N-Difluoromethylation of monosubstituted polydentate azoles

Article abstract of DOI:10.1007/s10593-019-02465-x

[Figure not available: see fulltext.] This study was focused on N-difluoromethylation of monosubstituted polydentate azoles (imidazoles, pyrazoles, and 1,2,4-triazoles) having two or three reactive sites. The substituent effects and role of reaction conditions in determining the product ratio was explored. In the majority of cases, the obtained mixtures of isomers were separated. The target products containing halogen substituents, amino or carboxy groups in the ring can serve as valuable starting compounds in the synthesis of practically useful products.

Full text of DOI:10.1007/s10593-019-02465-x

DOI 10.1007/s10593-019-02465-x
Chemistry of Heterocyclic Compounds 2019, 55(4/5), 359–366
N-Difluoromethylation of monosubstituted
polydentate azoles
Kirill I. Petko1*, Taras M. Sokolenko1, Andrey A. Filatov1,
Vitaliy V. Polovinko2, Eduard B. Rusanov1,
Vadim A. Dudko2, Yurii L. Yagupolskii1
1
Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
5 Murmanska St., Kyiv 02094, Ukraine; e-mail: kirpet@ukr.net
2
Enamine Ltd.,
78 Chervonotkatska St., Kyiv 02094, Ukraine
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(4/5), 359–366
Submitted January 29, 2019
Accepted after revision March 6, 2019
This study was focused on N-difluoromethylation of monosubstituted polydentate azoles (imidazoles, pyrazoles, and 1,2,4-triazoles)
having two or three reactive sites. The substituent effects and role of reaction conditions in determining the product ratio was explored.
In the majority of cases, the obtained mixtures of isomers were separated. The target products containing halogen substituents, amino or
carboxy groups in the ring can serve as valuable starting compounds in the synthesis of practically useful products.
Keywords: imidazoles, pyrazoles, 1,2,4-triazoles, difluoromethylation, separation of isomers.
Compounds containing a difluoromethyl group are very
common in the pharmaceutical industry and among
chemicals used for crop protection, as well as other
products with practical importance.1,2 The difluoromethyl
group has significant lipophilicity and at the same time is
capable of hydrogen bonding.3 Drug molecules containing
difluoromethoxy- or difluoromethylsulfanyl groups often
have low toxicity. This is a major factor enabling the use of
such compounds in medicinal chemistry. Some of the
compounds containing difluoromethyl group have been
approved for pharmaceutical use, for example, the
anaesthetic agent desflurane, the antihypertensive drug
foridone (riosidine, riodipine), antiulcer medication
pantoprazole, and the anti-psoriasis drug diftorant. A
specific antagonist of neuropeptide Y that contains an
NCHF2 moiety is currently in clinical trial phase.4 Some
derivatives of N-(difluoromethyl)pyridin-2(1Н)-one have
been characterized as enzyme inhibitors and thus have
attracted the attention of researchers as potential drug
molecules.5 In agrochemical industry, herbicides
sulfentrazone and carfentrazone-ethyl have been used for a
long time. These herbicides are N-difluoromethyl
derivatives of 1,2,4-triazol-5-one. Strong herbicidal activity
has been also observed for some other N-difluoro-
methylazole derivatives.6–8
Difluoromethylation of organic compounds can be
performed on multikilogram scale by using such affordable
reagents as chlorodifluoromethane (Freon 22) or
fluoroform.9 The difluoromethylation reactions of phenols,
thiophenols, azoles, and other heterocyclic compounds
have been considered in several review articles.10–12
Difluoromethylation of ambidentate (polydentate)
heterocyclic systems, as a rule, produces a mixture of
isomers.13–16 The separation of such mixtures is a key task
0009-3122/19/55(4/5)-0359©2019 Springer Science+Business Media, LLC
359

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 359–366
Scheme 1
Figure 1. The starting azoles in the synthesis of N-difluoromethyl
derivatives.
for preparing practically useful products and requires
additional studies. However, in the case of the simplest
monosubstituted azoles, such studies have not yet been
performed or isomers could not be separated. Thus, the
reaction products from N-difluoromethylation of 4(5)-methyl-
imidazole were described as inseparable mixture.13
In the current work, we performed systematic studies
involving the N-difluoromethylation of monosubstituted
polydentate azoles. The starting compounds were the simple
azoles: imidazoles 1a–d, pyrazoles 2a–d, and 1,2,4-tri-
azoles 3a,b,d that contained one substituent each (Fig. 1).
The N-difluoromethyl derivatives of such heterocycles can
serve as important precursors in the synthesis of other
practically useful compounds.
We studied the correlation between the properties of
heterocycle and the difluoromethylation conditions by
selecting substituents with various electronic nature. Three
different methods for accomplishing these reactions were
tested (Scheme 1, Table 1). Method I: difluoromethylation
by reaction with Freon 22 in the presence of aqueous 50%
KОН solution and THF as organic solvent. The reaction
was performed in the presence of phase-transfer catalyst
(18-Crown-6) at 30–40°С (without external heating).
Method II: difluoromethylation by reaction with Freon 22
in the presence of K2CO3 at a higher temperature (90–100°С)
and in a more polar solvent (DMF). Method III: difluoro-
methylation by treatment with sodium chlorodifluoro-
acetate in DMF in the presence of K2CO3 at 130–140°С.
An important feature of the latter method, besides the
higher temperature, was the short reaction time – only
about 3–4 min.
Imidazole derivatives 1а–с containing a methyl group
and halogen substituents were found to be quite sensitive to
high temperatures and the presence of excess alkali under
the difluoromethylation reaction conditions. The N-difluoro-
methyl derivatives of these heterocycles could be obtained in
high yields only by using the reaction conditions of method I.
When using these conditions, the alkali solution has to be
added gradually and no more than 2.2 equiv of alkali must
be used. Otherwise, similarly as in the case of methods II
and III, significant resinification occurs and the yields of
the target products are much lower. Besides that, it is very
difficult to remove the solvent (DMF) from compounds 4а
and 5а that have been synthesized according to methods II
and III, as they have comparable boiling points and
noticible solubility in water. The ratio of isomers 4 and 5
(as determined by 19F NMR spectra after aqueous workup
and extraction) in all cases was close to 1:1 and only for the
iodo derivatives of imidazole isomer 4с was predominant,
which could be explained by the influence of steric factors.
Compounds 4а and 5а have been described earlier as in-
separable mixture with a boiling point of 64–65°С (10 Torr).13
We found that these products can be separated on multi-
gram scale by fractional distillation. However, a highly
effective distillation column is needed due to the close
boiling points of the isomers. Thus, isomer 4а has a boiling
point of 61–62°С (10 mmHg) and in pure state forms
crystals with mp 27–29°С, while isomer 5а has a boiling
1
point of 67–68°С (10 mmHg). H NMR spectra of isomer
5а show the signal of methyl group that has been shifted
downfield compared to the analogous signal of isomer 4а,
due to the presence of an adjacent difluoromethyl group.
The structure of isomer 5а was conclusively proved by
using a SELNOESY experiment. The nuclear Overhauser
effect was detected for the proton signal of CHF2 group by
saturating the methyl group signal.
Imidazoles 1b,c containing halogen substituents formed
mixtures of isomers with markedly different boiling points
during the difluoromethylation reactions. Their separation
could be easily accomplished by fractional distillation
using a regular distillation column. Unlike in the case of
methyl derivatives where isomer 4а was more volatile,
compounds 5b,c (the products with opposite configuration)
had the lower boiling points. Among the iodo derivatives,
the more volatile isomer 5с had a melting point of 65°С
and could be separated from the higher boiling isomer 4с
by sublimation using a column. The structures of isomers
1
5b,c were proved by Н–13С HMBC experiments, which
revealed correlation between the proton signal of CHF2
group and the most upfield signal of С-5 carbon atom
carrying a halogen substituent.
In contrast to imidazoles 1а–с, 5-nitroimidazole (1d) did
not participate in difluoromethylation reaction under the
conditions of method I. Potassium salt of nitroimidazole 1d
had low nucleophilicity and did not react with Freon 22 in
the presence of aqueous 50% alkali solution without
heating. Applying higher temperatures (method II) led to the
formation of difluoromethylation products at a low degree
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Chemistry of Heterocyclic Compounds 2019, 55(4/5), 359–366
Table 1. Products obtained by N-difluoromethylation of monosubstituted azoles, their yields and isomer ratios
Method I
Method II
Method III
The starting The reaction products
Yield of isomer
Yield of isomer
Yield of isomer
azole
(separation method)
Ratio of isomers, %
Ratio of isomers, %
Ratio of isomers, %
mixture, %
mixture, %
mixture, %
4а + 5а (*)
4b + 5b (*)
4c + 5c (*)
4d + 5d (**)
6a + 7a (***)
6b + 7b (**)
6c + 7c (**)
6d + 7d (*)
48
80
56
0
60
90
92
93
12
14
0
50:50
50:50
55:45
–
50:50
50:50
50:50
5:95
22*4
24
15
50:50
60:40
70:30
85:15
50:50
45:55
40:60
10:90
50:40:10
55:35:10
–
Resinification
–
1а
1b
1c
1d
2a
2b
2c
2d
3а
3b
3d
15
65:35
–
Resinification
12
54
100:0
50:50
40:60
35:65
15:85
55:40:5
75:20:5
100:0:0
25*4
55
30*4
50
48
45
80
75
8а + 9а + 10а (***)
8b + 9b + 10b (*)
8d
45:35:20
50:40:10
–
25*4
26
42*4
32
0
69
* Isomers were separated by fractional distillation.
** Isomers were separated chromatographically.
*** Isomers were not separated.
*4 The product contained residual solvent (DMF).
of conversion. As a result, a mixture of isomers 4d and 5d
containing a significant excess of isomer 4d was obtained
in low yield and was separated chromatographically.
However, the application of method III gave only one
target product 4d in 54% yield. This compound has been
previously obtained by heating imidazole 1d with
(trifluoromethyl)trimethylsilane in the presence of LiI at
170°С. The physicochemical characteristics and NMR
spectral data of compound 4d matched the literature data.17
Compared to imidazoles 1a–c, pyrazole derivatives 2a–c
containing a methyl group and halogen substituents were
more stable under basic conditions. The N-difluoro-
methylation reactions of these compounds could be
accomplished either by mild procedures or by using forcing
reaction conditions. In all of the cases, resinification was
observed to a significantly lesser degree. The difluoro-
methylation reaction of methylpyrazole 2а (according to
the methods I–III) in all of the cases gave a mixture of
isomers 6а and 7а in 1:1 ratio. In the case of the
halogenated pyrazoles 6b,c and 7b,c, the ratio was
somewhat affected by the more forcing reaction conditions:
there was a trend observed in that the content of the less
sterically hindered isomers 7b,c increased. The products
generated by N-difluoromethylation of 3-methylpyrazole
(compounds 6a and 7a) were quite volatile and could not
be effectively separated from the solvent (DMF) by
applying methods II and III. Using the method I allowed to
separate the obtained products from THF (even though
with some loss of yield), but isomers 6а and 7а themselves,
as well as the halogen-containing isomers 6b,c and 7b,c,
had very close boiling points. We were not able to isolate
the individual compounds 6а–с and 7а–с by fractional
distillation. The application of preparative HPLC did not
allow to separate isomers 6а and 7а due to the volatility of
these products, but compounds 6b, 7b, 6c, and 7c were
isolated in pure state from solvent mixtures.
upfield signal that was assigned to the C-5 carbon atom
bearing bromine substituent in the case of compound 6b
and the most downfield signal of СН group (С-5 carbon
atom) in the case of compound 7с.
3-Nitropyrazole (2d), in contrast to 5-nitroimidazole
(1d), readily participated in difluoromethylation reaction
upon treatment with Freon 22 according to the method I.
This procedure gave a high yield of primarily isomer 7d
containing only a 5–6% impurity of the other isomer 6d.
Using more forcing conditions (methods II and III), unlike
in the case of 5-nitroimidazole (1d), gave somewhat lower
yields of the target products, while the content of isomer 6d
in the mixture increased to 10% when method II was used
and to 15% for the method III. N-difluoromethylpyrazoles
6d and 7d containing a nitro group, in contrast to the
aforementioned compounds 6а–с and 7а–с, can be separated
by fractional distillation. The structure of compound 7d
was confirmed by a SELNOESY experiment. Saturation of
the signal assigned to the proton bonded to the С-5 carbon
atom produced nuclear Overhauser effect on the signals of
CHF2 group, while saturation of the signal assigned to the
proton bonded to the С-4 carbon atom failed to give NOE.
In the case of the alternative isomer, no effect would be
observed in both of the cases.
The difluoromethylation reactions of monosubstituted
1,2,4-triazole derivatives 3a,b containing a methyl group or
bromine substituent gave low yields under the conditions
of method I due to the low nucleophilicity of the hetero-
cycle. Better conversion was achieved by applying methods
II and III. In all of the cases, the reaction produced
mixtures containing all three possible isomers, but isolation
of the target products was complicated by their significant
volatility and noticeable solubility in water. As a result, we
were not able to isolate the products arising from N-di-
fluoromethylation of methyl-1,2,4-triazole (3а) in indivi-
dual state. A mixture of compounds 8а, 9а, and 10а had a
boiling point of 127–135°С.
The structure of compounds 6b and 7с was confirmed
1
by Н–13С HMBC experiments that revealed correlation
Fractional distillation and two crystallization steps
allowed to isolate small amounts of individual compounds
between the proton signal of CHF2 group and the most
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Chemistry of Heterocyclic Compounds 2019, 55(4/5), 359–366
8b and 9b from the three isomeric difluoromethylation
products of bromotriazole 3b. Compound 8b was the only
product among our obtained N-difluoromethylazoles that
could be crystallized for X-ray structural analysis, thus its
structure was confirmed by monocrystal X-ray diffraction
method (Fig. 2). The distribution of bond lengths and
valence angles in the triazole ring was typical for similar
systems and had no notable deviations, with the ring itself
being planar (the deviation of ring atoms from the least
squares plane did not exceed 0.0052(28) Å). The length of
N(2)–C(3) bond was 1.440(6) Å, which was similar to the
standard length of ordinary C–N bond (1.45 Å).
The structure of compound 9b was confirmed by two
Figure 2. The molecular structure of compound 8b with atoms
represented by thermal vibration ellipsoids of 50% probability.
1Н–13С HMBC and 1Н–15N HMBC experiments. A
1
correlation was observed in Н–13С HMВС spectrum of
compound 9b between the signal of proton of difluoro-
methyl group and the most upfield signal of carbon atom
bearing the bromine substituent. This observation pointed
to the location of CHF2 group near one of the two nitrogen
N-Difluoromethylpyrazole amino derivative 12 was
more stable and existed in solution phase, however, it
decomposed upon isolation. Treatment with gaseous HCl
allowed to obtain a sample of hydrochloride 13. The
most stable of these compounds due to the presence of
more electron-withdrawing triazole ring was 1-(difluoro-
methyl)-1Н-1,2,4-triazol-3-amine (14). This compound
could be isolated, purified by sublimation at reduced
pressure, and stored for long duration without
decomposition.
The presence of a carboxy functionality in the molecule
allowed to easily synthesize a large number of derivatives,
namely, salts, amides, and esters. We explored the
possibilities for introducing a carboxy group in the studied
N-difluoromethylazole derivatives. Imidazole iodo deriva-
1
atoms adjacent to the bromine substituent. Н–15N HMВС
spectrum featured a correlation between the proton signal
of CHF2 group and two signals of nitrogen atoms, pointing
to its location near one of the two adjacent nitrogen atoms.
In contrast to the methyl- and bromotriazoles 3a,b,
3-nitro-1,2,4-triazole (3d) practically did not participate in
reactions with Freon 22 under the conditions of methods I
and II, but gave a high yield of product when treated
according to the method III, forming only one isomer 8d.
1
The structure of compound 8d was confirmed by Н–15N
HMBC and SELNOESY experiments. A correlation was
found between the proton signal of CHF2 group and the
signals of two nitrogen atoms, pointing to the presence of a
difluoromethyl group at one of the adjacent nitrogen atoms.
The observation of NOE on the proton signal of CHF2 group
upon saturation of the heterocycle proton signal provided
unequivocal proof for the structure of compound 8d.
Scheme 2
CHF2
N
CHF2
N
H2, Pd/C
H2N
H2N
O2N
dioxane
rt, 4 h
N
N
11
4d
Despite the presence of four nitrogen atoms in the
molecule, compound 8d was not explosive, unlike 2-difluoro-
methyltetrazole that we have recently characterized.18 It
can be distilled at reduced pressure and does not
decompose when heated to 150°С. At higher temperatures,
compound 8d decomposed without explosion.
Our syntheses of N-difluoromethylazoles containing
nitro groups or halogen substituents open possibilities for
further functionalization of such molecules, enabling the
synthesis of related amines and carboxylic acids.
H2, Pd/C
N
N
CHF2
CHF2
O2N
dioxane
rt, 4h
N
12
N
7d
HCl
N
CHF2
H2N
· HCl
dioxane
N
13
N
N
H2, Pd/C
N-Difluoromethylazoles containing an amino group in
the heterocycle remain practically unknown. The
introduction of an amino group (a strongly electron-
donating substituent) in the heterocycle lowers the
hydrolytic stability of the difluoromethyl group, therefore
such amino derivatives, as a rule, are unstable. We explored
the possibilities for nitro group reduction in compounds 4d,
7d, and 8d (Scheme 2). The reduction reactions were
accomplished by heterogeneous catalytic hydrogenation in
the presence of palladium (10% Pd/C). It was observed that
amino derivative of N-difluoromethylimidazole 11 was
unstable even in solution form and the amine could not be
isolated as a free base nor as hydrochloride salt.
N
N
CHF2
dioxane
rt, 4h
CHF2
O2N
H2N
N
8d
N
14
O
CHF2
N
CHF2
Pd(dppf)2Cl2, Et3N
CO
N
I
MeO
N
N
4c, 5c
MeOH
100°C, 16 h
15, 16
CHF2
O
N
LiOH
HO
N
17, 18
H2O
50°C
362

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 359–366
tives 4с and 5с were used in a carbonylation reaction with
dried over anhydrous K2СО3, the solvent was evaporated at
reduced pressure (for mixtures of compounds 6а and 7а, as
well as by using a distillation column for compounds 8а,
9а, and 10а), then the residue was distilled.
СО in MeOH in the presence of Pd(dppf)2Cl2 catalyst at
100°С. As a result, esters 15 and 16 were obtained, which
were hydrolyzed to the respective carboxylic acids 17 and 18.
Thus, we have studied some trends in the N-difluoro-
methylation reactions of polydentate azoles having two or
three reactive sites. The obtained products containing
halogen substituents, amino or carboxy groups in the ring
can serve as important starting materials for the synthesis
of practically significant compounds.
Difluoromethylation of azoles (General method).
Method II. A solution of the appropriate azole (0.2 mol) in
DMF (100 ml) was stirred and treated by adding freshly
calcinated K2CO3 (56.0 g, 0.4 mol). A stream of Freon 22
was bubbled through the solution with vigorous stirring,
while gradually raising the temperature to 90−100°С.
Bubbling of Freon 22 was continued at this temperature
until the absorption of gas ceased (approximately 2 h).
Then water (300 ml) was added, the mixture was extracted
with MTBE (200 ml), the organic layer was separated, the
aqueous layer was extracted with MTBE (2×300 ml), the
organic extracts were combined and washed with water
(5×300 ml), dried over anhydrous K2СО3, the solvent was
evaporated at reduced pressure, the residue was separated
by fractional distillation or by chromatography.
Experimental
1H NMR spectra were acquired on a Bruker Avance 400
spectrometer (400 MHz), using TMS as internal standard.
19F NMR spectra were acquired on a Bruker Avance DRX 500
instrument (470 MHz for compounds 5d, 13, 14, 16–18,
376 MHz for the rest of the compounds), using ССl3F as
internal standard (δ 0 ppm). 13С NMR spectra (125 MHz)
and two-dimensional 1H–13C HMBC (125 MHz) and 1Н–15N
HMBC (41 MHz) spectra were acquired on a Bruker Avance
DRX 500 instrument. Elemental analysis was performed at
the Analytical Chemistry Laboratory of the Institute of
Organic Chemistry, National Academy of Sciences of
Ukraine. The content of halogens was determined by
Schöniger method.19 Melting points were determined in
open capillaries and were not corrected. Chromatographic
separation of isomers was performed on a Companion liquid
chromatograph equipped with a UV detector (λ 254 nm),
using a column with 70–230 mesh silica gel (Sigma-
Aldrich), eluent 20:1 hexane–MTBE. The reaction progress
was controlled by TLC on Silufol 254 plates (visualization
under UV light at λ 254 nm).
Difluoromethylation of azoles (General method).
Method III. A mixture of azole (0.2 mol), ClF2CCO2Na
(60.8 g, 0.4 mol), and calcinated K2CO3 (56.0 g, 0.4 mol)
in DMF (150 ml) was vigorously stirred in a flask (of at
least 1 l volume), gradually raising the temperature to
110−120°С. At this temperature, a strongly exothermic
reaction started with vigorous evolution of gas, boiling, and
foaming of the reaction mixture. The reaction mixture
temperature spontaneously increased to 130–140°С. The
evolution of gas ceased after 2–3 min, and the reaction
mixture was cooled, water (350 ml) was added. The target
product was extracted with MTBE (5×300 ml), the organic
extracts were washed with water (300 ml), dried over
anhydrous K2СО3, the solvent was evaporated at reduced
pressure, and the residue was distilled at reduced pressure.
When separating mixtures of compounds 8b, 9b, and 10b,
distillation was performed at reduced pressure (10 mmHg)
using a distillation column, first separating the fraction
with bp 55−57°С (enriched in isomer 9b and containing a
small amount of DMF), then the fraction with bp 67−68°С
(enriched in isomer 8b). Both fractions were low-melting
semisolid materials. After two crystallization steps from
5:1 hexane–CH2Cl2 mixture, 5–6 g of pure compound 8b
(12−15% yield) and 1−2 g of pure compound 9b (2−5%
yield) were obtained from each fraction.
Difluoromethylation of azoles. Synthesis of N-di-
fluoromethylimidazoles (General metod). Method I. A
solution of imidazole 1а–с (0.3 mol) and 18-Crown-6 (2.0 g,
7.57 mmol) in THF (400 ml) was treated by bubbling a
stream of Freon 22 until saturation, then vigorously stirred
under Freon 22 stream and treated by dropwise addition of
KOH (40.0 g, 0.7 mol) solution in H2O (40 ml) at such a
rate that the temperature of the reaction mixture did not
exceed 40°С. The mixture was stirred until the absorption
of gas ceased, extracted by shaking with H2O (1 l) and
MTBE (500 ml), the organic layer was separated, washed
with H2O (3×300 ml), dried over anhydrous K2СО3, the
solvent was removed by evaporation at reduced pressure,
and the residue was separated by fractional distillation.
Synthesis of N-difluoromethylpyrazoles and N-di-
fluoromethyl-1,2,4-triazoles (General method). Method I.
A solution of azole 2a–d or 3a,b (0.2 mol) and 18-Crown-6
(1.0 g, 3.78 mmol) in THF (200 ml) was stirred and treated
by adding a solution of KOH (60 g, 1.0 mol) in H2O (60 ml)
in a single portion. In the case of nitropyrazole, voluminous
precipitate of potassium nitropyrazolide was formed and
then gradually dissolved during the reaction. Freon 22 was
bubbled through the vigorously stirred reaction mixture at
40−45°С until the absorption of gas ceased (exothermic
effect was observed). Water (300 ml) was added, the product
was extracted by shaking with MTBE (200 ml), the organic
layer was separated and washed with water (3×300 ml),
1-Difluoromethyl-4-methyl-1H-imidazole (4а). Colorless
crystals, mp 27−28°С, bp 61−62°С (10 mmHg) (bp 65–66°C
1
(10 Torr)13). H NMR spectrum (CDCl3), δ, ppm (J, Hz):
2.13 (3Н, s, СН3); 6.82 (1Н, s, СН); 7.00 (1Н, t, J = 60.0,
СHF2); 7.61 (1Н, s, СН). 13C NMR spectrum (CDCl3),
δ, ppm (J, Hz): 12.9 (СН3); 107.7 (t, J = 245.0, СHF2); 110.6;
133.3; 139.8. 19F NMR spectrum (CDCl3), δ, ppm (J, Hz):
−91.7 (d, J = 60.0, СHF2). Found, %: C 45.70; H 4.60;
N 21.33. C5H6F2N2. Calculated, %: C 45.46; H 4.58; N 21.20.
1-Difluoromethyl-5-methyl-1H-imidazole (5а). Colorless
liquid, bp 67−68°С (10 mmHg) (bp 65–66°C (10 Torr)13).
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.31 (3Н, s,
СН3); 6.80 (1Н, s, СН); 7.01 (1Н, t, J = 60.0, СHF2); 7.67
(1Н, s, СН). 13C NMR spectrum (CDCl3), δ, ppm (J, Hz):
8.7 (СН3); 108.2 (t, J = 246.0, СHF2); 125.8; 128.3; 134.2.
363

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 359–366
19F NMR spectrum (CDCl3), δ, ppm (J, Hz): −93.5 (d,
J = 60.0, СHF2); 7.70 (1Н, s, СH). 13C NMR spectrum
(CDCl3), δ, ppm (J, Hz): 110.3 (t, J = 247.0, СHF2); 111.4;
112.2; 143.2. 19F NMR spectrum (CDCl3), δ, ppm (J, Hz):
−95.3 (d, J = 60.0, СHF2). Found, %: C 24.27; H 1.59;
Br 40.44. C4H3BrF2N2. Calculated, %: C 24.39; H 1.54;
Br 40.56.
3-Bromo-1-(difluoromethyl)-1Н-pyrazole (7b). Colorless
liquid, bp 90−92°С (75 mmHg). 1H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 6.44 (1Н, s, СH); 7.11 (1Н, t,
J = 60.0, СHF2); 7.69 (1Н, s, СH). 13C NMR spectrum
(CDCl3), δ, ppm (J, Hz): 110.3 (t, J = 247.0, СHF2); 111.8;
128.5; 129.5. 19F NMR spectrum (CDCl3), δ, ppm (J, Hz):
−94.7 (d, J = 60.0, СHF2). Found, %: C 24.33; H 1.48;
Br 40.87. C4H3BrF2N2. Calculated, %: C 24.39; H 1.54;
Br 40.56.
1-(Difluoromethyl)-5-iodo-1Н-pyrazole (6с). Colorless
liquid, bp 82−83°С (10 mmHg). 1H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 6.56 (1Н, s, СH); 7.21 (1Н, t,
J = 60.0, СHF2); 7.63 (1Н, s, СH). 13C NMR spectrum
(CDCl3), δ, ppm (J, Hz): 75.0; 111.3 (t, J = 245.0, СHF2);
119.3; 143.8. 19F NMR spectrum (CDCl3), δ, ppm (J, Hz):
−93.5 (d, J = 60.0, СHF2). Found, %: C 19.61; H 1.16;
I 51.95. C4H3IF2N2. Calculated, %: C 19.69; H 1.24;
I 52.01.
J = 60.0, СHF2). Found, %: C 45.65; H 4.49; N 21.28.
C5H6F2N2. Calculated, %: C 45.46; H 4.58; N 21.20.
4-Bromo-1-(difluoromethyl)-1Н-imidazole (4b). Colorless
crystals, mp 31−32°С, bp 103−105°С (10 mmHg).
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 7.09 (1Н, t,
J = 60.0, СHF2); 7.26 (1Н, s, СН) 7.74 (1Н, s, СН).
13C NMR spectrum (CDCl3), δ, ppm (J, Hz): 107.4 (t,
J = 247.0, СHF2); 114.1; 117.1; 134.0. 19F NMR spectrum
(CDCl3), δ, ppm (J, Hz): −92.7 (d, J = 60.0, СHF2). Found,
%: C 24.61; H 1.49; Br 40.78. C4H3BrF2N2. Calculated, %:
C 24.39; H 1.54; Br 40.56.
5-Bromo-1-(difluoromethyl)-1Н-imidazole
(5b).
Colorless liquid, bp 69−71°С (10 mmHg). 1H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 7.05 (1Н, t, J = 60.0, СHF2); 7.07 (1Н,
s, СН); 7.95 (1Н, s, СН). 13C NMR spectrum (CDCl3), δ, ppm
(J, Hz): 99.5; 107.9 (t, J = 245.0, СHF2); 130.7; 134.9.
19F NMR spectrum (CDCl3), δ, ppm (J, Hz): −94.7 (d,
J = 60.0, СHF2). Found, %: C 24.22; H 1.69; Br 40.37.
C4H3BrF2N2. Calculated, %: C 24.39; H 1.54; Br 40.56.
1-(Difluoromethyl)-4-iodo-1Н-imidazole (4c). Colorless
1
crystals, mp 34–35°С, bp 82−84°С (0.5 mmHg). H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 7.07 (1Н, t, J = 60.0,
СHF2); 7.32 (1Н, s, СН); 7.71 (1Н, s, СН). 13C NMR
spectrum (CDCl3), δ, ppm (J, Hz): 83.7; 107.2 (t,
J = 246.0, СHF2); 120.1; 135.6. 19F NMR spectrum
(CDCl3), δ, ppm (J, Hz): −92.4 (d, J = 60.0, СHF2). Found,
%: C 19.61; H 1.29; I 51.88. C4H3IF2N2. Calculated, %:
C 19.69; H 1.24; I 52.01.
1-(Difluoromethyl)-3-iodo-1Н-pyrazole (7с). Colorless
liquid, bp 82−83°С (10 mmHg). 1H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 6.75 (1Н, s, СH); 7.72 (1Н, t,
J = 60.0, СHF2); 8.17 (1Н, s, СH). 13C NMR spectrum
(CDCl3), δ, ppm (J, Hz): 98.0; 109.3 (t, J = 246.0, СHF2);
116.8; 127.0. 19F NMR spectrum (CDCl3), δ, ppm (J, Hz):
−94.7 (d, J = 60.0, СHF2). Found, %: C 19.78; H 1.51; I
52.11. C4H3IF2N2. Calculated, %: C 19.69; H 1.24; I 52.01.
1-(Difluoromethyl)-5-nitro-1H-pyrazole (6d). Pale-yellow
liquid, bp 45−46°С (0.5 mmHg). 1H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 7.18 (1H, d, J = 2.0, СН); 7.75 (1H, d,
J = 2.0, СН); 7.82 (1Н, t, J = 60.0, СHF2). 13C NMR
spectrum (CDCl3), δ, ppm (J, Hz): 108.5 (t, J = 247.0,
СHF2); 109.2; 141.2; 146.3. 19F NMR spectrum (CDCl3),
δ, ppm (J, Hz): −96.9 (d, J = 60.0, СHF2). Found, %:
C 29.37; H 1.71; N 25.81. C4H3F2N3O2. Calculated, %:
C 29.46; H 1.85; N 25.77.
1-(Difluoromethyl)-5-iodo-1Н-imidazole (5c). Colorless
crystals, mp 64−65°С (hexane), bp 58−60°С (0.5 mmHg,
1
subl.). H NMR spectrum (CDCl3), δ, ppm (J, Hz): 7.07
(1Н, t, J = 60.0, СHF2); 7.19 (1Н, s, СН); 8.00 (1Н, s, СН).
13C NMR spectrum (CDCl3), δ, ppm (J, Hz): 63.9; 109.4 (t,
J = 247.0, СHF2); 136.9; 137.9. 19F NMR spectrum (CDCl3),
δ, ppm (J, Hz): −94.0 (d, J = 60.0, СHF2). Found, %:
C 19.55; H 1.32; I 51.91. C4H3IF2N2. Calculated, %:
C 19.69; H 1.24; I 52.01.
1-(Difluoromethyl)-5-nitro-1Н-imidazole (5d). Yellow
liquid. Was not distilled (due to the small amount
available), after chromatographic separation was purified
from solvent traces (MTBE–hexane) by keeping under
1-(Difluoromethyl)-3-nitro-1H-pyrazole (7d). Colorless
1
1
vacuum (0.5 mmHg) for 1 h at 20°С. H NMR spectrum
crystals, mp 29−30°С, bp 58−59°С (0.5 mmHg). H NMR
(CDCl3), δ, ppm (J, Hz): 7.80 (1Н, t, J = 60.0, СHF2); 8.02
(1H, s, СН); 8.05 (1H, s, СН). 13C NMR spectrum (CDCl3),
δ, ppm (J, Hz): 107.9 (t, J = 246.0, СHF2); 133.7; 137.2;
138.1. 19F NMR spectrum (CDCl3), δ, ppm (J, Hz): −94.9
(d, J = 60.0, СHF2). Found, %: C 29.70; H 1.61; N 25.54.
C4H3F2N3O2. Calculated, %: C 29.46; H 1.85; N 25.77.
1-(Difluoromethyl)-5-methyl-1Н-pyrazole (6а) and 1-(di-
fluoromethyl)-3-methyl-1Н-pyrazole (7а), unseparated
mixture. Colorless liquid, bp 113−114°С (760 mmHg).
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.29 (3Н, s,
СН3); 2.44 (3Н, s, СН3); 6.13 (1Н, s, СН); 6.22 (1Н, s,
СН); 7.10 (1Н, t, J = 60.0, СHF2); 7.21 (1Н, t, J = 60.0,
СHF2); 7.46 (1Н, s, СН); 7.68 (1Н, s, СН).
spectrum (CDCl3), δ, ppm (J, Hz): 7.04 (1H, d, J = 2.0,
СН); 7.24 (1Н, t, J = 60.0, СHF2); 7.93 (1H, d, J = 2.0, СН).
13C NMR spectrum (CDCl3), δ, ppm (J, Hz): 104.6; 110.2 (t,
J = 245.0, СHF2); 129.9; 157.3. 19F NMR spectrum
(CDCl3), δ, ppm (J, Hz): −96.1 (d, J = 60.0, СHF2). Found,
%: C 29.62; H 1.55; N 25.61. C4H3F2N3O2. Calculated, %:
C 29.46; H 1.85; N 25.77.
1-(Difluoromethyl)-3-methyl-1H-1,2,4-triazole (8а),
1-(difluoromethyl)-5-methyl-1H-1,2,4-triazole (9а), 4-(di-
fluoromethyl)-3-methyl-1H-1,2,4-triazole (10а), unseparated
mixture. Colorless liquid, bp 127−135°С (760 mmHg).
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.42 (3Н, s,
СН3); 2.44 (3Н, s, СН3); 2.49 (3Н, s, СН3); 7.13 (1Н, t,
J = 60.0, СHF2); 7.18 (1Н, t, J = 60.0, СHF2); 7.25 (1Н, t,
J = 60.0, СHF2); 7.82 (1Н, s, СН); 7.96 (1Н, s, СН); 8.40
(1Н, s, СН).
5-Bromo-1-(difluoromethyl)-1Н-pyrazole (6b). Colorless
liquid, bp 90−92°С (75 mmHg). 1H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 6.47 (1Н, s, СH); 7.19 (1Н, t,
364

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 359–366
3-Bromo-1-(difluoromethyl)-1Н-1,2,4-triazole (8b).
Synthesis of methyl 1-(difluoromethyl)-1Н-imidazole-
4(or 5)-carboxylates 15, 16 (General method). Compound
4с or 5с (2 g, 8.0 mmol) was dissolved in anhydrous
MeOH (50 ml), then Et3N (1 g, 9.6 mmol) was added,
followed by Pd(dppf)Cl2 (200 mg, 3 mol %) and the
reaction mixture was sealed in a high-pressure autoclave.
Carbon monoxide gas was introduced at 40 bar pressure,
and the reaction mixture was stirred at 100°С for 16 h.
After cooling to room temperature, the residual pressure
was vented, the reaction mixture was evaporated to dryness
at reduced pressure, quenched with water (50 ml), and then
extracted with EtOAc (2×30 ml). The extract was dried
over anhydrous Na2SO4 and evaporated at reduced pressure.
The obtained mixture was purified by flash chromato-
graphy, using 1:4 EtOAc–hexane mixture as eluent.
Methyl 1-(difluoromethyl)-1Н-imidazole-4-carboxylate
(15). Yield 0.74 g (51%), colorless crystals, mp 91−92°С.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 3.87 (3Н, s,
ОСН3); 7.30 (1Н, t, J = 60.0, СHF2); 7.89 (1Н, s, СН); 7.90
(1Н, s, СН). 13C NMR spectrum (CDCl3), δ, ppm (J, Hz):
51.9 (СН3); 108.4 (t, J = 245.0, СHF2); 121.1; 134.9; 135.4;
162.4 (СО). 19F NMR spectrum (CDCl3), δ, ppm (J, Hz):
−93.3 (d, J = 60.0, СHF2). Found, %: C 40.78; H 3.55;
N 5.72. C6H6F2N2O2. Calculated, %: C 40.92; H 3.43; N 15.91.
Methyl 1-(difluoromethyl)-1Н-imidazole-5-carboxylate
(16). Yield 0.93 g (65%), colorless crystals, mp 53−54°С.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 3.83 (3Н, s,
ОСН3); 7.70 (1Н, s, СН); 7.87 (1Н, t, J = 60.0, СHF2); 8.05
(1Н, s, СН). 13C NMR spectrum (CDCl3), δ, ppm (J, Hz):
52.2 (СН3); 107.8 (t, J = 245.0, СHF2); 121.1; 138.1; 138.4:
159.9 (СО). 19F NMR spectrum (CDCl3), δ, ppm (J, Hz): −94.4
(d, J = 60.0, СHF2). Found, %: C 40.78; H 3.55; N 15.72.
C6H6F2N2O2. Calculated, %: C 40.92; H 3.43; N 15.91.
Synthesis of carboxylic acids 17, 18 (General method).
Compound 15 or 16 (0.93 g, 5.2 mmol) was suspended in
water (20 ml), LiOH (0.24 g, 5.7 mmol) was added, and the
reaction mixture was heated at 50°C until complete
dissolution. After cooling the solution, it was acidified with
10% HCl solution to pH 1–2. The obtained precipitate was
filtered off, washed with H2O (2×20 ml), and dried at 80°С
under air atmosphere. Using NaOH as base also led to the
target products, albeit at lower yields (60–65%).
1-(Difluoromethyl)-1Н-imidazole-4-carboxylic acid (17).
Yield 0.72 g (84%), colorless crystals, mp 235−236°С.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 7.82 (1Н, t,
J = 60.0, СHF2); 8.19 (1Н, s, СН); 8.24 (1Н, s, СН);
10.0−11.0 (1H, br. s, СООН). 13C NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 109.1 (t, J = 245.0, СHF2); 122.3; 135.5;
136.8; 163.5 (СО). 19F NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): −92.7 (d, J = 60.0, СHF2). Found, %: C 36.84;
H 2.52; N 17.42. C5H4F2N2O2. Calculated, %: C 37.05;
H 2.49; N 17.28.
Colorless crystals, mp 53−54°С, bp 68−69°С (10 mmHg).
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 7.15 (1Н, t,
J = 60.0, СHF2); 8.37 (1H, s, СН). 13C NMR spectrum
(CDCl3), δ, ppm (J, Hz): 108.7 (t, J = 247.0, СHF2); 142.3;
143.1. 19F NMR spectrum (CDCl3), δ, ppm (J, Hz): −97.2
(d, J = 60.0, СHF2). Found, %: C 17.97; H 1.09; Br 40.24.
C3H2BrF2N3. Calculated, %: C 18.20; H 1.02; Br 40.36.
5-Bromo-1-(difluoromethyl)-1Н-1,2,4-triazole (9b).
Colorless crystals, mp 48−49°С, bp 55−57°С (10 mmHg).
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 7.24 (1Н, t,
J = 60.0, СHF2); 7.94 (1H, s, СН). 13C NMR spectrum
(CDCl3), δ, ppm (J, Hz): 108.7 (t, J = 247.0, СHF2); 128.1;
153.7. 19F NMR spectrum (CDCl3), δ, ppm (J, Hz): −97.3
(d, J = 60.0, СHF2). Found, %: C 17.91; H 0.97; Br 40.57.
C3H2BrF2N3. Calculated, %: C 18.20; H 1.02; Br 40.36.
1-(Difluoromethyl)-3-nitro-1Н-1,2,4-triazole
(8d).
Pale-yellow liquid, bp 82−83°С (0.5 mmHg). 1H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 7.39 (1Н, t, J = 60.0,
СHF2); 8.68 (1H, s, СН). 13C NMR spectrum (CDCl3),
δ, ppm (J, Hz): 108.7 (t, J = 247.0, СHF2); 143.3; 162.6.
19F NMR spectrum (CDCl3), δ, ppm (J, Hz): −97.7 (d,
J = 60.0, СHF2). Found, %: C 21.75; H 1.11; N 34.24.
C3H2F2N4O2. Calculated, %: C 21.96; H 1.23; N 34.15.
Synthesis of N-difluoromethylaminoazoles 13, 14. To
a stirred solution of compound 7d or 8d (0.1 mol) in dioxane
that was free of peroxides (100 ml), 10% Pd/C (1 g) was
added. The flask was connected to vacuum and then filled
with hydrogen. The reaction mixture was stirred under H2
atmosphere until the absorption of gas ceased (about 4 h),
then the catalyst was removed by filtration. The procedure
for the reduction of nitropyrazole derivative 7d was
concluded by passing gaseous HCl through the solution
of the respective amine 12 until the absorption of gas
was complete, the obtained precipitate was filtered off,
washed with MTBE, and dried at 80°С under air
atmosphere. In the case of reducing nitrotriazole derivative
8d, the solvent was evaporated at reduced pressure, and the
product was sublimated under vacuum (0.5 mmHg) at
100−120°С.
1-(Difluoromethyl)-1Н-pyrazol-3-amine hydrochloride
(13). Yield 14.0 g (82%), colorless crystals, mp 162−164°С
(decomp.). 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
+
6.38 (1H, s, СН); 6.80−6.93 (3H, br. s, NH3 ); 7.78 (1Н, t,
J = 60.0, СHF2); 8.24 (1H, s, СН). 13C NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 102.0; 110.2 (t, J = 247.0,
СHF2); 132.6; 146.9. 19F NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): −94.5 (d, J = 60.0, СHF2). Found, %: C 27.95;
H 3.44; N 24.65. C4H6ClF2N3. Calculated, %: C 28.33;
H 3.57; N 24.78.
1-(Difluoromethyl)-1Н-1,2,4-triazol-3-amine (14).
Yield 12.0 g (90%), colorless crystals, mp 90−91°С.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 5.85 (2Н, s,
NH2); 7.61 (1Н, t, J = 60.0, СHF2); 8.49 (1H, s, СН).
13C NMR spectrum (CDCl3), δ, ppm (J, Hz): 108.7 (t,
J = 247.0, СHF2); 144.3; 165.7. 19F NMR spectrum
(CDCl3), δ, ppm (J, Hz): −96.7 (d, J = 60.0, СHF2). Found,
%: C 25.95; H 3.04; N41.55. C3H4F2N4. Calculated, %:
C 26.80; H 3.01; N 41.78.
1-(Difluoromethyl)-1Н-imidazole-5-carboxylic acid (18).
Yield 0.59 g (82%), colorless crystals, mp 145−146°С.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 7.73 (1Н,
s, СН); 8.06 (1Н, t, J = 60.0, СHF2); 8.45 (1Н, s, СН);
10.0−11.0 (1H, br. s, СООН). 13C NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 108.9 (t, J = 245.0, СHF2); 123.3; 137.8; 139.4;
162.9 (СО). 19F NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
365

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 359–366
−94.4 (d, J = 60.0, СHF2). Found, %: C 36.84; H 2.52; N 17.42.
C5H4F2N2O2. Calculated, %: C 37.05; H 2.49; N 17.28.
1H–15N HMBC spectra of compounds 8d, 9b is available at
the journal website at http://link.springer.com/journal/10593.
X-ray structural analysis of compound 8b. Crystals
suitable for X-ray structural analysis were obtained by slow
evaporation of a solution of compound 8b in CH2Cl2–
hexane mixture. The selected monocrystal of compound 8b
had linear dimensions of 0.21 × 0.30 × 0.39 mm. X-ray
structural analysis was performed at room temperature on a
Bruker AXS Smart Apex II diffractometer (λMoKα
radiation, graphite monochromator, θmax 8.3°, segment of
sphere: 10 ≤ h ≤ 10, –10 ≤ k ≤ 11, –12 ≤ l ≤ 11). A total of
4942 reflections were collected, of which 1448 were
independent (averaging R-factor 0.0482). The structure was
solved by direct method and refined by method of least
squares in full-matrix anisotropic approximation, using the
Bruker SHELXTL software suite.20 The positions of all
hydrogen atoms bonded to the carbon atoms were
calculated geometrically and refined according to the riding
model. A total of 1448 independent reflections were used in
the refinement, of which 1219 had I > 2σ(I) (82 parameters
in refinement). The applied weighting scheme was
ω = 1/[σ2(Fo2) + (0.0392P)2], where Р = (Fo2 + 2Fc2)/3, the
ratio of the maximum(mean) deviation to the error in the
last iteration was 0.004(0.001). The final values of
probability factors were R1(F) 0.0310, wR(F2) 0.0679 by
reflections with I > 2σ(I), R1(F) 0.0412, wR2(F2) 0.0711,
GOF 0.88 by all independent reflections. The residual
electron density from the Fourier difference series after the
last refinement cycle was 0.42 and –0.60 е/Å3. The main
geometrical parameters of the molecule were: N(1)–C(1)
1.306(6) Å, N(1)–N(2) 1.362(5) Å, N(2)–C(2) 1.327(6) Å,
N(3)–C(2) 1.308(7) Å, N(3)–C(1) 1.360(7) Å, Br(1)–C(1)
1.859(5) Å; C(1)–N(1)–N(2) 100.6(4)°, C(2)–N(2)–N(1)
110.7(4)°, C(2)–N(3)–C(1) 101.8(4)°, N(1)–C(1)–N(3)
116.5(4)°, N(3)–C(2)–N(2) 110.5(5)°. The data obtained by
X-ray structural analysis were deposited at the Cambridge
Crystallographic Data Center (deposit CCDC 1892635).
The authors would like to express their gratitude to the
glassblower Valery Ilyich Lazarev for the design and fabrica-
tion of an exclusive ''vortex'' distillation column that enabled
separating small amounts of liquids with close boiling points.
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1
Supplementary information file containing H, 13C, and
19F NMR spectra of the synthesized compounds, as well as
SELNOESY spectra of compounds 5a, 7,
8
d,
1H–13C HMBC spectra of compounds 5, 6, 9b, 5, 7 c, and
366