A mild and efficient method for the regioselective iodination of pyrazoles

Article abstract of DOI:10.1016/S0040-4039(00)02136-5

The iodination of N-H or N-benzylpyrazoles using elemental iodine in the presence of CAN as the in situ oxidant is a mild and efficient method to prepare 4-iodopyrazoles containing even electron-withdrawing substituents. The reaction is regioselective since the iodine atom preferred pyrazole instead of the benzyl group, and the 4-pyrazolic position instead of other possible positions in the heterocycle.

Full text of DOI:10.1016/S0040-4039(00)02136-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 863–865
A mild and efficient method for the regioselective iodination of
pyrazoles
†
Mar ´ı a Isabel Rodr ´ı guez-Franco,* Isabel Dorronsoro, Ana I. Hern a´ ndez-Higueras and
Gema Antequera
Instituto de Qu ´ı mica M e´ dica (C.S.I.C.), Juan de la Cierva 3, 28006 Madrid, Spain
Received 17 July 2000; accepted 10 November 2000
Abstract—The iodination of N-H or N-benzylpyrazoles using elemental iodine in the presence of CAN as the in situ oxidant is
a mild and efficient method to prepare 4-iodopyrazoles containing even electron-withdrawing substituents. The reaction is
regioselective since the iodine atom preferred pyrazole instead of the benzyl group, and the 4-pyrazolic position instead of other
possible positions in the heterocycle. © 2001 Elsevier Science Ltd. All rights reserved.
1
. Introduction
reactants. The iodine–ammonium hydroxide combina-
tion has been used in N-alkylated pyrazoles, but it gave
1
5
Since Sugiyama demonstrated in 1981 that ceric ammo-
nium nitrate [ammonium hexanitratocerate (IV): CAN]
and iodine can iodinate benzenoid aromatics, this
method has been used for the iodination of some
aromatic and heteroaromatic compounds (e.g. uracil
nucleosides ). However, to our knowledge, there is no
mixtures of 3,4-diiodo- and 3,4,5-triiodopyrazoles.
The oxidative iodination using I –HIO3 has been
2
1
applied to 1-methylpyrazoles with electron-withdrawing
1
6
substituents, also yielding diiodinate derivatives.
2
Continuing with our work on biologically active pyra-
1
7,18
published work about CAN-mediated iodination of
pyrazoles.
zoles that showed muscarinic properties
complexation of neurotransmitters,
or selective
we are now
1
9,20
interested in the regioselective iodination of the 4-pyra-
zolic position as a way to obtain 4-functionalized
derivatives. In this work, we report our findings con-
cerning the oxidative iodination of N-H or N-substi-
tuted pyrazoles using elemental iodine in the presence
of CAN as the in situ oxidant. This constitutes a mild
and efficient method to prepare 4-iodopyrazoles con-
taining even electron-withdrawing substituents.
4
-Iodopyrazoles are valuable starting products in the
3,4
synthesis of biologically active compounds.
have been used in cross-coupling reactions with termi-
nal acetylenes, organotin aryl derivatives, or aryl
boronic acids. In addition, halogen-metal exchange is
an attractive route to enter electrophiles in the position
4
direct metalation.
They
4
,5
6
7
of the pyrazolic nucleus, not always accessible by
8,9
Although there are reports on the iodination of pyra-
10
R3
N
R3
N
zoles, it presents rather complicated problems. The
I
1
1–13
iodine–iodide method (I , KI)
and the more reac-
have been applied to
2
8
,14
R5
+
I2
R5
tive iodine monochloride (ICl)
N
R1
N
R1
pyrazoles with alkyl- or electron-donating groups, but
have as a disadvantage the use of large quantities of
1
2
1
3
5
a, R = H; R = OMe; R = Me
1
5
3
e, R = R = H; R = Me
1
3
5
b, R = H; R = R = Me
1
3
5
f, R =CH Ph; R = R = H
2
1
3
5
Keywords: pyrazole; iodination; ceric ammonium nitrate; regioselec-
tivity.
c, R = H; R = R = CO Et
2
1
3
5
g, R =CH Ph; R = R = Me
2
1
3
5
d, R = R = R = H
*
Corresponding author. E-mail: iqmrf32@iqm.csic.es
This paper comprises a part of Isabel Dorronsoro’s PhD Thesis.
†
Scheme 1.
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02136-5

8
64
M. I. Rodr ´ı guez-Franco et al. / Tetrahedron Letters 42 (2001) 863–865
Table 1. Reactions of pyrazoles 1(a–g) with iodine
trast to the iodine–iodide procedure, where one-half of
part of the iodine is discarded.
Starting
pyrazole
Method
Reaction
conditions
Product (%
yield)
In order to explore the scope of the I –CAN iodination
2
method, other N-H and N-benzylpyrazoles (1d–g) were
subjected to this procedure, obtaining the correspond-
ing 4-iodopyrazole (2d–g) in good yields (see Table 1).
There are some remarkable features in the CAN-medi-
ated iodination of pyrazoles. In every case, only a
1
1
1
1
1
1
1
1
1
a
b
c
b
c
d
e
f
A
A
A
B
B
B
B
B
B
Reflux, 24 h
Reflux, 48 h
Reflux, 72 h
Rt, 3 h
Reflux, 6 h
Rt, 3 h
Rt, 3 h
Rt, 4 h
Rt, 6 h
2a (80)
2b (55)
2c (0)
2b (93)
2c (80)
2d (98)
2e (90)
2f (79)
2g (80)
monoiodinated product was obtained, in contrast to
15,16
other reported methods.
In addition, the iodination
was found to be regioselective since the iodine atom
preferred pyrazole instead of the benzyl group, and the
g
4
-pyrazolic position instead of other possible positions
Method A: 2I , 6NaI, 2CH CO Na, H O.
2
3
2
2
in the heterocycle. This iodination method only failed
when 3-nitro-4-ethoxycarbonylpyrazole was used as
starting material, due to the presence of a substituent in
the 4-position of the pyrazolic nucleus.
Method B: 0.6I , 0.5CAN, CH CN.
2
3
2
. Results and discussion
Preliminary experiments have been carried out using
the classical iodine–iodide method, using 2 equiv. of
iodine, 6 equiv. of sodium iodide and 2 equiv. of
sodium acetate in water to reflux for 24–48 h (Scheme
In the final products (2a–g) the position of iodination
13
was established by comparison of their C NMR sig-
nals with those of the starting pyrazoles (Table 2), since
it is known that the iodine atom causes a large upfield
1). Under these conditions (Table 1, method A), the
21,22
shift of the carbon directly bounded to it.
In all
iodination reaction afforded good yields only with acti-
vated pyrazoles (e.g. 4-iodo-3-methoxy-5-methylpyra-
zole 2a, 80% yield), but it provided poor yields with
pyrazoles bearing alkyl groups (e.g. 3,5-dimethyl-4-
iodopyrazole 2b, 55%), and it failed completely with
pyrazoles with electron-withdrawing substituents [e.g.
cases, only the signal of pyrazolic C-4 suffered an
upfield shift of 42–49 ppm, confirming that the iodine
atom only went to position 4 of the pyrazole system.
Typical experimental procedure for method B: A mix-
ture of pyrazole (1 mmol), iodine (0.6 mmol) and CAN
3,5-bis(ethoxycarbonyl)-4-iodopyrazole 2c, 0% yield].
(
0.6 mmol) in 10 mL of anhydrous acetonitriline was
stirred at room temperature until a TLC control
showed that the starting pyrazole had disappeared (1–3
h). The diester 1c needed more drastic conditions:
reflux, 3 h. Then, the solvent was evaporated under
reduced pressure and the resulting residue was dissolved
in 25 mL of ethyl acetate. The organic solution was
washed with 25 mL of an ice-cold aqueous solution of
In contrast, the treatment of the starting pyrazoles 1b,c
with 0.6 molar equivalents of iodine in the presence of
0.5 molar equivalents of CAN in acetonitrile for 3 h at
room temperature (1b) or at reflux (1c) afforded the
corresponding 4-iodopyrazoles in excellent yields (Table
1
, method B), even with electron-withdrawing sub-
stituents in the pyrazolic nucleus. This iodination
method (I –CAN) proceeded with better yields, in
NaHSO (5%), then with 25 mL of saturated solution
3
2
shorter time, and under milder conditions than the
iodine–iodide mixture. It is worth mentioning that in
of NaCl, and finally dried over Na SO and evaporated
2
4
to dryness. Products were purified on silica gel using
flash column chromatography and their microanalytical
data are summarized in Table 3.
the I –CAN method 0.6 mol of iodine per mol of
2
substrate is enough to complete the reaction, in con-
13
Table 2. C NMR chemical shifts (CDCl , l, ppm) of starting pyrazoles (1) and their 4-iodinated derivatives (2)
3
No.
C3
C4
C5
Other carbon atoms
Compare Ref.
1
2
1
2
1
2
1
2
1
2
1
2
1
2
a
a
b
b
c
c
d
d
e
e
f
164.3
163.4
145.3
146.1
140.0
141.9
133.5
138.8
142.8
146.0
139.0
144.5
147.5
149.3
88.5
141.0
142.9
145.3
146.1
140.0
141.9
133.5
138.8
134.5
140.2
128.8
133.5
139.1
140.6
56.2; 11.2
56.4; 11.9
12.8
–
–
45.3
104.8
62.6
111.3
66.3
104.7
56.6
104.1
60.4
105.5
56.3
105.5
63.2
2
1
13.5
–
2
3
160.5; 61.6; 14.2
161.4; 60.9; 15.0
–
2
1
–
2
1
11.7
13.2
–
2
2
136.4; 128.3; 127.5; 127.2; 55.4
135.8; 128.8; 128.2; 127.8; 56.4
137.3; 128.6; 127.3; 126.5; 52.5; 13.5; 11.0
136.6; 128.7; 127.6; 126.6; 54.0; 14.0; 12.0
2
2
f
g
g
–
–

M. I. Rodr ´ı guez-Franco et al. / Tetrahedron Letters 42 (2001) 863–865
Table 3. Microanalytical data of prepared 4-iodopyrazoles
865
No.
Formula (MW)
Calcd
H (%)
Found
H (%)
C (%)
N (%)
C (%)
N (%)
2
2
2
2
2
2
2
a
b
c
d
e
f
C H IN O (238.03)
25.23
27.05
31.97
18.58
23.10
42.28
46.17
2.96
3.18
3.28
1.56
2.42
3.19
4.20
11.77
12.62
8.29
14.44
13.47
9.86
25.42
26.85
31.67
18.22
23.01
42.34
46.30
3.10
3.01
3.09
1.28
2.14
3.08
4.15
11.63
12.45
7.97
14.39
13.29
9.54
5
7
2
C H IN (222.03)
5
7
2
C H IN O (338.10)
9
11
2
4
C H IN (193.97)
3
3
2
C H IN (208.00)
4
5
2
C H IN (284.10)
10
9
2
g
C H IN (312.15)
8.97
8.61
12
13
2
Acknowledgements
Potts, K. T., Ed.; Pergamon Press: Oxford, 1984; Vol. 5,
pp. 167–303.
11. H u¨ ttel, R.; Sch a¨ fer, O.; Jochum, P. Liebigs Ann. Chem.
The authors gratefully acknowledge the financial sup-
ports of C.I.C.Y.T. (SAF 99-098) and Comunidad de
Madrid (08.5/0045.1/99) and the fellowship to one of us
1955, 593, 200–207.
12. Hansen, J. F.; Kim, Y. I.; Griswold, L. J.; Hoelle, G. W.;
Taylor, D. L.; Vietti, D. E. J. Org. Chem. 1980, 45,
76–80.
(
I.D.) from the Fundaci o´ n Ram o´ n Areces. We also
thank Mr. E. Barbero for technical assistance by the
microanalysis.
13. Holzer, W.; Gruber, H. J. Heterocycl. Chem. 1995, 32,
1351–1354.
1
4. Ohsawa, A.; Kaihoh, T.; Itoh, T.; Okada, M.; Kawabata,
C.; Yamaguchi, K.; Igeta, H. Chem. Pharm. Bull. 1988,
36, 3838–3848.
References
15. Giles, D.; Parnell, E. W.; Renwick, J. D. J. Chem. Soc.
1
2
. Sugiyama, T. Bull. Chem. Soc. Jpn. 1981, 54, 2847–2848.
. Asakura, J.-I.; Robins, M. J. Tetrahedron Lett. 1988, 29,
(C) 1966, 1179–1184.
16. Tretyakov, E. V.; Vasilevsky, S. F. Mendeleev Commun.
1995, 233–234.
2
855–2858.
3
4
5
. Sliskovic, D. R.; Roth, B. D.; Wilson, M. W.; Hoefle, M.
L.; Newton, R. S. J. Med. Chem. 1990, 33, 31–38.
, ,
. Tolf, B.-R.; Dahlbom, R.; Theorell, H.; Akeson, A. Acta
Chem. Scand. B 1982, 36, 101–107.
. Manfredini, S.; Bazzanini, R.; Baraldi, P. G.; Simone, D.;
Vertuani, S.; Pani, A.; Pinna, E.; Scintu, F.; Lichino, D.;
La Colla, P. Bioorg. Med. Chem. Lett. 1996, 6, 1279–
17. Rodr ´ı guez-Franco, M. I.; Dorronsoro, I.; Mart ´ı nez, A.;
P e´ rez, C.; Bad ´ı a, A.; Ba n˜ os, J. E. Arch. Pharm., Pharm.
Med. Chem. 2000, 333, 118–122.
18. Rodr ´ı guez-Franco, M. I.; Dorronsoro, I.; Castro, A.;
Mart ´ı nez, A. Tetrahedron 2000, 56, 1739–1743.
19. Rodr ´ı guez-Franco, M. I.; San Lorenzo, P.; Mart ´ı nez, A.;
Navarro, P. Tetrahedron 1999, 55, 2763–2772.
20. Rodr ´ı guez-Franco, M. I.; Fierros, M.; Mart ´ı nez, A.;
Navarro, P.; Conde, S. Bioorg. Med. Chem. 1997, 5,
363–367.
21. Begtrup, M.; Boyer, G.; Cabildo, P.; Cativiela, C.; Clara-
munt, R. M.; Elguero, J.; Garc ´ı a, J. I.; Toiron, C.; Vedsø,
P. Magn. Reson. Chem. 1993, 31, 107–168.
22. Holzer, W.; P o¨ cher, I. J. Heterocycl. Chem. 1995, 32,
189–194.
1
284.
. Elguero, J.; Jaramillo, C.; Pardo, C. Synthesis 1997,
63–566.
6
7
8
5
. Collot, V.; Dallemagne, P.; Bovy, P. R.; Rault, S. Tetra-
hedron 1999, 55, 6917–6922.
. Felding, J.; Kristensen, J.; Bjerregaard, T.; Sander, L.;
Vedsø, P.; Begtrup, M. J. Org. Chem. 1999, 64, 4196–
4
198.
. Balle, T.; Vedsø, P.; Begtrup, M. J. Org. Chem. 1999, 64,
366–5370.
9
23. Iturrino, L.; Navarro, P.; Rodr ´ı guez-Franco, M. I.; Con-
treras, M.; Escario, J. A.; Mart ´ı nez, A.; Pardo, M. R.
Eur. J. Med. Chem. 1987, 22, 445–451.
5
1
0. Elguero, J. In Comprehensive Heterocyclic Chemistry;
.
.