Simple preparations of 4 and 5-iodinated pyrazoles as useful building blocks

Article abstract of DOI:10.1016/j.tet.2011.09.029

The pyrazole nucleus has recently become a recurrent scaffold in the research fields of CropScience and oncology. We report here the preparation of an array of 4- and 5-iodinated pyrazole derivatives, such as 4-iodo-3-trifluoromethylpyrazole or ethyl 5-io

Full text of DOI:10.1016/j.tet.2011.09.029

Tetrahedron 67 (2011) 8451e8457
Contents lists available at SciVerse ScienceDirect
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Simple preparations of 4 and 5-iodinated pyrazoles as useful building blocks
,
b
a
,
,b,
Sandrine Guillou a , Frederic J. Bonhomme b, Mikhail S. Ermolenko c, Yves L. Janin a
*
ꢀ ꢀ
a Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France
b CNRS, URA 2128, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France
c Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, UPR2301, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 May 2011
Received in revised form 20 June 2011
Accepted 8 September 2011
Available online 14 September 2011
The pyrazole nucleus has recently become a recurrent scaffold in the research fields of CropScience and
oncology. We report here the preparation of an array of 4- and 5-iodinated pyrazole derivatives, such as
4-iodo-3-trifluoromethylpyrazole or ethyl 5-iodo-4-carboxy-3-trifluoromethylpyrazoles. This work
provide access to many new pyrazole derivative, including 11 original out of 16 iodinated building blocks,
thus opening accesses to new chemical entities featuring a pyrazole nucleus.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Building blocks
5-Iodopyrazoles
4-Iodopyrazoles
4,5-Diiodopyrazoles
1. Introduction
part, we found that the electron-poor 3-trifluoromethylpyrazole 1e
and its 5-phenyl homologue 1f were most conveniently iodinated
Pyrazole chemistry1,2 is currently enjoying the focus of renewed
research3e20 aiming at developing accesses to original derivatives
of potential interest, for instance in the research fields of CropS-
cience21,22 or oncology.23e29 We recently reported on the synthesis
of 5-iodo-3-ethoxypyrazoles as original building blocks for the
preparation of whole arrays of new chemical entities.30 We wish to
report here preparations of many additional 4 or 5-iodinated as
well as 4,5-diiodopyrazoles derivatives. These compounds are ob-
vious building blocks, which should open accesses to even more
new chemical entities featuring a pyrazole nucleus.
Table 1 sums up the iodination of pyrazoles 1aef, their prepa-
ration was either reported elsewhere31e34 or, for compound 1f, an
improved one is described in the experimental part. As for many
pyrazoles,35 the 4-iodinations of 3-alkoxypyrazoles, such as 1aec
were very easily achieved with iodine under mild basic conditions
leading to compounds 2a and 2c.36,37 Accordingly, with the same
reaction conditions, we also prepared compound 2b or the 5-
trifluoromethyl-bearing homologue 2d both in 90% yield. On the
other hand, attempts to iodinated the 3-trifluoromethylpyrazoles
1eef on carbon 4 with these conditions completely failed. This
pointed out that these electron-poor substrates called for rather
stronger reaction conditions. A literature search showed that the 4-
iodination of 3-trifluoromethylpyrazole (1e) can be achieved with
a mixture of cerium ammonium nitrate and iodine.38,39 For our
with N-iodosuccinimide (NIS) in 50% sulfuric acid.40e43 With these
conditions we could prepare compounds 2e and 2f both in 85%
yield. However, from compound 1f, the occurrence of a small
proportion of a bis-iodinated byproduct could not be avoided.
With the use of NIS and heat under neutral conditions, the 5-
iodination of alkoxypyrazoles was generalized to many sub-
strates, such as compound 3bee. Again, the synthesis of the start-
ing materials can be found in the experimental part. Compared to
our previous results,30 switching from cyclohexane to refluxing
dichloroethane actually led to a substantial improvement (from 60
to 82% yield) especially in the case of large scale preparation of 4a.30
Table 1
4-Iodination of pyrazoles 1aef
H
H
N N
N N
R3
R5
R3
R5
I
1a-f
2a-f
R3
R5
Yield %
Conditions
a
b
c
d
e
f
EtO
EtO
EtO
EtO
CF3
CF3
H
91
90
75
90
85
85
I2, NaI, K2CO3, EtOH/H2O
I2, NaI, K2CO3, EtOH/H2O
I2, NaI, K2CO3, EtOH/H2O
I2, NaI, K2CO3, EtOH/H2O
NIS, H2SO4 50% v/v, 20 ꢀC
NIS, H2SO4 50% v/v, 20 ꢀC
Me
Ph
CF3
H
Ph
* Corresponding author. E-mail address: yves.janin@pasteur.fr (Y.L. Janin).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.029

8452
S. Guillou et al. / Tetrahedron 67 (2011) 8451e8457
The reaction could also be run in a closed vessel using a microwave
oven, which allowed to heat beyond the boiling point and thus
shortened the reaction duration. Some difficulties were encoun-
tered with the iodination of the 4-phenyl derivative 3d as poly-
iodination sometime marred the reaction. The best yield in this
case (66%) was obtained in refluxing dichloroethane and was ac-
companied by the recovery of 14% of the starting material 3d. At-
tempts to 5-brominated compound 3d were far less successful,44 in
accord with the extensive side-ring polybromation reported for
other examples.45e48 The 4,5-diodopyrazole 4e was also easily
obtained from the 4-iodopyrazole 2a/3e or, rather more simply,
directly from compound 1a under the same reaction conditions by
doubling the amount of NIS. Again, the 3-trifluromethylpyrazoles
3fej were far less reactive. The 5-iodination of 3i, has been re-
ported in an unspecified yield and required the use of [bis(tri-
fluoroacetoxy)iodo]benzene and iodine.49 However, the fairly high
temperature accessible with a microwave oven allowed the syn-
thesis of the 5-iodinated pyrazoles 4fej just with the use of NIS.
Interestingly, if some polyiodination was noted for the electron-rich
3-ethoxy-4-phenyl-pyrazole (3d), it was not the case with the 3-
trifluoromethyl-4-phenylpyrazole (3h). With this method, we
could also prepare the 4,5-diiodo derivative 4j albeit from the 4-
iodopyrazole 2e/3j only. Indeed, contrary to the preparation of
the diiodo derivative 4e attempts to mono or bis-iodinated 3-
trifluromethypyrazole (1e) with NIS at high temperature failed as
no reaction was observed. More unexpectedly, chlorination of 1e,
with N-chlorosuccinimide under the same conditions, was possible
and led to the 4-chloropyrazole 3i in a 73% yield (see experimental
part) (Table 2).
much of the 4H-pyrazole ring strain (the 4-chlorination could also
take place after this step).54 The 1H NMR spectra of a trial at room
temperature also pointed out the occurrence of compound 7 along
with a mixture of other products. The reductive treatment59 of the
crude reaction extract with sodium sulfite in a boiling mixture of
water and THF led, with an important loss of material, to the isolation
of the two additional products 8 and 9. The structure elucidation of
these compounds, resulting from the reduction of 6 and 7, further
confirmed the mechanistic process suggested above. Another series
of unexpected reactions were also observed in the course of this
study. Thus, the iodine on carbon 4 of compound 2a turns out to be
quite labile as its completed reduction, along with iodine (or iodi-
nemonochloride) evolution, was achieved in boiling 2 N hydrochloric
acid in the course of 90 min. Control experiments demonstrated that
both acidic conditions and the presence of oxygen are crucial for this
reaction to proceed. A similar and specific reduction of the 4,5-diiodo
derivative 4e into the known30 5-iodopyrazole 10 also took place
although far more slowly as a 62% conversionwas observed after 10 h
of reflux. These results are reminiscent of the reported regioselective
carbon 4 reduction of the 3,4-diiodo-5-methylpyrazoles or 3,4,5-
triodopyrazole. Such reductions were achieved by using either trie-
thylamine trihydrofluoride or hydrogen fluoride although the re-
ductions were apparently run in closed vessels.50,60 Attempts to
reduce the 4,5-diiodo-3-trifluoromethyl 4j under the same reaction
conditions only pointed out a very slow reduction rate as this com-
pound is readily removed from the reaction mixture into the con-
denser by steam-extraction (Scheme 1).
H
H
N N
N N
i
OH
O
O
I
Table 2
O
5-Iodination of pyrazoles 3aej
5
4c (81 %)
H
H
N N
N N
H
N
O
N N
R3
R3
I
N
ii
O
N
N
R4
R4
O
COOEt
O
Cl
O
3a-j
4a-j
O
O
6
3a
R3
R4
Yield %
Conditions
a
b
c
d
e
f
g
h
i
EtO
EtO
EtO
EtO
EtO
CF3
CF3
CF3
CF3
CF3
CO2Et
CN
CH3
Ph
82
74
72
66
85
56
90
82
54
85
NIS, ClCH2CH2Cl, reflux
iii
NIS, ClCH2CH2Cl, MW, 150 ꢀC
NIS, ClCH2CH2Cl, reflux
H
H
O
N N
O
N N
NIS, ClCH2CH2Cl, reflux
NIS, ClCH2CH2Cl, reflux
O
N
N
OR
N
N
I
O
O
COOEt
Cl
CO2Et
CH3
Ph
Cl
I
NIS, ClCH2CH2Cl, MW, 190 ꢀC
NIS, ClCH2CH2Cl, MW, 140 ꢀC
NIS, ClCH2CH2Cl, MW, 140 ꢀC
NIS, ClCH2CH2Cl, MW, 190 ꢀC
NIS, ClCH2CH2Cl, MW, 190 ꢀC
O
O
O
O
8
: R = Et (9 %)
: R = H (10 %)
7
(23 %)
9
j
H
H
N N
iv
N N
O
R
O
R
I
The preparation of compound 4c was actually achieved in a better
81% yield from acid 5. This approach involved a remarkable iodo-
decarboxylation reaction in the presence of an anionic surfactant,
which was previously reported for the triiodination of 3-pyrazole
carboxylic acid.50 With this method, we also avoided the low yield-
ing preparations of 3c, either by decarboxylation of 5 or by the con-
densation of hydrazine hydrochloride with ethyl 2-methyl-3-
oxopropanoate.51 We also attempted the 5-chlorination of 3a with
N-chlorosuccinimide (NCS), which could have led in a few steps to the
preparation of 5-chloro-4-iodo-3-ethoxypyrazole. Quite un-
expectedly, at 130 ꢀC, we could isolate from the reaction products the
dimeric derivative 7. Its occurrence is actually reminiscent of trimeric
structures reported in the past in the course of the preparation of
simple 3-halogenopyrazoles.52e58 Mechanistically-wise, we suggest
the hydrolysis of the 4-chlorinated ethoxypyrazole moiety of in-
termediate 6 upon work-up of the reaction, which would release
2a: R = H
4e: R = I
1a: R = H (95 %)
10: R = I (62 % in 10 hours)
Scheme 1. i: NaOH, CH3(CH2)11C6H4SO3Na, I2, H2O. ii: NCS, dichloroethane, 130 ꢀC iii:
(a) NCS, dichloroethane, 20 ꢀC (b) Na2SO3, THF/H2O reflux. iv: 2 N HCl, air, reflux.
In conclusion, the simple preparations of the 4- and 5-iodinated
pyrazoles described in this work should be useful for the synthesis
of a vast array of more elaborated derivatives with the use of car-
bonecarbon or carboneheteroatom coupling reactions. We should
actually report on the palladium-catalyzed transformations of
some of these building blocks in the near future. Moreover, the
selective labile character of the iodine atom on C-4 observed for
compound 4e may help in designing regioselective transformations
of such 4,5-diiodopyrazoles.

S. Guillou et al. / Tetrahedron 67 (2011) 8451e8457
8453
2. General methods
and N-iodosuccinimide (18.5 g, 82 mmol) was added. The suspen-
sion was stirred 10 min at 0 ꢀC and then stirred, 3 h for 1e and two
days for 1f, at room temperature. This was dispersed in water
(500 mL) and stirred overnight. The precipitate was filtered,
washed with water and redispersed in boiling water (400 mL),
a small amount of sodium disulfite was added and the suspension
was left to cool, filtered again and dried under vacuum to yield
compound 2e or 2f as described below.
A Biotage initiator 2 microwave oven was used for reactions
mentioning such heating method. 1H NMR and 13C NMR spectra
were recorded on a Bruker Avance 400 spectrometer at 400 MHz
and 100 MHz, respectively. Shifts (d) are given in parts per million
with respect to the TMS signal and coupling constants (J) are given
in hertz. Column chromatography were performed either on Merck
silica gel 60 (0.035e0.070 mm) or neutral alumina using a solvent
pump and an automated collecting system driven by a UV detector
set to 254 nm unless required otherwise. Sample deposition was
carried out by absorption of the mixture to be purified on a small
amount of the solid phase followed by its deposition of the top of the
column. The low resolution mass spectra were obtained on an
Agilent 1100 series LC/MSD system using an atmospheric electro-
spray ionization system and the high resolution mass spectra
(HRMS) were obtained using a Waters Micromass Q-Tof with an
electrospray ion source. Preparations and characterization of com-
pounds 2a,30 2c,30 3c,51 830 and 1030 have been reported previously.
2.6. 4-Iodo-3-(trifluoromethyl)-1H-pyrazole (2e)
Obtained as a white solid in 85% yield; mp 141 ꢀC 1H NMR
(CDCl3): 7.80 (s, 1H); 13.1 (s (br), 1H). 13C NMR (CDCl3): 54.4; 121.0
(q, J¼268 Hz); 136.9; 143.9 (q, J¼39 Hz). HRMS: calcd for
C4H2F3IN2ꢁH: 260.9137; Found: 260.9126.
2.7. 4-Iodo-5-phenyl-3-(trifluoromethyl)-1H-pyrazole (2f)
Obtained as a white solid in 85% yield still containing 1% of
unreacted pyrazole 1f and 4% of a bis-iodinated material. A sample
was triturated (with losses) in boiling dichloromethane for ana-
lytical purposes; mp 177 ꢀC 1H (DMSO-d6): 7.48e7.57 (m, 3H);
7.67e7.70 (m, 2H); 14.24 (s (br), 1H). 13C (DMSO-d6): 57.0; 121.9
(J¼269 Hz); 128.5; 128.9; 129.2; 130.0; 143.7 (J¼39 Hz); 146.5.
HRMS: calcd for C10H6F3IN2ꢁH: 336.9450; Found: 336.9409.
2.1. 5-Phenyl-3-(trifluoromethyl)-1H-pyrazole (1f)
4,4,4-Trifluoro-1-phenylbutane-1,3-dione (7.1 g, 0.032 mol) and
hydrazine hydrate (1.75 mL, 0.036 mol) were refluxed in ethanol
(140 mL) for 2 h. The reaction mixture was concentrated to dryness
to yield 3-phenyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-
ol.61 1H NMR (DMSO-d6): 3.40 (d, 1H, J¼18.0 Hz); 3.37 (d, 1H,
J¼18.0 Hz); 7.39 (m, 4H); 7.64 (m, 2H); 7.93 (s (br), 1H). 13C NMR
(DMSO-d6): 41.3; 91.1 (J¼30 Hz); 124.1(J¼280 Hz); 125.5; 128.5;
129.0; 132.2; 147.4. This compound was then boiled in 2 N hydro-
chloric acid (40 mL) for 1 min. After cooling, the precipitate was
filtered, washed with water and dried under vacuum to yield
compound 1f as a white solid (6.91 g, 98%) with analytical data
identical to the reported one.62,63
2.8. 3-Ethoxy-1H-pyrazole-4-carbonitrile (3b)
This compound was prepared from 3a30 in two steps as follow.
Step 1: in a 400 mL steel reactor, compound 3a (48.7 g, 0.26 mol)
and ammonium chloride (3.6 g, 0.066 mol)64e66 were mixed with
32% ammonia (200 mL, 3.31 mol). The reactor was closed and
heated to 80 ꢀC for 29 h. After cooling back to room temperature,
the solution was concentrated to dryness under vacuum. The
resulting dry solid was suspended in a 1/1 mixture of dichloro-
methane and toluene (300 mL), filtered and the collected solid
dried under vacuum at 70 ꢀC to yield 38.11 g of 3-ethoxy-1H-pyr-
azole-4-carboxamide as white solid (34.51 g, 84%, taking into ac-
count the 3.6 g of ammonium chloride that could be present in this
solid). The NMR analysis of the filtrate (5.78 g when concentrated to
dryness) showed the presence of some decarboxylated material,30
some unreacted ester and a small amount of the amide. A sample
was recrystallized in a small amount of water with much loss for
analytical purposes; mp 168 ꢀC 1H (DMSO-d6): 1.35 (t, 3H,
J¼7.0 Hz); 4.26 (q, 2H, J¼7.0 Hz); 6.56 (s (br), 1H); 7.00 (s (br), 1H);
7.91 (s, 1H). 13C (DMSO-d6): 15.1; 65.0; 102.4; 133.1; 160.0; 163.6.
HRMS: calcd for C6H9N3O2þH: 156.0773. Exptl: 156.0749. Step 2: in
a flask protected from moisture by a calcium chloride guard, 3-
ethoxy-1H-pyrazole-4-carboxamide (20.3 g, 0.130 mol) was dis-
2.2. Iodination of 1b and 1d
The considered alkoxypyrazole (57 mmol), sodium iodide so-
dium iodide (8.6 g, 57 mmol) and potassium carbonate (23.8 g,
1.7 mmol) were dissolved in a 4:1 water/ethanol mixture (250 mL).
Iodine (19 g, 74 mmol) was added and the suspension was stirred
for 1 h. The mixture was treated with sodium sulfite, diluted with
brine (500 mL) and the resulting white precipitate was filtered. This
was washed with water and dried under vacuum at 80 ꢀC until all
the byproduct triiodomethane has sublimed to yield compounds 2b
or 2d as described below.
2.3. 3-Ethoxy-4-iodo-5-methyl-1H-pyrazole (2b)
Obtained as an off-white solid in 90% yield; mp 104 ꢀC 1H NMR
(CDCl3): 1.40 (t, 3H, J¼7.0 Hz); 2.22 (s, 3H); 4.26 (q, 2H, J¼7.0 Hz);
10.10 (s (br), 1H). 13C NMR (CDCl3): 12.1; 14.8; 46.5; 65.1; 142.6;
163.2. HRMS: calcd for C6H9IN2OþH: 252.9838; Found: 252.9788.
solved in acetonitrile (300 mL, dried over 4 A molecular sieve).
ꢁ
Phosphorus oxychloride (26.8 mL, 0.287 mol) was added and the
mixture was heated to reflux for 4.5 h. The resulting dark mixture
was poured onto 600 g of ice with stirring. After decomposition of
phosphorus oxychloride, the mixture was made basic with 20%
ammonia, saturated with sodium chloride and extracted three
times with ethyl acetate. The organic phase was dried over mag-
nesium sulfate and concentrated to dryness to yield crude com-
pound 3b. This solid was extracted with boiling isopropyl ether
(three time 300 mL) and filtered. The filtrate was concentrated to
dryness to yield compound 3b as a yellow powder still containing
a small proportion of water (13.96 g, 77%). A small sample (from
a less clean batch) could be purified by a chromatography over silica
gel (cyclohexane/dichloromethane from 1/2 to 1/1); mp 102 ꢀC 1H
(CDCl3): 1.46 (t, 3H, J¼7.1 Hz); 4.37 (q, 2H, J¼7.1 Hz); 7.79 (s, 1H);
10.15 (s (br), 1H). 13C (CDCl3): 14.6; 66.0; 79.0; 112.9; 135.0; 163.9.
This compound did not ionize under the HRMS conditions.
2.4. 3-Ethoxy-4-iodo-5-(trifluoromethyl)-1H-pyrazole (2d)
Obtained as a white solid in 90% yield; mp 125 ꢀC 1H NMR
(CDCl3): 1.45 (t, 3H, J¼7.0 Hz); 4.33 (q, 2H, J¼7.0 Hz); 9.5 (s (br), 1H).
13C NMR (CDCl3): 14.6; 44.4; 66.8; 119.0 (q, J¼268 Hz); 136.4 (q,
J¼39 Hz); 162.3. HRMS: calcd for C6H6F3IN2OþH: 306.9555; Found:
306.9557.
2.5. Iodination of compound 1e and 1f
The considered 3-trifluoromethylpyrazole (68 mmol) was dis-
solved in 50% aqueous sulfuric acid (20 mL). This was cooled to 0 ꢀC

8454
S. Guillou et al. / Tetrahedron 67 (2011) 8451e8457
2.9. 4-Phenyl-3-ethoxy-1H-pyrazole (3d)
vinylether and trifluoroacetic anhydride, previously described un-
der the same conditions.34 In any case, this solution was cooled to
ꢀC and hydrazine hydrate (5.47 mL, 0.11 mol) diluted in ethanol
This compound was prepared in two step as follow. Step 1
0
compound 1a (2.06 g, 8.65 mmol) was dissolved in ethyl acetate
(150 mL), triethylamine (1.9 mL, 13.8 mmol; dried over 4 A molec-
(50 mL) was added drop-wise. The resulting solution was concen-
trated to dryness and the residue dispersed in water (400 mL). The
white precipitate was filtered, washed with water and dried in
open air before a recrystallisation in cyclohexane (three crops),
which yielded compound 3g as a white powder (7.54 g, 53%); mp
105 ꢀC 1H NMR (CDCl3): 2.23 (s, 3H); 7.49 (s, 1H); 12.9 (s (br), 1H).
13C NMR (CDCl3; D1 set at 10s): 7.8; 114.8; 122.3 (q, J¼269 Hz);
129.7; 140.2 (q, J¼36 Hz). HRMS: calcd for C5H5F3N2þH: 151.0483;
Found: 151.0497.
ꢁ
ular sieves) was added followed by mesylchloride (1.0 mL,
13.0 mmol). The solution was protected from moisture by a calcium
chloride guard and stirred for 2 h at room temperature. This was
washed with 2 N potassium carbonate, 0.5 N hydrochloric acid and
brine, dried over sodium sulfate and concentrated to dryness to
yield the 2/5 mixture of the two isomers 5-ethoxy-4-iodo-1-
(methylsulfonyl)-1H-pyrazole and 3-ethoxy-4-iodo-1-(methyl-
sulfonyl)-1H-pyrazole as an oil that slowly solidified (2.68 g, 98%).
1H (CDCl3): 1.45 (d, 5/7 of 3H, J¼7.1 Hz); 1.49 (d, 2/7 of 3H, J¼7.1 Hz);
3.25 (s, 5/7 of 3H); 3.31 (s, 2/7 of 3H); 4.41 (m, 2H); 7.61 (s, 2/7 of 1H);
7.90 (s, 5/7 of 1H). m/z (LC/MS)¼253. Step 2: in a 10 mL biotage-
adapted tube, the mixture of the mesyl-protected pyrazoles
(1.38 g, 4.37 mmol), phenyl boronic acid (0.7 g, 5.68 mmol), caesium
carbonate (3.56 g; 10.9 mmol) were dispersed in a mixture of
propanol (3 mL) and water (2 mL). The oxygen was removed by
a slow stream of argon and [1,10-bis(diphenylphosphino)ferrocene]
dichloropalladium complexed with dichloromethane (0.178 g,
0.218 mmol) was then added before sealing the tube. This was
heated in the microwave oven for 40 min at 120 ꢀC. This was diluted
in water, extracted with ethyl acetate; the organic layer was washed
with brine and dried over sodium sulfate and concentrated to dry-
ness. The residue was dissolved in ethanol (150 mL) and potassium
hydroxide (0.8 g) this was heated at 90 ꢀC for 2 h. This was diluted in
water, made slightly acid with ammonium chloride, extracted with
ethyl acetate, the organic layer was washed with brine and dried
over sodium sulfate and concentrated to dryness. The resulting
residue was purified by a chromatography over neutral alumina
containing 1.5% of water (dichloromethane/ethanol 99/1) and the
corresponding fraction was further purified by a recrystallisation in
cyclohexane to yield compound 3d (57%) as a white powder; mp
176 ꢀC 1H (CDCl3): 1.49 (t, 3H, J¼7.0 Hz); 4.39 (q, 2H, J¼7.0 Hz); 7.23
(m, 1H); 7.38 (m, 2H); 7.66 (s, 1H); 7.68 (m, 2H); 9.16 (s (br.), 1H). 13C
(CDCl3): 14.9; 64.7; 107.2; 125.8; 125.9; 127.0; 128.5; 131.9; 160.7.
HRMS: calcd for C11H12N2OþH: 189.1028. Found: m/z, 189.0984.
2.12. 4-Chloro-3-(trifluoromethyl)-1H-pyrazole (3i)
From the indications on page 343 of Ref. 49, the following pro-
cedure was designed: 3-(trifluoromethyl)-1H-pyrazole32e34 (1e)
(5.54 g, 40.7 mol) and N-chlorosuccinimide (5.97 g, 44.7 mmol) in
acetonitrile (13 mL) were heated in a microwave oven at 120 ꢀC for
1 h. The resulting mixture was concentrated to dryness and dis-
persed in water (300 mL). The precipitate was filtered, rinsed with
water and left to dry over 3 days to yield compound 3i (5.08 g, 73%)
as a powder; mp 94 ꢀC 1H NMR (CDCl3): 7.69 (s,1H); 11.2 (s (br),1H).
13C NMR (CDCl3): 109.6; 120.2 (q, J¼267 Hz); 129.5; 130.0 (q,
J¼37 Hz). HRMS: calcd for C4H2ClF3N2ꢁH: 168.9780; Found:
168.9747.
2.13. Ethyl 3-ethoxy-5-iodo-1H-pyrazole-4-carboxylate (4a)
Compound 3a (70 g, 0.386 mol) and 95% N-iodosuccinimide
(100.6 g, 0.418 mol) were boiled in dichloroethane (700 mL) for 17 h
under an inert atmosphere. While stirring, water (100 mL) was
added to the cooled solution followed by powdered sodium
disulfite until disappearance of the purple colour. This was dec-
anted, the organic layer was washed four times with water
(150 mL) once with a saturated sodium hydrogenocarbonate solu-
tion (100 mL) and dried over magnesium sulfate before concen-
tration to dryness. The resulting yellow solid was dispersed in 1 N
hydrochloric acid (500 mL) at room temperature, filtered, washed
thoroughly with water and dried under vacuum at 35 ꢀC to yield
compound 4a (96.6 g, 82%) featuring analytical data identical with
the previously reported one.30
2.10. Ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (3f)
Hydrazine hydrate (10 g, 0.199 mol) was dissolved in ethanol
(400 mL). This was cooled to 0 ꢀC and a solution of ethyl 2-
2.14. 5-Ethoxy-3-iodo-1H-pyrazole-4-carbonitrile (4b)
(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate
(47.03
g,
0.19 mol) in ethanol (200 mL) was added drop-wise over 90 min at
0 ꢀC. The solution was left to warm to room temperature for 3 h and
concentrated to dryness. The residue was dispersed in boiling cy-
clohexane (200 mL) and left to cool to room temperature. The
precipitate was filtered, washed with cyclohexane and dried under
vacuum at 75 ꢀC to yield compound 3f as a yellow powder (38.67 g,
95%); mp 145 ꢀC 1H NMR (CDCl3): 1.40 (t, 3H, J¼7.0 Hz); 4.39 (q, 2H,
J¼7.0 Hz); 8.26 (s, 1H); 13.2 (s (br), 1H). 13C NMR (CDCl3): 14.0; 61.2;
113.4; 121.0 (q, J¼268 Hz); 135.3; 142.0 (q, J¼38 Hz); 160.8. HRMS:
calcd For C7H7F3N2O2ꢁH: 207.0381; Found: 207.0377.
Compound 3b (2.5 g, 0.018 mol) and N-iodosuccinimide (4.5 g,
0.020 mol) were heated in a microwave oven in dichloroethane
(15 mL) at 150 ꢀC for 1 h. The resulting purple solution was diluted
in ethyl acetate and decolorized with a sodium disulfite solution.
The organic layer was washed five times with brine, dried over
magnesium sulfate and concentrated to dryness. The residue (4.5 g)
was purified by a chromatography over silica gel (cyclohexane/
ethyl acetate 2.5/1) to yield compound 4b as a slightly yellow
powder (3.56 g, 74%); mp 147 ꢀC 1H (DMSO-d6): 1.30 (t, 3H,
J¼7.0 Hz); 4.24 (q, 2H, J¼7.0 Hz); 13.4 (s (br), 1H). 13C (DMSO-d6, D1
set to 10s): 14.4; 65.1; 85.5; 91.9; 113.5; 163.9. HRMS: calcd for
C6H6IN3OþH: 263.9634. Exptl: 263.9581.
2.11. 4-Methyl-3-(trifluoromethyl)-1H-pyrazole (3g)
In a moisture-protected atmosphere at 0 ꢀC, trifluoroacetic an-
hydride (13.2 mL, 0.0949 mol) was added drop-wise to a mixture of
the isomers of 1-ethoxyprop-1-ene (8.1 g, 0.094 mol) in dry pen-
tane (60 mL). This was stirred at 0 ꢀC for 2 h and at 20 ꢀC for 24 h.
The 1H NMR spectra of a sample pointed out the occurrence of
a diastereoisomeric mixture of 1-ethoxy-4,4,4-trifluoro-2-methyl-
3-oxobutyl 2,2,2-trifluoroacetate, which did not spontaneously
eliminate trifluoroacetic acid, contrary to the reaction between
2.15. 3-Ethoxy-5-iodo-4-methyl-1H-pyrazole (4c)
Compound 3c (0.65 g, 0.0051 mol) N-iodosuccinimide (1.22 g,
0.0054 mmol) were refluxed in dichloroethane (40 mL) under an
inert atmosphere for 2h. This was diluted in ethyl acetate, washed
with a solution of sodium sulfite, with brine, dried over magnesium
sulfate and concentrated to dryness. The residue was purified by
a chromatography over silica gel (cyclohexane/ethyl acetate 4/1) to

S. Guillou et al. / Tetrahedron 67 (2011) 8451e8457
8455
yield compound 4c (0.94 g, 72%). Alternative procedure from 5: In
an oversized flask (500 mL), compound 5 (2.73 g, 0.016 mol), so-
dium hydroxide (0.55 g, 0.0162 mol), sodium dodecylbenzenesul-
fonate (0.048 g, 0.14 mmol) were dissolved in boiling water
(50 mL). Upon dissolution, iodine (4.11 g, 0.0162 mol) was added
portion-wise to avoid over-foaming of the solution. The resulting
suspension was then heated for three more hours, this was diluted
in boiling water (100 mL) decolorized with a solution of sodium
sulfite and left to cool under stirring. The precipitate was filtered,
washed with water and dried to yield compound 4c (3.28 g, 81%) as
an off-white solid; mp 94 ꢀC 1H NMR (CDCl3): 1.40 (t, 3H, J¼7.0 Hz);
1.92 (s, 3H); 4.23 (q, 2H, J¼7.0 Hz); 9.0 (s (br), 1H). 13C (CDCl3, D1 set
at 5s): 8.2; 14.9; 64.6; 82.2 (br); 107.1; 161.2 (br). HRMS: calcd for
C6H9IN2Oþ H: 252.9838. Exptl: 252.9803.
2.18.2. 5-Iodo-4-methyl-3-(trifluoromethyl)-1H-pyrazole (4g). The
reaction was heated in a microwave oven 30 min at 140 ꢀC. The
residue was dispersed in boiling water (100 mL) filtered and dried
in open air to yield compound 4g as a white powder (7.2 g, 90%);
mp 117 ꢀC 1H NMR (CDCl3): 2.14 (s, 3H); 12.2 (s (br), 1H). 13C NMR
(CDCl3): 9.6; 77.2; 120.6; 120.8 (q, J¼272 Hz); 139.2 (br). HRMS:
calcd for C5H4IF3N2þH: 276.9450; Found: 276.9436.
2.18.3. 5-Iodo-4-phenyl-3-(trifluoromethyl)-1H-pyrazole (4h). The
reaction was heated in a microwave oven 2 h at 140 ꢀC. The residue
was purified by a chromatography over silica gel (cyclohexane/
ethyl acetate 8/1) to yield compound 4h as a white powder (2.43 g,
82%); mp 160 ꢀC 1H NMR (CDCl3): 7.42 (m, 2H); 7.48 (m, 3H); 11.90
(s (br), 1H). 13C NMR (CDCl3): 77.2; 120.4 (q, J¼267 Hz); 126.7;
128.4; 128.5; 129.7; 129.8 (br); 130.0. HRMS: calcd for
C10H6IF3N2ꢁH: 336.9450; Found: 336.9495.
2.16. 3-Ethoxy-5-iodo-4-phenyl-1H-pyrazole (4d)
2.18.4. 4-Chloro-5-iodo-3-(trifluoromethyl)-1H-pyrazole (4i). The
reaction was heated in a microwave oven for 1 h at 190 ꢀC. The
residue was purified by a chromatography over silica gel (dichlor-
omethaneeethanol from 100/0 to 98/2) to yield compound 4i as
a white powder (2.98 g, 54%) along with less pure chromatographic
fractions. (Note: this compound is hardly visible on TLC, however
the UV detector of the chromatography apparatus detects it fine);
mp 96 ꢀC 1H NMR (DMSO-d6): 14.5 (s (br), 1H). 13C NMR (DMSO-d6,
D1 set to 10 s): 88.8; 114.3; 120.7 (q, J¼267 Hz); 138.5 (q, J¼37 Hz).
HRMS: calcd For C4HClF3IN2ꢁH: 296.8904; Found: 296.8908.
Compound 3d (1.33 g, 0.0070 mol) N-iodosuccinimide (1.67 g,
0.0074 mmol) were refluxed in dichloroethane (50 mL) under an
inert atmosphere for 2 h. This was diluted with ethyl acetate,
washed with a solution of sodium sulfite, with brine, dried over
magnesium sulfate and concentrated to dryness. The residue was
purified by a chromatography over silica gel (cyclohexane/ethyl
acetate 4/1) to yield compound 4d (1.47 g, 66%). Further elution led
to the isolation of unreacted compound 3d (0.19 g, 14%). Mp 144 ꢀC
1H NMR (CDCl3): 1.44 (t, 3H, J¼7.0 Hz); 4.32 (q, 2H, J¼7.0 Hz); 7.32
(m, 1H); 7.43 (m, 2H); 7.61; (m, 2H); 9.50 (s (br), 1H). 13C (CDCl3; D1
set at 5s): 14.8; 65.0; 80.9 (br); 111.6; 127.0; 128.2; 128.8; 130.7;
159.9. HRMS: calcd for C11H11IN2Oþ H: 314.9994. Exptl: 314.9970.
2.18.5. 4,5-Diiodo-3-(trifluoromethyl)-1H-pyrazole (4j). The re-
action was heated in a microwave oven for 45 min at 190 ꢀC. The
residue was purified by a chromatography over silica gel (cyclo-
hexane/ethyl acetate 7/1) to yield compound 4j as a white powder
2.17. 4,5-Diiodo-3-ethoxy-1H-pyrazole (4e)
(5.3 g, 85%); mp 129 ꢀC 1H NMR (DMSO-d6): 14.47 (s (br), 1H). 13
C
NMR (DMSO-d6, D1 set to 10 s): 70.8; 98.0; 120.5 (q, J¼268 Hz);
143.7 (q, J¼39 Hz). HRMS: calcd for C4HF3I2N2þH: 388.8260;
Found: 388.8258.
3-Ethoxy-1H-pyrazole (1a) (3.48 g, 0.031 mol) N-iodosuccini-
mide (14.66 g, 0.065 mol) were refluxed in dichloroethane (80 mL)
under an inert atmosphere for 11h. This was diluted with ethyl
acetate, washed with a solution of sodium sulfite, with brine, dried
over magnesium sulfate and concentrated to dryness. The residue
was purified by a chromatography over silica gel (cyclohexane/
ethyl acetate 4/1) to yield compound 4e as a slightly yellow powder
(9.69 g, 85%). A similar procedure, from compound 3e, with
1.1 equiv of NIS led to compound 4e in a similar yield; mp 108 ꢀC 1H
NMR (CDCl3): 1.42 (t, 3H, J¼7.0 Hz); 4.28 (q, 2H, J¼7.0 Hz); 9.65 (s
(br), 1H). 13C NMR (CDCl3): 14.7; 59.2; 65.7; 91.7; 136.6. HRMS:
calcd for C5H6I2N2þH: 364.8648; Found: 364.8649.
2.18.6. 3-Ethoxy-4-methyl-1H-pyrazole-5-carboxylic acid (5). Ethyl
3-ethoxy-4-methyl-1H-pyrazole-5-carboxylate31(3.6 g, 0.018 mol)
and sodium hydroxide (1.5 g, 0.036 mol) were refluxed in water
(40 mL) for 45 min. The solution was cooled and made acid with 2 N
hydrochloric acid. The resulting precipitate was filtered, washed
with water and dried under vacuum at 65 ꢀC to yield compound 5
as a white solid (2.8 g, 93%); mp 194 ꢀC 1H NMR (DMSO-d6): 1.30 (t,
3H, J¼7.0 Hz); 2.02 (s, 3H); 4.16 (q, 2H, J¼7.0 Hz); 12.4 (s (br), 1H);
13.1 (s (br), 1H). 13C (DMSO-d6; D1 set at 5s): 7.3; 15.2; 64.5; 103.7;
131.7; 161.5; 161.6. HRMS: calcd for C7H10N2O3þH: 171.0770. Exptl:
171.0770.
2.18. Iodination of 3fej, preparation of compounds 4fej
The considered 3-trifluoromethylpyrazole (9.6 mmol) and
N-iodosuccinimide (2.38 g,10 mmol) in dichloroethane (14 mL) were
heated in a microwave oven as described for each case. The resulting
mixture was diluted with ethyl acetate and decolorized with a solu-
tion of sodium disulfite. The organic layer was washed with brine five
times, dried over magnesium sulfate and concentrated to dryness.
The residue was further purified as described below.
2.19. Ethyl 1-(4-chloro-4-(ethoxycarbonyl)-5-oxo-4,5-dihydro-
1H-pyrazol-3-yl)-3-ethoxy-1H-pyrazole-4-carboxylate (7)
Pyrazole 3a (3 g, 0.0162 mol) and N-chlorosuccinimide (2.4 g,
0.0179 mol) were heated in dichloroethane (14 mL) using a micro-
wave oven at 130 ꢀC for 40 min. The resulting solution was con-
centrated to dryness and purified by a chromatography over silica
gel (cyclohexane/ethyl acetate 4/1). The main fraction collected
(1.21 g) was further purified by a recrystallisation in a mixture of
toluene and cyclohexane to yield compound 7 as an off-white solid
(0.7 g, 23%); mp 129 ꢀC 1H NMR (DMSO-d6): 1.24 (t, 3H, J¼7.0 Hz);
1.28 (t, 3H, J¼7.0 Hz); 1.32 (t, 3H, J¼7.0 Hz); 4.33 (m, 6H); 8.68 (s,
1H); 12.40 (s (exch.), 1H). 13C NMR (DMSO-d6): 14.2; 14.6 (two
signals); 60.6; 61.0 (C4); 64.7; 65.9; 104.8 (C40); 133.5 (CH-50); 147.6
(C3); 160.7; 160.8; 162.6; 167.4 (C5). HRMS: calcd for
C14H17Cl35N4O6þH: 373.0915; Found: 373.0891.
2.18.1. Ethyl 3-iodo-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate
(4f). The reaction was heated in a microwave oven for 1 h and
a half at 190 ꢀC. The residue was purified by a chromatography over
silica gel (cyclohexane/ethyl acetate 3/1) to yield compound 4f as
a white powder (1.81 g, 56%); mp 119 ꢀC 1H NMR (CDCl3): 1.40 (t,
3H, J¼7.0 Hz); 4.40 (q, 2H, J¼7.0 Hz); 12.7 (s (br), 1H). 13C NMR
(CDCl3; D1 set to 10 s): 14.0; 61.7; 88.7 (br); 116.0; 119.6 (q,
J¼268 Hz); 142.6 (br); 160.5. HRMS: calcd for C7H6IF3N2O2þH:
334.9504; Found: 334.9502.

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S. Guillou et al. / Tetrahedron 67 (2011) 8451e8457
3. Schlosser, M.; Volle, J.-N.; Leroux, F.; Schenk, K. Eur. J. Org. Chem. 2002,
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Pyrazole 3a (2.23 g, 0.0121 mol) and N-chlorosuccinimide (1.7 g,
0.0127 mol) were dissolved in dichloroethane (10 mL) and stirred at
20 ꢀC for 24 h. The resulting solution was diluted in ethyl acetate,
washed with a sodium sulfite solution, water, brine, dried over
magnesium sulfate and concentrated to dryness. The not fully re-
duced resulting residue (2.38 g) was then boiled for 10 min in a 1/2
mixture of water and THF (100 mL) containing sodium sulfite (2 g).
This was diluted in ethyl acetate and water, the organic layer was
washed with water, brine, dried over magnesium sulfate and con-
centrated to dryness. The resulting residue was purified by a chro-
matography over silica gel (cyclohexane/ethyl acetate 2/1 to 0/1). The
main fraction collected (0.38 g) was further purified by a recrystalli-
sation in a mixture of toluene and cyclohexane to yield compound 8
(0.2 g, 9%). The aqueous layer of the last extraction was made acid
with 2 N hydrochloric acid, extracted with ethyl acetate, the organic
layer was washed with water, brine, dried over magnesium sulfate
and concentrated to dryness. The resulting residue (0.37 g) was
recrystallized in toluene to yield compound 9 (0.22 g, 10%).
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2.20.1. Diethyl 3,50-diethoxy-20H-1,30-bipyrazole-4,40-dicarboxylate
(8). Pale yellow solid, mp 153 ꢀC 1H NMR (CDCl3): 1.36 (m, 6H);
1.44 (m, 6H); 9.18 (s(br), 1H); 10.2 (s(br), 1H). 13C NMR (CDCl3; D1
set at 6s): 14.1; 14.3; 14.4; 14.6; 60.3; 60.6; 65.2 (br); 65.8; 88.7;
103.4; 137.3; 140.4 (br); 161.7; 162.1 (br); 162.2; 163.0. HRMS: calcd
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2.20.2. Ethyl
3-ethoxy-1-(4-(ethoxycarbonyl)-5-oxo-2,5-dihydro-
1H-pyrazol-3-yl)-1H-pyrazole-4-carboxylate (9). White solid, mp
159 ꢀC 1H NMR (DMSO-d6): 1.12 (t, 3H, J¼7.0 Hz); 1.25 (t, 3H,
J¼7.0 Hz); 1.34 (t, 3H, J¼7.0 Hz); 4.08 (q, 2H, J¼7.0 Hz); 4.20 (m, 4H);
8.37 (s, 1H); 11.80 (s (br), 1H); 12.80 (s (br), 1H). 13C (DMSO-d6; D1
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2.21. Reduction of 4e into 10 by treatment with hydrochloric
acid
In a flask equipped with a condenser, compound 4e (0.63 g,
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Extensive sublimation into the condenser of iodine or iodinemo-
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noted.
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Part of this work was supported by the Medicen initiative
ꢀ
(Chemical Library Project; grants of the Region Ile de France no I 06-
222/R and I 09-1739/R, which included a fellowship for S.G.).
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