A mild halogenation of pyrazoles using sodium halide salts and Oxone

Article abstract of DOI:10.1016/j.tetlet.2017.09.042

A mild, inexpensive, and operationally simple pyrazole halogenation method utilizing Oxone and sodium halide salts is reported. This work documents 17 examples of alkyl, aryl, allyl, and benzyl substituted 4-chloro and 4-bromopyrazoles, obtained in up to 93% yield. Reactions are performed in water under ambient conditions and generation of organic byproducts is avoided.

Full text of DOI:10.1016/j.tetlet.2017.09.042

Accepted Manuscript
A mild halogenation of pyrazoles using sodium halide salts and Oxone
Kathryn L. Olsen, Matthew R. Jensen, James A. MacKay
PII:
S0040-4039(17)31169-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.09.042
TETL 49312
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
29 June 2017
12 September 2017
15 September 2017
Please cite this article as: Olsen, K.L., Jensen, M.R., MacKay, J.A., A mild halogenation of pyrazoles using sodium
halide salts and Oxone, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.09.042
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A mild halogenation of pyrazoles using
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Kathryn L. Olsen, Matthew R. Jensen, James A. MacKay*

1
Tetrahedron Letters
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A mild halogenation of pyrazoles using sodium halide salts and Oxone
Kathryn L. Olsen, Matthew R. Jensen, James A. MacKay*
Department of Chemistry and Biochemistry, Elizabethtown College, 1 Alpha Drive, Elizabethtown PA
ARTICLE INFO
ABSTRACT
Article history:
Received
A mild, inexpensive, and operationally simple pyrazole halogenation method utilizing Oxone
and sodium halide salts is reported. This work documents 17 examples of alkyl, aryl, allyl, and
benzyl substituted 4-chloro and 4-bromopyrazoles, obtained in up to 93% yield. Reactions are
performed in water under ambient conditions and generation of organic byproducts is avoided.
Received in revised form
Accepted
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Pyrazole
Halogenation
Oxone
Green Chemistry
Pyrazoles are an intriguing class of molecules that are
uncommon in nature yet have become a ubiquitous heterocyclic
substructure among bioactive molecules. In particular, 4-
use as a component of denture bleaches. Owing to its low cost,
ease of handling, relative stability, water solubility, and generally
‘green’ chemical profile, Oxone has become a common oxidant
in organic synthesis. Synthetic applications of Oxone include
1
halopyrazoles are common in both pharmaceuticals and
agrochemicals where the halogen atom may be employed to
enhance biological properties. Additionally, the halogen atom
5
6
7
olefin epoxidation , oxidation of alcohols and aldehydes,
8
oxidative cleavage of alkenes, and the Hoffman rearrangement
2
9
of carboxamides. Halogenation reactions employing Oxone in
the presence of halide salts have also been explored (Scheme 1).
can be utilized as a synthetic handle to install further
functionalization, allowing for elaboration of the ring system and
providing access to more complex systems. Most notably,
halogenated pyrazoles can be used in cross-coupling reactions to
3
afford various 4-substituted products.
Pyrazoles are highly electron rich heterocycles and therefore
readily undergo electrophilic aromatic substitution at the 4-
4
position with a host of different halogenating agents. However,
many of the known halogenation methods require harsh
conditions and/or generate unwanted organic byproducts. For
example, several reports utilize N-halosuccinimides in organic
4
c-e
4c
solvents,
including reactions assisted by microwaves or
4
d
sonication. These methods are robust and provide products in
high yields, yet the use of N-halosuccinimides produces
stoichiometric succinimide as an unwanted organic byproduct.
One report utilizes
transformation with the generation of minimal waste, however
I
2
/H
2
O
2
to accomplish the desired
4
b
the methodology is limited to iodination. We were interested in
an inexpensive, operationally simple, and green method that
would be more general for incorporating chlorine and bromine
onto the pyrazole ring.
Oxone is
KHSO ·KHSO
a
·K
triple salt with the composition
The active oxidant, potassium
2
5
4
2
SO4.
peroxymonosulfate, has various commercial and practical
applications, including use as a swimming pool shock oxidizer,
wool shrinkproofing, odor control in wastewater treatment, and

2
Tetrahedron
One of the first applications of this mixture was Dieter’s report
on the oxidation of α,β-enones and alkenes to prepare 2-
Previously published methods for pyrazole halogenations in
water typically involve low molecular weight N-H pyrazoles
and/or N-Aryl pyrazoles. We were curious if more hydrophobic
alkylated pyrazoles could be efficiently halogenated using the
NaX/Oxone method. Not surprisingly, as hydrophobicity of the
pyrazoles increased, conversions and yields decreased or the
reactions proved irreproducible due to the heterogeneous nature
of the reaction mixture. To overcome this problem, a series of
co-solvents was screened in the chlorination of 1-benzyl-3,5-
dimethyl-1H-pyrazole using a 70:30 water to co-solvent ratio and
rapid stirring for 1 hour (Table 2). Both miscible (entries 2-4) and
immiscible solvents (entries 5-7) were used, and in each case
there was an increase in the amount of product obtained relative
to the reaction with no co-solvent. Clean products and high
conversions were obtained for acetonitrile (entry 2), acetone
(entry 3), tetrahydrofuran (entry 4) and ethyl acetate (entry 7) as
co-solvents. Dichloromethane and toluene (entries 5 & 6) both
led to lower conversions and more complex product mixtures.
Ethyl acetate was thus chosen as the preferred co-solvent due to
its lower cost, availability, and safety profile compared to
10
haloenones and vicinal dihalides. When used with ammonium
bromide in the presence of olefins, Oxone affords vicinal
1
1
bromohydrins and dibromides (Scheme 1a). Similarly, aromatic
methyl ketones are α-halogenated using Oxone and sodium
halide salts where it was noted that electron rich heterocyclic
systems such as pyrroles afforded ring halogenation in preference
1
2
to α-halogenation at the ketone (Scheme 1b), however a
systematic study of this aspect was not reported. Oxone has also
been used with halide salts in electrophilic aromatic substitutions
1
3
14
of electron rich benzenes and pyrimidines (Scheme 1c) but we
are unaware of its use in the halogenation of pyrazoles. Herein,
we report our findings using Oxone/NaX as a method for
electrophilic pyrazole halogenation (Scheme 1d).
Halogenations were performed with the reaction exposed to
the atmosphere. Treating a suspension of the pyrazole substrate
in water with sodium halide and Oxone resulted in a mildly
exothermic reaction which was followed by stirring at ambient
temperature. Reaction conditions were first screened on 3,5-
dimethylpyrazole with one-half equivalent of Oxone
15
acetone, acetonitrile and tetrahydrofuran. In addition, the
resulting biphasic mixture was more easily manipulated during
workup and isolation of product. Given that the ethyl acetate co-
solvent results in a biphasic mixture, an additional experiment
was attempted with slower stirring (entry 8). Not surprisingly,
the reaction resulted in lower conversions and yields which
underscores the importance of vigorously mixing the biphasic
solution.
(
5
corresponding to 1 equivalent of the active oxidant, KHSO ) and
two equivalents of NaCl or NaBr. Sodium halide stoichiometry
was briefly explored using 1, 1.5, 2, and 5 equivalents of NaBr
with the best results obtained using 2 equivalents. Reactions
worked well on 1 mmol to 5 mmol scales, and order of addition
did not noticeably affect the outcome.
The results of several halogenations performed in water are
summarized in Table 1, with reactions producing good yields
4c-e
comparable with NXS halogenation methods.
Notably, both
chlorination and bromination afforded similar yields. Most
reactions were complete within one hour, with the time necessary
to reach full conversion related to the electronics of the
heterocycle.
With the optimal co-solvent selected, a series of pyrazoles was
treated with Oxone and sodium halide salts in a water/ethyl
acetate mixture (Table 3). Most reactions gave highly pure
products demonstrating the method’s tolerance to alkene and aryl
functional groups. In particular, the alkene double bond in 1-
allyl-3,5-dimethylpyrazole was not halogenated in the
chlorination or bromination reactions to any significant extent
(
Table 3, entries 3 & 4). This is in contrast to 1-allylpyrazole
which did halogenate the pyrazole 4-position, but led to
inseparable mixtures of over-halogenation products (entry 5).
Halogenation of 3,5-dimethyl-1-phenylpyrazole (Table 3, entries
1
0 & 11) required three additions of 0.35 equivalents of Oxone
added over a period of 20 hours due to the formation of
byproducts under standard reaction conditions.

3
Halogenation of electron poor pyrazoles such as diethyl 3,5-
pyrazoledicarboxylate afforded low conversions and yields, even
under forcing conditions at reflux. This is unsurprising given the
presumed electrophilic aromatic substitution mechanism.
Additionally, attempts to apply this method to other heterocycles
including imidazoles and indoles have been unsuccessful to date.
References
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1
1
1
1
2
5
In summary, an operationally simple and efficient method of
pyrazole halogenation using Oxone and NaX in water has been
developed. The reaction works well for a variety of electron rich
N-H, N-alkyl, and N-aryl pyrazoles.
3
3. Tamhankar, BV, Desai, UV, Mane, RB, Wadgaonkar, PP, Bedekar,
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1
1
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Acknowledgements
1
The authors wish to acknowledge Kenneth Wiest for
experimental contributions and the Elizabethtown College E.
Jane Valas Undergraduate Research Fund and Scholarship and
Creative Arts Program for financial support.
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1
2
Supplementary data (general experimental information,
1
13
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2
2
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4
Tetrahedron
Table 1. Pyrazole halogenation reactions
a
performed in water
b
Entry
Product
Time (h) Yield (%)
1
1
1
93
2
3
4
5
6
93
84
Cl
Me
1
Me
N
N
Et
2
74
2.5
4.5
74
c
73 (80)
a
Unless otherwise noted, reactions were carried out
using 1-7 mmol
pyrazole substrate, 2 equiv. NaX, and 0.5 equiv.
Oxone
(corresponding to 1 equiv. KHSO5)
Isolated yield following recrystallization or by
b
silica gel column
chromatography
c
Reaction was scaled up to 30 mmol with a 48 hour
reaction time,
giving pure product without recrystallization

5
a
Table 2. Solvent studies
Co-
solvent
None
CH CN
3
acetone
THF
CH Cl
2 2
toluene
EtOAc
b
Isolated yield
Entry
Conversion (%)
c
(%)
1
2
3
4
5
6
7
63
95
94
92
73
79
>96
50
44
81
81
79
48
57
93
41
e
8
EtoAc
a
Unless otherwise noted all reactions involved 1
equiv. of pyrazole
substrate, 2 equiv. of NaCl, 0.5 equiv. of Oxone,
0
.7 mL of H
.3 mL of co-solvent and vigorous stirring >1000
rpm for 1 h.
2
O,
0
b
1
Determined by H NMR
Yield obtained after purification by silica gel
c
column chromatography
d
1 mL of H O
2
Reaction run with moderate stirring at ca. 350 rpm
e

6
Tetrahedron
Table 3. Pyrazole halogenation reactions
a
performed in water/EtOAc
b
Entry
Product
Time (h)
Yield (%)
1
2
(X = Cl)
(X = Br)
1
1
93
71
3
4
(X = Cl)
(X = Br)
2
5
77
74
c
-
5
3
6
7
(X = Cl)
(X = Br)
2
1
73
89
8
9
(X = Cl)
(X = Br)
1
1
77
73
1
0 (X =
Cl)
1 (X =
Br)
d
20
24
78
d
86
1
12
1
46
a
Unless otherwise noted, reactions were carried out
using 2 equiv.
NaX, and 0.5 equiv. Oxone (corresponding to 1
5
equiv. KHSO )
b
Isolated yield following recrystallization or by
silica gel column
chromatography
c
Halogenated product was obtained in low yield
with inseparable
overhalogenation byproducts.
Three portions of 0.35 equiv. Oxone added over 20
d
h.

7
A mild halogenation of pyrazoles using
sodium halide salts and Oxone
Kathryn L. Olsen, Matthew R. Jensen, James A.
MacKay*
Highlights
•
•
•
•
An operationally simple pyrazole halogenation
is reported.
Reagents are safe and the method avoids
organic byproducts.
Reactions are performed in water under ambient
conditions.
Halogenation yields are high for a series of 9
different substrates.