Synthesis and oxidation of all isomeric 2-(pyrazolyl)ethanols

Article abstract of DOI:10.1007/s10593-020-02662-z

[Figure not available: see fulltext.] An efficient approach to the preparation of N-substituted 2-(pyrazol-4-yl)ethanols based on recyclization reaction of 3-(dimethoxymethyl)-2-methoxytetrahydrofuran with hydrazines is described. Oxidation by KMnO₄ led to 2-(pyrazol-4-yl)-2-oxoacetic acids. In contrast, 2-(pyrazol-5-yl)ethanol under similar conditions gave only pyrazole-5-carboxylic acid, which formed as a result of oxidation followed by decarbonylation. 2-(Pyrazol-3-yl)ethanol in this oxidation reaction gave a mixture of 2-oxo-2-(pyrazol-3-yl)acetic acid and pyrazole-3-carboxylic acid.

Full text of DOI:10.1007/s10593-020-02662-z

DOI 10.1007/s10593-020-02662-z
Chemistry of Heterocyclic Compounds 2020, 56(3), 320–325
Synthesis and oxidation of all isomeric 2-(pyrazolyl)ethanols
Sergey P. Ivonin1, Eduard B. Rusanov1, Dmitriy M. Volochnyuk1,2,3
*
1 Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
5 Murmanska St., Kyiv 02660, Ukraine
2 Enamine Ltd.,
78 Chervonotkatska St., Kyiv 02094, Ukraine
3 Taras Shevchenko National University of Kyiv,
60 Volodymyrska St., Kyiv 01601, Ukraine; е-mail: d.volochnyuk@gmail.com
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2020, 56(3), 320–325
Submitted January 21, 2020
Accepted February 4, 2020
An efficient approach to the preparation of N-substituted 2-(pyrazol-4-yl)ethanols based on recyclization reaction of 3-(dimethoxy-
methyl)-2-methoxytetrahydrofuran with hydrazines is described. Oxidation by KMnO4 led to 2-(pyrazol-4-yl)-2-oxoacetic acids. In
contrast, 2-(pyrazol-5-yl)ethanol under similar conditions gave only pyrazole-5-carboxylic acid, which formed as a result of oxidation
followed by decarbonylation. 2-(Pyrazol-3-yl)ethanol in this oxidation reaction gave a mixture of 2-oxo-2-(pyrazol-3-yl)acetic acid and
pyrazole-3-carboxylic acid.
Keywords: keto acids, pyrazoles, building blocks, oxidation, recyclization.
Pyrazoles are class of heterocycles which provides
important scaffolds for development of compounds for
medicine,1 agriculture,2 supramolecular chemistry,3 as well
as for materials science.4 Among the diverse pyrazole
derivatives with various beneficial features, compounds
bearing the pyrazole moiety linked with another functional
group or heterocyclic fragment by a linker of two carbon
atoms are of special interest. For example, such compounds
include anxiolytic drug enpiprazole (1),5 5-hydroxy-
tryptamine 1F receptor agonist 2,6 dopamine D3 receptor
antagonist 37 (Fig. 1). Also such pyrazole derivatives were
actively used for the structure–activity relationship studies
as potential γ-secretase modulators8 or PDE8B inhibitors.9
Therefore, compounds of general formula 4 and 5, which
can be used for easy synthesis of the above-mentioned
biologically active compounds, are important building
blocks for medicinal chemistry. The pyrazolylethyl and
pyrazolylacetyl moieties represented by compounds 4 and
5, respectively, are small alkyl substituents which comply
with the "rule of two" (Ro2),10 therefore, compounds 4 and
5 were selected as the targets of our the investigation.
Figure 1. Examples 1–3 of biologically active compounds
containing a pyrazole ring linked to another pharmacophore through
two carbon atoms and building blocks 4, 5 for their synthesis.
0009-3122/20/56(3)-0320©2020 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2020, 56(3), 320–325
Scheme 1
Scheme 2
Surprisingly, the synthesis of such simple compounds has
not been described properly, ready-to-use synthesis proto-
cols as well as characterization data of the compounds
obtained are absent, although these building blocks are
commercially available and mentioned as starting materials
in patents.11 The synthesis of compound 5 (R = Me) was
recently published by us.12 Meanwhile the synthesis and
characteristics of compound 4 with R = Me have not been
described yet. Therefore, continuing our in-house program
directed toward design and synthesis of azolyl-containing
building blocks relevant to medicinal chemistry,13 we
decided to expand their spectrum by compounds 4 and 5.
In an earlier project,12,13a we developed the synthesis of
2-(pyrazol-4-yl)acetic acids 5 starting from commercially
available aldehydes 6 through nitriles 7. In the case of
R = Me the sequence gave 65% yield on TosMIC-mediated
formation of nitrile 7 and 65% on the alkaline hydrolysis
step using about 10 g of the starting compound 6. The scale-up
of the sequence appeared to be problematic, and the
synthesis of 2-(pyrazol-4-yl)ethanol 4 from aldehydes 6
through synthesis and reduction of acid 5 by LiAlH4
proved to be cost-inefficient (Scheme 1). Alternatively, we
decided to investigate the way to compounds 4 via
recyclization reaction of hydrazines with 3-formylated
dihydrofuran 8 which is a synthetic equivalent of malon-
dialdehyde 9 bearing CH2CH2OH function in position 2.
Earlier we used similar approach for the cyclization leading
to fused pyrimidines decorated by CH2CH2OH sub-
stituent.14
Among synthetic equivalents of aldehydes 8, we chose
3-(dimethoxymethyl)-2-methoxytetrahydrofuran (11), easily
accessible from 2,3-dihydrofuran (10) by treatment with
trimethyl orthoformate in the presence of BF3·Et2O
(Scheme 2).15 Moreover the ethyl analog of reagent 11 was
previously tested in similar recyclization reaction with the
parent hydrazine hydrate affording N-unsubstituted
pyrazole 4a.16 The reaction of compound 11 with
substituted hydrazine (alkyl-, sterically hindered alkyl-, and
aryl-substituted) in acidic medium also proceeded smoothly
giving the desired pyrazoles 4b–d. The products were
obtained in 72–95% preparative yields.
Table 1. Oxidation step optimization for the preparation
of oxo acid 13b
Entry
Conditions
Yield*, %
1
2
3
4
5
6
1.2 equiv KMnO4, H2O, K2CO3, 90°C
2.7 equiv KMnO4, H2O, K2CO3, 90°C
NaClO2/TEMPO, MeCN***
17**
64
–*4
1.2 equiv CrO3, 2.4 equiv H2SO4, H2O 70°C
2.5 equiv CrO3, 5 equiv H2SO4, H2O 70°C
7 equiv 30% aq H2O2, 60°C
18
27
–*4
* Isolated yield.
** The 76% of starting material was recovered.
*** The procedure for 2-(4-methoxyphenyl)ethanol oxidation was used.17
*4 No reaction was observed.
to oxidize the alcohol function to carboxylic acids of type 5
using various oxidants failed (Table 1). Under some
standard oxidation conditions (entries 3–6), the complex
reaction mixture formed. In turn, the use of KMnO4 as the
oxidant produced one main product (entries 1, 2). When
2.7 equiv of KMnO4 in slightly alkaline H2O at 90°C were
used oxo acids 13a–d formed in 64–89% preparative yields
(entry 2, see also Scheme 2).
1
The structure of products 13a–d was proved by H,
13C NMR spectroscopy as well as APCI HPLC MS spectro-
metry. It should be noted that in positive mode the [M+H]+
ions of compounds 13a–d were not registered, meanwhile
the [M–H]– ions in negative mode were successfully
detected, which agrees with the structure containing a
carboxylic group. Finally the structure of compound 13b
was unambiguously determined by single X-ray diffraction
study (Fig. 2). Keto acids 13a–c (with unsaturated pyrazole
The oxidation of pyrazolylethanols 4a–d was further
studied for the development of preparative approach to
2-(pyrazol-4-yl)acetic acids. Unexpectedly all our attempts
Figure 2. Molecular structure of compound 13b with atoms
represented as thermal vibration ellipsoids of 50% probability.
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Chemistry of Heterocyclic Compounds 2020, 56(3), 320–325
To sum up, an efficient approach to the preparation of
N-substituted 2-(pyrazol-4-yl)ethanols, relevant to medici-
nal chemistry, was elaborated and optimized, using the
approach based on recyclization of 3-(dimethoxymethyl)-
2-methoxytetrahydrofuran with hydrazines. The oxidation
of 2-(pyrazol-4-yl)ethanols and isomeric 2-(pyrazol-3-yl)-
and 2-(pyrazol-5-yl)ethanols were studied. The oxidation
unexpectedly lead to the corresponding 2-oxo-2-pyrazolyl-
acetic acids, their decarbonylation products, or mixtures
thereof. Such oxidative behavior of different isomeric
2-(pyrazolyl)ethanols is unclear and needs more profound
investigation.
Figure 3. Molecular structure of compound 14 with atoms repre-
sented as thermal vibration ellipsoids of 50% probability.
nitrogen and alkyl substituent at N-1) appeared to be stable
to recrystallization and could be kept at room temperature
during more than 6 months without decomposition.
Meanwhile compound 13d bearing an aryl substituent at
nitrogen atom slowly decomposed at room temperature and
quantitatively underwent decarbonylation upon recrystalli-
zation from EtOH giving acid 14. The structure of
compound 14 also was proved by spectral characterization
and single crystal X-ray diffraction study (Fig. 3).
Such unusual behavior of 2-(pyrazol-4-yl)ethanols 4a–d
upon oxidation prompted us to check another isomeric
2-(pyrazolyl)ethanols in the reaction. The model N-methyl-
2-(1H-pyrazol-3-yl)ethanol (16) was prepared by a BH3·THF
reduction of ester 15 previously synthesized by us.12
Oxidation of alcohol 16 using the conditions described
above led to formation of a mixture of keto acid 17 and the
product of its decarbonylation 18 (Scheme 3). Both
compounds were separated by column chromatography on
SiO2, purified, and characterized. In the case of substitution
at position 5, the model compound 2-(N-methylpyrazol-
5-yl)ethanol (20) was synthesized from N-methylpyrazole
(19) by lithiation with subsequent oxirane treatment.
Oxidation of alcohol 16 under the conditions described
above led to formation of decarbonylated acid 21 as the
sole reaction product (Scheme 4).
Experimental
1H and 13C NMR spectra were recorded on a Bruker 170
Avance 500 spectrometer (500 and 126 MHz, respec-
tively). NMR chemical shifts are referenced using NMR
1
solvent peaks at 7.26 and 77.2 ppm for H nuclei and
13C nuclei, respectively, in CDCl3, 2.50 and 39.5 ppm for
1H nuclei and 13C nuclei, respectively, in DMSO-d6.
13C signals were assigned with the help of APT experiment.
Mass spectra were recorded on an Agilent 1100 LCMSD
SL instrument (atmospheric pressure chemical ionization
(APCI)) or an Agilent 5890 Series II 5972 GCMS
instrument (electron impact ionization (EI)). Elemental
analyses were performed at the Analytical Laboratory of
the Institute of Organic Chemistry of NAS Ukraine.
Melting points were determined on an MPA100 OptiMelt
automated melting point system. The preparative HPLC
was performed on an Agilent 1260 HPLC-MSD instru-
ment. Analytical TLC was performed using Polychrom SI
F254 plates. Column chromatography was performed using
silica gel (230–400 mesh) as the stationary phase.
The starting compounds and purified solvents were
obtained from Enamine Ltd.
3-(Dimethoxymethyl)-2-methoxytetrahydrofuran (11).15b
Compound 10 (freshly distilled, 17.5 g, 0.25 mol) was
added dropwise to a stirred mixture of HC(OMe)3 (133.0 g,
1.25 mol) and BF3·Et2O (1 ml) at 30°C during 1 h. The
mixture was maintained at 30°C for 5 h. Then K2CO3 (5 g)
was added to the mixture, and after 1 h, the precipitate was
filtered off. The excess of HC(OMe)3 was distilled from the
filtrate at 130°C. The residue was distilled under reduced
pressure, and the fraction 87–90°C / 20 mmHg was
collected affording 35 g (80%) of compound 11 as
Scheme 3
1
colorless liquid. H NMR spectrum (CDCl3, the compound
exist as a mixture of two diastereomers), δ, ppm (J, Hz):
1.66–2.17 (2H, m, 4-CH2); 2.38–2.59 (1H, m, 3-CH); 3.28–
3.56 (9H, m, 3OCH3); 3.76–4.09 (2H, m, 5-CH2); 4.22
(0.63H, d, J = 8.0) and 4.49 (0.27H, d, J = 9.0, CH(OMe)2);
4.86 (0.27H, d, J = 4.0) and 4.90 (0.63H, d, J = 1.0, 2-CH).
13C NMR spectrum (CDCl3, major diastereomer), δ, ppm:
26.1 (C-4); 48.4 (C-3); 52.3 (OCH3); 53.5 (OCH3); 54.7
(OCH3); 66.5 (C-5); 104.4 (CH(OMe)2), 106.8 (C-2). Mass
spectrum (EI, 70 eV, major diastereomer), m/z (Irel, %): 85
[M+–2CH2O–MeO] (58), 75 (100).
Scheme 4
Synthesis of 2-(1H-pyrazol-4-yl)ethanols 4a–d (General
method). Concd aq HCl (50 ml) was added dropwise to a
mixture of compound 11 (90 g, 0.51 mol), the appropriate
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Chemistry of Heterocyclic Compounds 2020, 56(3), 320–325
hydrazine 12a–d (0.51 mol), and H2O (20 ml) at 0°C
temperature, and the precipitate that formed was filtered
off. The mother liquid was acidified by 0.1 M aq HCl to
pH 5. The precipitated product was filtered and dried at
room temperature in vacuo.
during 2 h. The temperature of the reaction mixture was
slowly raised to 100°C within 1 h, and then the mixture
was refluxed for 3 h, afterwards was cooled to room tempe-
rature, and solution of NaOH (20 g) in H2O (20 ml) was
added. The product was extracted by n-BuOH (2×100 ml). The
n-BuOH was evaporated under reduced pressure, and the
residue was purified by distillation in vacuo (for
compounds 4a–c) or by flash chromatography on SiO2 using
n-hexane–EtOAc, 1:1, as eluent (for compound 4d).
2-Oxo-2-(1H-pyrazol-4-yl)acetic acid (13a). Yield
1
10.6 g (76%). Colorless solid. Mp >280°C. H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 8.02 (1H, s, H-5);
8.17 (1H, s, H-3). 13C NMR spectrum (DMSO-d6), δ, ppm:
119.8 (C-4); 136.5 (C-3); 137.6 (C-5); 164.3 (CO); 185.8
(COOH). Mass spectrum (APCI), m/z: 139 [M–H]–. Found, %:
C 42.72; H 2.82; N 20.14. C5H4N2O3. Calculated, %:
C 42.87; H 2.88; N 20.00.
2-(1H-Pyrazol-4-yl)ethanol (4a).16 Yield 49.7 g (87%).
Viscous oil. Bp 185–187°C / 20 mm Hg. 1H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 2.57 (2H, t, J = 7.0,
CH2CH2OH); 3.51 (2H, t, J = 7.0, CH2CH2OH); 4.66 (1H,
s, OH); 7.42 (2H, s, H-3,5); 12.53 (1H, s, NH). 13C NMR
spectrum (DMSO-d6), δ, ppm: 28.1 (CH2CH2OH); 62.5
(CH2CH2OH); 117.2 (C-4); 127.1 (br. s, C-3(5)); 138.7
(br. s, C-5(3)). Mass spectrum (APCI), m/z: 113 [M+H]+.
Found, %: C 53.72; H 7.16; N 25.04. C5H8N2O. Calculated, %:
C 53.56; H 7.19; N 24.98.
2-(1-Methyl-1H-pyrazol-4-yl)-2-oxoacetic acid (13b).
Yield 9.9 g (64%). Colorless solid. Mp 125–127°C.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 3.91 (3H,
s, NCH3); 8.03 (1H, s, H-5); 8.55 (1H, s, H-3). 13C NMR
spectrum (DMSO-d6), δ, ppm: 40.0 (NCH3); 119.4 (C-4);
137.0 (C-3); 141.8 (C-5); 164.5 (CO); 179.9 (COOH). Mass
spectrum (APCI), m/z: 153 [M–H]–. Found, %: C 46.72;
H 3.82; N 18.11. C6H6N2O3. Calculated, %: C 46.76;
H 3.92; N 18.18.
2-[1-(tert-Butyl)-1H-pyrazol-4-yl]-2-oxoacetic acid (13c).
Yield 16.1 g (82%). Colorless solid. Mp 148–150°C.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 1.55 (9H, s,
3CH3); 8.08 (1H, s, H-5); 8.51 (1H, s, H-3). 13C NMR
spectrum (DMSO-d6), δ, ppm: 29.5 ((CH3)3C); 60.1 ((CH3)3C);
119.0 (C-4); 132.7 (C-3); 141.5 (C-5); 164.6 (CO); 180.1
(COOH). Mass spectrum (APCI), m/z: 195 [M–H]–. Found, %:
C 55.22; H 6.02; N 14.11. C9H12N2O3. Calculated, %:
C 55.09; H 6.16; N 14.28.
2-(1-Methyl-1H-pyrazol-4-yl)ethanol (4b). Yield 46.3 g
1
(72%). Viscous oil. Bp 129–130°C / 20 mm Hg. H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 2.53 (2H, t, J = 7.0,
CH2CH2OH); 3.50 (2H, t, J = 7.0, CH2CH2OH); 3.77 (3H,
s, NCH3); 4.68 (1H, s, OH); 7.29 (1H, s, H-5); 7.49 (1H, s,
H-3). 13C NMR spectrum (DMSO-d6), δ, ppm: 28.1
(CH2CH2OH); 38.7 (NCH3); 62.3 (CH2CH2OH); 118.4 (C-4);
129.9 (C-3); 138.4 (C-5). Mass spectrum (APCI), m/z: 127
[M+H]+. Found, %: C 57.42; H 7.96; N 22.04. C6H10N2O.
Calculated, %: C 57.12; H 7.99; N 22.20.
2-(1-tert-Butyl-1H-pyrazol-4-yl)ethanol (4c). Yield
80.5 g (94%). Viscous oil. Bp 150–152°C / 20 mm Hg.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.41 (9H, s,
3CH3); 2.57 (2H, t, J = 7.0, CH2CH2OH); 3.62 (2H, t,
J = 7.0, CH2CH2OH); 4.01 (1H, br. s, OH); 7.22 (1H, s,
H-5); 7.27 (1H, s, H-3). 13C NMR spectrum (CDCl3),
δ, ppm: 27.4 (C(CH3)3); 29.3 (CH2CH2OH); 57.6 (C(CH3)3);
62.3 (CH2CH2OH); 116.6 (C-4); 124.4 (C-3); 138.6 (C-5).
Mass spectrum (APCI), m/z: 169 [M+H]+. Found, %:
C 64.42; H 9.56; N 16.84. C9H16N2O. Calculated, %:
C 64.25; H 9.59; N 16.65.
2-[1-(4-Bromophenyl)-1H-pyrazol-4-yl]-2-oxoacetic acid
(13d). Yield 26.3 g (89%). Colorless solid. Mp 148–150°C
(decomp.). 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
7.73 (2H, d, J = 9.0, H Ar); 7.92 (2H, d, J = 9.0, H Ar);
8.36 (1H, s, H-5); 9.26 (1H, s, H-3). 13C NMR spectrum
(DMSO-d6), δ, ppm: 120.1 (C-4); 120.9 (C Ar); 121.2
(C Ar); 132.2 (C Ar); 132.8 (C Ar); 137.6 (C-3); 142.8
(C-5); 163.3 (CO); 179.4 (COOH). Mass spectrum (APCI),
m/z (Irel, %): 295 [M–H]– (100), 293 [M–H]– (99). Found, %:
C 44.56; H 2.46; N 9.56. C11H7BrN2O3. Calculated, %:
C 44.77; H 2.39; N 9.49.
2-[1-(4-Bromophenyl)-1H-pyrazol-4-yl]ethanol (4d).
1-(4-Bromophenyl)-1H-pyrazole-4-carboxylic acid (14).
Compound 13d (100 mg) was recrystallized from boiling
EtOH. Yield 85 mg (87%). Colorless solid. Mp 202–203°C
1
Yield 129.4 g (95%). Oil. H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 2.57 (2H, t, J = 7.0, CH2CH2OH); 3.55 (2H,
t, J = 7.0, CH2CH2OH); 4.66 (1H, br. s, OH); 7.54 (2H, d,
J = 7.2, H Ar); 7.55 (1H, s, H-5); 7.66 (2H, d, J = 7.2,
H Ar); 8.19 (1H, s, H-3). 13C NMR spectrum (DMSO-d6),
δ, ppm: 28.1 (CH2CH2OH); 61.9 (CH2CH2OH); 118.4 (C-4);
120.3 (C Ar); 121.5 (C Ar); 126.5 (C-3); 132.7 (C Ar);
139.2 (C-5); 142.1 (C Ar). Mass spectrum (APCI), m/z (Irel, %):
269 [M+H]+ (99), 267 [M+H]+ (100). Found, %: C 49.35;
H 4.16; N 10.55. C11H11BrN2O. Calculated, %: C 49.46;
H 4.15; N 10.49.
1
(mp 202–203°C18). H NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 7.71 (2H, d, J = 9.0, H Ar); 7.89 (2H, d, J = 9.0,
H Ar); 8.09 (1H, s, H-5); 9.04 (1H, s, H-3). 13C NMR
spectrum (DMSO-d6), δ, ppm: 117.9 (C-4); 120.1 (C Ar);
121.5 (C Ar); 131.8 (C Ar); 132.9 (C Ar); 138.7 (C-3);
142.8 (C-5); 163.9 (COOH). Mass spectrum (APCI), m/z
(Irel, %): 267 [M–H]– (100), 265 [M–H]– (100). Found, %:
C 45.05; H 2.46; N 10.55. C10H7BrN2O2. Calculated, %:
C 44.97; H 2.64; N 10.49.
Synthesis of keto acids 13a–d (General method).
KMnO4 (42.7 g, 0.27 mol) was added in small portions to a
solution (in case of compounds 4a–c) or suspension (in
case of compound 4d) of alcohol 4 (0.1 mol) and K2CO3 (5 g)
in H2O (200 ml) at 70°С during 1 h. The mixture was
heated with stirring at 80°С for 3 h, cooled to room
2-(1-Methyl-1H-pyrazol-3-yl)ethanol (16). 1.0 M solution
of BH3·THF complex in THF (1.3 l) was added to a
solution of compound 1512 (78 g, 0.5 mol) in THF (1 l).
The mixture was stirred at room temperature for 12 h.
MeOH (1 l) and H2O (1 l) were added, and the resulting
mixture was extracted with EtOAc (3×2 l). The organic
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Chemistry of Heterocyclic Compounds 2020, 56(3), 320–325
layers were combined and washed with brine (2 l). The
127 [M+H]+. Found, %: C 57.25; H 7.89; N 22.07. C6H10N2O.
Calculated, %: C 57.12; H 7.99; N 22.20.
organic phase was dried over Na2SO4 and evaporated
in vacuo. The residue was purified by distillation in vacuo.
Yield 46.3 g (72%). Viscous oil. Bp 129–130°C / 20 mmHg.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 2.80 (2H, t,
J = 7.0, CH2CH2OH); 3.50 (1H, s, OH); 3.76 (3H, s,
NCH3); 3.81 (2H, t, J = 7.0, CH2CH2OH); 7.29 (1H, s, H-5);
7.49 (1H, s, H-3). 13C NMR spectrum (DMSO-d6), δ, ppm:
32.2 (CH2CH2OH); 38.6 (NCH3); 61.4 (CH2CH2OH);
104.6 (C-4); 131.3 (C-3); 149.5 (C-5). Mass spectrum
(APCI), m/z: 127 [M+H]+. Found, %: C 57.42; H 7.96;
N 22.04. C6H10N2O. Calculated, %: C 57.12; H 7.99; N 22.20.
Oxidation of alcohol 16. Alcohol 16 (10.0 g, 0.079 mol)
was subjected to oxidation by KMnO4 following the
general method for oxidation of alcohols 4. After the
workup, about 8 g of crude mixture was obtained containing
acids 17 and 18 in 2:1 ratio according to 1H NMR.
A portion of this crude product (200 mg) was subjected to
preparative HPLC. The Waters SunFire C18 19 × 100 mm,
5 μm column was used. Gradients: from 5 to 30% of MeCN
in H2O or from 15 to 40% of MeCN in H2O in 6.5 min, flow
rate 34 ml/min. After lyophilization of two main fractions,
compound 17 and compound 18 were obtained.
1-Methyl-1H-pyrazole-5-carboxylic acid (21) was
synthesized from alcohol 20 (9.7 g) in accordance with
procedure described above for alcohols 4. After reaction
mixture treatment. Yield 6.2 g (64%). Colorless solid.
1
Mp 222–224°C (mp 221–222°C20). H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 4.06 (3H, s, NCH3); 6.80 (1H,
s, H-4); 7.49 (1H, s, H-3); 13.30 (1H, s, COOH). 13C NMR
spectrum (DMSO-d6), δ, ppm: 39.6 (NCH3); 111.4 (C-4);
133.4 (C-5); 137.9 (C-3); 161.1 (COOH). Mass spectrum
(APCI), m/z: 127 [M+H]+. Found, %: C 47.82; H 4.88;
N 21.92. C5H6N2O2. Calculated, %: C 47.62; H 4.80;
N 22.21.
X-ray structural study of compounds 13b and 14.
Crystal data for compound 13b: C6H6N2O3, M 154.13,
monoclinic, space group P21/c; а 8.3083(3), b 12.2717(4),
c 7.1688(3) Å; β 112.252(3)°; V 676.48(4) Å3; Z 4;
dcalc 1.513, μ 0.124 мм–1, F(000) 320, crystal size ca.
0.05 × 0.26 × 0.41 mm. All crystallographic measurements
were performed at 173 K on a Bruker Smart Apex II
diffractometer operating in the ω-scan mode. The intensity
data were collected within the θmax ≤ 26.37° using MoKα
radiation (λ 0.71078 Å). The intensities of 6424 reflections
were collected (1384 unique reflections, Rmerg 0.0365). The
structure was solved by direct methods and refined by the
full-matrix least-squares technique in the anisotropic
approximation for non-hydrogen atoms using the Bruker
SHELXTL program package.21 All carbon-bound hydrogen
atoms were placed at calculated positions and refined using
the riding model, and the hydrogen atom of the OH group
was located from difference Fourier synthesis and refined
isotropically. Convergence for molecule 13b was obtained
at R1 0.0493 and wR2 0.1328 for 1047 observed reflections
with I ≥ 2σ(I); R1 0.0673 and wR2 0.1469, GOF 1.03 for
1384 independent reflections, 104 parameters; the largest
and minimal peaks in the final difference map were 0.28
and –0.31 e/Å3, respectively.
Crystal data for compound 14: C10H7BrN2O2, M 267.09,
triclinic, space group P1; а 4.800(3), b 5.721(3),
c 18.122(10) Å; α 92.054(15), β 94.049(14), γ 99.636(16)°;
V 488.8(5) Å3; Z 2; dcalc 1.815; μ 4.183 мм–1; F(000) 264,
crystal size ca. 0.11 × 0.17 × 0.37 mm. All crystallographic
measurements were performed at ambient temperature on a
Bruker Smart Apex II diffractometer operating in the
ω-scan mode. The intensity data were collected within the
θmax ≤ 26.62° using MoKα radiation (λ 0.71078 Å). The
intensities of 5269 reflections were collected (2021 unique
reflections, Rmerg 0.0885). The structure was solved by
direct methods and refined by the full-matrix least-squares
technique in the anisotropic approximation for non-hydrogen
atoms using the Bruker SHELXTL program package.21 All
carbon-bound hydrogen atoms were placed at calculated
positions and refined using the riding model. Convergence
for molecule 14 was obtained at R1 0.0864 and wR2 0.1823
for 1256 observed reflections with I ≥ 2σ(I); R1 0.1410 and
wR2 0.2033, GOF 1.074 for 2021 independent reflections,
140 parameters, the largest and minimal peaks in the final
difference map were 1.08 and –1.17 e/Å3, respectively.
2-(1-Methyl-1H-pyrazol-3-yl)-2-oxoacetic acid (17).
Yield 0.103 g (52%). White solid. Mp 137–140°C (decomp.).
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 3.97 (3H,
s, NCH3); 6.90 (1H, d, J = 2.0, H-4); 7.92 (1H, d, J = 2.0,
H-5). 13C NMR spectrum (DMSO-d6), δ, ppm: 40.0 (NCH3);
108.4 (C-4); 134.1 (C-5); 146.7 (C-3); 166.7 (CO); 183.6
(COOH). Mass spectrum (APCI), m/z: 153 [M–H]–. Found, %:
C 46.79; H 3.87; N 18.21. C6H6N2O3. Calculated, %:
C 46.76; H 3.92; N 18.18.
1-Methyl-1H-pyrazole-3-carboxylic acid (18) . Yield
1
49 mg (26%). White solid. Mp 154–156°C. H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 3.97 (3H, s, NCH3);
6.90 (1H, d, J = 2.0, H-4); 7.92 (1H, d, J = 2.0, H-5); 12.6
(1H, br. s, COOH) 13C NMR spectrum (DMSO-d6),
δ, ppm: 39.6 (NCH3); 108.7 (C-4); 132.8 (C-5); 143.6
(C-3); 163.6 (COOH). Mass spectrum (APCI), m/z: 127
[M+H]+. Found, %: C 47.79; H 4.87; N 21.38. C5H6N2O2.
Calculated, %: C 47.62; H 4.80; N 22.21.
2-(1-Methyl-1H-pyrazol-5-yl)ethanol (20).19 1.6 M solu-
tion of n-BuLi in hexane (63 ml) was added dropwise with
stirring to a solution of pyrazole 19 (8.2 g, 0.1 mol) in THF
(100 ml) at –78°C during 1 h, and the reaction mixture was
left stirring at that temperature for 4 h. Then the solution of
oxirane (0.1 mol) in Et2O (50 ml) was added dropwise to
the mixture formed. The temperature of the mixture was
allowed slowly warm to 20°C for 2 h. Saturated aq NH4Cl
(20 ml) was added to the mixture formed. The ether layer
was separated, and the solvent was evaporated in vacuo.
The residue was purified by distillation in vacuo. Yield 9.7 g
1
(77%). Viscous oil. Bp 145–147°C / 20 mm Hg. H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 2.83 (2H, t, J = 7.0,
CH2CH2OH); 3.75 (3H, s, NCH3); 3.82 (2H, t, J = 7.0,
CH2CH2OH); 6.05 (1H, d, J = 2.0, H-4); 7.31 (1H, d,
J = 2.0, H-3). 13C NMR spectrum (CDCl3), δ, ppm: 28.8
(CH2CH2OH); 36.0 (NCH3); 60.6 (CH2CH2OH); 104.3
(C-4); 137.6 (C-3); 139.6 (C-5). Mass spectrum (APCI), m/z:
324

Chemistry of Heterocyclic Compounds 2020, 56(3), 320–325
Hirose, M.; Hu, Y.; Kakei, H.; Lee, H. M.; Motoyaji, T.;
Crystallographic data for the structures in this paper
have been deposited at the Cambridge Crystallographic
Data Center (deposits CCDC1976447 (compound 13b) and
CCDC1976448 (compound 14)).
Nii, N.; Shi, Z.; Vyskocil, S.; Watanabe, H. WO Patent
2015161142 A1.
12. Nosik, P. S.; Ryabukhin, S. V.; Pashko, M. O.; Grabchuk, G. P.;
Grygorenko, O. O.; Volochnyuk, D. M. J. Fluorine Chem.
2019, 217, 80.
Supplementary information file containing 1H, 13C NMR
and mass spectra of the synthesized compounds is available
at the journal website at http://link.springer.com/journal/10593.
13. (a) Nosik, P. S.; Artamonov, O. S.; Ryabukhin, S. V.;
Grygorenko, O. O. SynOpen 2017, 0084. (b) Nosik, P. S.;
Ryabukhin, S. V.; Artamonov, O. S.; Grygorenko, O. O.
Monatsh. Chem. 2016, 147, 1629. (c) Ivonin, S. P. Chem.
Heterocycl. Compd. 2011, 47, 1048. [Khim. Geterotsikl.
Soedin. 2011, 1270.] (d) Slobodyanyuk, E. Y.; Andriienko, A. A.;
Vashchenko, B. V.; Volochnyuk, D. M.; Ryabukhin, S. V.;
Grygorenko, O. O. Chem. Heterocycl. Compd. 2019, 55, 421.
[Khim. Geterotsikl. Soedin. 2019, 55, 421.] (e) Nosik, P. S.;
Poturai, A. S.; Pashko, M. O.; Melnykov, K. P.;
Ryabukhin, S. V.; Volochnyuk, D. M.; Grygorenko, O. O.
Eur. J. Org. Chem. 2019, 4311. (f) Slobodyanyuk, E. Y.;
Berezowska, Y. L.; Solomin, V. V.; Volochnyuk, D. M.;
Rozhenko, A. B.; Ryabukhin, S. V.; Grygorenko, O. O. Eur.
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