A mild and efficient method for halogenation of 3,5-dimethyl pyrazoles by ultrasound irradiation using N-halosuccinimides

Article abstract of DOI:10.1016/j.tetlet.2005.08.027

The 4-halo-3,5-dimethyl pyrazoles have been synthetisized in good yields in short reaction times in the absence of a catalyst by reaction of 3,5-dimethyl pyrazoles with N-halosuccinimides (NBS, NCS and NIS) under ultrasound irradiation. Finally, the halogenation of pyrazoles with Br₂, IC1 and I₂ was showed in similar conditions.

Full text of DOI:10.1016/j.tetlet.2005.08.027

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6833–6837
A mild and efficient method for halogenation of 3,5-dimethyl
pyrazoles by ultrasound irradiation using N-halosuccinimides
a,
a,
a
b
*
*
´
Helio A. Stefani, Claudio M. P. Pereira, Roberta B. Almeida, Rodolpho C. Braga,
Karla P. Guzenb and Rodrigo Cellac
a
ˆ ˆ
Laborato´rio de Sı´ntese de Mole´culas Bioativas, Departamento de Farma´cia, Faculdade de Ciencias Farmaceuticas,
Universidade de Sa˜o Paulo, 055083-000 Sa˜o Paulo, SP, Brazil
bDepartamento de Biofı´sica, Universidade Federal de Sa˜o Paulo, SP, Brazil
cDepartamento de Quı´mica, Universidade de Sa˜o Paulo, Sa˜o Paulo, SP, Brazil
Received 15 July 2005; revised 2 August 2005; accepted 3 August 2005
Available online 19 August 2005
Abstract—The 4-halo-3,5-dimethyl pyrazoles have been synthetisized in good yields in short reaction times in the absence of a cat-
alyst by reaction of 3,5-dimethyl pyrazoles with N-halosuccinimides (NBS, NCS and NIS) under ultrasound irradiation. Finally, the
halogenation of pyrazoles with Br2, ICl and I2 was showed in similar conditions.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
sound irradiation. We have recently reported a conve-
nient and inexpensive ultrasound-assisted preparation
of functionalized arylacetylenes using metallic lithium.14
For the halogenation of pyrazoles nucleous, the exami-
nation of previously reported methods reveals serious
synthetic drawbacks, such as mixture of products, long
reaction time, high temperatures and use of catalyst.15
Pyrazoles are an important class of compounds, which
possess widespread pharmacological properties such as
anti-hyperglycemic, analgesic, antiinflammatory, anti-
pyretic, anti-bacterial, hypoglycemic and sedative-hyp-
1–5
noticatcivity.
Recently, some pyrazole derivatives
were reported to have non-nucleoside HIV-1 reverse
transcriptase inhibitory activity.6 Extensive studies have
been devoted to pyrazole derivatives such as celecoxib,
the well-known cyclooxygenase-2 inhibitor.7 In particu-
lar, 4-halopyrazoles are key substructures in a large vari-
ety of compounds of important biological activities.8,9
Stephens and co-workers described the methodology for
the halogenation of 3,5-diarylisoxazoles using N-
halosuccinimides.16
As a continuation of our program in sonochemistry,
with the aim of improving the halogenation of 3,5-di-
methyl pyrazoles we have explored the use of N-halosuc-
cinimides, NXS (i.e., NCS, NBS and NIS) as more
convenient and mild sources of electrophilic halogen.
As a result of our work in this area, we wish to report
4-Halopyrazoles have been used as reagents in organic
synthesis, especially in cross-coupling reactions with ter-
minal acetylenes9,10 organotin aryl derivatives,11 or aryl
12
boronicacids.
Ultrasound has increasingly been used
13
in organicsynthesis in the last three deacdes.
Com-
pared with traditional methods, this technique is more
convenient and easily controlled. A large number of
organic reactions can be carried out in high yields,
shorter reaction time and milder conditions under ultra-
X
CH3
CH3
NXS, acetone
6-90 min.
)))
N
N
H3C
H3C
N
R
N
R
67-98%
Keywords: Heterocycles; Pyrazoles; Halogenation; Ultrasound irradi-
ation; N-Halosuccinimides.
X = Cl, Br, I
R = H, Me, Ph, p-NO2C6H4, C6F5
*
Corresponding authors. Tel.: +55 11 30913654; fax: +55 11 3815
4418; e-mail addresses: hstefani@usp.br; claudiom@usp.br
Scheme 1.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.027

6834
H. A. Stefani et al. / Tetrahedron Letters 46 (2005) 6833–6837
convenient C-4 halogenation of 3,5-dimethyl pyrazoles
using N-halosuccinimides under ultrasound irradiation
(Scheme 1).
However, the same reaction in the absence of Amberlist
15 furnished the product with 98% yield. In our studies,
we found that the acetone solvent reaction appropriated
for these reactions gave the best results. The progress of
the reactions was monitored by GLC. The important
particularity of this reaction process is the work-up, in
which we observed that the use of successive treatment
of aqueous Na2S2O3 gave the products without purifica-
tions. The 4-halo-3,5-dimethyl-pyrazoles (6–10) were
synthesized treating 3,5-dimethyl pyrazoles with N-halo-
succinimide (NXS, X = Cl,Br,I) in acetone and N2
atmosphere using a ultrasound bath in short reaction
times (6–90 min) and good yields (67–98%). The scope
and generality of this process is illustrated by a series
of five pyrazoles and the results are presented in Table 1.
In preliminary experiments, we have observed a delicate
compromise between the reaction and the catalyst,
Amberlist 15, based on the work of Meshram et al.,17
regarding the 2-halogenation of 1,3-keto-esters and cyc-
licketones using N-halosuccinimides. First, the pyrazole
1 was chosen as a model substrate for bromination in
order to find the optimal conditions. Compound 1 was
treated with 1.5 equiv of NBS in the presence of Amber-
list 15 in ethyl acetate, under ultrasound irradiation. The
reaction was complete after 6 min to give the 4-halopy-
razole derivative (6a), in 90% yield.
Table 1. Halogenation of 3,5-dimethyl pyrazoles using NXS under ultrasound irradiation
Pyrazole 1–5
4-Halopyrazole 6–10
X
Equiv
Time (min)
Yield (%)a
CH3
X
X
X
CH3
(a) Cl
(b) Br
(c) I
1.5
1.5
1.5
15
6
20
98
98
85
N
N
H3C
H3C
H3C
H3C
H3C
H3C
N
H
1
N
H
6
CH3
CH3
(a) Cl
(b) Br
(c) I
1.5
1.5
1.5
20
6
15
67
86
75
N
N
N
Me
2
N
Me
7
CH3
CH3
N
N
(a) Cl
(b) Br
(c) I
1.0
2.0
3.0
90
15
60
80
96
92
N
N
3
8
CH3
X
CH3
N
N
H3C
H3C
N
N
(a) Cl
(b) Br
(c) I
2.0
2.0
2.0
20
15
20
94
91
76
NO2
NO2
4
9
CH3
X
CH3
N
N
H3C
F
H3C
F
N
N
(a) Cl
(b) Br
(c) I
2.0
2.0
2.0
20
10
90
95
90
97
F
F
F
F
F
F
F
F
10
5
a Yields of isolated products.

H. A. Stefani et al. / Tetrahedron Letters 46 (2005) 6833–6837
6835
and NIS). The present procedure is carried out in a
shorter time, easier work-up and good yields. The meth-
od reported here is not only simple to operate but also
efficient. Further development of the halogenation tech-
nology and extension of the approach to a wider range
of valuable nitrogen heterocycles are underway.
X
CH3
CH3
NXS, AcOEt
6-60 min
N
N
H3C
H3C
N
N
R
)))
R
6,8
1,3
Product
R
X
Time (min)
Yield (%)a
2. Experimental
H
H
Br
I
15
30
60
60
6b
6c
8b
8c
80
71
82
70
2.1. General methods
Ph
Br
Ph
I
Starting pyrazoles (1–5) were prepared according to the
literature and characterized by 1H NMR and 13C
NMR.18 All solvents and reagents were obtained from
Merck or Aldrich and used without further purification,
except acetone, which was distilled from CaH2.
a Yields of isolated products.
Scheme 2. Reaction in large scale (20 mmol).
Br
CH3
Sonication was performed in a Branson ultrasonic clea-
ner, Model-3510, frequency of 40 kHz and a nominal
power of 130 W. Flash chromatography (FC) was per-
formed using silica gel (Merck 60, 230–400 mesh) when
Br2, AcOEt
N
H3C
N
R
CH3
)))
1
necessary. Melting points are uncorrected. H, 13C and
6,8b-c
N
NMR spectra were acquired on a Bruker DPX 300
instrument (300.13 MHz for 1H and 75.48 MHz for
13C), at 300 K in CDCl3 as solvent. Low resolution mass
spectra were obtained on a Shimadzu QP5050A spec-
trometer operating at 70 eV.
H3C
N
R
I
CH3
1,3
I2 or ICl / AcOEt
N
R = H, Ph
H3C
N
)))
R
6,8b-c
2.2. General procedure
A mixture of 1,3-dimethyl pyrazole (2 mmol) and N-
halosuccinimide (Table 1), in ethyl acetate (10 mL),
was irradiated in a water bath of the ultrasoniccleaner
at 25–30 ꢁC for the appropriate time (see Table 1). After
the indicated time, the organic phase was washed with a
solution of Na2S2O3 (3 · 20 mL). The organicextratc
was dried (MgSO4) and the solvent removed under
reduced pressure. Finally, the 4-halo-3,5-dimethyl pyr-
azoles were obtained in good purity.
Product
R
Reagent Time (min)
X
Yield
(%)a
H
Ph
H
Br2
Br2
I2
15
30
60
60
15
15
Br
Br
I
98
96
40
17
94
90
6b
8b
6c
8c
6c
8c
Ph
H
I2
I
ICl
ICl
I
Ph
I
a Yields of isolated products.
Compound 6a: C5H11ClN2, MW 130.0, mp 103–106 ꢁC;
1H NMR (CDCl3, 300 MHz) d 2.24 (s, 6H, 2CH3), 10.2
(s, 1H, NH); 13C NMR (CDCl3, 75 MHz) d 10.3 (2CH3),
107.7 (C-4), 140.9 (C-3, C-5); MS (m/z, %) 130 (M+,
100), 95 (95), 42 (80).
Scheme 3.
In addition, it was observed that the halogenation of
3,5-dimethyl pyrazole 1,3 on a large-scale (20 mmol) fur-
nished the products 6b, 6c, 8b and 8c in good yields (70–
82%) using the same reaction conditions (Scheme 2).
Compound 6b: C5H7BrN2, MW 174.0, mp 124–125 ꢁC,
1H NMR (CDCl3, 300 MHz) 2.26 (s, 6H, 2CH3); 13C
NMR (CDCl3, 75 MHz) d 10.6 (2CH3), 96.5 (C-4),
143.4 (C-3, C-5); MS (m/z, %) 174 (M+, 100), 95 (98),
65 (49), 42 (100).
Scheme 3 shows that the reaction of Br2, I2 and ICl with
3,5-dimethyl pyrazoles (1,3) in acetone under ultrasound
irradiation gave the desired products with 17–98% yields
in 15–60 min, and the I2 was the reagent less reactive for
halogenation of these pyrazoles. In this context, we have
found that the Br2 and ICl are also versatile reagents for
halogenation of pyrazoles by sonochemistry methodol-
ogy. All halogenated pyrazoles (6–10) were character-
1
Compound 6c: C5H7IN2, MW 222.0, 136–138 ꢁC, H
NMR (CDCl3, 300 MHz) d 2.73 (s, 6H, 2CH3); 13C
NMR (CDCl3, 75 MHz) d 13.1 (2CH3), 62.6 (C-4),
146.4 (C-3, C-5). MS (m/z, %) 222 (M+, 100), 65 (40),
42 (49).
1
ized by NMR H, 13C and mass spectrometry.
1
Compound 7a: C6H9ClN2, MW 144.0, oil, H NMR
In conclusion, we have developed a mild, convenient
and improved protocol for 4-halogenation of 3,5-di-
methyl pyrazoles with N-halosuccinimides (NBS, NCS
(CDCl3, 300 MHz) d 2.21 (s, 6H, 2CH3) 3.85 (s, 3H,
N-Me); 13C NMR (CDCl3, 75 MHz) d 11.2 (2CH3),
32.7 (N-Me), 109.4 (C-4), 134.5, 144.7 (C-3, C-5); MS

6836
H. A. Stefani et al. / Tetrahedron Letters 46 (2005) 6833–6837
(m/z, %) 144 (M+, 100), 129 (35), 109 (51), 65 (34), 56
(60), 42 (49).
141.0, 144.5 (6C, Ar), 145.5, 152.4 (C-3, C-5); MS
(m/z, %) 343 (M+, 21), 39 (19), 28 (100).
Compound 7b: C6H9BrN2, MW 188.0, 30–32 ꢁC, 1H
NMR (CDCl3, 300 MHz) d 2.26 (s, 3H, CH3), 2.27 (s,
3H, CH3), 3.83 (s, 3H, N-Me); 13C NMR (CDCl3,
75 MHz) d 10.3 (CH3), 11.8 (CH3), 36.7 (N-Me), 94.5
(C-4), 138.6, 145.3 (C-3, C-5); MS (m/z, %) 188 (M+,
100), 109 (40), 56 (90), 39 (93), 28 (100).
Compound 10a: C11H6ClF5N2, MW 296.0, oil, 1H
NMR (CDCl3, 300 MHz) d 2.17 (s, 3H, CH3), 2.29 (s,
3H, CH3); 13C NMR (CDCl3, 75 MHz) d 9.29, 11.4
(2CH3), 110.4 (C-4), 136.2, 139.5, 142.1, 145.6 (m, 6C,
C6F5), 137.4, 148.9 (C-3, C-5); MS (m/z, %) 296 (M+,
63), 261 (38), 208 (100), 194 (70), 117 (90), 93 (33).
Compound 7c: C6H9IN2, MW 236.0, 71–72 ꢁC, 1H
NMR (CDCl3, 300 MHz) d 1.99 (s, CH3, 3H), 2.26 (s,
CH3, 3H), 3.79 (N-Me); 13C NMR (CDCl3, 75 MHz)
d 11.2, 11.3 (2CH3), 32.8 (N-Me), 109.4 (C-4), 135.3,
144.7 (C-3, C-5); MS (m/z, %) 236 (M+, 100), 109
(95), 66 (65), 56 (100).
Compound 10b: C11H6BrF5N2, MW 340.0, mp 62–
63 ꢁC, 1H NMR (CDCl3, 300 MHz) d 2.18 (s, 3H,
CH3), 2.30 (s, 3H, CH3); 13C NMR (CDCl3, 75 MHz)
d 10.3, 12.5 (2CH3), 96.8 (C-4), 136.2, 139.5, 142.2,
145.6 (m, 6C, C6F5), 140.3, 150.5 (C-3, C-5); MS (m/z,
%) 340 (M+, 62), 208 (100), 117 (63), 65 (25).
1
Compound 8a: C11H11ClN2, MW 206.1, oil, H NMR
Compound 10c: C11H6F5IN2, MW 387.9, mp 76–79 ꢁC,
1H NMR (CDCl3, 300 MHz) d 2.21 (s, 3H, CH3), 2.30
(s, 3H, CH3); 13C NMR (CDCl3, 75 MHz) d 11.4, 11.5
(2CH3), 96.8 (C-4), 136.2, 139.5, 142.2, 145.6 (m, 6C,
C6F5), 140.3, 150.5 (C-3, C-5); MS (m/z, %) 388 (M+,
100), 208 (87), 167 (50), 117 (60), 65 (69).
(CDCl3, 300 MHz) d 2.28 (s, 3H, CH3) 2.29 (s, 3H,
CH3), 7.33–747 (m, 5H, Ph); 13C NMR (CDCl3,
75 MHz) d 10.8, 11.4 (2CH3), 124.5, 127.7, 129.2,
135.7 (6C, Ph), 106.9 (C-4), 139.7, 146.0 (C-3, C-5);
MS (m/z, %) 206 (M+, 100), 154 (50), 130 (35), 118
(53), 77 (100), 51 (75).
1
Compound 8b: C11H11BrN2, MW 250.0, oil, H NMR
Acknowledgements
(CDCl3, 300 MHz) d 2.29 (s, 3H, CH3), 2.98 (s, 3H,
CH3), 7.36–7.47 (m, 5H, Ph); 13C NMR (CDCl3,
75 MHz) 11.7, 12.3 (2CH3), 96.4 (C-4), 125.8, 127.0,
129.1, 132.2 (6C, Ph), 137.5, 139.7 (C-3, C-5); MS
(m/z, %) 250 (M+, 75), 170 (55), 154 (48), 144 (46),
130 (60), 118 (74), 77 (100), 65 (65), 51 (85).
The authors wish to thank FAPESP (Grants 03/01751-8
and 03/13475-5), CAPES and CNPq agencies for finan-
cial support.
1
References and notes
Compound 8c: C11H11IN2, MW 298.0, oil, H NMR
(CDCl3, 300 MHz) d 2.30 (s, 3H, CH3), 2.32 (s, 3H,
CH3), 7.32–7.47 (m, 5H, Ph); 13C NMR (CDCl3,
75 MHz) d 13.5, 14.2 (2CH3), 65.6 (C-4), 124.4, 127.6,
129.0, 139.5 (6C, Ph), 140.5, 150.4 (C-3, C-5); MS
(m/z, %) 298 (M+, 88), 170 (35), 130 (50), 118 (60),
77 (100), 65 (50), 51 (70).
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