Efficient iodination of structurally varying pyrazoles in heterophase medium

Article abstract of DOI:10.1007/s11172-013-0140-z

A synthesis of 4-iodo-substituted pyrazoles by iodination of pyrazole and its derivatives in the heterophase (H₂O/CHCl₃ (CCl ₄)) medium with the system KI-KIO₃ in the presence of H₂SO₄ additives was accomplished. The yields of 4-iodo-substituted pyrazoles in the iodination of pyrazole, 3,5- dimethylpyrazole, pyrazole-3(5)-carboxylic acid, 1-methylpyrazole-3-carboxylic acid, 1-methylpyrazole-5-carboxylic acid, 3-nitropyrazole, 1-methyl-3- nitropyrazole, 1-methylpyrazole, 1-ethylpyrazole, and 1-isopropylpyrazole were within 80-97%, whereas in the case of 3-nitropyrazole-5-carboxylic acid it was 32%.

Full text of DOI:10.1007/s11172-013-0140-z

1044
Russian Chemical Bulletin, International Edition, Vol. 62, No. 4, pp. 1044—1051, April, 2013
Efficient iodination of structurally varying pyrazoles in heterophase medium*
B. V. Lyalin and V. A. Petrosyan
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
4
7 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: lyalin@ioc.ac.ru
A synthesis of 4ꢀiodoꢀsubstituted pyrazoles by iodination of pyrazole and its derivatives in
the heterophase (H O/CHCl (CCl )) medium with the system KI—KIO in the presence of
2
3
4
3
H SO additives was accomplished. The yields of 4ꢀiodoꢀsubstituted pyrazoles in the iodination
2
4
of pyrazole, 3,5ꢀdimethylpyrazole, pyrazoleꢀ3(5)ꢀcarboxylic acid, 1ꢀmethylpyrazoleꢀ3ꢀcarbꢀ
oxylic acid, 1ꢀmethylpyrazoleꢀ5ꢀcarboxylic acid, 3ꢀnitropyrazole, 1ꢀmethylꢀ3ꢀnitropyrazole,
1
ꢀmethylpyrazole, 1ꢀethylpyrazole, and 1ꢀisopropylpyrazole were within 80—97%, whereas in
the case of 3ꢀnitropyrazoleꢀ5ꢀcarboxylic acid it was 32%.
Key words: iodination, KI—KIO system, pyrazole, 3,5ꢀdimethylpyrazole, pyrazoleꢀ3(5)ꢀ
3
carboxylic acid, 1ꢀmethylpyrazoleꢀ3ꢀcarboxylic acid, 1ꢀmethylpyrazoleꢀ5ꢀcarboxylic acid,
3
ꢀnitropyrazole, 1ꢀmethylꢀ3ꢀnitropyrazole, 1ꢀmethylpyrazole, 1ꢀethylpyrazole, 1ꢀisopropylꢀ
pyrazole, 3ꢀnitropyrazoleꢀ5ꢀcarboxylic acid.
1
Iodine is known to be the least reactive in the halogeꢀ
fairly well iodinated upon the action of ICl (the yields of
4ꢀiodopyrazoles are within 51—92%) in aqueous HCl (see
nation reactions of arenes. This stimulates the search for
the more efficient methods of iodination of pyrazoles (Pz),
since the interest to the preparation of Pz iodo derivatives
is caused by their use in the synthesis of biologically active
compounds with antitumor, antiviral, antibacterial acꢀ
1
8,19
Ref. 14) or organic (AcOH, EtOAc) media,
as well as
upon the action of a mixture of I with diacetoxyiodobenzꢀ
2
2
0
ene in CH Cl , however, in this case the target products
2
2
require chromatographic purification. Good results (the
yields of the target products of 80—90%) were obtained
when I —(NH )Ce(NO ) in MeCN (see Ref. 21) and
tivity2 or as reagents in organic synthesis.
—5
6—8
Analysis of the literature data showed that existing
methods for the preparation of iodopyrazoles are not withꢀ
out disadvantages, because of the limitations concerning
either the structures of starting Pz, or the high cost or
toxicity of the iodinating agents, or the environmental
problems. Thus, the use of the system9
2
4
3 6
I —AgOAc in CH Cl (see Ref. 22) were used as the iodiꢀ
2
2
2
nating agents, though the use of aprotic medium and
expensive enough reagents is required to effect such
processes.
—12
I2—NaI—
Finally, the iodination of pyrazoles of virtually any
structure is described upon the action of I —HIO in
K CO in aqueous EtOH gives good results (the yields of
5—90%) only for Pz with electronꢀdonating substituents
2
3
2
3
2
3—25
7
AcOH with CCl additives.
The reaction is efficient
4
in the ring. Note that Pz with donor substituents in the
ring are also iodinated in high (63—99%) yields in aqueꢀ
ous medium with the mixture1 of I —H O (30%), howꢀ
enough and does not produce toxic waste, that makes this
process the most attractive. That is why in the present
work, in the development of a new approach to the iodinaꢀ
tion of Pz of various structure, we attempted to modify
this process with respect to the aqueous media and have
chosen a mixture of KI—KIO in the presence of H SO
3
2
2
2
ever, the reaction is slow enough (24—72 h). When the
system1 I —NH (aqueous) was used, the process was
4
2
3
nonselective (monoꢀ, diꢀ, and triiodopyrazoles were
formed) and could lead to the generation of explosive
3
2
4
additives as the key system.
9
,15—18
nitrogen iodide. NꢀIodosuccinimide
is used for
the iodination of Pz with any substituents in the ring in
good (70—90%) yield in 50% aqueous H SO or other
Results and Discussion
2
4
(
CF SO H, CF COOH, EtOAc) media, however, the high
Proceeding from the literature analogies,26 it could have
been expected that the iodination process under study
would follow Scheme 1.
3
3
3
cost of the reagent limits the scope of its application. Pyrꢀ
azoles with alkyl or phenyl substituents in the ring can be
Since there are no literature data on the iodination of
Pz using the system KI—KIO in aqueous acid (H SO )
*
Dedicated to Academician of the Russian Academy of Sciences
3
2
4
I. P. Beletskaya on the occasion of her anniversary.
medium, in the first stage we have chosen iodination of
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 1043—1050, April, 2013.
066ꢀ5285/13/6204ꢀ1044 © 2013 Springer Science+Business Media, Inc.
1

Pyrazoles iodination in heterophase medium
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
1045
Scheme 1
I2 dissolved in the organic phase would be transferred into
the aqueous phase as it is consumed.
A series of experiments performed confirmed the posꢀ
sibility of the iodination of Pz with the system KI—KIO3
in the heterophase medium. However, for the stoichioꢀ
metric (see Scheme 1) ratio of the starting Pz, KI, and
H SO , the yield of the target product (Table 1, entry 1)
2
4
turned out to be low (13%). We further attempted to opꢀ
timize this process and determine the nature of the
key iodinating agent, since no efforts were undertaken to
clarify the nature of such an agent in the works cited
24,26
above
.
1
i
2
3
R = H, Me, Et, Pr ; R = H, Me, NO , COOH; R = H, Me, COOH
2
The yield of the target product 1´ turned out to inꢀ
crease with the increase in the concentration of Pz 1 (see
Table 1, cf. entries 2, 4, and 5), as well as with the increase
of the reaction temperature from 30 to 50 C. Simulꢀ
taneously, the reaction time became shorter, which was
2 h at 50 C instead of 4 h at 30 C (cf. entries 5 and 6).
The iodination process was considered to reach comꢀ
pletion when the solution lost its color because of the
unsubstituted Pz (1) as a model substrate to study both
a possibility of its realization and specific features of this
process. In the second stage, a wide enough variety of
functionally substituted Pz 1—11 were studied to discover
factors determining efficiency of the iodination system
suggested.
Unsubstituted Pz. It is quite obvious that when the
process shown in Scheme 1 is effected, the reaction of KI
consuming of the intermediately formed I . However,
note that a possibility to increase the temperature is limitꢀ
2
and KIO in aqueous acid medium would lead to the forꢀ
ed to 50 C, since the boiling point of the azeotrope CHCl /
3
3
2
7
mation of I poorly soluble in aqueous medium (mainly
H O is 56 C.
2
2
precipitates), which (see below) is an active intermediate
of the iodination process. That is why we used a twoꢀphase
system H O/CHCl as the medium in the assumption that
The increase in the v/v ratio of aqueous and organic
phases from 2.5 : 1 to 5 : 1 promoted the process even to
a greater extent, that led to a sharp decrease in the time
2
3

1
046
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
Lyalin and Petrosyan
Table 1. Influence of the experimental conditions on the yield of 4ꢀiodopyrazole (1´) in the chemical iodination of Pz (1) in
H O/CHCl by the system KIO —KI—H SO (the molar ratio 1 : KIO : KI = 3 : 1 : 2)
2
3
3
2
4
3
a
b
Entry
Loading/mol
Aqueous solution : CHCl3 T/C
vol.)
/h Conversion of KIO3 Yield of 1´
(
1
H SO4
%
2
1
2
3
4
5
6
7
0.015
0.015
0.015
0.030
0.090
0.090
0.090
0.0075
0.0150
0.0300
0.0300
0.0900
0.0900
0.0900
2.5 : 1
2.5 : 1
2.5 : 1
2.5 : 1
2.5 : 1
2.5 : 1
5 : 1
30
30
30
30
30
50
50
4.0
4.0
4.0
4.0
4.0
2.0
0.5
43.2
56.0
75.3
66.3
89.1
98.7
93.1
13.0
19.9
58.3
30.2
68.0
98.6
88.8
a
Conversion of KIO was determined by iodometric analysis.
Yield of 4ꢀiodopyrazole was calculated based on the H NMR spectroscopic data for the isolated mixture of products.
3
b
1
necessary for the reaction to reach completion: 0.5 h inꢀ
stead of 2 h (cf. entries 6 and 7).
genation reactions involving hypohalic acids (HOHal).
Therefore, it can be considered that the iodination process
under conditions studied also proceeds through the inꢀ
termediate formation of HOI, especially as the fact of
the formation of HOI by the reaction of I with KIO in
Concerning specific features of realization of this proꢀ
2
8
cess, based on the analogy with iodination of arenes
–
upon the action of I /IO3 in sulfuric acid it could have
2
2
3
+
been suggested that in our case the triiodide cation I3
an acidified aqueous solution is confirmed by the literaꢀ
3
0
(
formed by oxidation of I ) could also serve as the iodinatꢀ
ture data.
2
ing agent. But it turned out that the rate of the iodination
Based on the stated above, the process of iodination of
reaction and, therefore, the yield of 4ꢀiodopyrazole (1´),
Pz in the system KI—KIO in aqueous acid medium was
3
as well as the conversion of KIO , increased with the inꢀ
described by Scheme 2 (eqs (1)—(4)). According to
Scheme 2, HIO (formed from KIO in acidic medium)
3
crease in the concentration of H SO (cf. entries 1—3 in
2
4
3
3
Table 1). This fact is difficult to explain in the suggestion
that the cation I3+ is the iodinating agent. At the same
time, the direct dependence of the process efficiency from
the concentration of the acid is characteristic29 of the haloꢀ
reacts with KI generating I (the fast step), whose reaction
2
with HIO is accompanied by the formation of HOI servꢀ
3
ing as a key iodinating agent with respect to Pz (the slow
31
step). It is known that pКBH+ of the starting Pz is equal
Scheme 2
C is the ꢀcomplex.

Pyrazoles iodination in heterophase medium
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
1047
to 2.52, therefore, under the experimental conditions
in the iodination of the strongly basic Pz, the process,
33
(
10% aqueous H SO ), a protonated form would underꢀ
according to the data in the work, proceeds through the
generation of a ꢀcomplex, however in this case the
electrophilic agent (HOI) is coordinated already at N(2)
nitrogen atom of the heterocycle, with the acid (H SO )
2
4
go the iodination. This process (see eq. (4)) most likely
proceeds through the generation of a ꢀcomplex, where
the electrophilic agent (HOI) is coordinated at C(4) atom
of the pyrazole ring (which possesses the highest electron
2
4
still playing the role of a catalyst with the electrophilic
assistance to the elimination of the OH group from HOI
3
2
density ) and is catalyzed by H SO , which provides the
2
4
electrophilic assistance in the elimination of the OH group
from HOI. The neutralization (addition of Na CO to
pH 7—8) of the reaction mixture containing protonated
(leaves as H O). The thus formed Nꢀiodopyrazole underꢀ
2
goes rearrangement to generate the target 4ꢀiodopyrazole.
2
3
2
1,34
As it was shown earlier,
the efficiency of iodinaꢀ
4
ꢀiodopyrazole leads to the target product.
To sum up this part of our studies, note that under the
tion of Pz strongly depends on the nature of the substituꢀ
ent and its position in the pyrazole ring. For example, the
high yield (80%) of 4ꢀiodopyrazole was obtained by the
2
1
optimal conditions (the medium: H O—CHCl (5 : 1);
2
3
loadings of Pz 1, KI, KIO , and H SO are equal to 0.09,
iodination with the system I —NaI—NaOAc in aqueous
3
2
4
2
0
.06, 0.03, and 0.09 mol, respectively, T = 50 C, the
medium (boiling with a reflux condenser for 24—48 h) for
Pz with the strong donor substituents in the ring (3ꢀmethꢀ
oxyꢀ4ꢀmethylpyrazole), the moderate yield (55%) was obꢀ
tained for 3,5ꢀdimethylpyrazole, whereas 3,5ꢀbis(ethoxyꢀ
carbonyl)pyrazole with two acceptor groups in the ring
did not give the iodination reaction at all. This prompted
us to study iodination of Pz with substituents of different
nature: electronꢀdonating (3,5ꢀdimethylpyrazole (2)) and
electronꢀwithdrawing (pyrazoleꢀ3ꢀcarboxylic acid (3) and
3ꢀnitropyrazole (6)), as well as Nꢀalkylated Pz (1ꢀmethylꢀ
pyrazolecarboxylic acids (4, 5), 1ꢀmethylꢀ3ꢀnitropyrazole
(7), and 1ꢀalkylpyrazoles (8—10)). The results obtained
are summarized in Table 2.
reaction time of 0.5 h) the iodination of Pz leads to the
preparation of the target 4ꢀiodopyrazole in high (88.8%)
yield calculated from the starting pyrazole.
Substituted Pz. As compared to the unsubstituted Pz,
its alkyl derivatives possess even higher basicity, and
the mechanism of their iodination is also described by
Eqs (1)—(4) (see Scheme 2), whereas the Pz nitro deriꢀ
vatives (6, 7, and 11) are weakly basic (for example,
3
1
pКBH (6) is equal to –4.66) and under the experimental
+
conditions they mainly are present in the unprotonated
form. The mechanism of iodination of thisꢀtype of comꢀ
pounds should be described by Eq. (5) (see Scheme 2). As
Table 2. Influence of the experimental conditions on the yield of 4ꢀiodoꢀsubstituted pyrazoles in the chemical iodination of pyrazoles
(
(
Pz) with KIO —KI—H SO (loadings of Pz of 0.09 mol, the molar ratio Pz : KIO : KI : H SO = 3 : 1 : 2 : 3) in the system H O/CHCl
3
2
4
3
2
4
2
3
CCl ) with the v/v ratio of phases of 5 : 1
4
a
Entry
Starting
Pz
T/C
Organic
phase
/min
Conversion of (%)
Product of
iodination
Yield of product (%)
KIO b
Pza
I
II
3
1
2
3
4
5
6
7
8
9
2
3
4
5
5
5
6
7
8
50
50
50
50
50
66
66
66
50
50
50
66
СHCl3
СHCl3
СHCl3
СHCl3
СHCl3
CCl4
CCl4
CCl4
СHCl3
СHCl3
СHCl3
CCl4
7
10
25
10
60
99.0
95.5
92.0
61.1
71.1
93.6
85.3
63.5
90.5
89.5
89.9
36.2
96.7
97.4
99.7
59.4
63.4
98.0
93.0
70.6
95.0
90.1
90.3
51.5
2´
3´
4´
5´
5´
5´
6´
7´
8´
96.7
92.1
92.6
49.4
60.0
86.8
83.5
58.7
84.0
80.2
82.0
32.2
100.0
94.6
92.9
83.2
94.6
88.5
89.9
92.4
88.8
89.0
90.8
62.5e
c
60
c,d
180
180
30
30
30
с,d
10
11
12
9
10
11
9´
10´
11´
с,d
e
180
a
1
Conversion of the starting Pz and yields of products were calculated based on the H NMR spectroscopic data for the isolated mixture
of products: I calculated based on the starting Pz, II calculated based on the reacted Pz.
b
Conversion of KIO was determined by iodometric analysis.
3
c
CCl was used as the organic phase instead of CHCl , since the boiling point of the CCl /H O azeotrope is higher than that in the
4
3
4
2
2
7
case of CHCl and is equal to 66 C.
3
d
Loading of Pz was 0.0045 mol, the molar ratio Pz : KIO : KI : H SO = 3 : 1 : 2 : 6.
3
2
4
e
1
Since product 11´ does not give characteristic signals in the H NMR spectrum, to determine the molar ratio of the reaction products,
1
the obtained mixture of acids 11´—11 was converted to a mixture of their methyl esters and then analyzed by H NMR. The yield of
acid 11´ is given in calculation on its methyl ester.

1
048
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
Lyalin and Petrosyan
A comparison of the data on the iodination of unsubꢀ
However, note for the comparison that in the iodinaꢀ
3
4
stituted Pz 1 and substituted Pz 2, 3, and 4 (cf. entry 7 in
Table 1 and entries 1—3 in Table 2) showed that the presꢀ
ence in the pyrazole ring of two methyl groups (Pz 2), the
COOH group at the carbon atom (Pz 3), or the methyl
group at the nitrogen atom and the COOH group at the
carbon atom (Pz 4) has low influence on the yield of 4ꢀiodo
derivative, which remained around 90%. It is obvious, that
this is due to the high reactivity of HOI as the iodinating
agent, that essentially levels the negative influence of the
moderately strong electronꢀwithdrawing substituents in the
pyrazole ring on the iodination process.
tion of 3ꢀnitropyrazole (6) by the system KIO —I —
3 2
H SO in AcOH (with H O and CCl additives), 21 h at
2
4
2
4
80—85 C are required for the yield of the target prodꢀ
uct 6´ to reach 86% calculated on the loaded Pz 6, whereꢀ
as in our experiment, the iodination of Pz 6 (see Table 2,
entry 7) proceeds at lower temperature and decreases the
reaction time by the factor of 7 with the yield of the target
product 6´ being comparable.
As it was expected, the introduction into the molecule
of Pz 6 of the second (besides the NO group) electronꢀ
2
withdrawing substituent (the COOH group), Pz 11, led to
the decrease (by 50%) in the yield of the corresponding
4ꢀiodo derivative (see Table 2, cf. entries 7 and 12). At the
same time, from the data of entry 12 (see Table 2) it is seen
that the conversion of both the starting Pz 11 and KIO3
was only 50%. From this it follows that the efficiency of
iodination of Pz with two electronꢀwithdrawing substituꢀ
ents can be principally increased through the increase of
the experimental time.
The data on the iodination of Nꢀalkylated Pz deserved
special attention; on the whole it proceeded less efficiently
as compared to the iodination of Pz unsubstituted at
position 1. This effect is especially pronounced for Pz
having a strong acceptor substituent in the ring. Thus, as
compared to 3ꢀnitropyrazole 6, the iodination of Nꢀmethꢀ
yl derivative (7) proceeded with the decrease in the
yield of the target product and the conversion of the startꢀ
ing pyrazole by 25% (see Table 2, cf. entries 7 and 8).
In the iodination of pyrazoleꢀ3ꢀcarboxylic acid (3), this
effect is less pronounced than in the case of 1ꢀmethylꢀ
pyrazoleꢀ3ꢀcarboxylic acid (4). Nevertheless, to obtain
the same yield of the target product of iodination of
Pz 4, the twice as long reaction time is required (see
Table 2, cf. entries 2 and 3). Even iodination of 1ꢀmethꢀ
ylpyrazole (8) proceeds with the yield lower than in
the case of unsubstituted Pz 1 by 10% (cf. entry 7 in
Table 1 and entry 9 in Table 2), in this case the nature of
In conclusion, we studied and suggested a new apꢀ
proach to the efficient performing of chemical iodination
of pyrazoles, which under the optimal conditions (the
H O—CHCl (CCl ) (5 : 1) medium; the loadings of Pz,
2
3
4
KIO , KI, and H SO equal to 0.045—0.09, 0.015—0.03,
3
2
4
0.03—0.06, and 0.09 mol, respectively; the reaction time
of 0.5—3.0 h, 50—66 C) allows one to obtain the target
products in good yields (59—93% calculated on the loadꢀ
ed or 92—93% calculated on the reacted Pz).
In general, the method of iodination of pyrazoles deꢀ
scribed in the present work is not inferior to the best of the
known methods in its yield of the target products and
is favorably distinguished by the use of available, inexꢀ
pensive, and nontoxic reagents, the rapidness of the overꢀ
all process carried out in aqueous medium and can be
applied for the efficient iodination of pyrazoles of various
structures.
i
the Nꢀalkyl (Me, Et, Pr ) substituent virtually does not
influence the efficiency of the process (see Table 2, cf.
entries 9—11).
In the case of Pz 5, the yield of the iodination product
(
5´), as well as the conversion of KIO and the starting Pz,
3
are significantly lower than in the iodination of pyrazole 4
cf. entries 3, 4, and 5 in Table 2). The obvious explanaꢀ
(
tion for this is the poor solubility of Pz 5 in aqueous soluꢀ
tion and, as a consequence, the low rate of chemical reacꢀ
tion because of the low effective concentration of Pz 5. In
fact, the increase in the yield of the target product to the
acceptable level (86.8%, entry 6) was accomplished (see
Table 2, entries 4—6) only by the increase of the reaction
time to 60 min, as well as by the increase of its temperaꢀ
ture to 66 C.
Experimental
Pyrazole (1) and 3,5ꢀdimethylpyrazole (2) were commerꢀ
cially available products (Acros) and were used without addiꢀ
tional purification. Pyrazoleꢀ3(5)ꢀcarboxylic (3), 1ꢀmethylpyrꢀ
azoleꢀ3ꢀcarboxylic (4), and 1ꢀmethylpyrazoleꢀ5ꢀcarboxylic (5)
acids,35 3ꢀnitropyrazole (6), 1ꢀmethylꢀ3ꢀnitropyrazole (7),
36
24
37
38
It should be emphasized that the replacement of the
COOH group in the pyrazole ring (Pz 3) with the more
1ꢀmethylpyrazole (8), 1ꢀethylpyrazole (9), 1ꢀisopropylpyrꢀ
azole (10),39 3ꢀnitropyrazoleꢀ5ꢀcarboxylic acid (11) were synꢀ
thesized according to the procedures described earlier.
Compounds obtained by iodination were identified by H NMR
spectroscopy by the comparison with the spectra of standard
40
electronꢀwithdrawing NO group (Pz 6) decreases the efꢀ
2
1
ficiency of iodination. As a consequence, for the preparaꢀ
tion of iodo derivative 6´ with a high enough yield (83.5%
calculated on the loaded Pz 6) more vigorous conditions
are required than for the preparation of 4ꢀiodopyrazoleꢀ
4
1
samples described in the literature: 4ꢀiodopyrazole (1´),
18
34
4
4
ꢀiodoꢀ3,5ꢀdimethylpyrazole (2´), 4ꢀiodoꢀ3ꢀnitropyrazole (6´),
24
ꢀiodoꢀ1ꢀmethylꢀ3ꢀnitropyrazole (7´), 4ꢀiodoꢀ1ꢀmethylpyrꢀ
azole (8´), 1ꢀethylꢀ4ꢀiodopyrazole (9´); and those syntheꢀ
3
(5)ꢀcarboxylic acid (3´): 66 C instead of 50 C, with the
42
43
reaction time of 3 h instead of 10 min (see Table 2,
cf. entries 2 and 7).
sized according to the known procedures: 4ꢀiodopyrazoleꢀ3(5)ꢀ
carboxylic (3´), 4ꢀiodoꢀ1ꢀmethylpyrazoleꢀ3ꢀcarboxylic (4´)
4
1

Pyrazoles iodination in heterophase medium
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
1049
2
4
and 4ꢀiodoꢀ1ꢀmethylpyrazoleꢀ5ꢀcarboxylic (5´) acid , 4ꢀiodoꢀ
C. Iodination of pyrazoleꢀ3ꢀcarboxylic acid (3) (taking entry 2
in Table 2 as an example). The reaction was carried out similarly
to example A with the following composition of the reaction
1
ꢀisopropylpyrazole (10´);43 4ꢀiodoꢀ3ꢀnitropyrazoleꢀ5ꢀcarbꢀ
oxylic acid (11´) was identified (see below) as its methyl ester.
4
4
1
H NMR spectra were recorded on a Bruker AMꢀ300
mixture: acid 3 (10.08 g, 0.09 mol), KIO (6.42 g, 0.03 mol), KI
3
spectrometer (300 MHz), DMSOꢀd was used as the solvent.
(9.96 g, 0.06 mol), H O (100 mL), CHCl (20 mL), and conc.
6
2
3
Chemical shifts are given relative to SiMe4.
H SO (5.2 mL, 0.09 mol). After carrying out the reaction (see
2 4
A. Chemical iodination of pyrazole (1) (taking entry 7 in Table 1
as an example). Carrying out the reaction. Pyrazole 1 (6.12 g,
example A) for 10 min, CHCl3 was evaporated, the aqueous
solution left was neutralized to pH 1 by the addition of NaOH.
A precipitate formed was filtered off, washed with water, and
0
.09 mol), KIO (6.42 g, 0.03 mol), KI (9.96 g, 0.06 mol), H O
3
2
1
(
100 mL), and CHCl (20 mL) were placed in a threeꢀneck flask
dried to obtain a residue (19.35 g) containing ( H NMR spectroꢀ
3
equipped with a dropping funnel, thermometer, mechanical stirꢀ
rer, and refluxed condenser and placed in a bath with controlled
temperature. The reaction mixture was vigorously stirred, folꢀ
scopic data) a mixture of 4ꢀiodopyrazoleꢀ3(5)ꢀcarboxylic acid
(3´) and the starting compound 3. Their molar ratio of 35.1 : 1.0
was determined from the integral intensities of the signals for
compounds 3´ at  7.90 (s, 1 H, H(5)) and 3 at  7.70 (s, 1 H,
H(5)). After the precipitate was isolated, the amount of the unꢀ
lowed by a dropwise addition (cooling, T  40 C) of conc. H SO4
2
(
5.2 mL, 0.09 mol). Then, the temperature was increased to
5
0 C, the solution was stirred for 30 min (until the violet color of
reacted KIO (4.5%) in the mother liquor was determined (see
3
I2 emerged after addition of H SO4 disappeared) and cooled
example A), then water was evaporated under reduced pressure.
2
to 20 C.
The residue was extracted with Me CO (2×25 mL) and EtOH
2
a. Isolation of the main portion of the target product. Chloroꢀ
(2×25 mL), the extracts were combined and after evaporation of
form was evaporated at the atmospheric pressure, the aqueous
the solvents, an additional amount (0.65 g) of the mixture conꢀ
taining (see H NMR spectroscopic data given above) comꢀ
1
solution left was neutralized by the addition of Na CO3 (to
2
pH 7—8). A precipitate formed was filtered off, washed with
water, and dried to obtain 4ꢀiodopyrazole (1´) (15.2 g), which
was identified by the melting point of 109 C (cf. Ref. 45:
pounds 3´ and 3 in the molar ratio of 70 : 1.0 was isolated.
The mixtures of compounds 3´ and 3 (19.35 and 0.65 g) were
combined, mixed with hot H O (80 mL), and cooled to 20 C
2
1
m.p. 108.5 C) and the H NMR spectral characteristics. After
in order to isolate product 3´. A precipitate formed was filtered
off and dried to obtain the purified product 3´ (16 g, 73.7%),
which was identified by the melting point of 240 C (cf. Ref. 34:
the isolation of the main portion of the target product, an aliquot
was collected from the mother liquor, and the amount of
the unreacted KIO3 (6.9%) was determined by iodometric
analysis.46
1
m.p. 240 C) and H NMR spectral characteristics. According to
1
the H NMR spectroscopic data, the yield of product 3´ conꢀ
b. Additional isolation. For the salting out the residual amount
of the target product, NaCl (30 g) was added to the mothꢀ
er liquor. A precipitate formed was extracted with CHCl3
taining in the mixture with 3 was 92.1%, with the conversion of
compound 3 being 97.6%.
D. Iodination of 1ꢀmethylpyrazoleꢀ3ꢀcarboxylic acid (4) (takꢀ
ing entry 3 in Table 2 as an example). The reaction was carried
out similarly to example A with the following composition of the
reaction mixture: acid 4 (11.34 g, 0.09 mol), KIO3 (6.42 g,
0.03 mol), KI (9.96 g, 0.06 mol), H O (100 mL), CHCl (20 mL),
(
2×30 mL), the extracts were combined and dried with CaCl2.
The evaporation of CHCl gave a white powder (0.52 g), which
3
1
according to the H NMR spectroscopic data was a mixture of
the target product 1´ and the starting Pz 1. Their molar ratio of
2
3
1
: 1 was determined from the integral intensities of the signals
and conc. H SO4 (5.2 mL, 0.09 mol). After carrying out the
2
for 1´ at  7.75 (s, 2 H, H(3(5))) and 1 at  7.60 (s, 2 H, H(3(5))).
Taking these data into account, the total yield of product 1´ was
reaction (see example A) for 25 min, the products were isolated
as described in example C to obtained 4ꢀiodoꢀ1ꢀmethylpyrazoleꢀ
3ꢀcarboxylic acid (4´) (19.5 g, 86.6%) as the main product, which
was identified by the melting point 182 C (cf. Ref. 24: m.p.
8
8.8%, with the conversion of the starting Pz 1 being 93.1%.
B. Iodination of 3,5ꢀdimethylpyrazole (2) (taking entry 1 in
1
Table 2 as an example). The reaction was carried out similarly to
180—181.5 C) and H NMR spectral characteristics. The conꢀ
example A with the following composition of the reaction mixꢀ
version of KIO was 92.0%. After isolation of the main portion of
3
ture: Pz 2 (8.64 g, 0.09 mol), KIO (6.42 g, 0.03 mol), KI (9.96 g,
the product, an additional amount (1.53 g) of a precipitate was
3
0
.06 mol), H O (100 mL), CHCl (20 mL), and conc. H SO
isolated from the mother liquor left (as described in example C),
which was ( H NMR spectroscopic data) a mixture of comꢀ
2
3
2
4
1
(
5.2 mL, 0.09 mol). After the reaction reached completion (disꢀ
appearance of the reaction mixture color, the reaction time of
min), the products were isolated and analyzed as described
above (see example A, a) to obtain 4ꢀiodoꢀ3,5ꢀdimethylpyrazole
2´) (18.85 g, 94.3%), which was identified by its melting point
pounds 4´ and 4. The molar ratio of these compounds in reacꢀ
tion mixture of 25.9 : 1.0 was determined from the integral inꢀ
tensities of the signals for 4´ at  8.0 (s, 1 H, H(5)) and 4 at  7.75
(c, 1 H, H(5)). Because of the difficulty of isolation of product 4´
from the reaction mixture, the obtained target product 4´ (19.5 g)
and the mixture of compounds 4´ and 4 (1.53 g) were combined
to determine the total yield (92.6%) of product 4´ based on the
7
(
1
1
37 C (cf. Ref. 47: m.p. 137—138 C) and H NMR spectral
characteristics. The conversion of KIO was 94.0%. An addiꢀ
tional amount (0.67 g) of the product was isolated from the mothꢀ
er liquor as described above (see example A, b), which ( H NMR
3
1
1
H NMR spectroscopic data, with the conversion of compound 4
spectroscopic data) was a mixture of the target product 2´ and
the starting 2. The molar ratio of these compounds in the reacꢀ
tion mixture of 0.58 : 1.0 was determined from the integral inꢀ
tensities of the signal for Pz 2 at  5.70 (s, 1 H, H(4)) and the
being 99.7%.
E. Iodination of 1ꢀmethylpyrazoleꢀ5ꢀcarboxylic acid (5) (takꢀ
ing entry 6 in Table 2 as an example). The reaction was carried
out similarly to example A, but at T = 66 C and the following
composition of the reaction mixture: acid 5 (11.34 g, 0.09 mol),
KIO (6.42 g, 0.03 mol), KI (9.96 g, 0.06 mol), H O (100 mL),
overlapped signal for Pz 2 and 2´ at  2.15 (s, 6 H, CH ). Taking
3
these data into account, the total yield of product 2´ was 96.7%,
3
2
with the conversion of Pz being 2 96.7%.
CCl (20 mL), and conc. H SO (5.2 mL, 0.09 mol). After carryꢀ
4
2
4

1
050
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
Lyalin and Petrosyan
ing out the reaction (see example A) for 60 min, the products
were isolated as described in example C. The conversion of KIO3
was 93.6%. The residue (19.05 g) obtained was ( H NMR specꢀ
troscopic data) a mixture of 4ꢀiodoꢀ1ꢀmethylpyrazoleꢀ3ꢀcarbꢀ
oxylic acid (5´) and compound 5. The molar ratio of these comꢀ
pound in the reaction mixture of 45 : 1.0 was determined from
the integral intensities of the signals for compounds 5´ at  7.60
spectroscopic data was, with the conversion of compound 7
being 70.6%.
H. Iodination of 1ꢀmethylpyrazole (8) (taking entry 9 in Table 2
as an example). The reaction was carried out similarly to exꢀ
ample A with the following composition of the reaction mixture:
1
pyrazole 8 (7.38 g, 0.09 mol), KIO , 9.96 g (6.42 g, 0.03 mol), KI
3
(0.06 mol), H O (100 mL), CHCl (20 mL), and conc. H SO
4
2
3
2
(
s, 1 H, H(3)) and 5 at  7.50 (s, 1 H, H(3)). Then, the mother
(5.2 mL, 0.09 mol). After carrying out the reaction for 30 min,
the products were isolated as described in example A. The conꢀ
version of KIO3 was 90.5%. The oil (16.6 g) obtained was
liquor was treated as described in example C to additionally isoꢀ
late some product (0.86 g), which was ( H NMR spectroscopic
data) a mixture of compounds 5´ and 5 in the molar ratio of
1
1
( H NMR spectroscopic data) a mixture of 4ꢀiodoꢀ1ꢀmethylpyraꢀ
3
0
1 : 1.0. The thus obtained mixtures of compounds (19.05 and
zole (8´) and the starting compound 8. The molar ratio of these
compound in the reaction mixture of 15 : 1.0 was determined
from the integral intensities of the signals for compounds 8´ at
 7.50 (s, 1 H, H (3), H (5)) and 8 at  7.38 (s, 1 H, H(3), H(5)).
The yield of product 8´ (84.0%) in the mixture was determined
.86 g) were combined to determine the total yield (86.8%) of
1
product 5´ based on the H NMR spectroscopic data, with the
conversion of compound 5 being 98.0%.
F. Iodination of 3ꢀnitropyrazole (6) (taking entry 7 in Table 2
as an example). The reaction was carried out similarly to examꢀ
ple A, but at T = 66 C and the following composition of the
1
based on the H NMR spectroscopic data, with the conversion
of compound 8 being 95.0%.
reaction mixture: pyrazole 6 (5.09 g, 0.045 mol), KIO (3.21 g,
I. Iodination of 1ꢀethylpyrazole (9) (taking entry 10 in Table 2
as an example). The reaction was carried out similarly to examꢀ
ple A with the following composition of the reaction mixture:
3
0
.015 mol), KI (4.98 g, 0.03 mol), H O (100 mL), CCl (20 mL),
2 4
and conc. H SO (5.2 mL, 0.09 mol)). After the reaction mixꢀ
2
4
ture was kept at T = 66 C for 180 min, the products were isolatꢀ
pyrazole 9 (8.64 g, 0.09 mol), KIO (6.42 g, 0.03 mol), KI (9.96 g,
3
ed as indicated in example E. the conversion of KIO was 85.3%.
The thus isolated residue (8.54 g) was ( H NMR spectroscopic
data) a mixture of 4ꢀiodoꢀ3ꢀnitropyrazole (6´) and pyrazole 6.
The molar ratio of these compound in the reaction mixture of
0.06 mol), H O (100 mL), CHCl (20 mL), and conc. H SO
4
3
2
3
2
1
(5.2 mL, 0.09 mol). After carrying out the reaction for 30 min,
the products were isolated as described in example A. The conꢀ
version of KIO3 was 89.5%. The oil obtained (17.8 g) was
1
3
0.3 : 1.0 was determined from the integral intensities of the
signals for compounds 6´ at  8.25 (s, 1 H, H(5)) and 6 at  8.0
s, 1 H, H(5)). Solid Na SO was added to the mother liquor left
( H NMR spectroscopic data) a mixture of 1ꢀethylꢀ4ꢀiodopyrꢀ
azole (9´), the starting compound 9, and CHCl . The molar
3
(
ratio of these compound in the reaction mixture of 19.0 : 3.5 : 1.0
was determined from the integral intensities of the signals for
product 9´ at  7.50 (s, 1 H, H(3), H(5)), the starting compound
2
3
after isolation of the precipitate to destroy the large amount of
unreacted KIO until the solution became colorless (disappearꢀ
3
ance of the color from I , formed by the reaction of KIO and
9 at  7.40 (s, 1 H, H(3), H(5)), and CHCl at  8.30 (s, 1 H).
2
3
3
Na SO ). Then, the mother liquor was treated as in example E
The yield of product 9´ (80.2%) in the mixture was determined
based on the H NMR spectroscopic data, with the conversion
of compound 9 being 90.1%.
2
3
1
1
to additionally isolate 0.79 g of the product, which was ( H NMR
spectroscopic data) a mixture of product 6´ and the starting
compound 6 in the molar ratio of 1.2 : 1.0. The thus obtained
mixtures of the target product 6´ and the starting compound 6
J. Iodination of 1ꢀisopropylpyrazole (10) (taking entry 11 in
Table 2 as an example). The reaction and the isolation of prodꢀ
ucts were carried out similarly to example A with the following
composition of the reaction mixture: pyrazole 10 (9.90 g,
0.09 mol), KIO (6.42 g, 0.03 mol), KI (9.96 g, 0.06 mol), H O
(
8.54 and 0.79 g) were combined to determine the total yield of
1
product 6´ (83.5%) based on the H NMR spectroscopic data,
with the conversion of compound 6 being 93.0%.
3
2
G. Iodination of 1ꢀmethylꢀ3ꢀnitropyrazole (7) (taking entry 8
in Table 2 as an example). The reaction was carried out similarly
to example A, but at T = 66 C and the following composition of
(100 mL), CHCl (20 mL), and conc. H SO (5.2 mL, 0.09 mol).
3 2 4
The conversion of KIO was 89.9%. The oil (19.0 g) obtained
3
1
was ( H NMR spectroscopic data) a mixture of 4ꢀiodoꢀ1ꢀisoꢀ
the reaction mixture: pyrazole 7 (5.71 g, 0.045 mol), KIO (3.21 g,
propylpyrazole (10´), the starting compound 10, and CHCl3.
The molar ratio of these compound in the reaction mixture of
8.5 : 1.0 : 0.6 was determined from the integral intensities of the
signals for product 10´ at  7.50 (s, 1 H, H (3), H(5)), the starting
3
0
.015 mol), KI (4.98 g, 0.03 mol), H O (100 mL), CCl (20 mL),
2 4
and conc. H SO (5.2 mL, 0.09 mol). After the reaction mixture
2
4
was kept at T = 66 C for 180 min, the products were isolated as
indicated in example F. The conversion of KIO3 was 63.5%.
compound 10 at  7.40 (s, 1 H, H(3), H(5)), and CHCl at  8.30
3
1
The thus isolated residue (7.92 g) was ( H NMR spectroscopic
(s, 1 H). The yield of product 10´ (82.0% in the mixture was
1
data) a mixture of 4ꢀiodoꢀ1ꢀmethylꢀ3ꢀnitropyrazole (7´) and
the starting compound 7. The molar ratio of these compounds
in the reaction mixture of 2.4 : 1.0 was determined from
the integral intensities of the signals for compounds 7´ at  8.25
determined based on the H NMR spectroscopic data, with the
conversion of compound 10 being 90.3%.
K. Iodination of 3ꢀnitropyrazoleꢀ5ꢀcarboxylic acid (11) (takꢀ
ing entry 12 in Table 2 as an example). The synthesis and the
isolation of products were carried out as indicated in example E,
with the following composition of the reaction mixture: acid 11
(
s, 1 H, H(5)) and 7 at  8.0 (s, 1 H, H(5)). The mother liꢀ
quor left after isolation of the precipitate was treated as in exꢀ
ample F to additionally isolate 0.44 g of the product, which was
(7.07 g, 0.045 mol), KIO (3.21 g, 0.015 mol), KI (4.98 g, 0.03 mol),
3
1
(
H NMR spectroscopic data) a mixture of the target product 7´
CCl4 (20 mL), H O (100 mL), and conc. H SO (5.2 mL,
2
2
4
and the starting compound 7 in the molar ratio of 0.24 : 1.0.
The thus obtained mixtures of the target product 7´ and the
starting compound 7 (7.92 and 0.44 g) were combined to deterꢀ
0.09 mol). The conversion of KIO was 36.5%. A solid comꢀ
3
pound (1.03 g) was obtained. The mother liquor left after isolaꢀ
tion of the precipitate was treated as in example E to additionally
isolate 6.5 g of the compound. The products were combined,
1
mine the total yield of product 7´ (58.7%) based on the H NMR

Pyrazoles iodination in heterophase medium
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
1051
dissolved in MeOH (50 mL), followed by the addition of SOCl2
22. M. Iglesias, O. Schuster, M. Albrecht, Tetrahedron Lett.,
2010, 51, 5423.
(
6.7 mL, 0.09 mol) and reflux of the reaction mixture with water
condenser for 14 h. After cooling of the solution, MeOH was
evaporated (at reduced pressure), the residue was dissolved in
EtOAc (50 mL), sequentially washed with saturated aqueous
NaHCO3 (3×15 mL) and NaCl (1×10 mL), and dried with
Na SO . The evaporation of the organic solvent gave a residue
23. A. N. Sinyakov, S. F. Vasilevskii, M. S. Shvartsberg, Bull.
Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.), 1977, 26,
778 [Izv. Akad. Nauk SSSR, Ser. Khim., 1977, 2306].
24. S. F. Vasilevskii, M. S. Shvartsberg, Bull. Acad. Sci. USSR.
Div. Chem. Sci. (Engl. Transl.), 1980, 29, 778 [Izv. Akad.
Nauk SSSR, Ser. Khim., 1980, 1071].
25. S. F. Vasilevskii, E. V. Tret´yakov, Russ. Chem. Bull.
(Engl. Transl.), 1996, 45, 2585 [Izv. Akad. Nauk, Ser. Khim.,
1996, 2722].
2
4
1
(
7.03 g), which ( H NMR spectroscopic data) was a mixture of
methyl esters of 4ꢀiodoꢀ3ꢀnitropyrazoleꢀ5ꢀcarboxylic (11´) and
ꢀnitropyrazoleꢀ5ꢀcarboxylic (11) acids. The molar ratio of these
3
compound in the reaction mixture of 1.0 : 1.5 was determined
from the integral intensities of the signals for ester 11 at  7.30
26. S. Adimurthy, G. Ramachandraiah, P. K. Grosh, Tetraꢀ
hedron Lett., 2003, 44, 5099.
(
s, 1 H, H(4)) and the overlapped signal for esters of product 11´
and the starting compound 11 at  3.90 (s, 3 H, OCH ). The
27. A. J. Gordon, R. A. Ford, The Chemist´s Companion, Wiley,
New York—London—Sidney—Toronto, 1972.
28. J. Arotsky, A. C. Darby, J. A. Hamilton, J. Chem. Soc. (B),
1968, 739.
3
yield of methyl ester 11´ (32.0%) in the mixture was determined
1
based on the H NMR spectroscopic data (calculated based on
the loaded acid 11 with its conversion of 51.5%).
2
9. Comprehensive Organic Chemistry. The Synthesis and Reacꢀ
tion of Organic Compound, Eds D. Barton, W. D. Olles, v. 1,
Stereochemistry, Hydrokarbons, Halo Compounds, Ed. J. F.
Stoddart, Pergamon Press Ltd, Oxford—New York—Toronꢀ
to—Sydney—Paris—Frankfurt, 1979.
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