Green iodination of pyrazoles with iodine/hydrogen peroxide in water

Article abstract of DOI:10.1016/j.tetlet.2008.04.082

In this Letter, we describe a practical, green iodination of pyrazoles to form the corresponding 4-iodopyrazole derivatives. The reaction takes place in water, using only 0.5 equiv of iodine and 0.6 equiv of hydrogen peroxide, a system that generates water as the only reaction by-product.

Full text of DOI:10.1016/j.tetlet.2008.04.082

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 4026–4028
Green iodination of pyrazoles with iodine/hydrogen peroxide in water
Mary M. Kim *, Rebecca T. Ruck *, Dalian Zhao, Mark A. Huffman
Department of Process Research, Merck Research Laboratories, Rahway, NJ 07065, USA
Received 13 March 2008; revised 9 April 2008; accepted 14 April 2008
Available online 6 May 2008
Abstract
In this Letter, we describe a practical, green iodination of pyrazoles to form the corresponding 4-iodopyrazole derivatives. The reac-
tion takes place in water, using only 0.5 equiv of iodine and 0.6 equiv of hydrogen peroxide, a system that generates water as the only
reaction by-product.
Ó 2008 Elsevier Ltd. All rights reserved.
Pyrazole moieties, particularly those functionalized at
the 4-position, are frequently found in biologically active
compounds.1,2 4-Iodopyrazoles, which possess a useful
functional handle at the 4-position, represent valuable
intermediates toward the syntheses of these targets. For
example, these compounds have been employed as partici-
pants in cross-coupling chemistry3 and for halogen-metal
exchange reactions.4 Unfortunately, existing methodolo-
gies for the synthesis of 4-iodopyrazoles are not ideal for
large scale processing.5 The use of iodine with potassium
iodide6 or iodine monochloride4a,7 to iodinate pyrazoles
suffers from limited substrate scope and the use of excess
reagent. Iodine, in addition to ammonium hydroxide8 or
HIO3,9 reacts unselectively with pyrazoles to form di-
and tri-iodopyrazoles. The combination of iodine and
diacetoxyiodobenzene provides a simple method for the
regioselective synthesis of 4-iodopyrazoles, but requires
chromatography to remove the reagent by-products.10 N-
Iodosuccinimide iodinates pyrazoles in a variety of sol-
vents, but is expensive for use on scale.11 The oxidative
iodination of pyrazoles using only 0.6 equiv of iodine and
0.6 equiv of ceric ammonium nitrate (CAN) generates a
large amount of cerium waste that can be difficult to
remove.12 These last three methods also suffer from prob-
lems of atom economy.
We sought to develop a process-friendly, efficient, and
green procedure for the 4-iodination of pyrazoles. Despite
the shortcoming of the I2/CAN system mentioned above,
this result provided the foundation for the development
of our green iodination of pyrazoles. Additionally, it has
been shown that stoichiometric iodine, aqueous hydrogen
peroxide, and catalytic acid can be employed for the iodin-
ation of dimethoxy- and trimethoxy-substituted aromatic
compounds.13 The same group had earlier demonstrated
that alkenes, later demonstrating the viability of a H2O2/
I2 system in water for similar iodinations14 undergo Mark-
ovnikov iodo-alkoxylation in alcohol solvent, using
0.5 equiv of iodine and hydrogen peroxide.15 The fusion
of these concepts has enabled the development of an I2/
H2O2 system for the 4-iodination of pyrazoles (Scheme
1). In this Letter, we present the facile, green synthesis of
4-iodopyrazoles in water with additional water as the only
reaction by-product. This technology has been employed
on a large scale with minimal waste formation.
Initial efforts focused on the iodination of 1-methylpyr-
azole (1a). Iodination was attempted in a series of solvents
I
I2/H2O2
N
N
N
N
Me
Me
1a
2a
*
Corresponding authors. Tel.: +1 732 594 4572; fax: +1 732 594 5170.
Scheme 1.
E-mail address: rebecca_ruck@merck.com (R. T. Ruck).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.082

M. M. Kim et al. / Tetrahedron Letters 49 (2008) 4026–4028
4027
(water, methanol, ethanol, isopropanol, acetonitrile) using
0.5 equiv of iodine and 0.6 equiv of 30% hydrogen perox-
ide. Gratifyingly, all of these conditions afforded the
desired 4-iodo-1-methylpyrazole (2a) in moderate to high
conversions and high selectivity for mono-iodination at
the 4-position. Optimal conversion was obtained in aque-
ous solution. 1-Methylpyrazole is water-soluble, but identi-
cal results were achieved for the iodination of more non-
polar substrates that are only sparingly soluble in water.
The use of water as solvent offered two practical advanta-
ges: (1) most products could be isolated by direct crystalli-
zation from the corresponding reaction mixtures and (2)
the aqueous waste stream and minimal organic content
were easily discarded.
Table 1
Iodination of pyrazoles 1a–h
R3
R3
N
I
0.5 equiv I2
N
0.6 equiv H2O2
R5
R5
N
N
R1
R1
water
1
2
Entry Substrate
Product
Isolation Isolated
methoda yieldb
(%)
The reaction conditions employed for the regioselective
4-iodination of 1-methylpyrazole were applied to a series of
pyrazole derivatives 1a–h, leading to the isolation of
4-iodo compounds 2a–h in 63–100% yield (Table 1). All
starting material substitution patterns allowed for the
regioselective formation of the corresponding 4-iodopyraz-
ole products. The reaction proceeded well for substrates
without substitution on nitrogen and with N-alkyl (entries
1, 4 and 5) and N-aryl substituents (entries 3, 7, and 8).
Substitution was also tolerated at both the 3- and 5-posi-
tions. Electron-rich pyrazoles underwent rapid iodination
(<1 h, entry 6), while other substrates required extended
reaction times (24–72 h). Most products crystallized
directly from the reaction mixture and were isolated as
pure after treatment of the suspension with 5% NaHSO3(aq)
(method A).16 Those products that failed to crystallize were
isolated by work-up and silica gel chromatography
(method B).17
The utility of this green iodination procedure was dem-
onstrated on a large scale; 7.0 kg of 1-methylpyrazole (1a)
was subjected to the optimized reaction conditions afford-
ing 16.4 kg (91% yield) of 4-iodo-1-methylpyrazole (2a).
Each iodine atom of I2 was incorporated into the product,
meaning that the primary by-product from this procedure
was the water formed by the reduction of H2O2. As such,
the filtrate and subsequent water washes were easily dis-
posed of as neutral aqueous waste.
1a
I
2a
N
N
1
A
A
91
63
N
N
Me
Me
I
I
1b
2b
2c
N
N
N
2
N
N
H
H
1c
1d
N
N
N
N
N
3
4
A
B
94
67
I
2d
2e
N
N
Me
N
Me
N
I
1e
5
6
A
A
95
82
N
N
Me
Me
Me
Me
NH2
N
NH2
N
I
1f
2f
N
N
H
H
We have developed a green procedure for the regioselec-
tive 4-iodination of pyrazoles using only 0.5 equiv of iodine
and 0.6 equiv of hydrogen peroxide in water. This protocol
was successful for a series of differentially substituted
pyrazole starting materials to afford the corresponding
4-iodopyrazole products in good to excellent yields. In many
cases, the product crystallized directly from the reaction
mixture, resulting in water as the only significant reaction
by-product. Efforts are underway to identify other hetero-
cycles that also undergo this green iodination chemistry.
Me
Me
I
2g
1g
N
N
7
B
100
N
N
Me
N
Me
N
I
2h
1h
N
N
H2N
H2N
8
A
75
References and notes
1. Sliskovic, D. R.; Roth, B. D.; Wilson, M. W.; Hoefle, M. L.; Newton,
Me
Me
R. S. J. Med. Chem. 1990, 33, 31.
a
˚
˚
Method A: Isolated by direct crystallization from the reaction mixture
2. Tolf, B.-R.; Dahlbom, R.; Theorell, H.; Akeson, A. Acta Chem.
Scand. B 1982, 36, 101.
following treatment with 5% NaHSO3(aq). Method B: isolated by work-up
in EtOAc, followed by column chromatography.
3. (a) Manfredini, S.; Bazzanin, R.; Baraldi, P. G.; Simone, D.;
Vertuani, S.; Pani, A.; Pinna, E.; Scintu, F.; Lichino, D.; La Colla,
b
Product purity was confirmed by 1H NMR spectroscopy.

4028
M. M. Kim et al. / Tetrahedron Letters 49 (2008) 4026–4028
14. Jereb, M.; Zupan, M.; Stavber, S. Chem. Commun. 2004, 2614.
P. Bioorg. Med. Chem. Lett. 1996, 6, 1279; (b) Elguero, J.; Jaramillo,
´
C.; Pardo, C. Synthesis 1997, 563; (c) Rodrıguez-Franco, M. I.;
15. Jereb, M.; Zupan, M.; Stavber, S. Green Chem. 2005, 7, 100.
16. Method A. 4-Iodo-1-methylpyrazole (2a): To a solution of 1-methyl-
pyrazole (20.0 mL, 0.241 mol) and iodine (30.7 g, 0.121 mol) in water
(85.0 mL) was added 30% H2O2(aq) (16.4 mL, 0.144 mol). The
reaction mixture was stirred for 24 h at room temperature. At this
´
Dorronsoro, I.; Martınez, A. Synthesis 2001, 1711.
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time, the reaction was complete, and a cold solution of 5%
NaHSO3(aq) (50.0 mL) was added to the mixture, affording an off-
white slurry. The product was filtered and washed with water to
provide 2a as an off-white crystalline solid (45.6 g, 91%). The material
was purified by 1H NMR spectroscopy.
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17. Method B. 4-Iodo-3-methyl-1-phenylpyrazole (2g): To a mixture of 3-
methyl-1-phenylpyrazole (3.00 g, 18.6 mmol) and iodine (2.36 g,
9.29 mmol) in water (12.8 mL) was added 30% H2O2(aq) (1.14 mL,
11.2 mmol), and the reaction mixture was stirred for 52 h at room
temperature. At this time, the reaction was complete, and a cold
solution of 5% NaHSO3(aq) (10.0 mL) was added to the mixture. The
biphasic mixture was extracted with ethyl acetate, washed with water,
and evaporated under reduced pressure to afford a yellow oil. This
material was purified by silica gel chromatography to afford 2g as a
light yellow oil (5.27 g, 100%). The material was purified by 1H NMR
spectroscopy.
´
´
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