Hypervalent iodine in synthesis. 90. A mild and efficient method for the iodination of pyrazoles

Article abstract of DOI:10.1081/SCC-120021987

The combined reagent of iodobenzene diacetate (or polymer-supported iodobenzene diacetate) with iodine was used as an effective iodinating agent of pyrazoles to the corresponding 4-iodopyrazole derivatives at room temperature with high yields.

Full text of DOI:10.1081/SCC-120021987

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Hypervalent Iodine in Synthesis. 90. A Mild and
Efficient Method for the Iodination of Pyrazoles
b c
a b
d
Dong-Ping Cheng
, Zhen-Chu Chen
& Qin-Guo Zheng
a
Ningbo Institute of Technology, Zhejiang University, Ningbo, P.R. China
b
c
d
Department of Chemistry, Zhejiang University (Campus Xixi), Hangzhou, P.R. China
College of Pharmaceutical Sciences, Zhejiang University of Technology, P.R. China
Pharmaceutical Sciences, School of Life and Health Sciences, Aston University,
Birmingham, UK
Version of record first published: 17 Aug 2006.
To cite this article: Dong-Ping Cheng , Zhen-Chu Chen & Qin-Guo Zheng (2003): Hypervalent Iodine in Synthesis. 90. A
Mild and Efficient Method for the Iodination of Pyrazoles, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:15, 2671-2676
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 15, pp. 2671–2676, 2003
Hypervalent Iodine in Synthesis. 90. A Mild and
Efficient Method for the Iodination of Pyrazoles
2
,3
1,2,
4
Dong-Ping Cheng, Zhen-Chu Chen, * and Qin-Guo Zheng
1
Ningbo Institute of Technology, Zhejiang University,
Ningbo, P.R. China
2
Department of Chemistry, Zhejiang University
(
CampusXixi), Hangzhou, P.R. China
3
College of Pharmaceutical Sciences, Zhejiang
University of Technology, P.R. China
4
Pharmaceutical Sciences, School of Life and Health
Sciences, Aston University, Birmingham, UK
ABSTRACT
The combined reagent of iodobenzene diacetate (or polymer-
supported iodobenzene diacetate) with iodine was used as an effective
iodinating agent of pyrazolesto the corre ps onding 4-iodopyrazole
derivativesat room temperature with high yields.
*
Correspondence: Zhen-Chu Chen, Ningbo Institute of Technology, Zhejiang
University, Ningbo, 315104, P.R. China; Department of Chemistry, Zhejiang
University (Campus Xixi), Hangzhou, 310028, P.R. China.
2
671
DOI: 10.1081/SCC-120021987
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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2
672
Cheng, Chen, and Zheng
Asa mild oxidative reagent, the ys nthetic utility of iodobenzene
diacetate, PhI(OAc) (IBD) has attracted significant research interest in
2
[
1]
view of itslow toxicity, ready availability, and ea sy handing.
it was sh own the combined reagent of the IBD with iodine isa convenient
reagent for the iodination of aromatic compounds. It occursthrough
acetyl hypoiodite formed in situ. However, to our knowledge, there is
seldom published work about using IBD/I system for the iodination of
heteroaromatic compounds. It prompted usto examine the po si bility
of achieving iodination of pyrazolesto 4-iodopyrazolesu isn g IBD/I
system as iodinating reagent.
Recently,
[
2]
2
[
3]
2
4-Iodopyrazoles are valuable starting products in the synthesis of
biologically active compounds. They have been used in cross-coupling
[
4]
[
5]
[6]
arylstannanes, or aryl boronic
reactionswith terminal acetylene,s
acids.
[7]
We found that the IBD/I system is an excellent reagent for the
2
iodination of pyrazole derivatives. Simple stirring of a mixture of IBD,
iodine and a pyrazole derivative in CH Cl at room temperature gave,
2
2
after work-up and isolation, the desired 4-iodopyrazole with high yield
Sch. 1). The results are summarized in Table 1(Entries 1–6). The pro-
(
1
ductswere characterized by H-NMR, IR, MS, and elemental analyses.
Compared with the hitherto used direct iodination methods, the pre-
sent one has the advantages of higher yields, milder conditions, shorter
time, and simpler isolation of the products. For example, using the clas-
sical iodine–iodide method, the preparation of 3,5-dimethyl-4-iodopyra-
[
8]
zole needsrefluxing for 48 h and the yield isonly 55%.
On the other
hand, it isworth mentioning that in the pre se nt method 0.5 mol of iodine
per mole of substrate is enough to complete the reaction, in contrast to
the iodine–iodide procedure, where one-half of part of the iodine isdis-
carded. Recently the oxidative iodination using CAN-I hasbeen applied
2
[9]
to pyrazoles, but the reaction time is st ill long and the CAN istoxic and
expensive. The more reactive iodine monochloride is also used as an
iodinating agent of pyrazoles, but it is necessary to use an excessive
[10]
quantity of reagent.
R2
R2
I
IBD/I
2
N
N
CH2Cl2
N
R3
N
R3
R1
(a-f)
R1
2(a-f)
1
Scheme 1.

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Hypervalent Iodine in Synthesis. 90
Table 1. Iodination of pyrazole derivatives.
Time
2673
a
Yield
(%)
Entry
Substrate, R
1
, R
2
, R
3
Product
(t, min)
1
2
3
4
5
6
7
8
9
1a, H, CH
1b, H, CH
3
, CH
6
, C H
3
2a
2b
2c
2d
2e
2f
15
20
15
20
30
30
25
30
30
30
40
35
40
90
88
91
86
90
91
87
87
89
86
87
89
3
5
1c, H, C H , C H
5
6
5
6
1d, C H , C H , C H
6
6
5
6
5
5
1e, 2,4-(NO
1f, p-ClC
1a, H, CH , CH
2
)
2
C
6
H
3
, CH
3
, CH
3
6
H
4
, CH
3
, C
6
H
5
2a
2b
2c
2d
2e
2f
3
3
1b, H, CH
1c, H, C
3
, C
, C
6
H
5
6
H
5
6 5
H
1
1
1
1
0
1
2
3
1d, C H , C H , C H
6
5
6
5
6
5
1e, 2,4-(NO
1f, p-ClC
1f, p-ClC H , CH , C H
2
)
2
C
6
H
3
, CH
3
5
5
, CH
3
6
H
4
, CH
3
, C
6
H
b
2f
87
6
4
3
6
a
Isolated yields based on pyrazole derivatives.
Recycle.
b
R2
R2
I
PIBD/I2
CH Cl
+
N
N
I
N
R3
2
2
N
R3
R1
(a-f)
R1
2(a-f)
1
Scheme 2.
The advantages of polymer-supported reactive species are now
widely recognized by organic chemists and the exploitation of these
[
11]
systems is developing both in academic and industrial laboratories.
Recently we studied the property and application of polymer-supported
[
iodobenzene diacetate (PIBD) in our lab. In order to explore the scope
12]
of the application of PIBD, we used the PIBD/I system to the iodination
2
[13]
of pyrazoles. It was also successful (Table 1, Entries 7–12) (Sch. 2). The
side product of the reaction is polymer-supported iodobenzene (PIB).
After the completion of the reaction, ether wasadded to the reaction
mixture to precipitate the PIB, and the product can be obtained easily
by the simple filtration. Thus the manipulation is simplified.
As usual, we also examined the regeneration and recycling of the
polymer reagent. The spent resin was collected by filtration and reoxi-

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674
Cheng, Chen, and Zheng
[11]
dized with peracetic acid. The regenerated resin was used to repeat the
reaction with no loss of activity (Table 1, Entry 13).
In summary, we think that the iodine/IBD and iodine/PIBD system
are effective iodinating reagentsfor pyrazol e. s The advantagesof
present method are ease manipulation, mild reaction conditions, and
high yields.
EXPERIMENTAL
1
Melting pointsare uncorrected. H NMR spectra were recorded on a
Bruker 400 MHz instrument as CDCl solutions using TMS as internal
3
standard. Infrared spectra were determined on a Bruker Vector-22 spec-
trometer. Elemental analyses were performed on a EA-1110 instrument.
MS wasrecorded on HP-5989B MasSpectrometer. Pyrazole derivatives
[
14]
are prepared according to described procedures.
[
according to our preciously reported method.
PIBD isprepared
12a]
General Procedure for the Iodination of Pyrazole Derivatives
In a 50 mL round-bottomed flask, iodine (0.5 mmol) was added to
IBD (0.5 mmol) or PIBD (1 g) in dichloromethane (10 mL). The mixture
was st irred for half an hour, then the pyrazole derivative (1 mmol) was
added to the solution. The time of the reaction was indicated in Table 1.
After completion of the reaction, the solvent was distilled off under
reduced pressure. The residue obtained was purified on a silica-gel
plate. If the reagent isPIBD, ether (20 mL) wasadded to the mixture,
then filtered. After removal of the solvent, the product obtained was
recrystallized with ethanol or water. The characterization and spectral
data of the productsare given asfollowing:
ꢀ
[15]
ꢀ
2
a. 4-iodo-3, 5-dimethylpyrazole. M.p. 134–136 C. (Lit.
H NMR: ꢀ 4.11 (brs, 1H), 2.24–2.26 (d, 6H). m/z (%): 222 (M , 100),
137 C)
1
þ
1
27 (13.97), 95 (30.79), 65 (45.96), 54 (41.68), 42 (63.63), 41 (64.06).
ꢀ
1
b. 4-iodo-3-methyl-5-phenylpyrazole. M.p. 113–115 C. H NMR:
2
7.69–7.72 (m, 2H), 7.39–7.42 (m, 3H), 2.24 (s, 3H). m/z (%): 284
ꢀ
þ
(
M , 100), 127 (27.00), 116 (28.19), 102 (17.40), 89 (22.38), 77 (25.45),
5
4
1 (24.49). Anal. calcd. for C H IN : C 42.28, H 3.19, N 9.86; Found: C
10 9 2
2.31, H 3.05, N 9.62.
ꢀ
1
c. 4-iodo-3, 5-diphenylpyrazole. M.p. 194–196 C. H NMR: ꢀ 7.72–
2
.75 (m, 4H), 7.42–7.48 (m, 6H), 5.95 (brs, 1H). m/z (%): 346 (M , 100),
þ
7
189 (42.23), 116 (26.57), 89 (48.81), 77 (45.81), 63 (39.86), 51 (57.69), 50

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Hypervalent Iodine in Synthesis. 90
2675
(
30.80). Anal. calcd. for C H IN : C 52.05, H 3.20, N 8.09; Found: C
2
1
5
11
5
2.04, H 3.05, N 8.27.
ꢀ
1
d. 4-iodo-1, 3, 5-triphenylpyrazole. M.p. 139–140 C. H NMR: ꢀ
2
.72–7.75 (m, 4H), 7.42–7.48 (m, 6H), 5.95 (brs, 1H). m/z (%): 422
7
þ
(M , 100), 294 (38.03), 189 (31.99), 77 (68.79), 51 (40.21). Anal. calcd.
for C H IN : C 59.73, H 3.58, N 6.63; Found: C 59.61, H 3.45, N 6.57.
2
1
15
2
2
e. 4-iodo-3, 5-dimethyl-1-(2,4-dinitrophenyl)pyrazole. M.p. 162.5–
ꢀ
1
63.5 C. H NMR: ꢀ 8.82 (s, 1H), 8.54–8.57 (d, 1H), 7.67–7.72 (d, 1H),
1
2
þ
.26–2.29 (d, 6H). m/z (%): 388 (M , 70.00), 221 (34.63), 77 (21.85), 75
(
29.35), 63 (21.41), 43 (100.00). Anal. calcd. for C H IN O : C 34.04, H
11 9 4 4
2.34, N 14.44; Found: C 34.28, H 2.41, N 14.29.
2
f. 4-iodo-3-methyl-5-phenyl-1-( p-chlorophenyl)pyrazole. M.p. 137–
ꢀ
1
39 C. H NMR: ꢀ 7.37–7.38 (m, 3H), 7.22–7.25 (m, 5H), 7.10–7.13
1
(
þ
þ
d, 2H), 2.40 (s, 3H). m/z (%): 396 (M þ2, 33.02), 394 (M , 100.00),
66 (23.94), 128 (22.32), 111 (34.38), 75 (41.38). Anal. calcd.
for C H IClN : C 48.69, H 3.06, N 7.10; Found: C 48.72, H 3.21,
2
1
6
12
2
N 6.98.
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2
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Cheng, Chen, and Zheng
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Received in Japan November 12, 2002