Electrosynthesis of 4-iodopyrazole and its derivatives

Article abstract of DOI:10.1007/s11172-010-0277-y

Electrosynthesis of 4-iodo-substituted pyrazoles has been accomplished by iodination of the corresponding precursors on a Pt-anode in aqueous solutions of KI under conditions of the diaphragm galvanostatic electrolysis. Efficiency of the process depends on the donor-acceptor properties of substituents and their positions in the pyrazole ring. Thus, iodination of pyrazole, 3,5-dimethylpyrazole, 3-nitropyrazole, 1-methylpyrazole, 1,3-dimethylpyrazole, pyrazole-3(5)-carboxylic acid or methyl esters furnished 4-iodo derivatives in 57, 86, 2, 5, 35, 30, and 40% yields, respectively.

Full text of DOI:10.1007/s11172-010-0277-y

Russian Chemical Bulletin, International Edition, Vol. 59, No. 8, pp. 1549—1555, August, 2010
1549
Electrosynthesis of 4ꢀiodopyrazole and its derivatives
B. V. Lyalin, V. A. Petrosyan, and B. I. Ugrak
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: petros@ioc.ac.ru
Electrosynthesis of 4ꢀiodoꢀsubstituted pyrazoles has been accomplished by iodination of
the corresponding precursors on a Ptꢀanode in aqueous solutions of KI under conditions of the
diaphragm galvanostatic electrolysis. Efficiency of the process depends on the donorꢀacceptor
properties of substituents and their positions in the pyrazole ring. Thus, iodination of pyrazole,
3,5ꢀdimethylpyrazole, 3ꢀnitropyrazole, 1ꢀmethylpyrazole, 1,3ꢀdimethylpyrazole, pyrazoleꢀ3(5)ꢀ
carboxylic acid or methyl esters furnished 4ꢀiodo derivatives in 57, 86, 2, 5, 35, 30, and 40%
yields, respectively.
Key words: electrosynthesis, pyrazoles, iodination.
It is known that 4ꢀiodopyrazoles are important interꢀ
mediate products in the synthesis of biologically active
compounds possessing antiviral, antitumor, and antibacꢀ
terial activity,1—4 they are used for obtaining purine and
nucleoside derivatives5 and as reagents in organic syntheꢀ
sis (crossꢀcoupling reactions with terminal acetylenes,6
reactions with organotin aryl derivatives,7 or alkylboronic
acids8). This is the reason for the interest to search new
efficient methods for the synthesis of 4ꢀiodo derivatives of
pyrazole. In the present work, we for the first time study
their preparation by electrochemical method.
To solve the problem, we proceeded from the data on
electrosynthesis of 4ꢀchloroꢀ and 4ꢀbromoꢀsubstituted
pyrazoles,9—11 as well as from the results reported on
chemical iodination of pyrazole12 and its derivatives.13,14
Iodination of pyrazoles was studied under conditions
of galvanostatic diaphragm electrolysis of aqueous soluꢀ
tions of KI or methanol solutions of NaI.
The yield of the target product under these conditions
(see Table 1, entry 1) turned out to be not high enough
(39%), and in this case the reaction mixture contained,
together with 4ꢀiodopyrazole, considerable amount of ioꢀ
dine (the current efficiency was 29%). Variations in the
electrolysis conditions (current density, the ratio pyrazole/
NaI in the reaction mixture) did not led to the increase in
the yield of 4ꢀiodopyrazole (see Table 1, entries 1—3),
amount of iodine virtually did not decrease either. Apparꢀ
ently, the rate of EI of pyrazole in methanol solutions has
proved low. Intensification of the process by the removal
of HI formed in the course of the reaction due to the
addition of a base (NaOAc) failed. The yield of 4ꢀiodoꢀ
pyrazole was even lower by 6% (see Table 1, entries 6
and 9). This fact, as well as a decrease in the amount of
iodine in the reaction mixture (the current efficiency
decreased by 17%), indicate a noticeable contribution of
a side process, viz., the reaction of I2 with MeOH with
oxidation or iodination of the latter.
Further, we studied EI of pyrazoles in aqueous soluꢀ
tions, where the side processes indicated previously are
not possible. However, iodine generated on the anode
was poorly soluble in water and mainly precipitated. This
was the reason that we started to carry out the EI in the
twoꢀphase system (aqueous KI—CHCl3), using NaNO3
as a supporting electrolyte. The yield of 4ꢀiodopyrazole
under indicated conditions (see Table 1, entry 5) was low
(28%), and the final reaction solution contained a large
amount of iodine (the current efficiency was 47%). The
formal process of EI of pyrazole, proceeding through
the intermediate formation of Nꢀiodo derivative,16 is given
in Scheme 1.
Results and Discussion
There are literature data on electroiodination (EI) of
terminal acetylenes15 under conditions of the diaphragm
electrolysis of solutions of NaI in MeOH, which leads to
the corresponding 1ꢀiodoacetylenes in high (70—90%)
yields. On the authors’ opinion,15 the process proceeds
through the intermediate formation of highly reactive
cation I+, present apparently in the solution as a complex
with involvement of MeOH. Therefore, we started attempꢀ
tion of EI of pyrazoles exactly under these conditions
using unsubstituted pyrazole. Due to the consumption of
NaI during the EI reaction, supporting electrolyte NaClO4
(C = 0.3 mol L–1) was used to maintain electroconductivity
of the anolyte.
When effects of various factors on the efficiency of EI
was studied, it was found that an increase in the amount
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1512—1518, August, 2010.
1066ꢀ5285/10/5908ꢀ1549 © 2010 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 59, No. 8, August, 2010
Lyalin et al.
Table 1. Effect of experimental conditions on the yield of 4ꢀiodopyrazole (IP) upon anode iodination of pyrazolea (P)
Entry
Mediumb
Amount of
metal iodide
(M+I–)/mol
P : M+I–
Т/°С
iа/mA cm–2
Product yieldsc (%)
IP on substance
iodine on the current
1
2
3
4
5
6
7
8
A
A
A
A
В
В
В
В
В
В
В
В
В
В
0.01
0.01
0.03
0.01
0.01
0.02
0.01
0.01
0.01
0.01
0.01
0.01
0.02
0.02
1 : 1
1 : 1
1 : 3
1 : 1
1 : 1
1 : 2
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 2
1 : 1
30
30
30
30
30
30
30
30
50
30
30
50
30
30
7.5
15.0
7.5
7.5
7.5
39
38
35
33
28
29
30
25
36
57
60
66
52
46
28
32
24
11
47
48
47
45
27
13
21
29
26
26
7.5
15.0
22.5
7.5
7.5
15.0
7.5
9
10
11
12
13
14
7.5
7.5
a Ptꢀanode, Cuꢀcathode, supporting electrolyte (C = 0.3 mol L–1), Q = Qcalc = 2 F•(mol P)–1. In entries 1—13 amount of
pyrazole was 0.01 mol, in entry 14, 0.02 mol.
b
A: MeOH as the solvent, NaI as the source of iodine, NaClO4 as the supporting electrolyte, in entry 4 NaOAc
(0.015 mol) was added as a base; B: the twoꢀphase system H2O—CHCl3 (7 : 3), KI as the source of iodine, NaNO3 as the
supporting electrolyte, in entries 10—14 NaHCO3 (0.015 mol) was added as a base.
c The yield of IP was calculated from the data on analysis of isolated mixture of the electrolysis products by 1H NMR. The yield
of iodine was determined by titration of a sample of the reaction mixture with 0.1 N aq. Na2S2O3.
to 0.02 moles (see Table 1, entries 10 and 13) results in
the decrease (by ~5%) in the yield of the target product.
An increase in the current density (from 7.5 to 15 mA cm–2,
see Table 1, entries 10 and 11) is accompanied by only
small (by ~2%) increase in the yield of the target product.
Scheme 1
Scheme 2
of KI from 0.01 to 0.02 moles (see Table 1, entries 5
and 6) leads only to an insignificant (by ~2%) increase in
the yield of the target product. The dependence of the
yield of 4ꢀiodopyrazole from the change of the current
density passes the maximum (see Table 1, entries 5, 7,
and 8), reaching 30% at j = 15 mA cm–2. An increase in
the temperature of electrolysis from 30 to 50 °C caused a
somewhat (to 36%) increase in the yield of 4ꢀiodopyrazole
and a considerable decrease in the content of iodine in
the reaction mixture (the current efficiency of iodine
decreased from 47 to 27%, see Table 1, entries 5 and 9).
When the temperature has been increased, the rate of
iodination was apparently increased, however, since the
boiling point of the aseotrope CHCl3/H2O is17 56 °C,
further increase in the temperature under these condiꢀ
tions is impossible.
(1)
(2)
(3)
To optimize the EI process, we carried out the elecꢀ
trolysis in the presence of a base (NaHCO3) combining
with HI (Scheme 2). Under these conditions, the yield
of 4ꢀiodopyrazole rises more than twoꢀfold (see Table 1,
entries 5 and 10). An increase in the amount of KI from 0.01
An increase in the temperature of electrolysis from
30 to 50 °C, though led to the increase in the yield of
4ꢀiodopyrazole (by ~8%, see Table 1, entries 10 and 12),
however, the content of the "active" iodine (electroꢀ

4ꢀIodoꢀsubstituted pyrazole and its derivatives
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 8, August, 2010
1551
generated free iodine and products of its reaction with
water, i.e., HIO and NaIO3) considerably increased (see
Scheme 2) (an increase in the current efficiency by ~16%)
in the reaction mixture.
genation strongly depends on the nature of substituent in
the pyrazole ring. This prompted us to study EI of
pyrazoles with electronꢀdonating and electronꢀwithdrawꢀ
ing substituents.
According to Scheme 2 (see reaction (1)), an equilibꢀ
rium a exists in the solution of electrolyte, which in the
presence of NaHCO3 is significantly shifted to the right
due to the rapid ionic reaction in step b. In this case, an
efficient removal of HI takes place, whereas HIO (a weak
acid) is formed and accumulated in the solution. At elevated
temperatures, HIO has a tendency to disproportionation18
(see Scheme 2, Eq. (2)), leading to the strong acids HIO3
and HI, which in the presence of NaHCO3 form NaIO3
and NaI, respectively. Unlike HIO capable to iodinate
pyrazole, NaIO3 does not react with it under these condiꢀ
tions (alkaline solution) (see Scheme 2, reaction (3)).
This is the reason that elevated temperature, though
assists in the increase in the yield of 4ꢀiodopyrazole, but
efficiency of the use of KI in the electrosynthesis is
decreased, and some iodine generated by anode oxidation
of KI is not used in the synthesis of the target product.
Summarizing this part of the study, it should be noted
that EI of pyrazole under optimum conditions (electrolyꢀ
sis in the heterophase system aqueous KI—CHCl3 (7 : 3),
Ptꢀanode, amounts of pyrazole and KI of 0.01 mol,
ja = 7.5—15 mA cm–2, Т = 30 °C) allows us to obtain
4ꢀiodopyrazole in 57—60% yield calculated on the startꢀ
ing pyrazole.
Table 2. Effect of experimental conditions on the yield of 4ꢀiodoꢀ
substituted pyrazoles upon anode iodination of pyrazoles in the
а
heterophase system aq. KI—CHCl3
Entry Pyrazole Iodination
product
Product yieldsb (%)
of iodination of "active" iodine
on substance
on the current
1
2
3
4
5
6
7
8
9
10
1
2
3
4
5
6
7
8
9
1а
2а
3а
4а
5а
6а
7а
8а
9а
86
2
0
30
40
0
0
5
71
35
14
95
98
51
55
91
96
90
27
64
10
10а
a Ptꢀanode, Cuꢀcathode, amount of pyrazoles and KI was 0.01
mole, NaNO3 (0.3 M) was a supporting electrolyte, amount of
NaHCO3 was 0.015 mole, Q = Qcalc = 2 F (mole of the starting
pyrazole)–1, ja = 7.5 mA cm–2
.
The yield of IP was calculated from the 1H NMR data
of isolated mixture of the electrolysis products, the yield of
"active" iodine (a mixture of I2 and HIO) was determined by
iodometric analysis.
b
The works9—11 on electrochemical chlorination and
bromination of pyrazoles reported that efficiency of haloꢀ

1552
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 8, August, 2010
Lyalin et al.
Comparison of the results obtained on the EI of
pyrazole and 3,5ꢀdimethylpyrazole 1 (cf. Table 1, entry 10
and Table 2, entry 1) showed that the presence of two methyl
groups at carbon atoms in the pyrazole ring leads to a
considerable increase in the yield of 4ꢀiodo derivative 1a
(from 57 to 86%, calculated on the amount of pyrazole used).
3ꢀNitropyrazole (2) was the following object for our
study. No data on its chemical iodination have been found
in the literature, therefore, initially we studied this process.
It turned out that chemical iodination of compound 2
takes place only under drastic conditions (AcOH as a
solvent with additives of H2O and CCl4; a mixture of I2,
KIO3, and H2SO4 as a iodination agent; the reaction temꢀ
perature of 80—85 °C; the reaction time 21 h). As a result,
4ꢀiodoꢀ3ꢀnitropyrazole (2a) was obtained in 86% yield
(calculated on the amount of pyrazole 2 used).
Further, we found that the presence of an NO2 group
in the pyrazole ring sharply decreases efficiency of EI.
For instance, upon EI of pyrazole 2 under the same conꢀ
ditions as in the EI of pyrazole (see above), the yield of its
iodo derivative 2a was only 2% calculated on the starting
pyrazole 2 (see Table 2, entry 2). EI of pyrazoles with
other less electronꢀwithdrawing groups (COOH, COOMe)
showed that under the optimum conditions electrolysis
of pyrazolꢀ3(5)ꢀcarboxylic acid (4) leads to 4ꢀiodoꢀ
pyrazolꢀ3(5)ꢀcarboxylic acid (4a) in relatively low (~30%
calculated on the amount of the acid used) yield (see
Table 2, entry 4). In this case, the yield of "active" iodine
(I2, HIO) has proved high enough (~50% on the current).
We suggest that this effect is due to the relatively low
rate of chemical reaction of the electrogenerated
iodine with acid 4. On replacement of the COOH group
with less electronꢀwithdrawing COOMe group going
from pyrazole 4 to methyl pyrazolꢀ3(5)ꢀcarboxylate (5),
it was found that upon the EI of the latter, the yield
of iodination product (methyl 4ꢀiodopyrazolꢀ3(5)ꢀcarꢀ
boxylate (5a)) increased more than 1.3ꢀfold (see Table 2,
entries 4 and 5).
We carried out additional experiments on the influꢀ
ence of the Me substituent in the pyrazole ring on the
efficiency of EI. Pyrazoles containing Me groups
on both the nitrogen atom (1ꢀmethylpyrazole (8), 1,3ꢀdiꢀ
methylpyrazole (10)) and carbon atom of the pyrazol ring
(3(5)ꢀmethylpyrazole (9)) were chosen as the starting
compounds. It turned out that exchange of the H atom
on the nitrogen atom in unsubstituted pyrazole for the Me
group leads to a sharp (more than tenꢀfold) decrease in
the yield of the iodinated product (4ꢀiodoꢀ1ꢀmethylꢀ
pyrazole (8a)) (cf. Table 1, entry 10 and Table 2, entry 8).
The content of electrogenerated "active" iodine in the
reaction mixture also sharply increased. And vice versa,
replacement of the H atom with the Me group on the
carbon atom in unsubstituted pyrazole led to the expected
result: an increase in the yield of the target product
(4ꢀiodoꢀ3(5)ꢀmethylpyrazole 9a) (cf. Table 1, entry 10
and Table 2, entry 9). This indicates a strong decrease in
the rate of iodination going from unsubstituted pyrazole
to 1ꢀmethylpyrazole.
An exchange of the H atom for the Me group on the
carbon atom in 1ꢀmethylpyrazole (pyrazole 10) leads to a
certain decrease in the "wrong" influence of the Me subꢀ
stituent on the nitrogen atom and, consequently, to the
increase in the yield of 4ꢀiodo derivative from 5 to 35%
(see Table 2, entries 8 and 10).
The data on nontypical (as compared to chlorination
and bromiination) effect of the Me group in the reaction
of EI mentioned above are of special interest. To explain
such facts, we have thoroughly analyzed available literaꢀ
ture information on chemical iodination of pyrazoles.
In the work,19 it was found that the rate of iodination
of unsubstituted pyrazole is inversely proportional to the
concentration of H3O+. This was an evidence that not
pyrazole itself undergoes iodination, but its anion. Pyrꢀ
azole anion is much more reactive (the ratio of the iodiꢀ
nation rate constants of the ionized and unionized forms
of pyrazole20 is equal to 3•109).
Earlier,10,11 during study of electrohalogenation (chloꢀ
rination, bromiination) processes, it was found that reꢀ
placement of H atom on the nitrogen atom of the pyrazole
ring with the electronꢀdonating Me group facilitates the
process indicated. Therefore, it could have been expected
that upon EI of 1ꢀmethylꢀ3ꢀnitropyrazole (3) the yield
of the target product would be higher than upon EI of
pyrazole 2. However, we obtained an unexpected result:
under the same experimental conditions, which were used
in the EI of unsubstituted pyrazole (see above), pyrazole 3
was not subjected to EI (see Table 2, entry 3). Note that
on the replacement of H atom on the nitrogen
atom in 3(5)ꢀpyrazolecarboxylic acid with the Me
group (going from acid 4 to 1ꢀmethylpyrazolꢀ3ꢀcarboxyꢀ
lic (6) and 1ꢀmethylpyrazolꢀ5ꢀcarboxylic (7) acids),
the EI of such pyrazoles does not occur (see Table 2,
entries 6 and 7).
Since 1ꢀmethylpyrazole cannot give anion, only its
unionized form undergoes iodination. This leads to a
strong decrease in the reaction rate. By analysis of the
data19,20 on kinetics of iodination, we found that going
from pyrazole to 1ꢀmethylpyrazole the reaction rate
decreases ~300ꢀfold. Note that replacement of the H atom
with the Me group on the carbon atom in the pyrazole
ring increases the rate of iodination (going from pyrazole
to 3(5)ꢀmethylpyrazole, the iodination rate increases20
150ꢀfold).
In connection with the aforementioned facts, it
becomes clear why the yields of 4ꢀiodopyrazoles decrease
on the exchange of the H atom for the Me group at the
nitrogen atom and the yield of the target product increases
going from 1ꢀmethylpyrazole to 1,3ꢀdimethylpyrazole.
In conclusion, the presence of electronꢀdonating subꢀ
stituents at the carbon atom of the pyrazole ring facilitates

4ꢀIodoꢀsubstituted pyrazole and its derivatives
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 8, August, 2010
1553
m.p. 108 °C (cf. Ref. 12: m.p. 108.5 °C) and characteristics
of the H NMR spectrum.
EI, whereas the presence of electronꢀwithdrawing subꢀ
stituents makes the process more difficult. In addition,
position of substituents in the ring play a significant role.
The presence of alkyl substituents at the nitrogen atom
of the pyrazole ring retards the EI process.
1
Electrochemical iodination of pyrazole in methanol solution
of NaI (using entry 2 as an example, see Table 1). A methanol
solution (100 mL) containing NaI (1.5 g, 0.01 mol), NaClO4
(3.67 g, 0.03 mol), and pyrazole (0.68 g, 0.01 mol) was placed
into the anode compartment of a cell, a solution of NaClO4 in
methanol (0.3 M, 150 mL) was placed into the cathode comꢀ
partment. Electrolysis was carried out with current of 445 mA,
the rest of conditions were analogous to those given above. The
content of iodine in the reaction mixture was determined (see
above), and these data were used to find its current efficiency
(32%). Then, MeOH was evaporated from the reaction mixture
under reduced pressure, followed by addition of water (20 mL),
conc. HCl (1 mL), and Na2SO3 (to combine with iodine, see
above) to the residue formed. The mixture obtained was
neutralized with Na2CO3 (to pH 7—8), and organic products
were extracted with CHCl3 (3×30 mL). After drying (see above)
the organic extract and evaporation of the solvent, 4ꢀiodoꢀ
pyrazole was obtained (0.74 g, 38%), which was identified by the
Experimental
Experiments were carried out in the galvanostatic regime,
using a source of direct current Bꢀ5ꢀ8 and a glass cell with a
diaphragm made of porous glass with Ptꢀanode (S = 30 cm2) and
Cuꢀcathode thermostated by a Uꢀ1 thermostat. A coulometer
constructed in the SCB of IOCh of the RAS was included into
the electric chain. A magnetic stirrer was used to stir solutions
during electrolysis.
Pyrazole, 3,5ꢀdimethylpyrazole (1), and 3(5)ꢀmethylpyrꢀ
azole (9) (Acros) were used as purchased. 1,3ꢀDimethylpyrazole
(10)21, 3ꢀnitropyrazole (2)22, 1ꢀmethylꢀ3ꢀnitropyrazole (3)14
,
pyrazolꢀ3(5)ꢀcarboxylic (4), 1ꢀmethylpyrazolꢀ3ꢀcarboxylic (6),
and 1ꢀmethylpyrazolꢀ5ꢀcarboxylic acids (7)23, as well as methyl
pyrazolꢀ3(5)ꢀcarboxylate (5),24 were synthesized according to
the procedures described earlier.
1
m.p. 108 °C and characteristics of the H NMR spectrum.
Electrochemical iodination of 3,5ꢀdimethylpyrazole (1) (using
entry 1 as an example, see Table 2). An aqueous solution (70 mL)
containing NaNO3 (1.79 g, 0.021 mol), KI (1.66 g, 0.01 mol),
NaHCO3 (1.26 g, 0.015 mol), pyrazole 1 (0.96 g, 0.01 mol), and
CHCl3 (30 mL) was placed into the anode compartment of a
cell. Electrolysis, analysis of the reaction mixture for the "active"
iodine, and isolation of the products were carried out as described
above. The yield of "active" iodine on the current was 14%. The
yield of 4ꢀiodoꢀ3,5ꢀdimethylpyrazole (1a) was 1.91 g (86%), it
was identified by the m.p. 137 °C (cf. Ref. 13: m.p. 137—138 °C)
and characteristics of the 1H NMR spectrum.
Chemical iodination of 3ꢀnitropyrazole (2). Iodine (6.12 g,
0.024 mol), KIO3 (2.56 g, 0.012 mol), H2O (9 mL), conc. H2SO4
(2.2 mL), and CCl4 (4.8 mL) were added to a solution of pyrazole
2 (6.78 g, 0.06 mol) in AcOH (40 mL). The reaction mixture was
heated to 80—85 °C and stirred at this temperature for 21 h.
After the reaction mixture was cooled, CCl4 was evaporated
under reduced pressure. Then, the mixture was poured on ice,
discolored (from unreacted I2) by addition of Na2SO3, and the
mineral acid was neutralized with Na2CO3. A precipitate formed
was filtered off, washed with water, and dried at 100 °C to obtain
4ꢀiodoꢀ3ꢀnitropyrazole (2a) (12.32 g, 86%), m.p. 227—228 °C.
1H NMR, δ: 8.05 (s, 1 H, H(5)). Found (%): C, 15.16; H, 0.86;
I, 53.07; N, 17.45. C3H2IN3O2. Calculated (%): C, 15.06;
H, 0.84, I, 53.14; N, 17.57.
Electrochemical iodination of 3ꢀnitropyrazole (2) (using
entry 2 as an example, see Table 2). An aqueous solution
(70 mL) containing NaNO3 (1.79 g, 0.021 mol), KI (1.66 g,
0.01 mol), NaHCO3 (1.26 g, 0.015 mol), compound 2 (1.13 g,
0.01 mol), and CHCl3 (30 mL) was placed into the anode
compartment of a cell. Electrolysis and analysis of the reaction
mixture for the "active" iodine were carried out as described
above. The yield of "active" iodine on the current was 95%. The
reaction mixture after electrolysis was acidified with conc. HCl
(2 mL), treated with Na2SO3 (see above), then neutralized with
Na2CO3 (to pH 7—8), and the aqueous and organic fractions
were separated. Products were isolated from the organic fraction
as described above to obtain yellowish powder (0.32 g), which
(1H NMR spectroscopic data) was a mixture of 2a—2. The molar
ratio of these compounds in the reaction mixture (1 : 11.25) was
Compounds obtained upon EI of pyrazoles were identified
by H NMR spectroscopy using comparison with the spectra of
1
standard samples described in the literature (4ꢀiodopyrazole,25
4ꢀiodoꢀ3,5ꢀdimethylpyrazole (1a),26 4ꢀiodoꢀ1ꢀmethylꢀ3ꢀnitroꢀ
pyrazole (3a),14 methyl 4ꢀiodopyrazolꢀ3(5)ꢀcarboxylate (5a),27
4ꢀiodoꢀ3(5)ꢀmethylpyrazole (9a),25 4ꢀiodoꢀ1ꢀmethylpyrazole
(8a), and 4ꢀiodoꢀ1,3ꢀdimethylpyrazole (10a)28), 4ꢀiodopyrazolꢀ
3(5)ꢀcarboxylic acid (4a) obtained according to the known
procedure,22 and 4ꢀiodoꢀ3ꢀnitropyrazole (2a) alternatively
synthesized by us (see below).
1H NMR spectra were recorded on a Bruker ACꢀ300
spectrometer, using DMSOꢀd6 as a solvent.
Electrochemical iodination of pyrazole in aqueous KI (using
entry 10 as an example, see Table 1). An aqueous solution (70 mL)
containing NaNO3 (1.79 g, 0.021 mol), KI (1.66 g, 0.01 mol),
NaHCO3 (1.26 g, 0.015 mol), pyrazole (0.68 g, 0.01 mol), and
CHCl3 (30 mL) was placed into the anode compartment of a
cell. A solution of NaNO3 (0.3 M, 150 mL) was placed into the
cathode compartment. Electrolysis was carried out using current
of 225 mA at 30 °C. After passing 2 F of electricity per 1 mol of
the starting compound (Q = 1930 C), the electrolysis was stopped,
the reaction mixture was stirred for 1.5 h. The aqueous and
organic fractions were separated using a separatory funnel. An
aliquot of the solution was taken from each fraction, and the
content of "active" iodine (I2 and HIO) was determined by
titration with Na2S2O3.29 Using the analysis results, the total
(both fractions) yield of the “active” iodine was determined
(13%). Then the aqueous and organic fractions were mixed,
acidified with concentrated HCl (2 mL), followed by addition of
Na2SO3 with stirring (to combine with iodine) until the solution
became colorless. Then, the reaction mixture was neutralized by
addition of Na2CO3 (to pH 7—8), the aqueous and organic
fractions were separated using a separatory funnel. Then, solid
NaCl was added to the aqueous solution (for the salting off the
products from the aq. solution), and the products were addiꢀ
tionally extracted with CHCl3 (2×30 mL). The organic solutions
were combined and dried with CaCl2. The solvent was evaporated
to obtain 4ꢀiodopyrazole (1.11 g, 57%) identified by the

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Lyalin et al.
determined using the integral intensities of the signals for
compounds 2a with δ 8.05 (s, 1 H, H(5)) and 2 with δ 7.80 (s, 1 H,
H(5)). The solvent from aqueous fraction was evaporated under
reduced pressure. The residue obtained was treated with Me2CO
(4×25 mL), then the solvent was evaporated, the residue was
washed with water (1×7.5 mL) and dried at 100 °C to obtain
yellow powder (0.36 g), which was (1H NMR spectroscopic
data) the starting pyrazole 2. The yield of product 2a was 2%.
Electrochemical iodination of 1ꢀmethylꢀ3ꢀnitropyrazole (3)
(using entry 3 as an example, see Table 2). An aqueous solution
(70 mL) containing NaNO3 (1.79 g, 0.021 mol), KI (1.66 g,
0.01 mol), NaHCO3 (1.26 g, 0.015 mol), pyrazole 3 (1.27 g,
0.01 mol), and CHCl3 (30 mL) was placed into the anode
compartment of a cell. Electrolysis, analysis of the reaction
mixture for the "active" iodine, and isolation of products were
carried out as described in the preceding experiment. The yield
of "active" iodine on the current was 98%. The products of
electrolysis contained (1H NMR spectroscopic data) only the
starting pyrazole 3 (no formation of 4ꢀiodoꢀ1ꢀmethylꢀ3ꢀnitroꢀ
pyrazole (3a) was detected).
Electrochemical iodination of pyrazolꢀ3(5)ꢀcarboxylic acid (4)
(using entry 4 as an example, see Table 2). An aqueous solution
(70 mL) containing NaNO3 (1.79 g, 0.021 mol), KI (1.66 g,
0.01 mol), NaHCO3 (1.26 g, 0.015 mol), acid 4 (1.12 g, 0.01 mol),
and CHCl3 (30 mL) was placed into the anode compartment of
a cell. Electrolysis and analysis of the reaction mixture for the
"active" iodine was carried out as described above. The yield
of "active" iodine on the current was 51%. The reaction mixture
was separated for aqueous and organic fractions. The aqueous*
fraction was acidified with conc. HCl (2 mL) and treated with
Na2SO3 (see above).
A precipitate formed was filtered off, washed with water
(2×5 mL), and dried at 100 °C to obtain 4ꢀiodopyrazolꢀ3(5)ꢀ
carboxylic acid (4a) (0.53 g, 22%), which was identified by the
m.p. 240 °C (cf. Ref. 22: m.p. 240—241 °C) and characteristics
of the 1H NMR spectrum. Water was evaporated under reduced
pressure from the mother liquor formed after isolation of the
major product. The residue obtained was treated with Me2CO
(2×25 mL) and EtOH (2×25 mL), the solvents were evaporated,
the residue was washed with water (2×4 mL) and dried at 100 °C
to obtain a powder (0.2 g), which was (1H NMR spectroscopic
data) a mixture of compounds 4a—4. The molar ratio of these
compounds in the reaction mixture (27.5 : 1) was determined
from the integral intensities of the signals for compounds 4a
with δ 7.88 (s, 1 H, H(3(5))) and 4 with δ 6.70 (s, 1 H, H(4)).
The total yield of product 4a was 30%.
Electrochemical iodination of methyl pyrazolꢀ3(5)ꢀcarboxylate
(5) (using entry 5 as an example, see Table 2). An aqueous
solution (70 mL) containing NaNO3 (1.79 g, 0.021 mol), KI
(1.66 g, 0.01 mol), NaHCO3 (1.26 g, 0.015 mol), compound 5
(1.26 g, 0.01 mol) and CHCl3 (30 mL) was placed into the
anode compartment of a cell. Electrolysis and analysis of
the reaction mixture for the "active" iodine was carried out
as described above. The yield of "active" iodine on the current
was 55%. After performing electrolysis, the reaction mixture
was acidified with conc. HCl, treated with Na2SO3 (see above),
then the aqueous and organic fractions were separated. The
products were additionally extracted from the aqueous fraction
with CHCl3 (2×30 mL). The organic solutions were combined
and dried with Na2SO4. The solvent was evaporated to obtain
white powder (1.37 g), which was (1H NMR spectroscopic data)
a mixture of compound 5 and methyl 4ꢀiodopyrazolꢀ3(5)ꢀ
carboxylate (5a). The molar ratio of these compounds (1.32 : 1)
in the reaction mixture was determined from the integral
intensities of the signals of compounds 5a with δ 7.95 (s, 1 H,
H(3(5))) and 5 with δ 6.75 (s, 1 H, H(4)). The aqueous fraction
was concentrated under reduced pressure to 10 mL and the
products were extracted with CHCl3 (2×15 mL). The organic
extracts were combined and dried with Na2SO4. The solvent was
evaporated to obtain white powder (0.1 g), which was (1H NMR
spectroscopic data) a mixture of 5a—5. The molar ratio of these
compounds was 0.07 : 1. The total yield of product 5a (40%) was
determined from the 1H NMR spectroscopic data of the products
isolated.
Electrochemical iodination of 1ꢀmethylpyrazolꢀ3ꢀcarboxylic
acid (6) (using entry 6 as an example, see Table 2). An aqueous
solution (70 mL) containing NaNO3 (1.79 g, 0.021 mol), KI
(1.66 g, 0.01 mol), NaHCO3 (1.26 g, 0.015 mol), acid 6 (1.26 g,
0.01 mol) and CHCl3 (30 mL) was placed into the anode
compartment of a cell. Electrolysis, analysis of the reaction
mixture for the "active" iodine and isolation of products were
carried out similarly to those described above for compound 4.
The yield of "active" iodine on the current was 91%. The products
isolated contained (1H NMR spectroscopic data) only the
starting acid 6 (no formation of 4ꢀiodoꢀ1ꢀmethylpyrazolꢀ
3ꢀcarboxylic acid (6a) was observed).
Electrochemical iodination of 1ꢀmethylpyrazolꢀ5ꢀcarboxylic
acid (7) (using entry 7 as an example, see Table 2). An aqueous
solution (70 mL) containing NaNO3 (1.79 g, 0.021 mol), KI
(1.66 g, 0.01 mol), NaHCO3 (1.26 g, 0.015 mol), acid 7 (1.26 g,
0.01 mol), and CHCl3 (30 mL) was placed into the anode
compartment of a cell. Electrolysis, analysis of the reaction
mixture for the "active" iodine and isolation of the products
were carried out as described in the preceding example. The
yield of "active" iodine on the current was 96%. The products
isolated contained (1H NMR spectroscopic data) only the
starting acid 7.
Electrochemical iodination of 1ꢀmethylpyrazole (8) (using
entry 8 as an example, see Table 2). An aqueous solution
(70 mL) containing NaNO3 (1.79 g, 0.021 mol), KI (1.66 g,
0.01 mol), NaHCO3 (1.26 g, 0.015 mol), pyrazole 8 (0.82 g,
0.01 mol), and CHCl3 (30 mL) was placed into the anode
compartment of a cell. Electrolysis, analysis of the reaction
mixture for the "active" iodine and isolation of products were
carried out similarly to those described above for compound 1.
The yield of "active" iodine on the current was 90%. After
isolation of the products, an oil was obtained (0.78 g), which
(1H NMR spectroscopic data) was a mixture of 4ꢀiodoꢀ1ꢀmethylꢀ
pyrazole (8a), pyrazole 8, and CHCl3. The molar ratio of these
compounds (1 : 12.67 : 4) was determined from the integral
intensities of the signals for compounds 8a with δ 7.72 (s, 1 H,
H(5)), 8 with δ 6.20 (s, 1 H, H(4)), and CHCl3 with δ 8.30 (s, 1 H).
The yield of product 8a was 5%.
Electrochemical iodination of 3(5)ꢀmethylpyrazole (9) (using
entry 9 as an example, see Table 2). An aqueous solution (70 mL)
containing NaNO3 (1.79 g, 0.021 mol), KI (1.66 g, 0.01 mol),
NaHCO3 (1.26 g, 0.015 mol), pyrazole 9 (0.82 g, 0.01 mol), and
CHCl3 (30 mL) was placed into the anode compartment of a
cell. Electrolysis, analysis of the reaction mixture for the "active"
iodine and isolation of products were carried out as described in
* Organic fraction contained no acids 4 and 4a.

4ꢀIodoꢀsubstituted pyrazole and its derivatives
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 8, August, 2010
1555
the preceding example. Compound 9a was obtained (1.48 g,
71%), which was identified by the m.p. 110—111 °C (cf. Ref. 12:
m.p. 110.5 °C) and characteristics of the H NMR spectrum.
11. B. V. Lyalin, V. A. Petrosyan, B. I. Ugrak, Elektrokhim.,
2010, 46, 131 [Russ. J. Electrochem. (Engl. Transl.), 2010,
46, 123].
1
Electrochemical iodination of 1,3ꢀdimethylpyrazole (10) (using
entry 10 as an example, see Table 2). An aqueous solution (70 mL)
containing NaNO3 (1.79 g, 0.021 mol), KI (1.66 g, 0.01 mol),
NaHCO3 (1.26 g, 0.015 mol), pyrazole 10 (0.96 g, 0.01 mol),
and CHCl3 (30 mL) was placed into the anode compartment of
a cell. Electrolysis, analysis of the reaction mixture for the
"active" iodine and isolation of products were carried out as
described in the preceding example. The yield of "active" iodine
on the current was 64%. After isolation of the products, an oil
was obtained (1.47 g), which (1H NMR spectroscopic data) was
a mixture of 4ꢀiodoꢀ1,3ꢀdimethylpyrazole (10a), pyrazole 10,
and CHCl3. The molar ratio of these compounds (2.08 : 3.02 : 1)
was determined from the integral intensities of the signals for
compounds 10a with δ 7.75 (s, 1 H, H(5)), 10 with δ 6.95 (s, 1 H,
H(4)), and CHCl3 with δ 8.30 (s, 1 H). The yield of product 10a
was 35%.
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Received March 2, 2010;
in revised form June 9, 2010