Effect of "anomalous" electrochemical halogenation of pyrazoles and its reasons

Full text of DOI:10.1007/s11172-012-0030-9

Russian Chemical Bulletin, International Edition, Vol. 61, No. 1, pp. 209—210, January, 2012
209
Effect of "anomalous" electrochemical halogenation of pyrazoles
and its reasons
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 (495) 135 5328. Eꢀmail: lyalin@ioc.ac.ru
We have previously1—3 found that the nature of haloꢀ
gen determines, to a noticeable extent, the yield of target
products in the electrochemical halogenation of pyrazoles
the conversion of the Nꢀchloroderivative was only 6%,
whereas for the Nꢀbromoderivative it attained 40%, which
agrees with our hypothesis. In order to establish the transꢀ
formation products of 1ꢀbromoꢀ4ꢀnitropyrazole, the reꢀ
action was carried out for 72 h until completion (the conꢀ
version of the Nꢀbromoderivative was 94%). As a result,
4
in aqueous solutions of alkaline metal halides. It is known
that pyrazole halogenation proceeds via the mechanism of
electrophilic aromatic substitution, and the reactivity of
halogen in these reaction decreases in the series Cl > Br > I.
This is consistent with the results of chlorination and iodiꢀ
13
the formation of 3,5ꢀdibromoꢀ4ꢀnitropyrazole ( С NMR)
1
and 4ꢀnitropyrazole ( Н NMR) was found. The presence
3
2
nation of pyrazoles ; however, the data on bromination
of earlier undescribed 3(5)ꢀbromoꢀ4ꢀnitropyrazole in
the reaction mixture was proved by highꢀresolution mass
spectrometry.
sharply fall out of the regularity. For instance, in spite of
the lower reactivity of Br compared to Cl , the yield of
2
2
target products and conversion of azole in the brominaꢀ
Taking into account that 3,5ꢀdibromoꢀ4ꢀnitropyrazole
gives no characteristic signals in the Н NMR spectrum
and with the purpose to estimate the molar ratio of the
products, the obtained reaction mixture was methylated at
the N atom of the pyrazole ring and then analyzed by
2
1
1
tion are substantially higher than those for chlorination.
5
Based on the data indicating that the halogenation of
pyrazoles 1 (Scheme 1) proceeds through the formation of
halogen derivative 2 followed by its rearrangement to
Сꢀhalogen derivative 3, we assumed that the reason for the
anomalous bromination is a higher (compared to chloriꢀ
nation) rate of rearrangement 2  3 for this process. To
check this hypothesis, we synthesized 1ꢀchloroꢀ4ꢀnitroꢀ
1
Н NMR. It turned out that the molar ratio of 3,5ꢀdiꢀ
bromoꢀ1ꢀmethylꢀ4ꢀnitropyrazole, 1ꢀmethylꢀ4ꢀnitropyrꢀ
azole, and a mixture of 3ꢀbromoꢀ1ꢀmethylꢀ4ꢀnitropyrazole
and 5ꢀbromoꢀ1ꢀmethylꢀ4ꢀnitropyrazole was 1.0 : 1.0 : 2.14.
As we found for the first time, during the bromination
of pyrazoles the intramolecular N—C rearrangement ocꢀ
curs with a higher rate than during chlorination, which
was observed in different yields of the target products.
Note that the lower rate of the N—C tranfer of halogen
atom for pyrazole chlorination allows one to perform
secondary processes leading to the formation of 4,4´ꢀdiꢀ
chloroꢀ1,3´(5´)ꢀbipyrazole along with the target 4ꢀchloroꢀ
6
7
pyrazole and 1ꢀbromoꢀ4ꢀnitropyrazole following earlier
described procedures and studied their transformation
under the conditions (aqueous solution of NaHCO3,
2
0—25 C) close to those of electrochemical halogenaꢀ
tion. The consumption of Nꢀhalopyrazoles was monitored
8
by iodometric titration. We showed that on stirring with
an AcOHꢀacidified aqueous solution of KI these comꢀ
pounds evolved I , which can be titrated off with a 0.1 М
2
1
solution of Na S O . It turned out that for 3 h of stirring
pyrazole.
2
2
3
Scheme 1
X = Cl, Br
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 206—207, January, 2012.
066ꢀ5285/12/6101ꢀ209 © 2012 Springer Science+Business Media, Inc.
1

2
10
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 1, January, 2012
Lyalin and Petrosyan
The starting 4ꢀnitropyrazole was synthesized according to an
References
. B. V. Lyalin, V. A. Petrosyan, B. I. Ugrak, Elektrokhimiya,
9
earlier described procedure. Pyrazoles obtained by methylation
1
were identified by comparing their Н NMR spectra with the
1
2
literature data.1
0,11
2
4
008, 44, 1418 [Russ. J. Electrochem. (Engl. Transl.), 2008,
4, 1320].
Identification of the N—C rearrangement products of 1ꢀbromoꢀ
ꢀnitropyrazole and estimation of their ratio. A suspension of
ꢀbromoꢀ4ꢀnitropyrazole (0.05 mol) in an aqueous solution of
4
1
. B. V. Lyalin, V. A. Petrosyan, B. I. Ugrak, Elektrokhimiya,
010, 46, 131 [Russ. J. Electrochem. (Engl. Transl.), 2010,
46, 123].
2
NaHCO (30 mL, 0.01 mol) was stirred for 72 h, acidified with
3
concentrated HCl (to pH 2—3), and extracted with Et O
2
3. B. V. Lyalin, V. A. Petrosyan, B. I. Ugrak, Izv. Akad. Nauk,
Ser. Khim., 2010, 1512 [Russ. Chem. Bull., Int. Ed., 2010,
(
2×20 mL). After the solvent was distilled off, a solid (1.26 g) was
obtained containing 3,5ꢀdibromoꢀ4ꢀnitropyrazole (identified by
5
9, 1549].
13
С NMR comparing with the spectrum of authentical 3,5ꢀdiꢀ
4
. H. G. O. Becker, Einführung in die Electronentheorie orꢀ
ganischꢀchemisher Reactionen, Veb Deutsсher Verlag der
Wissenschaften, Berlin, 1974.
1
2
bromoꢀ4ꢀnitropyrazole synthesized by a known procedure ),
ꢀnitropyrazole (identified by 1Н NMR), and 3(5)ꢀbromoꢀ4ꢀ
nitropyrazole (identified by highꢀresolution mass spectroꢀ
metry: calculated С Н ВrN O , M – 2 189.9247; found ESI
4
5
. M. S. Pevzner, Adv. Heterocycl. Chem., 1999, 75, 1.
3
2
3
2
6. R. Hüttel, О. Schäfe, G. Welzee, Justus Liebigs Ann. Chem.,
956, 598, 186
7. R. Hüttel, H. Wagner, Justus Liebigs Ann. Chem., 1955,
93, 179.
(
–) 189.9259).
Dimethyl sulfate (1.5 mL, 0.0159 mol) and K CO (3.3 g,
1
2
3
0
.24 mol) were added to a solution of a mixture of products (0.88 g)
5
in MeCN (40 mL). The reaction mixture was refluxed for
4 h and then cooled. The precipitate that formed was filꢀ
tered off and washed with MeCN, concentrated aqueous NH3
8
. I. M. Kolthoff, R. Belcher, Volumetric Analysis, vol. III,
Interscience, New York, 1957.
2
9. R. S. Gross, Z. D. Guo, C. T. Brian, J. Med. Chem., 2005,
8, 5780.
0. V. P. Perevalov, M. A. Andreeva, Yu. A. Manaev, Khim.
Geterotsikl. Soedin., 1983, 19, 1672 [Chem. Heterocycl. Comꢀ
pd. (Engl. Transl.), 1983, 19, 1322].
(
(
2.6 mL) was added, and the mixture was stirred for 20 min
binding of dimethyl sulfate excess). The resulting solution was
4
1
evaporated to dryness, and a solid residue was washed with H O
2
(
2×10 mL) and dried in air, and the product was obtained
in a yield of 0.24 g. Target substances (0.51 g) were additionalꢀ
ly isolated from the mother liquor by extraction with EtOAc
1
1
1. H. Neunhoeffer, S. Gerstung, T. Clausen, Ger. Offen DE
4
,234,8852; Chem. Abstr., 1994, 121, 35604u.
2. P. H. Juffermans, C. L. Habraken, J. Org. Chem., 1986,
1, 4656.
(
3×20 mL).
5
This work was financially supported by the Presidium
of the Russian Academy of Sciences (Program for Fundaꢀ
mental Research No. 7).
Received June 27, 2011;
in revised form November 2, 2011