Nitrogen's reactivity of various 3-alkoxypyrazoles

Article abstract of DOI:10.1016/j.tet.2009.01.099

Our current interest in the design of original chemical libraries featuring a pyrazole nucleus led us to focus on the chemistry of the 3-alkoxy-5-methylpyrazoles we have recently made readily available. With in mind the preparation of an array of the less

Full text of DOI:10.1016/j.tet.2009.01.099

Tetrahedron 65 (2009) 2660–2668
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Nitrogen’s reactivity of various 3-alkoxypyrazoles
*
´ ´
Sandrine Guillou, Frederic J. Bonhomme, Yves L. Janin
Institut Pasteur, URA 2128 CNRS-Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Our current interest in the design of original chemical libraries featuring a pyrazole nucleus led us to
focus on the chemistry of the 3-alkoxy-5-methylpyrazoles we have recently made readily available. With
in mind the preparation of an array of the less accessible 1-arylpyrazol-3-ones, the present report de-
scribes the respective nitrogen’s reactivity of various 3-alkoxypyrazoles toward arylation reaction, using
arylboronic acids, as well as alkylation reactions using methyl iodide or benzylbromide. The structure
assignments of the isomers obtained were achieved using long distance 15N–1H NMR correlation mea-
surements or by the recourse to unambiguous synthetic pathways.
Received 21 November 2008
Received in revised form 23 January 2009
Accepted 28 January 2009
Available online 4 February 2009
Keywords:
3-Alkoxypyrazole
N-Arylation
Ó 2009 Elsevier Ltd. All rights reserved.
N-Alkylation
1. Introduction
methylhydrazine without a base.17 A more recent method takes
place via a rearrangement of the reaction product between either
The starting point of this work stems from our simple prepa-
ration of a vast array of 3-alkoxylpyrazoles such as 1.1 With in mind
the preparation of libraries of original chemical entities, we in-
vestigated the chemistry of these 3-alkoxypyrazoles as much of it
has not been studied in the past. This aspect is likely due to the fact
that the starting 3-alkoxypyrazoles are fairly invisible on TLC and
were thus not readily available in the past. The inherent protection
of the oxygen along with a possible decrease of the nucleophilic
character of the neighboring nitrogen of the 3-alkoxypyrazole 1 led
us to focus on the reactivity of its N1 centre. In fact, few reports
describe the preparation of N1-aryl (or alkyl) pyrazol-3-ones iso-
mers. The first work describes a condensation between acylhy-
drazines and acetoacetates in the presence of phosphorus
biacetyldimer18 or the intermediate furanone19,20 and aryldiazo-
nium salts. The latest reported approach requires the polylithiation
of N0-phenylphenylacetohydrazides.21
Thus, from the many 3-alkoxylpyrazoles we could prepare in
a one-step process,1 we sought a simple and general access to N1-
aryl or N1-alkyl pyrazol-3-ones as most of the alternative synthesis
listed above may not lend themselves to easy generalization.
Moreover, we also investigated its combination with C4 arylation
reactions. The two general chemical pathways described in Scheme
1 sum up most of the investigations described in the present work
and in a following paper.22 Path A required the study of nitrogen 1
trichloride.2–5 More recently, the reaction of
b-acylarylhydrazines
with calcium hydride in refluxing dimethylformamide was shown
to lead to 1-arylpyrazol-3-ones and 1,4-diarylpyrazol-3-ones de-
void of a substituent on carbon 5.6 Another type of preparation
requires the oxidation7–9 of pyrazolidin-3-ones, which would, for
instance, result from the addition of arylhydrazines on acrylic es-
ters. Such reaction was actually at the base of early photographic
imaging processes.10 The reaction between arylhydrazines and
diketene also provides an access to this type of compounds.11,12
Another approach requires reactions between either 2,3-dichloro-
propionic acid amide13 or -ethoxyacryloylchloride14,15 and phe-
b
nylhydrazines as well as
a-acetylenic esters with either
phenylhydrazine in the presence of alkoxides16 or, in the last case,
* Corresponding author. Tel.: þ33 06 85 42 49 47; fax: þ33 1 45 68 84 04.
E-mail address: yves.janin@pasteur.fr (Y.L. Janin).
Scheme 1. General pathways investigated.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.099

S. Guillou et al. / Tetrahedron 65 (2009) 2660–2668
2661
arylation to give compounds such as 2. This choice took into ac-
count a previously reported work on the regioselective N-arylation
of 3-alkoxypyrazoles featuring copper-chelating moieties.23 Fol-
lowing this, we envisioned a halogenation/palladium-catalyzed
arylation sequence of carbon 4 of the pyrazole ring to give 3. Path B
undertook to attempt first the halogenation/arylation sequence
leading to 4 followed by the nitrogen arylation to provide com-
pound 3. The last step in this scheme implied a deprotection of
the oxygen on carbon 3 to give pyrazol-3-ones with the general
formula 5.
the arylation of compound such as 1 were usually obtained and
were most often separated by chromatography. The structure
assignment was quite often achieved using long distance 15N–1H
NMR correlation techniques. In the case of N-arylated com-
pounds, it is only for the N1-aryl-5-alkoxypyrazoles that the N1
and N2 signals were observed at a different value (around
ꢀ100 ppm and ꢀ185 ppm in respect to nitromethane). This fact,
along with the uncertainty of signal transmissions to achieve
a
15N resonance of both nitrogens especially in the case of N1-
aryl-3-alkoxypyrazoles made a comparison of the 15N–1H NMR
correlation spectrum of each isomer necessary. Moreover, this
NMR experiment requires the presence of hydrogen atoms in the
vicinity of the one of the two nitrogens to obtain a 15N signal.
Thus, as described below, we also resorted to unequivocal syn-
thesis in some cases or postponed the structural assignment to
a study of the product resulting from further transformation
steps. As depicted in Scheme 2, the arylation of compound 6 or 10
led to the separable pairs of isomers 8a–d/9a–d and 11b/12b. The
N1/N2 arylation ratio of the 3-alkoxypyrazoles 6 and 10, pointed
out a tendency in favor of the ‘N2-arylation products’ (more
correctly, the 1-aryl-5-alkoxypyrazoles). Moreover, an improve-
ment in the reaction yield was seen in the case of the preparation
of compounds 8c and 9c when we switched from dichloro-
methane (30 and less than 10% yield) to boiling acetonitrile (37
and 47% yield, respectively). This effect was not seen in the case of
the pair of compounds 8d and 9d although the very low UV ab-
sorption of compound 8d (either on TLC or with a liquid chro-
matography UV detector) probably lessens its isolated yield. An
even lower N-arylation yield has actually been reported in a pre-
vious case also using 2-methoxyphenylboronic acid.23 We also
undertook the N-arylation of compound 10, which leads to the
allyl-bearing compounds 11b and 12b in order to increase the
array of protecting groups possible in our synthetic schemes. In-
terestingly, we observed that, contrary to the N1-arylation prod-
uct 11b, the N2-arylation compound 12b was not stable upon
storage. It turns out that the allylic side chain undergoes a de-
composition process, which starts with a slow room temperature
Claisen rearrangement. Refluxing compound 12b in toluene
overnight led to a mixture of at least four compounds from which
we could isolate and fully characterize the allyl-bearing product
13 and the hydrated derivative 14 in, respectively, 30 and 12%
yield. Related Claisen rearrangements have actually been reported
to take place at 250 ꢁC for 3-(allyloxy)-1-phenyl-1H-pyrazole47
2. Results and discussion
We choose to study the room temperature N-arylation of the
model compound 6 using arylboronic acids 7a–d and copper
salts.23–30 This turned out to be reliably reproductive and free of the
necessity of the long heating time usually used with other N-ary-
lation methods involving halogenated aryl derivatives and copper
catalysts.31–42 Interestingly, only one report describes an N-aryla-
tion of pyrazoles using a palladium-based catalyst.43
We first used dichloromethane as solvent and as long as the
reaction was left in open air, we obtained N-arylation reactions in
usually 48 h. However, in order to either minimize the evapora-
tion taking place in the course of the reaction or improve the
solubility of the arylboronates used we also used acetonitrile. Few
interesting results came out of this change and are further de-
scribed below. The main point we found out is that water is
detrimental to this reaction but air is needed. Thus, it is necessary
to use reasonably dry solvents and add some molecular sieves if
the copper salt added is hydrated. As we used stoichiometric
amount of copper salts, this did not seem to be necessary on
a small scale as we observed that some N-arylation reactions
proceeded without molecular sieves. However, on a gram scale,
the molecular sieves and air were essential in achieving a trans-
formation in a high yield. Accordingly, the use of the hydrophobic
dichloromethane allowed running the reaction without any par-
ticular precautions. On the other hand, the use of the hygroscopic
acetonitrile required a calcium guard, which has the potential of
lessening a proper oxygenation of the reaction media in reactions
run at room temperature. In the course of this study, we did not
try to lower the proportion of copper salts used although recent
reports seem to point out that a catalytic version of this reaction
is possible.44–46 The two isomeric N-aryl products resulting from
Scheme 2. (i) Cu(OAc)2, pyridine, 4 Å molecular sieves, CH2Cl2 or MeCN, air, 25 ꢁC or reflux; (ii) toluene, reflux.

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S. Guillou et al. / Tetrahedron 65 (2009) 2660–2668
and at 40 ꢁC for 5-(allyloxy)-3-methyl-1-phenyl-1H-pyrazole-4-
carbaldehyde.48
yields from 2-methoxyphenylboronic acid were low and the N-2
arylation product corresponding to compound 23d was often
overlooked because of its lack of UV absorption properties. As an
alternative path we also undertook the iodination of the N1-phe-
nylated product 8a. Thus, using stronger iodination conditions,49
we could prepare the 4-iodo derivative 22a from the N-phenyl
compound 8a in a 90% yield. This experiment, along with the hy-
drolysis of the isopropyl group of compounds 8a and 8b, described
in the following paper,22 fully confirmed our structural assignments
including derivatives stemming from compound 22a.
As depicted in Scheme 4, further insights on the reactivity of
these 3-alkoxypyrazoles were obtained as the arylation of the 5-
phenyl-bearing compound 241 led to 2% of, for once, the least mi-
grating N1-arylation product 25 along with 83% of the N2-arylation
product 26. In the present case, the structural assignment of 26 had
to be made via the acid cleavage of its ethoxy moiety, which gave
the corresponding diaryl-1H-pyrazol-5(4H)-one 27 featuring the
unambiguous methylene 1H and 13C NMR signals. The arylation of
the trifluoromethyl-bearing substrate 28 also led to the N2-aryla-
tion product 29 in a 94% yield. None of the alternative isomer was
detected in the reaction mixture. Its structure assignment was
As shown in Scheme 3, the arylation of the 4-benzyl derivative
15 in dichloromethane gave a far more important 16/17 ratio in
favor of the N-1 arylation products 16a–c. For instance compounds
16a and 16c were obtained in at least 74% yield along with only
traces of compounds 17a and 17c. On a bigger scale, we could
properly isolate less than 10% of the N-2 arylation isomer 17b.
These results first underlie the influence of a substituent on car-
bon 4 of the pyrazole in governing the ratio of N1 or N2 arylation of
3-alkoxypyrazoles along with a somewhat smaller effect of the
arylboronate considered. The 1H–15N long distance correlation
experiments on compound 16a were of small help in its structural
assignment (only one 15N NMR signal is visible). Accordingly, as
described in the experimental part, the corresponding minor iso-
mer 17a was prepared unambiguously in a 37% yield from ethyl 2-
benzyl-3-oxobutanoate and phenylhydrazine hydrochloride, using
our improved procedure.1
From compound 6, good to excellent yields of the 4-bromo or
the 4-iodo derivatives 18 and 19 were obtained using simple ha-
logenation methods. The occurrence of so far unidentified side
products in the course of the preparation of compound 18 forced us
to purify it by chromatography over silica gel. On the other hand,
the preparation of the iodinated derivative 19 only required a fil-
tration and drying. The N-arylation of compounds 18 and 19, turned
out to lead to a large proportion of N-1 arylation products whatever
the solvent used (dichloromethane or acetonitrile). Again, the
Scheme 4. (i) Cu(OAc)2, pyridine, 4 Å molecular sieves, CH2Cl2, air, 25 ꢁC; (ii) 33% HBr/
AcOH, 110 ꢁC; (iii) NaH, DMF, MeI or BnBr, 25 ꢁC; (iv) BnBr, K2CO3, MeCN, MW, 140 ꢁC,
7 min.
Scheme 3. (i) Cu(OAc)2, pyridine, 4 Å molecular sieves, CH2Cl2, air, 25 ꢁC; (ii) Br2,
NaHCO3, EtOH, 25 ꢁC; (iii) I2, NaI, K2CO3, EtOH/H2O, 25 ꢁC.

S. Guillou et al. / Tetrahedron 65 (2009) 2660–2668
2663
made by comparison with the previously reported data50 as well as,
4. Experimental section
4.1. General methods
after the acid-assisted cleavage of the ethoxy moiety, a comparison
of the spectra of the resulting pyrazole-5-one 30 with un-
ambiguous data.50 Thus, for these two cases a preparation of the
alternative isomers remains a challenge.
A Biotage Initiator 2 microwave oven was used for reactions
requiring microwaves irradiations. 1H NMR and 13C NMR spectra
were recorded on a Bruker Avance 400 spectrometers at 400 MHz
and 100 MHz, respectively. Unless otherwise noted, CDCl3 was the
We also investigated the methylation of some of these 3-
alkoxypyrazoles. The 1H NMR monitoring of the methylation of
compound 6 or its iodinated derivative 19 using sodium hydride in
DMF and methyl iodide showed a 10:3 or 17:3 ratio in favor of the
N1-methylation product of compound 6 or 19, respectively. This
ratio improvement actually follows what has been observed for the
N-arylation reactions ratio of compound 6 and its 4-iodinated de-
rivative 19 described above. The notable lack of UV-absorbance of
the N2-methylation products 32a,b made them fairly hard to iso-
late. Moreover the volatility of the methylation product 31a prob-
ably explains the low isolated yield reported as an optimization of
the workup procedure was not undertaken. The structure assign-
ment of these methylation products could not be achieved with the
15N–1H correlation data as both nitrogens correlate with the methyl
residues. On the other hand, 13C–1H long distance correlations
allowed unequivocal structural assignments. The N-methyl resi-
dues of 31a and 32a,1 respectively, correlate with the carbon
bearing the methyl side chain or the one bearing the isopropyloxy
side chain. The same observation was made for the pair of com-
pounds 31b–32b.
solvent used. Shifts (d) are given in parts per million with respect to
the TMS signal and coupling constants (J) are given in hertz. Col-
umn chromatography were performed either Merck silica gel 60
(0.035–0.070 mm) or neutral alumina containing a suitable pro-
portion of water, using a solvent pump operating at pressure be-
tween 2 and 7 bar (25–50 mL/min) and an automated collecting
system driven by a UV detector set to 254 nm unless stated oth-
erwise (i.e., if ethyl acetate was used then it would be set to
280 nm). Sample deposition was always 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 reso-
lution mass spectra were obtained on an Agilent 1100 series LC/
MSD system using an atmospheric electrospray ionization system
and the high resolution mass spectroscopy spectra (HRMS) were
obtained using a Waters Micromass Q-Tof with an electrospray ion
source.
Benzylation of 6 also proceeded with a preference for the N1-
benzylation product 33, which was obtained in a 54% yield. As
described in the experimental part, the structure assignment of
compounds 33 and 34 were further established by the synthesis of
34 from isopropylacetoacetate and benzylhydrazine hydrochloride
under our reaction conditions.1 Moreover, we could also prepare
substantial amount (53%) of the pyrazolium 35 when heating the
reaction in a microwave-reactor.
4.2. General procedure for the N-arylation of 3-
alkoxypyrazoles
The corresponding alkoxypyrazole (1.45 mmol), arylboronic
acid (1.60 mmol), pyridine (3 mmol, dried over 4 Å molecular
sieves), 4 Å molecular sieves (0.6 g), and copper(II) acetate hydrate
(2.2 mmol) were dispersed in dichloromethane (20 mL). The re-
action was stirred in open air for 48 h. After concentration to
dryness, the residue was absorbed on a small amount of silica gel
and purified as described below. An alternative method was to
run the reaction in boiling acetonitrile (20 mL, dried over 4 Å
molecular sieves) for 12 h using the same reagents, as long as the
reaction media was protected from moisture by a calcium chloride
guard.
3. Conclusions
The originality of the chemical libraries that can be generated
from this work is due to the unique fact: the 3-alkoxypyrazoles
were previously tedious to prepare and this somehow hampered
the study of their chemistry. From the use of a stoichiometric re-
action protocol between alkylacetoacetates and hydrazine hydro-
chloride, the corresponding alkoxypyrazoles previously considered
as a side compound were quite often obtained in sizable 50% yield.1
From this, further chemical transformations insured accesses to
fully original chemical entities as the presence of an oxygen pro-
tecting group substantially altered the pyrazole reactivity.
In this work, depending on the substituents of the 3-alkoxy-
pyrazole ring system, a preference for the otherwise not so easy to
attain 1-aryl or 1-alkyl 3-alkoxypyrazoles was observed. This is of
interest as a brute statistical survey of all the pyrazolone-bearing
substances ever reported up to 2008 leads to the following facts. As
much as 76,790 compounds featuring this ring system were actu-
ally reported. However, most of these compounds (66,103) are N1-
substituted pyazol-5-ones and ‘only’ 4563 are N1-substituted
pyrazol-3-ones. This bias is very much due to the regiochemistry of
any Knorr reactions between the vast array of available arylhy-
drazines and acetoacetates.51,52 Interestingly, small amount of the
alternative aryl isomers have been reported in some Knorr reaction,
as mentioned recently.53 We hope that, amongst the many possi-
bilities offered by our results, this work will help in the preparation
and evaluation of 1-substituted pyrazol-3-ones featuring properly
designed substituents in regards with the considered medicinal
chemistry field. Moreover, a combination of these transformations
with the C4 arylation chemistry described in the following report,22
can lead to even more original chemical entities with potential
biological interest.
Isomers 8a and 9a: The reaction was run in dichloromethane;
a chromatography over silica gel (cyclohexane–ethyl acetate 9:1)
led to 39% of compound 8a followed by 53% of compound 9a.
4.2.1. 3-Isopropoxy-5-methyl-1-phenyl-1H-pyrazole 8a
Obtained as an oil. 1H (CDCl3): 1.39 (d, 6H, J¼6.1 Hz); 2.31 (s,
3H); 4.85 (sept, 1H, J¼6.1 Hz); 5.65 (s, 1H); 7.28–7.46 (m, 5H). 13C
(CDCl3): 13.2; 22.6; 71.7; 94.1; 124.8; 127.0; 129.3; 140.4 (two sig-
nals?); 163.0. 15N (CDCl3): ꢀ184 (CH3, H-4, Ar). HRMS: Calcd for
C13H16N2OþH: 217.1341. Found: m/z, 217.1372.
4.2.2. 5-Isopropoxy-3-methyl-1-phenyl-1H-pyrazole 9a
Obtained as an oil. 1H (CDCl3): 1.40 (d, 6H, J¼6.1 Hz); 2.31 (s,
3H); 4.45 (sept, 1H, J¼6.1 Hz); 5.48 (s, 1H); 7.21–7.73 (m, 5H). 13C
(CDCl3): 14.9; 22.3; 76.0; 87.4; 122.3; 126.0; 129.0; 139.4; 149.1;
154.4. 15N (CDCl3): ꢀ99 (CH3); ꢀ185 (H-4, Ar). HRMS: Calcd for
C13H16N2OþH: 217.1341. Found: m/z, 217.1381.
Isomers 8b and 9b: A chromatography over silica gel (cyclo-
hexane–ethyl acetate 98:2) led to 20% of compound 8b followed by
37% of compound 9b.
4.2.3. 1-(4-Chlorophenyl)-3-isopropoxy-5-methyl-1H-pyrazole 8b
Obtained as an oil. 1H (CDCl3): 1.38 (d, 6H, J¼6.1 Hz); 2.29 (s,
3H); 4.83 (sept, 1H, J¼6.1 Hz); 5.65 (s, 1H); 7.35–7.40 (m, 4H). 13C
(CDCl3): 12.9; 22.1; 71.4; 94.3; 125.3; 129.0; 132.1; 138.6; 140.0;
162.8. 15N (CDCl3): ꢀ185 (CH3, H-4, Ar). HRMS: Calcd for
C13H15N2O35ClþH: 251.0951. Found: m/z, 251.0967.

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S. Guillou et al. / Tetrahedron 65 (2009) 2660–2668
4.2.4. 1-(4-Chlorophenyl)-5-isopropoxy-3-methyl-1H-pyrazole 9b
Obtained as an oil. 1H (CDCl3): 1.38 (d, 6H, J¼6.1 Hz); 2.27 (s,
3H); 4.42 (sept, 1H, J¼6.1 Hz); 5.45 (s, 1H); 7.28–7.37 (m, 2H); 7.67–
7.71 (m, 2H). 13C (CDCl3): 14.3; 21.9; 75.9; 87.2; 123.0; 128.8; 131.2;
137.3; 149.1; 154.1. 15N (CDCl3): ꢀ100 (CH3); ꢀ184 (H-4 and Ar).
HRMS: Calcd for C13H15N2O35ClþH: 251.0903. Found: m/z, 251.0951.
Isomers 8c and 9c: The reaction was run in boiling acetonitrile. A
chromatography over silica gel (cyclohexane–ethyl acetate 4:1) led
to 37% of compound 8c and a fraction containing compound 9c and
unidentified material. This second fraction was further purified by
a second chromatography (cyclohexane–ethyl acetate 4:1) to give
40% of compound 9c.
4.2.10. 5-(Allyloxy)-1-(4-chlorophenyl)-3-methyl-1H-pyrazole 12b
Obtained as an oil. 1H (CDCl3): 2.29 (s, 3H); 4.65 (m, 2H); 5.33–
5.48 (m, 2H); 5.51 (s, 1H); 6.04 (m, 1H); 7.28 (m, 2H); 7.68 (m, 2H).
13C (CDCl3): 14.5; 69.4; 87.1; 118.6; 122.7; 128.8; 131.0; 131.7; 137.4;
149.0; 154.5. 15N (CDCl3): ꢀ100 (CH3); ꢀ185 (H-4 and ArCl). HRMS:
Calcd for C13H13N2O35ClþH: 249.0795. Found: m/z, 249.0821.
Isomers 16a and 17a: The reaction was run in dichloromethane
and a chromatography over silica gel (cyclohexane–dichloro-
methane 85:15) led to 75% of compound 16a followed by only
traces of compound 17a.
4.2.11. 4-Benzyl-3-ethoxy-1-phenyl-5-methyl-1H-pyrazole 16a
Obtained as a white solid. 1H (CDCl3): 1.22 (t, 3H, J¼7.0 Hz); 2.17
(s, 3H); 3.81 (s, 2H); 3.86 (q, 2H, J¼7.0 Hz); 7.21–7.74 (m, 10H). 13C
(CDCl3): 13.5; 15.6; 28.8; 70.9; 105.0; 122.3; 126.4; 125.5; 128.5;
128.8; 129.3; 151.7. 15N (CDCl3): ꢀ185 (CH3). HRMS: Calcd for
C19H20N2OþH: 293.1654. Found: m/z, 293.1684.
4.2.5. 3-Isopropoxy-1-(3-methoxyphenyl)-5-methyl-1H-
pyrazole 8c
Obtained as an oil. 1H (CDCl3): 1.39 (d, 6H, J¼6.1 Hz); 2.31 (s,
3H); 3.85 (s, 3H); 4.85 (sept, 1H, J¼6.1 Hz); 5.65 (s, 1H); 6.85–7.35
(m, 4H). 13C (CDCl3): 13.0; 22.2; 55.4; 71.4; 93.8; 110.2; 112.5; 116.5;
129.5; 140.0; 141.1; 160.1; 162.6. 15N (CDCl3): ꢀ182 (CH3, H-4).
HRMS: Calcd for C14H18N2O2þH: 247.1447. Found: m/z, 247.1468.
4.2.12. 4-Benzyl-5-ethoxy-1-phenyl-3-methyl-1H-pyrazole 17a
As this compound was not be isolated in sizable quantity in the
course of the arylation of compound 15, it was prepared in 37%
yield by using our reported method.1 Thus, ethyl-2-benzylaceto-
acetate (1 g, 4.54 mmol) and phenylhydrazine hydrochloride
(0.65 g, 4.54 mmol) were refluxed in ethanol (50 mL) for 4 h. This
was then concentrated to dryness and the residue dispersed in
water made basic with solid sodium hydrogenocarbonate, and
extracted with dichloromethane. The organic phase was washed
with 1 N sodium hydrogenocarbonate, dried over sodium sulfate
and concentrated to dryness. The resulting residue was further
purified by a chromatography over silica gel (cyclohexane–ethyl
acetate 4:1) to yield compound 17a as a white solid (0.5 g; 37%). 1H
(CDCl3): 1.22 (t, 3H, J¼7.0 Hz); 2.20 (s, 3H); 3.84 (s, 2H); 3.88 (q, 2H,
J¼7.0 Hz); 7.23–7.28 (m, 6H); 7.30–7.47 (m, 2H); 7.76–7.78 (d, 2H).
13C (CDCl3): 13.5; 15.6; 28.9; 70.9; 105.0; 122.3; 126.4; 128.7; 128.8;
129.3; 139.5; 140.8; 148.8; 151.7. 15N (CDCl3): ꢀ96 (CH3); ꢀ169 (Ar).
HRMS: Calcd for C19H20N2OþH: 293.1654. Found: m/z, 293.1684.
Isomers 16b and 17b: The reaction was run in dichloromethane
and a chromatography over silica gel (cyclohexane–ethyl acetate
98:2) led to 66% of compound 16b followed by less than 10% of
compound 17b as it still contained traces of unidentified compounds
and had to be purified again by another chromatography over silica gel.
4.2.6. 5-Isopropoxy-1-(3-methoxyphenyl)-3-methyl-1H-
pyrazole 9c
Obtained as an oil. 1H (CDCl3): 1.41 (d, 6H, J¼6.1 Hz); 2.29 (s,
3H); 3.86 (s, 3H); 4.45 (sept, 1H, J¼6.1 Hz); 5.48 (s, 1H); 6.80 (m,
1H); 7.32 (m, 3H). 13C (CDCl3): 14.5; 21.9; 55.3; 75.6; 87.1; 107.4;
111.8; 114.1; 129.3; 140.1; 148.7; 154.1; 159.9. 15N (CDCl3): ꢀ100
(CH3); ꢀ182 (H-4, ArH). HRMS: Calcd for C14H18N2O2þH: 247.1447.
Found: m/z, 247.1465.
Isomers 8d and 9d: The reaction was run in boiling acetonitrile.
A chromatography over silica gel (cyclohexane–ethyl acetate 4:1)
led to 15% of compound 8d and a fraction containing compound 9d
and some starting material. This second fraction was further puri-
fied by a second chromatography (cyclohexane–ethyl acetate 4/1)
to give 11% of compound 9d.
4.2.7. 3-Isopropoxy-1-(2-methoxyphenyl)-5-methyl-1H-
pyrazole 8d
Obtained as an oil. 1H (CDCl3): 1.36 (d, 6H, J¼6.1 Hz); 2.07 (s,
3H); 3.80 (s, 3H); 4.84 (sept, 1H, J¼6.1 Hz); 5.61 (s, 1H); 7.05 (m,
2H); 7.35 (m, 2H). 13C (CDCl3): 12.0; 22.6; 56.2; 71.4; 92.2; 112.6;
121.3; 129.2; 129.9; 130.0; 142.5; 155.3; 163.0. 15N (CDCl3): ꢀ192
(CH3, H-4). HRMS: Calcd for C14H18N2O2þH: 247.1447. Found: m/z,
247.1459.
4.2.13. 4-Benzyl-1-(4-chlorophenyl)-3-ethoxy-5-methyl-1H-
pyrazole 16b
Obtained as a wax. 1H (CDCl3): 1.42 (t, 3H, J¼7.0 Hz); 2.21 (s, 3H);
3.76 (s, 2H); 4.34 (q, 2H, J¼7.0 Hz); 7.21–7.42 (m, 9H). 13C (CDCl3):
11.4; 14.9; 28.1; 64.3; 105.2; 125.4; 125.8; 128.2; 128.3; 129.0;
4.2.8. 5-Isopropoxy-1-(2-methoxyphenyl)-5-methyl-1H-
pyrazole 9d
Obtained as a solid. 1H (CDCl3): 1.28 (d, 6H, J¼6.1 Hz); 2.28 (s,
3H); 3.78 (s, 3H); 4.37 (sept, 1H, J¼6.1 Hz); 5.44 (s, 1H); 6.99 (m,
2H); 7.32 (m, 2H). 13C (CDCl3): 14.7; 21.9; 55.6; 75.0; 85.6; 111.9;
120.4; 127.2; 128.9; 129.5; 148.7; 154.8; 154.9. 15N (CDCl3): ꢀ95
(CH3); ꢀ191 (H-4, ArH). HRMS: Calcd for C14H18N2O2þH: 247.1447.
Found: m/z, 247.1469.
131.9; 137.4; 138.8; 141.0; 162.2. 15N (CDCl3): ꢀ187 (CH3 and ArCl).
35
HRMS: Calcd for C19
H
ClN2OþH: 327.1264. Found: m/z, 327.1244.
19
4.2.14. 4-Benzyl-1-(4-chlorophenyl)-5-ethoxy-3-methyl-1H-
pyrazole 17b
Obtained as an oil. 1H (CDCl3): 1.21 (t, 3H, J¼7.0 Hz); 2.15 (s, 3H);
3.81 (s, 2H); 3.87 (q, 2H, J¼7.0 Hz); 7.15–7.71 (m, 9H). 13C (CDCl3):
13.1; 15.2; 28.5; 70.6; 104.8; 122.9; 126.1; 128.1; 128.4; 129.0; 131.4;
Isomers 11b and 12b: A chromatography over silica gel (cyclo-
hexane–ethyl acetate 99:1) led to 31% of compound 11b followed
by 42% of compound 12b when the reaction was run in acetonitrile
and to 39% of compound 11b followed by 28% of compound 12b
when it was run in dichloromethane.
137.6; 140.2; 148.9; 151.4. 15N (CDCl3): ꢀ100 (CH3); ꢀ180 (ArCl).
35
HRMS: Calcd for C19
H
ClN2OþH: 327.1264. Found: m/z, 327.1258.
19
Isomers 16c and 17c: The reaction was run in dichloromethane
and a chromatography over silica gel (cyclohexane–ethyl acetate
98:2) led to 75% of compound 16c followed by only traces of
compound 17c.
4.2.9. 3-(Allyloxy)-1-(4-chlorophenyl)-5-methyl-1H-pyrazole 11b
Obtained as an oil. 1H (CDCl3): 2.30 (s, 3H); 4.73 (m, 2H); 5.27 (d,
1H, J¼9.0 Hz); 5.41 (d, 1H, J¼15.0 Hz); 5.70 (s, 1H); 6.09 (m, 1H);
7.36–7.42 (m, 4H). 13C (CDCl3): 12.9; 69.4; 93.7; 117.6; 125.4; 129.1;
132.3; 133.4; 138.5; 140.4; 163.2. 15N (CDCl3): ꢀ180 (CH3 and H-4).
HRMS: Calcd for C13H13N2O35ClþH: 249.0795. Found: m/z,
249.0815.
4.2.15. 4-Benzyl-3-ethoxy-1-(3-methoxyphenyl)-5-methyl-1H-
pyrazole 16c
Obtained as an oil. 1H (CDCl3): 1.44 (t, 3H, J¼7.0 Hz); 2.23 (s, 3H);
3.79 (s, 2H); 3.86 (s, 3H); 4.38 (q, 2H, J¼7.0 Hz); 6.86–7.37 (m, 9H).

S. Guillou et al. / Tetrahedron 65 (2009) 2660–2668
2665
13C (CDCl3): 11.5; 15.0; 28.1; 55.4; 64.2; 104.7; 110.3; 112.3; 116.7;
125.8; 128.2; 128.3; 129.5; 137.5; 141.2; 141.3; 160.1; 162.0. 15N
(CDCl3): ꢀ186 (CH3). HRMS: Calcd for C20H22N2O2þH: 323.1760.
Found: m/z, 323.1751.
Isomers 20a and 21a: The reaction was run either in dichloro-
methane or in acetonitrile; a chromatography over silica gel (cy-
clohexane–dichloromethane 4:6) led to 75% of compound 20a
followed by 14% of compound 21a in both cases.
72.4; 126.6; 127.2; 129.1; 140.1; 141.3;162.2.15N (CDCl3): ꢀ182 (CH3).
HRMS: Calcd for C13H15IN2OþH: 343.0307. Found: m/z, 343.0323.
4.2.22. 4-Iodo-5-isopropoxy-3-methyl-1-phenyl-1H-pyrazole 23a
Obtained as an oil. 1H (CDCl3): 1.21 (d, 6H, J¼6.2 Hz); 2.29 (s,
3H); 4.53 (sept, 1H, J¼6.2 Hz); 7.31 (m, 1H); 7.43 (m, 2H); 7.65 (m,
2H). 13C (CDCl3): 14.9; 22.3; 50.7; 78.6; 122.7; 126.8; 128.9; 138.7;
150.4; 152.6. 15N (CDCl3): ꢀ90 (CH3); ꢀ170 (Ar). HRMS: Calcd for
C13H15IN2OþH: 343.0307. Found: m/z, 343.0321.
4.2.16. 4-Bromo-3-isopropoxy-5-methyl-1-phenyl-1H-
pyrazole 20a
Isomers 22b and 23b: The reaction was run in dichloromethane;
a chromatography over silica gel (cyclohexane–dichloromethane
7:3) led to 69% of compound 22b followed by 15% of compound
23b.
Obtained as an oil. 1H (CDCl3): 1.42 (d, 6H, J¼6.2 Hz); 2.31 (s,
3H); 5.00 (sept, 1H, J¼6.2 Hz); 7.35–7.48 (m, 5H). 13C (CDCl3): 12.4;
22.6; 72.7; 83.3; 124.8; 127.6; 129.2; 138.7; 140.3; 159.7. 15N
79
(CDCl3): ꢀ182 (CH3, Ar). HRMS: Calcd for C13
H
BrN2OþH:
4.2.23. 4-Iodo-1-(4-chlorophenyl)-3-isopropoxy-5-methyl-1H-
15
295.0446. Found: m/z, 295.0471.
pyrazole 22b
Obtained as
a
solid. Mp¼96 ꢁC. 1H (CDCl3): 1.41 (d, 6H,
4.2.17. 4-Bromo-5-isopropoxy-3-methyl-1-phenyl-1H-
J¼6.2 Hz); 2.33 (s, 3H); 4.95 (sept, 1H, J¼6.2 Hz); 7.36 (m, 2H); 7.43
(m, 2H). 13C (CDCl3): 13.6; 22.1; 51.4; 72.5; 125.5; 129.2; 132.8;
138.7; 141.4; 162.3. 15N (CDCl3): ꢀ184 (CH3 and Ar). HRMS: Calcd
for C13H14N2OI35ClþH: 376.9918. Found: m/z, 376.9940.
pyrazole 21a
Obtained as an oil. 1H (CDCl3): 1.24 (d, 6H, J¼6.1 Hz); 2.29 (s,
3H); 4.62 (sept, 1H, J¼6.1 Hz); 7.28 (m, 1H); 7.41 (m, 2H); 7.66 (m,
1H). 13C (CDCl3): 13.1; 22.3; 78.1; 82.8; 122.6; 126.7; 128.8; 138.7;
147.4; 149.5. 15N (CDCl3): ꢀ95 (CH3); ꢀ175 (Ar). HRMS: Calcd for
4.2.24. 4-Iodo-1-(4-chlorophenyl)-5-isopropoxy-3-methyl-1H-
pyrazole 23b
79
C13
H
BrN2OþH: 295.0446. Found: m/z, 295.0472.
15
Isomers 20b and 21b: The reaction was run in dichloromethane;
Obtained as an oil. 1H (CDCl3): 1.22 (d, 6H, J¼6.2 Hz); 2.28 (s,
3H); 4.59 (sept, 1H, J¼6.2 Hz); 7.41 (m, 2H); 7.63 (m, 2H). 13C
(CDCl3): 14.9; 22.4; 50.7; 78.8; 123.9; 129.3; 132.2; 137.2; 150.8;
152.6. 15N (CDCl3): ꢀ92 (CH3); ꢀ174 (Ar). HRMS: Calcd for
C13H14N2OI35ClþH: 376.9918. Found: m/z, 376.9928.
a chromatography over silica gel (cyclohexane–dichloromethane
7:3) led to 70% of compound 20b followed by 17% of compound 21b
still containing 5% of 20b, which could be removed by a second
chromatography.
Isomers 22c and 23c: The reaction was run in dichloromethane;
a chromatography over silica gel (cyclohexane–dichloromethane
1:1) led to 63% of compound 22c and 13% of compound 23c.
4.2.18. 4-Bromo-1-(4-chlorophenyl)-3-isopropoxy-5-methyl-1H-
pyrazole 20b
Obtained as a white solid. Mp¼75 ꢁC. 1H (CDCl3): 1.41 (d, 6H,
J¼6.1 Hz); 2.31 (s, 3H); 4.97 (sept, 1H, J¼6.1 Hz); 7.37 (m, 2H); 7.42
(m, 2H). 13C (CDCl3): 12.4; 22.5; 72.8; 83.9; 125.7; 129.6; 133.1;
4.2.25. 4-Iodo-1-(3-methoxyphenyl)-3-isopropoxy-5-methyl-1H-
pyrazole 22c
138.7; 138.8; 159.9. 15N (CDCl3): ꢀ185 (CH3 and Ar). HRMS: Calcd
Obtained as an oil. 1H (CDCl3): 1.42 (d, 6H, J¼6.1 Hz); 2.35 (s,
3H); 3.84 (s, 3H); 4.99 (sept, 1H, J¼6.1 Hz); 6.88 (m, 1H); 6.98 (m,
2H); 7.34 (m, 1H). 13C (CDCl3): 14.1; 22.6; 51.3; 55.9; 72.7; 109.4;
113.3; 117.1; 129.3; 141.5; 141.8; 160.5; 162.4. 15N (CDCl3): ꢀ190
(CH3-5, Ar). HRMS: Calcd for C14H17IN2O2þH: 373.0413. Found: m/z,
373.0437.
35
for C13
H
Cl79BrN2OþH: 329.0056. Found: m/z, 329.0083.
14
4.2.19. 4-Bromo-1-(4-chlorophenyl)-5-isopropoxy-3-methyl-1H-
pyrazole 21b
Obtained as an oil. 1H (CDCl3): 1.25 (d, 6H, J¼6.1 Hz); 2.26 (s,
3H); 4.68 (sept, 1H, J¼6.1 Hz); 7.41 (m, 1H); 7.63 (m, 2H); 7.66 (m,
1H). 13C (CDCl3): 13.6; 22.8; 72.8; 78.5; 123.8; 129.4; 132.5; 137.7;
4.2.26. 4-Iodo-1-(3-methoxyphenyl)-5-isopropoxy-3-methyl-1H-
pyrazole 23c
148.2; 149.9. 15N (CDCl3): ꢀ96 (CH3); ꢀ178 (Ar). HRMS: Calcd for
35
C13
H
Cl79BrN2OþH: 329.0056. Found: m/z, 329.0079.
Obtained as an oil. 1H (CDCl3): 1.22 (d, 6H, J¼6.1 Hz); 2.29 (s,
3H); 3.85 (s, 3H); 4.54 (sept, 1H, J¼6.1 Hz); 6.86 (m, 1H); 7.26 (m,
3H). 13C (CDCl3): 15.3; 22.7; 51.4; 55.8; 78.9; 108.4; 113.4; 115.2;
130.0; 140.1; 150.8; 153.0; 160.3. 15N (CDCl3): ꢀ95 (CH3-5); ꢀ168
(Ar). HRMS: Calcd for C14H17IN2O2þH: 373.0413. Found: m/z,
373.0432.
14
Isomers 20d and 21d: The reaction was run in dichloromethane;
a chromatography over silica gel (cyclohexane–dichloromethane
1:1) led to 21% of compound 20d and no compound 21a could be
isolated.
4.2.20. 4-Bromo-1-(2-methoxyphenyl)-3-isopropoxy-5-methyl-
1H-pyrazole 20d
Isomers 22d and 23d: The reaction was run in dichloromethane;
a chromatography over silica gel (cyclohexane–dichloromethane
1:1) led to 25% of compound 22d and no isomeric compound 23d
could be isolated.
Obtained as a white solid. Mp¼80 ꢁC. 1H (CDCl3): 1.39 (d, 6H,
J¼6.1 Hz); 2.08 (s, 3H); 3.97 (s, 3H); 4.95 (sept, 1H, J¼6.1 Hz); 7.05
(m, 2H); 7.39 (m, 2H). 13C (CDCl3): 10.9; 22.2; 55.8; 72.1; 81.1; 112.2;
121.0; 128.7; 129.2; 130.0; 140.4; 154.7; 159.2. 15N (CDCl3): ꢀ192
4.2.27. 4-Iodo-1-(2-methoxyphenyl)-3-isopropoxy-5-methyl-1H-
pyrazole 22d
79
(CH3-5). HRMS: Calcd for C14
325.0564.
H
BrN2O2þH: 325.0552. Found: m/z,
17
Obtained as a solid. Mp¼95 ꢁC. 1H (CDCl3): 1.39 (d, 6H,
J¼6.2 Hz); 2.11 (s, 3H); 3.82 (s, 3H); 4.94 (sept, 1H, J¼6.2 Hz); 7.04
(m, 2H); 7.30 (m, 1H); 7.39 (m, 1H). 13C (CDCl3): 12.4; 22.2; 48.5;
55.8; 72.1; 112.2; 120.9; 128.9; 129.2; 130.0; 143.5; 154.7; 162.1. 15N
(CDCl3): ꢀ190 (CH3-5). HRMS: Calcd for C14H17IN2O2þH: 373.0413.
Found: m/z, 373.0434.
Isomers 22a and 23a: The reaction was run in dichloromethane;
a chromatography over silica gel (cyclohexane–dichloromethane
3:7) led to 70% of compound 22a followed by 11% of compound 23a
still containing traces (7%) of 22a.
4.2.21. 4-Iodo-3-isopropoxy-5-methyl-1-phenyl-1H-pyrazole 22a
Obtained as an oil. 1H (CDCl3): 1.41 (d, 6H, J¼6.1 Hz); 2.34 (s, 3H);
4.97 (sept, 1H, J¼6.1 Hz); 7.39 (m, 5H). 13C (CDCl3): 13.5; 22.2; 50.8;
Isomers 25 and 26: The reaction was run in dichloromethane;
a chromatography over silica gel (cyclohexane–dichloromethane
4:1) led to 83% of compound 26 followed by 2% of compound 25.

2666
S. Guillou et al. / Tetrahedron 65 (2009) 2660–2668
4.2.28. 1-(4-Chlorophenyl)-3-ethoxy-5-phenyl-1H-pyrazole 25
Obtained as a colorless solid in a 2% yield. Mp¼72 ꢁC. 1H (CDCl3):
1.46 (t, 3H, J¼7.1 Hz); 4.32 (q, 2H, J¼7.1 Hz); 5.97 (s, 1H); 7.24 (m,
5H); 7.35 (m, 3H). 13C (CDCl3): 14.9; 64.7; 94.3; 125.8; 128.6 (two
4.2.34. 4-Iodo-3-isopropoxy-5-methyl-1H-pyrazole 19
Compound (6.52 g, 0.046 mol), sodium iodide (7.68 g,
1
0.051 mol), and potassium carbonate (16 g, 0.116 mol) were dis-
solved in water (250 mL) and ethanol (60 mL). To this was added
iodine (15.3 g, 0.06 mol). The resulting suspension was stirred for
90 min, decolorized (if necessary) with sodium bisulfite, and di-
luted with brine (1 L). The resulting precipitate was filtered,
washed with water, and dried under vacuum while heating at 80 ꢁC
in a large Petri dish in order to sublimate the iodoform also oc-
curring in this reaction to yield compound 19 as an yellow solid
(10.2 g, 82%). Mp¼98–100 ꢁC. 1H (CDCl3): 1.38 (d, 6H, J¼6.3 Hz);
2.25 (s, 3H); 4.84 (sept, 1H, J¼6.3 Hz). 13C (CDCl3): 12.6; 22.5; 48.3;
73.8; 142.9; 162.9. HRMS: Calcd for C7H11IN2OþH: 266.9994.
Found: m/z, 267.0023.
Claisen rearrangement of 12b, isolation of compounds 13 and 14:
Compound 12b (0.16 g, 0.64 mmol) was heated to reflux in toluene
(30 ml) overnight. The resulting solution was concentrated to
dryness and purified by a chromatography over silica gel (cyclo-
hexane–ethyl acetate 95:5) to yield, in this order, compound 13 and
compound 14 as described below.
signals); 128.7; 128.9; 130.5; 132.1; 138.7; 144.2; 163.7. 15N (CDCl3):
35
ꢀ188 (H-4 and Ar). HRMS: Calcd for C17
H
ClN2OþH: 299.0951.
15
Found: m/z, 299.0969.
4.2.29. 1-(4-Chlorophenyl)-5-ethoxy-3-phenyl-1H-pyrazole 26
Obtained as a white solid in an 83% yield. Mp¼90 ꢁC. 1H (CDCl3):
1.51 (t, 3H, J¼7.1 Hz); 4.26 (q, 2H, J¼7.1 Hz); 6.01 (s, 1H); 7.37 (m,
1H); 7.42 (m, 4H); 7.83 (m, 4H). 13C (CDCl3): 14.6; 68.2; 83.9; 122.9;
125.5; 128.2; 128.5; 128.9; 131.4; 133.3; 137.6; 150.8; 155.4. 15N
35
(CDCl3): ꢀ184 (H-4 and Ar). HRMS: Calcd for C17
H
ClN2OþH:
15
299.0951. Found: m/z, 299.0974.
4.2.30. 1-(4-Chlorophenyl)-3-phenyl-1H-pyrazol-5(4H)-one 27
Structural characterization of compound 26 by its hydrolysis:
Compound 26 (0.032 g, 0.1 mmol) and 33% hydrogen bromide in
acetic acid (1 mL) were heated in a sealed flask at 110 ꢁC for 36 h.
The solution was dispersed in water and the precipitate extracted
with dichloromethane. The organic phase was washed with water,
dried over sodium sulfate, and concentrated to dryness to yield
compound 27 (0.025 g, 86%) as a solid. Mp¼163 ꢁC. 1H (CDCl3): 3.86
(s, 2H); 7.40 (m, 2H); 7.48 (m, 2H); 7.78 (m, 2H); 7.99 (m, 2H). 13C
4.2.35. 4-Allyl-2-(4-chlorophenyl)-5-methyl-1H-pyrazol-3(2H)-
one 13
Obtained (0.05 g, 31%) as an oil. 1H (CDCl3): 1.79 (s, 3H); 2.77 (q,
1H, J¼6.5 and 13.8 Hz); 3.50 (q, 1H, J¼7.5 and 13.8 Hz); 4.98 (q, 1H,
J¼2.1 and 9.5 Hz); 5.18 (m, 2H); 7.29 (m, 2H); 7.75 (m, 2H). 13C
(CDCl3): 39.6; 120.0; 126.0; 128.9; 129.0; 130.4; 130.7; 130.9; 154.9;
35
170.1. HRMS: Calcd for C15
271.0657.
H
ClN2OþH: 271.0638. Found: m/z,
(CDCl3): 14.9; 31.7; 59.1; 120.1; 121.4; 129.1; 129.3; 130.9; 135.6;
11
35
159.8; 171.8. HRMS: Calcd for C13
m/z, 249.0812.
H
ClN2OþH: 249.0795. Found:
13
4.2.31. 5-Ethoxy-1-phenyl-3-(trifluoromethyl)-1H-pyrazole 29
Obtained as an oil in a 94% yield after a chromatography over
silica gel (cyclohexane–dichloromethane 7:3). 1H (CDCl3): 1.48 (t,
3H, J¼7.1 Hz); 4.23 (q, 2H, J¼7.1 Hz); 5.94 (s, 1H); 7.37 (m, 1H);
7.45 (m, 2H); 7.73 (m, 2H). 13C (CDCl3): 14.6; 68.7; 84.7; 121.0 (q,
J¼260 Hz); 122.9; 127.5; 129.2; 138.0; 141.9 (q, J¼36 Hz); 154.9.
HRMS: Calcd for C12H11F3N2OþH: 257.0902. Found: m/z,
257.0928.
4.2.36. 2-(4-Chlorophenyl)-4-(2-hydroxypropyl)-5-methyl-1H-
pyrazol-3(2H)-one 14
Obtained (0.02 g, 12%) as an oil. 1H (CDCl3): 1.50 (d, 6H,
J¼6.1 Hz); 1.68 (q, 1H, J¼4.4 and 8.5 Hz); 1.90 (q, 1H, J¼4.5 and
8.5 Hz); 1.95 (s, 3H); 2.13 (m, 1H); 7.36 (m, 2H); 7.94 (m, 2H). 13C
(CDCl3): 10.8; 12.4; 25.9; 28.3; 37.7; 119.7; 129.8; 129.6; 137.5;
35
159.9; 171.7. HRMS: Calcd for C13
H
ClN2OþH: 249.0795. Found:
13
m/z, 249.0790 (MHꢀH2O; respective polarities of compound 13 and
4.2.32. 1-Phenyl-3-(trifluoromethyl)-1H-pyrazol-5(2H)-one 30
Compound 29 (0.5 g, 1.95 mmol) and 48% hydrogen bromide in
water (1 mL) were heated in a sealed flask at 140 ꢁC for 4 h. The
solution was dispersed in water and the precipitate extracted with
ethyl acetate. The organic phase was washed with water, dried over
sodium sulfate, and concentrated to dryness. The residue was fur-
ther purified by a chromatography over silica gel (cyclohexane–
dichloromethane 1:1) to yield compound 30 (0.38 g, 85%) as a solid.
Mp¼190 ꢁC (sublime). 1H (DMSO-d6): 5.93 (s,1H); 7.38 (m,1H); 7.51
(m, 2H); 7.71 (m, 2H). 13C (DMSO-d6): 86.1; 121.0 (q, J¼260 Hz);
122.7; 127.7; 129.6; 138.2; 140.9 (q, J¼37 Hz); 154.1. Spectra iden-
tical with the reported one.50 HRMS: Calcd for C10H7F3N2OþH:
229.0589. Found: m/z, 229.0606.
14 preclude a bicyclic structure for 14).
Methylation of compound 6 and 19: compound 6 and 19
(4.2 mmol) were dissolved in dimethylformamide (10 mL, dried
over 4 Å molecular sieves). To this solution was added sodium hy-
dride (60% in mineral oil, 4.6 mmol) and at the end of the hydrogen
evolution methyl iodide (4.6 mmol) was added. The solution was
stirred overnight at room temperature in a flask protected from
moisture by a calcium chloride guard. It was then concentrated to
dryness, the residue was absorbed on a small amount of silica gel
and purified as described below.
4.2.37. 1,5-Dimethyl-3-isopropoxy-1H-pyrazole 31a
Obtained in a 19% yield after two consecutive chromatography
over silica gel (dichloromethane and then dichloromethane–cy-
clohexane 7:3) as a volatile oil. Note: this compound is detected by
the UV monitor but not by TLC, its isomer was not seen by the UV
monitor although it was visible on as a minor component on 1H
NMR spectra of the crude mixture. 1H (CDCl3): 1.33 (d, 6H,
J¼6.2 Hz); 2.19 (s, 3H); 3.62 (s, 3H); 4.66 (sept, 1H, J¼6.2 Hz); 5.41
(s, 1H). 13C (CDCl3): 14.4; 22.2; 35.4; 71.3; 90.6; 139.5; 161.2. 15N
(CDCl3): ꢀ108 (CH3); ꢀ200 (CH3, H-4, N-CH3). HRMS: Calcd for
C8H14N2OþH: 155.1184. Found: m/z, 155.1186.
4.2.33. 4-Bromo-3-isopropoxy-5-methyl-1H-pyrazole 18
Compound 6 (3.94 g, 28.1 mmol), sodium hydrogenocarbonate
(2.80 g, 35.2 mmol), and bromine (1.73 mL, 33.7 mmol) were mixed
in 100 mL of ethanol. The solution was stirred at room temperature
for 1 h. After concentration to dryness, the residue was washed
with sodium hydrogenocarbonate 1 N and extracted with
dichloromethane. The organic phase was dried over anhydrous
sodium sulfate and concentrated to dryness. The residue was pu-
rified by flash chromatography on silica gel (dichloromethane–
ethanol 99:1) to provide compound 18 (3.97 g, 64%) as a colorless
solid. Mp <50 ꢁC. 1H (CDCl3): 1.38 (d, 6H, J¼6.1 Hz); 2.24 (s, 3H);
4.2.38. 1,5-Dimethyl-4-iodo-3-isopropoxy-1H-pyrazole 31b
Obtained in a 56% yield as a solid still containing 2.5% of 32b
after a chromatography over silica gel (dichloromethane–cyclo-
hexane 1:1). 1H (CDCl3): 1.36 (d, 6H, J¼6.1 Hz); 2.24 (s, 3H); 3.71 (s,
3H); 4.81 (sept, 1H, J¼6.1 Hz). 13C (CDCl3): 11.9; 22.2; 36.9; 46.8;
4.85 (sept, 1H, J¼6.1 Hz); 8.10 (s(l), 1H). 13C (CDCl3): 11.1; 22.5; 73.2;
79
81.2; 139.6; 159.8. HRMS: Calcd for C7H BrN2OþH: 219.0133.
11
Found: m/z, 219.0169.

S. Guillou et al. / Tetrahedron 65 (2009) 2660–2668
2667
72.4; 141.1; 160.9. 15N (CDCl3): ꢀ108 (CH3, N-CH3); ꢀ197 (N-CH3).
HRMS: Calcd for C18H13IN2OþH: 281.0151. Found: m/z, 281.0170.
(CDCl3): (one signal overlapped); 13.6; 22.3; 49.3; 51.5; 79.9; 95.9;
126.1; 127.4; 128.9; 129.2; 129.5; 129.6; 132.5; 150.2; 157.1. 15N
(CDCl3): ꢀ195 (2CH2, H-4 and CH3). HRMS: Calcd for C21H25N2O:
321.1967. Found: m/z, 321.1986.
4.2.39. 1,3-Dimethyl-4-iodo-5-isopropoxy-1H-pyrazole 32b
Obtained in a 1.8% yield as an oil still containing 10% of 31b in
a second fraction of the chromatography described above. Again
contrary to its isomer, this compound is barely detected by the UV
monitor. 1H (CDCl3): 1.36 (d, 6H, J¼6.1 Hz); 2.19 (s, 3H); 3.65 (s, 3H);
4.74 (sept, 1H, J¼6.1 Hz). 13C (CDCl3): 11.9; 22.5; 34.5; 46.1; 77.8;
149.0; 152.7. 15N (CDCl3): ꢀ90 (CH3, N-CH3); ꢀ190 (N-CH3). HRMS:
Calcd for C18H13IN2OþH: 281.0151. Found: m/z, 281.0188.
Acknowledgements
This work was supported by the Medicen initiative (Chemical
Library Project; grant of the Region Ile de France no. I 06-222/R,
which included a fellowship for S.G.). Dr. Daniel Larzul as well as Dr.
Emile Bisagni are also acknowledged for their interest and support.
´
Benzylation of 6: Compound 6 (0.3 g, 2.14 mmol) was dissolved
in dimethylformamide (25 mL, dried over 4 Å molecular sieves). To
this solution was added sodium hydride (60% in mineral oil,
0.062 g, 2.57 mmol) and at the end of the hydrogen evolution
benzylbromide (0.305 mL, 2.57 mmol) was added. The solution was
stirred overnight at room temperature in a flask protected from
moisture by a calcium chloride guard. It was then concentrated to
dryness, the residue was absorbed on a small amount of silica, and
References and notes
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4.2.40. 1-Benzyl-3-isopropoxy-5-methyl-1H-pyrazole 33
1H (CDCl3): 1.35 (d, 6H, J¼6.2 Hz); 2.10 (s, 3H); 4.73 (sept, 1H,
J¼6.2 Hz); 5.10 (s, 2H); 5.49 (s, 1H); 7.11 (m, 2H); 7.24 (m, 1H); 7.29
(m, 2H). 13C (CDCl3): 11.3; 22.2; 52.3; 71.2; 91.7; 126.6; 127.3; 128.6;
137.7; 139.7; 161.5. 15N (CDCl3): ꢀ109 (CH2); ꢀ191 (CH3, CH2, H-4).
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4.2.41. 1-Benzyl-5-isopropoxy-3-methyl-1H-pyrazole 34
1H (CDCl3): 1.30 (d, 6H, J¼6.2 Hz); 2.21 (s, 3H); 4.34 (sept, 1H,
J¼6.2 Hz); 5.08 (s, 2H); 5.33 (s, 1H); 7.24 (m, 3H); 7.31 (m, 2H). 13C
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