6.8) and 4.57 (1H, ddd, J = 9.4, J = 5.7, J = 3.0, CH2O); 4.73 (1H, sept., J = 6.4, CHN); 5.95 (1H, s,
SCHO). 13C NMR spectrum, , ppm: 10.0 (5-CH3); 10.1 (3-CH3); 21.6 (CH(CH3)2); 34.1 (CH2S); 52.8
(Me2CHN); 71.9 (CH2O); 77.8 (OCHS), 115.3 (C-4); 141.2 (C-5); 144.9 (C-3). Mass spectrum, m/z (Irel, %): 227
[M+1]+ (6), 226 [M]+ (36), 167 (19), 166 (61), 165 (14), 151 (53), 137 (11), 125 (11), 124 (58), 123 (100).
Found, %: C 50.08; H 7.31; Cl 13.44; N 10.61; S 12.25. C11H18N2OS·HCl. Calculated, %: C 50.27; H 7.29;
Cl 13.49; N 10.66; S 12.20.
Preparation of a Mixture of 2,2'-{[(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)methanediyl]disulfane-
diyl}diethanol Hydrochloride (2d) and 1-Benzyl-3,5-dimethyl-4-(1,3-oxathiolan-2-yl)-1H-pyrazole Hydro-
chloride (3d) by Reaction of Aldehyde (1d) with an Equivalent Amount of Mercaptoethanol.
2-Mercaptoethanol (0.234 g, 3 mmol) was added dropwise with stirring to a mixture of aldehyde 1d (0.643 g,
3 mmol) and Me3SiCl (3.08 ml, 24 mmol). The reaction was accompanied by spontaneous heating and formation
of a white, viscous precipitate. After 15 min stirring at room temperature the upper layer was separated and the
oily residue was washed three times with ether, dried in vacuum to give 0.53 g of a 5:1 mixture of the products
2d and 3d.
1
1-Benzyl-3,5-dimethyl-4-(1,3-oxathiolan-2-yl)-1H-pyrazole Hydrochloride (3d). H NMR spectrum
2
(CD3OD), , ppm (J, Hz): 2.46 (3H, s, CH3); 2.47 (3H, s, CH3); 3.32 (2H, m, SCH2); 3.86 (1H, ddd, J = 9.2,
3
2
3
3
3J = 8.9, J = 6.7) and 4.59 (1H, ddd, J = 9.2, J = 5.6, J = 2.9, CH2O); 5.55 (2H, s, NCH2); 6.14 (1H, s,
SCHO); 7.23 (2H, m, H-3',5); 7.42 (3H, m, H-2',4',6'). 13C NMR spectrum, , ppm: 10.1 (5-CH3); 10.3 (3-CH3);
34.9 (CH2S); 53.0 (NCH2); 73.2 (CH2O); 79.1 (OCHS); 117.8 (C-4); 120.2, 128.1, 129.8, and 131.3 (C Ph);
141.2 (C-5); 144.9 (C-3).
Dehydrochlorination of the Pyrazole Dithioacetal Series Salts (General Method). The hydro-
chlorides 2a-f (with the exception of hydrochloride 2e) were dissolved in a small amount of water and a dilute
aqueous ammonia solution (5-7%) was added dropwise until weakly basic to litmus. The oily precipitate as a
lower layer was separated and dissolved in methanol. The aqueous solution was additionally washed with ether
and the combined ether extract and methanol solution were dried in vacuum over P2O5. The hydrochloride 2e
was poorly soluble in water and was treated by dissolving in methanol, addition of a very dilute solution of
NH4OH to a weakly basic medium, extraction with dichloromethane, removal of the organic layer, evacuation,
and drying over P2O5. The freshly prepared 4-[bis(2-hydroxyethylsulfanyl)methyl]pyrazoles 4a-f are oils but
compounds 4b-e crystallize upon storage.
2,2'-{[(1,3,5-Trimethyl-1H-pyrazol-4-yl)methanediyl]disulfanediyl}diethanol (4a). Yield 0.255 g
1
(92%). IR spectrum (thin film), , cm-1: 3308 (OH). H NMR spectrum (CD3OD), , ppm (J, Hz): 2.25 (3H, s,
2
3
2
3
CH3); 2.32 (3H, s, CH3); 2.61 (2H, dt, J = 13.6, J = 6.6) and 2.73 (2H, dt, J = 13.6, J = 6.6, 2CH2S); 3.64
2
3
2
3
(2H, dt, J = 11.0, J = 6.6) and 3.69 (2H, dt, J = 11.0, J = 6.6, 2CH2O); 3.68 (3H, s, NCH3); 5.19 (1H, s,
SCHS). 13C NMR spectrum, , ppm: 10.2 (CH3); 12.3 (CH3); 35.8 (NCH3); 35.9 (CH2S); 44.9 (SCHS); 62.6
(CH2O); 114.9 (C-4); 138.5 (C-3); 145.7 (C-5). Mass spectrum, m/z (Irel, %): 277 [M+1]+ (< 1), 276 [M]+ (< 1),
78 (12), 66 (14), 60 (32), 59 (18), 56 (33), 48 (15), 47 (24), 46 (12), 45 (34). Found, %: C 47.75; H 7.27;
N 10.11; S 23.25. C11H20N2O2S2. Calculated, %: C 47.80; H 7.29; N 10.13; S 23.20.
2,2'-{[(3,5-Dimethyl-1-propyl-1H-pyrazol-4-yl)methanediyl]disulfanediyl}diethanol (4b). Yield
0.259 g (85%). Mp 71-74ºC. IR spectrum (thin film), , cm-1: 3305 (OH). 1H NMR spectrum (CD3OD), , ppm
(J, Hz): 0.87 (3H, t, 3J = 7.3, CH2CH3); 1.75 (2H, m, CH2CH3); 2.28 (3H, s, CH3); 2.34 (3H, s, CH3); 2.62 (2H,
2
3
2
dt, J = 13.7, J = 6.6) and 2.74 (2H, dt, J = 13.7, 3J = 6.6, 2CH2S); 3.64 (2H, dt, 2J = 11.0, 3J = 6.6) and 3.68
2
3
3
13
(2H, dt, J = 11.0, J = 6.6, 2CH2O); 3.97 (2H, t, J = 7.1, NCH2); 5.22 (1H, s, SCHS). C NMR spectrum, ,
ppm: 10.3 (CH3); 12.3 (CH3); 11.2 (CH2CH3); 24.4 (CH2CH3); 36.0 (CH2S); 44.9 (SCHS); 51.0 (NCH2); 62.6
(CH2O); 116.4 (C-4); 139.9 (C-5); 146.8 (C-3). 15N NMR spectrum, , ppm: -177.5 (N-1); -110.7 (N-2). Mass
spectrum, m/z (Irel, %): 305 [M+1]+ (6), 304 [M]+ (< 1), 228 (15), 227 (100), 226 (38), 167 (19), 166 (19), 165
(14), 151 (22), 138 (17), 137 (37), 124 (52), 123 (38), 61 (13), 60 (21), 59 (12), 48 (10), 47 (16), 45 (19). Found,
%: C 51.25; H 7.92; N 9.18; S 21.14. C13H24N2O2S2. Calculated, %: C 51.28; H 7.95; N 9.20; S 21.06.
1401

2,2'-{[(3,5-Dimethyl-1-(prop-2-en-1-yl)-1H-pyrazol-4-yl)methanediyl]disulfanediyl}diethanol (4c).
Yield 0.278 g (92%). Mp 76-78ºC. IR spectrum (thin film), , cm-1: 3338 (OH). 1H NMR spectrum (CD3OD), ,
ppm (J, Hz): 2.28 (3H, s, CH3); 2.31 (3H, s, CH3); 2.62 (2H, dt, 2J = 14.7, 3J = 6.7) and 2.75 (2H, dt, 2J = 13.7,
2
3
2
3
3J = 6.7, 2CH2S); 3.64 (2H, dt, J = 10.9, J = 6.5) and 3.69 (2H, dt, J = 10.9, J = 6.5, 2CH2O); 4.65 (2H, dt,
3J = 4.8, J = 1.5, NCH2); 4.87 (1H, dt, Jtrans = 17.2, J = J = 1.5) and 5.17 (1H, dt, Jcis = 10.5, J = J = 1.5,
CH2=); 5.22 (1H, s, SCHS); 5.92 (1H, m, CH=). 13C NMR spectrum, , ppm: 10.2 (CH3); 12.4 (CH3); 36.0
(CH2S); 44.9 (SCHS); 52.0 (NCH2); 62.6 (CH2O); 116.8 (C-4); 117.4 (CH2=); 134.0 (CH=); 140.2 (C-3); 147.3
(C-5). Mass spectrum, m/z (Irel, %): 303 [M+1]+ (1), 302 [M]+ (< 1), 226 (12), 225 (72), 224 (63), 223 (11), 165
(32), 164 (71), 163 (100), 149 (27), 137 (15), 135 (16), 123 (18), 121 (10), 94 (11), 78 (12), 61 (16), 60 (37), 59
(22), 48 (16), 47 (26), 45 (34). Found, %: C 51.60; H 7.29; N 9.22; S 21.25. C13H22N2O2S2. Calculated, %:
C 51.62; H 7.33; N 9.26; S 21.20.
4
4
2
4
2
2,2'-{[(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)methanediyl]disulfanediyl}diethanol (4d). Yield
0.268 g (76%). Mp 84-86ºC. IR spectrum (thin film), , cm-1: 3393 (OH). 1H NMR spectrum (CD3OD), , ppm
2
3
2
(J, Hz): 2.28 (3H, s, CH3); 2.33 (3H, s, CH3); 2.64 (2H, dt, J = 13.7, J = 6.7) and 2.77 (2H, dt, J = 13.7,
3J = 6.7, 2CH2S); 3.66 (2H, dt, J = 11.0, J = 6.7) and 3.71 (2H, dt, J = 11.0, J = 6.7, 2CH2O); 5.26 (1H, s,
SCHS); 5.26 (2H, s, NCH2); 7.06 (2H, m, H-2',6'); 7.27 (1H, m, H-4'); 7.32 (2H, m, H-3',5'). 13C NMR spectrum,
, ppm: 10.4 (CH3); 12.4 (CH3); 36.0 (CH2S); 44.9 (SCHS); 53.2 (NCH2); 62.6 (CH2O); 117.2 (C-4); 127.5
(C-2',6'); 128.8 (C-4'); 129.8 (C-3',5'); 137.9 (C-1'); 140.3 (C-3); 147.3 (C-5). Mass spectrum, m/z (Irel, %): 352
[M]+ (< 1), 275 (84), 274 (100), 215 (11), 214 (56), 213(75), 199 (29), 185 (10), 91 (100), 78 (13), 65 (28), 61
(14), 60 (14), 59 (11), 45 (18). Found, %: C 57.85; H 6.76; N 7.93; S 18.23. C17H24N2O2S2. Calculated, %:
C 57.92; H 6.86; N 7.95; S 18.19.
2
3
2
3
2,2'-{[(3,5-Dimethyl-1-(4-nitrophenyl)-1H-pyrazol-4-yl)methanediyl]disulfanediyl}diethanol (4e).
Yield 0.368 g (96%). Mp 58-60ºC. IR spectrum (thin film), , cm-1: 3341 (OH). 1H NMR spectrum (CD3OD), ,
ppm (J, Hz): 2.39 (3H, s, CH3); 2.46 (3H, s, CH3); 2.69 (2H, dt, 2J = 13.7, 3J = 6.9) and 2.82 (2H, dt, 2J = 13.7,
2
3
2
3
3J = 6.9 2CH2S); 3.70 (2H, dt, J = 11.1, J = 6.9) and 3.75 (2H, dt, J = 11.1, J = 6.9, 2CH2O); 5.32 (1H, s,
SCHS); 7.73 (2H, d, J = 9.1, H-2',6'); 8.39 (2H, d, J = 9.1, H-3',5'). 13C NMR spectrum, , ppm: 11.9 (CH3);
3
12.9 (CH3); 36.1 (CH2S); 45.0 (SCHS); 62.7 (CH2O); 119.6 (C-4); 125.8; 126.2 (C-2',3',5',6'); 139.9 (C-1');
145.5 (C-3); 147.8 (C-5); 150.9 (C-4'). Found, %: C 50.08; H 5.47; N 10.94; S 16.75. C16H21N3O4S2. Calculated,
%: C 50.11; H 5.52; N 10.96; S 16.72.
2,2'-{[(3,5-Dimethyl-1-(1-methylethyl)-1H-pyrazol-4-yl)methanediyl]disulfanediyl}diethanol (4f).
Yield 0.240 g (79%). IR spectrum (thin film), , cm-1: 3350 (OH). 1H NMR spectrum (CD3OD), , ppm (J, Hz):
1.40 (6H, d, 3J = 6.7, CH(CH3)2); 2.28 (3H, s, CH3); 2.33 (3H, s, CH3); 2.63 (2H, dt, 2J = 13.8, 3J = 6.7) and 2.75
2
3
2
3
2
3
(2H, dt, J = 13.8, J = 6.7, 2CH2S); 3.62 (2H, dt, J = 10.6, J = 6.7) and 3.64 (2H, dt, J = 10.6, J = 6.7,
2CH2O); 4.48 (1H, m, NCH), 5.21 (1H, s, SCHS). 13C NMR spectrum, , ppm: 10.1 (CH3); 12.6 (CH3); 22.5
(CH(CH3)2); 36.0 (CH2S); 45.1 (SCHS); 50.6 (NCH), 62.6 (CH2O); 115.7 (C-4); 138.3 (C-3); 147.1 (C-5). Mass
spectrum, m/z (Irel, %): 305 [M+1]+ (9), 304 [M]+ (< 1), 228 (14), 227 (100), 226 (18), 185 (10), 166 (11), 151
(18), 124 (21), 123 (28), 61 (10), 45 (22). Found, %: C 51.26; H 7.92; N 9.18; S 21.0. C13H24N2O2S2.
Calculated, %: C 51.28; H 7.95; N 9.20; S 21.06.
This work was carried out with the financial support of the Russian Foundation for Fundamental
Investigations (grant 10-03-00256a).
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