An improved preparation of 3-alkoxypyrazoles

Article abstract of DOI:10.1055/s-0028-1083186

The condensation between alkyl acetoacetates and hydrazines constitutes the very well-known Knorr synthetic method leading to pyrazol-3/5-ones. However, contemporary reports describe an alternate reaction pathway leading to low yields of 3/5-alkoxypyrazoles using hydrazine salts. No general method for the selective synthesis of 3-alkoxypyrazoles has been reported to date, hence we focused on this side reaction in an attempt to turn it into the main transformation. Depending on the starting material, various 3-alkoxypyrazoles (methoxy, ethoxy, benzyloxy, isopropoxy, allyloxy) were obtained in up to 56% yield. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083186

3504
PAPER
An Improved Preparation of 3-Alkoxypyrazoles
P
reparation of
a
3-Alkoxyp
n
yrazole
s
drine Guillou, Frédéric J. Bonhomme, Yves L. Janin*
URA 2128 CNRS-Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris cedex 15, France
Fax +33(1)45688404.; E-mail: yves.janin@pasteur.fr
Received 15 April 2008; revised 9 July 2008
Abstract: The condensation between alkyl acetoacetates and hy-
R
O
O
drazines constitutes the very well-known Knorr synthetic method
leading to pyrazol-3/5-ones. However, contemporary reports de-
scribe an alternate reaction pathway leading to low yields of 3/5-
alkoxypyrazoles using hydrazine salts. No general method for the
selective synthesis of 3-alkoxypyrazoles has been reported to date,
hence we focused on this side reaction in an attempt to turn it into
the main transformation. Depending on the starting material, vari-
ous 3-alkoxypyrazoles (methoxy, ethoxy, benzyloxy, isopropoxy,
allyloxy) were obtained in up to 56% yield.
N
N
i
O
O
OH
2a–c
1
R
R
N
N
N
HN
+
O
O
3a–c
4a–c
a: R = 4-EtOC6H4
b: R = Ph
c: R = H
Key words: condensation, cyclizations, heterocycles, pyrazoles,
Knorr reaction
Scheme 1 Reagents and conditions: (i) RNHNH2 or its salts (see
text).
The well known Knorr pyrazol-3/5-ones synthesis con-
sists of a double condensation reaction between, for ex-
ample, ethyl acetoacetate (1), and various hydrazines.1,2
The reaction proceeds via intermediates 2a–c followed by
an elimination reaction of the alcohol moiety to give pyra-
zol-5-ones 3a–c bearing, if relevant, a substituent on N1
(Scheme 1). However, very early (1895),3–5 the reaction
was noted to partially proceed in a different fashion, lead-
ing to 5-ethoxypyrazoles 4a–c via elimination of water in-
stead of ethanol.
strategy involves initial N-acetylation of the pyrazol-3-
ones, followed by selective O-benzylation, and then re-
moval of the acetyl group during the work up. This
strategy provides selective access to many 3-(benzyl-
oxy)pyrazoles21 and may actually be an excellent alterna-
tive to the method described in the present work. Related
approaches, based on a transitory N-carboxylation, have
also been reported.23,24 An even more recent report25 de-
scribing results related to ours prompted us to describe our
finding in the following. Scheme 2 provides an illustra-
tion of the selectivity problem encountered with the alky-
lation of pyrazol-3-ones.
Further studies were undertaken in 1926, in the course of
which intermediate 2c was postulated and compound 4c
was isolated in 30% yield along with 3c. This result was
obtained by reacting hydrazine with 1 in the presence of
two equivalents of hydrochloride acid in boiling alcohol;6
remarkably few reports followed these early studies.7–16
This is quite surprising as O-protected pyrazoles, such as
compound 4, could be starting materials for many synthe-
ses aimed at selective reactions either on N1 or C4. An-
other possible synthesis of 3-alkoxypyrazoles is by the
alkylation of the corresponding pyrazol-3-ones. However,
the selectivity of the reaction is highly dependent on the
alkylating agent, the reaction conditions, and the substrate
used. Diazomethane was used in the past17 as well as
Mitsunobu-based alkylation18 and we previously obtained
adequate amounts of a 3-isopropoxypyrazole derivative in
We indeed undertook the study of the benzylation of 5-
methyl-1,2-dihydro-3H-pyrazol-3-one (3c) under basic
conditions (without the preparatory acetylation step men-
tioned above). This led to the O-benzyl derivative 5 as
well as, at least, the fully characterized compounds 6–8.
This result not only illustrates the multiple reactive cen-
ters of pyrazol-3-ones, but also a potential for chemical di-
versity; although one needs to control the regioselectivity
of the chemical transformations. Even if the preparation
of compound 5 was reported in a 82% yield from benzyl
acetoacetate and hydrazine in acetic acid,14 in our hands,
using the described method, we only observed the occur-
rence of benzyl acetate and compound 3c.
one case.19 Moreover, we reported that a method using tri- Moreover, neither the partial description of 5 provided in
methyl orthocarboxylates could not be adapted to the se- this report14 nor data described more recently26 corre-
lective O-methylation of compound 3c.20 On the other spond with our data (see the experimental part). In any
hand, a very recent patent21 extended a method, which had case, the potential of this ancient synthetic access to 3-
been reported in one case,22 to many pyrazol-3-ones. The alkoxypyrazoles led to the present investigation. Trials
were undertaken with ethyl acetoacetate (1) under various
conditions. The use of 1.05 equivalents of hydrazine
SYNTHESIS 2008, No. 21, pp 3504–3508
Advanced online publication: 16.10.2008
DOI: 10.1055/s-0028-1083186; Art ID: T05908SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
8
monohydrochloride in boiling ethanol led to 3-ethoxy-
5-methyl-1H-pyrazole (4c) in 55% yield. Increasing the
proportion to two equivalents of hydrazine monohydro-

PAPER
Preparation of 3-Alkoxypyrazoles
Table 1 Formation of 3-Alkoxypyrazoles
3505
H
N
N
O
O
N
NH
NH2NH2⋅HCl, R1OH,
i
O
reflux, 8 h
R3
O
R1
3c
N
O
R1
R3
HN
+
R2
9a–o
R2
10b–o
5 (12%)
O
6 (17.3%)
N
Entry
Sub- R1
strate
R2 R3
Product
Yield
(%)
HN
N
HN
O
+
1
2
1
Et
H
H
H
H
H
Me
4c
55
+
O
9a
9b
9c
9d
9e
9f
Bn
Me
Me
Me
Me
5
22a
25
3
Me
10b
10c
7 (4.4%)
8 (1.4%)
4
i-Pr
55
Scheme 2 Reagents and conditions: (i) NaH, BnBr, DMF, r.t.
b
5
t-Bu
–
chloride led to a lower yield. A trial run with 0.5 equiva-
lents of hydrazine and 0.5 equivalents of hydrazine
monohydrochloride also led to a lower yield of 4c. Re-
placing the hydrazine monohydrochloride with hydrazine
sulfate in refluxing ethanol gave compound 4c, although
still in lower yield, whereas hydrazine acetate only led to
compound 3c. Other salts were tried (hydrobromide, tet-
rafluoroboride, or monophosphate) without any improve-
ment. The reaction could also be run with hydrazine
monohydrochloride overnight at room temperature and
gave a similar yield of 4c. The absence of ethanol or the
use of a different solvent (THF, toluene, DMF, H2O) at
room temperature gave lower yields of 4c. Compounds
10b–k were obtained by using the optimal conditions
found so far, i.e. alkyl acetoacetates 9a–k (1 equiv), hy-
drazine monohydrochloride (1.05 equiv), reflux, in either
the corresponding alkyl alcohol or isopropyl alcohol in the
case of compound 9a, for eight hours. From the allyl ace-
toacetate 9m, a transesterification was observed in boiling
isopropyl alcohol and, thus, the reaction was undertaken
at room temperature overnight instead.
6
Et
Et Me
Bn Me
10e
10f
10g
10h
10i
56
55
40
54
40
39
9c
7
Et
8
9g
9h
9i
Et
H
Ph
9
Et
(CH2)4
Me
10
11
12
13
14
15
16
Et
F
9j
Et
Me CO2Et 10j
9k
9l
Et
H
H
H
CO2Et 10k
Et
CF3
Me
10l
25
48d
9m
9n
9o
CH2CH=CH2
Et
10m
b
(CH2)3
Me
–
(CH2)2
0
a In i-PrOH.
b Mixture.
c See text and experimental part.
d Reaction performed in i-PrOH at r.t.
The results reported in Table 1 show that starting from
ethyl or isopropyl acetoacetates 1 or 9c the reaction led
mainly to the corresponding alkoxypyrazoles 4c and 10c
(55% yield). On the other hand, the methyl or benzyl ace-
toacetates 9a,b gave lower yield of alkoxypyrazoles. The
acidic lability of the benzyl and the methyl group may ex-
plain the lower yield observed and the volatility and water
solubility of 10b may also provide an explanation in this
case. However, concerning eventual acidic lability, trials
at room temperature or with shorter reaction time provid-
ed compound 5 or 10b in the same yield range. In the case
of the tert-butyl acetoacetate, a mixture of compounds
that could not be properly purified was obtained. The eth-
yl or the benzyl group of ethyl acetoacetates 9e and 9f do
not seem to hinder this reaction, however, the phenyl of
compound 9g leads to a lower yield of 10g. Interestingly,
a fluorine atom is compatible with the reaction conditions
and we obtained the 4-fluoropyrazole 10i in 40% yield.
Moreover, an ester function did not hinder the preparation
of the carboxy-bearing compound 10j in 39% yield from
diethyl 2-methyl-3-oxosuccinate (9j). From the commer-
cially available sodium salt of diethyl 2-oxosuccinate (9k)
a different procedure was used, which led to the expected
compound 10k although in an unoptimized 9% yield (see
experimental part). Finally, the comparison of the trials
starting with the cyclic compounds 9h and 9n,o illustrates
some of the structural constraints which limit this method.
Thus, the six-membered cyclic acetoacetate 9h gave the
corresponding 3-ethoxytetrahydroindazole 10h in 54%
yield, but the five-membered cyclic acetoacetate 9n led to
an inseparable mixture, which probably contained the tar-
get compound. In the case of 9o, the water elimination
seems to be even more disfavored and no O-alkylated sub-
stances could be detected in 1H NMR spectra of the reac-
tion mixture. This method has the advantage of providing
a very simple access to many 3-alkoxypyrazole-bearing
compounds as, quite often, an extraction is the sole work-
up required. By using 1.05 equivalents of hydrazine
monohydrochloride, we were able to double the yields of
this side reaction, when compared to previously reported
cases which used the sulfate or, more often,6 the dihydro-
chloride salts. As shown in Scheme 3, a similar yield in-
Synthesis 2008, No. 21, 3504–3508 © Thieme Stuttgart · New York

3506
S. Guillou et al.
PAPER
with H2O (5 × 50 mL) to remove the traces of DMF, dried (Na2SO4),
and concentrated to dryness. The resulting residue was dissolved in
CH2Cl2 (100 mL), extracted with 1 M NaOH (3 × 50 mL), washed
back to neutrality with brine (3 × 50 mL), dried (Na2SO4), and con-
centrated to dryness to give product mixture A. The basic aqueous
phase was made acid with concd HCl and extracted with CH2Cl2 (3
× 50 mL). This organic layer was washed to neutrality with brine (3
× 30 mL), dried (Na2SO4), and concentrated to dryness to give prod-
uct mixture B. Chromatography of mixture A (silica gel, CH2Cl2–
EtOH, 98:2) provided a mixture containing compounds 5 and 8, free
of mineral oil. This was recrystallized in toluene to provide com-
pound 8 (0.12 g, 1.4%). The filtrate was concentrated to dryness and
purified by chromatography (silica gel, cyclohexane–EtOAc, 3:1);
this provided two crude fractions. The least migrating fraction (1 g)
was purified again by chromatography (silica gel, 0.020–0.045 mm,
CH2Cl2–EtOH, 99.5:0.5) and yielded compound 5 (0.72 g, 12%).
N
O
N
O
O
O
i
11 (69%)
O
N
9c
ii
O
12 (6%)
Scheme 3 Reagents and conditions: (i) MeNHNH2, HCl, i-PrOH,
reflux 8 h; (ii) NH2OH·HCl, i-PrOH, r.t., 48 h.
crease was also observed when reacting 1.05 equivalents
of methylhydrazine monohydrochloride with isopropyl
acetoacetate (9c) as the corresponding 5-isopropoxy-1,3-
dimethyl-1H-pyrazole (11) was obtained in 69% yield in- Chromatography of mixture B (silica gel, CH2Cl2–EtOH, 98.5:1.5)
stead of the previously reported 30%.13 The regioselectiv-
provided, in order of elution, a fraction containing 7 and 6 and a sec-
ond fraction containing pure compound 6 (0.74 g, 12.7%). The mix-
ture of compounds 7 and 6 were further purified by chromatography
(silica gel, cyclohexane–EtOAc, 4:1 to 1:1), which gave compound
ity of this reaction, which corresponds to the reported
examples,7,13 was determined by 13C–1H long distance
correlations.
7 (0.37 g, 4.4%) and more compound 6 (0.27 g, 4.6%).
Finally, we also performed the condensation of 1.05
3-(Benzyloxy)-5-methyl-1H-pyrazole (5)
Oil that slowly crystallizes; mp 91 °C.
Note: the 1H NMR data previously reported26 for 5 fit much better
with the data we obtained for compound 6.
1H NMR (CDCl3): d = 2.24 (s, 3 H), 5.21 (s, 2 H), 5.55 (s, 1 H),
7.33–7.47 (m, 5 H).
13C NMR (CDCl3): d = 12.0, 71.0, 90.4, 128.1, 128.3, 128.9, 137.6,
141.3, 164.2.
equivalent of hydroxylamine hydrochloride on 9c in the
absence of the usual base (Scheme 3).27 To our surprise,
when running this trial at room temperature in isopropanol
(reflux was detrimental to the yield), we did isolate 6% of
the volatile 5-isopropoxy-3-methylisoxazole (12) also re-
sulting from an unprecedented water elimination from the
intermediate oxime. An HMBC–15N experiment was in-
strumental in the structural assignment of 12 as heteronu-
clear correlations were noted between the nitrogen 15N
signal and the methyl hydrogen’s on C3 as well as with the
hydrogen on C4.
MS (EI): m/z (%) = 91 (100), 188 (4).
HRMS could not be obtained as the compound readily loses its ben-
zyl moiety.
In conclusion, this work allows the preparation an array of
novel O-protected pyrazoles. Moreover, it paves the way
to our current work on the synthesis of new chemical en-
tities as most of the chemistry of 3-alkoxypyrazoles re-
mains to be explored.
1-Benzyl-5-methyl-1,2-dihydro-3H-pyrazol-3-one (6)28
A fraction was recrystallized (cyclohexane) for analytical purposes;
mp 171 °C (cyclohexane) (Lit.28 224–226 °C).
1H NMR (CDCl3): d = 2.15 (s, 3 H), 5.07 (s, 2 H), 5.46 (s, 1 H),
7.13–7.16 (m, 1 H), 7.28–7.35 (m, 4 H).
13C NMR (CDCl3): d = 11.7, 52.3, 91.8, 127.1, 128.0, 129.1, 137.3,
Melting points were measured on a Kofler bench and are uncorrect-
140.9, 161.9.
1
ed. H NMR and 13C NMR spectra were recorded on a Bruker
HRMS: m/z [M + Na] calcd for C11H12N2NaO: 211.0847; found:
Avance 400 spectrometer at 400 MHz and 100 MHz, respectively;
TMS was used as an internal reference. 15N NMR used MeNO2 (d =
0.00) as an external reference Column chromatography were per-
formed over Merck silica gel 60 (0.035–0.070 mm), using a solvent
pump operating at pressure between 2 and 7 bar (25–50 mL/min)
and an automated collecting system driven by a UV detector set to
254 nm unless otherwise stated. LR-MS data were obtained on an
Agilent 1100 series LC/MSD system using an atmospheric ESI sys-
tem. HRMS were obtained by the laboratoire de spectrométrie de
masse, CNRS.-ICSN, 91198 Gif/Yvette, France or on a Waters
Micromass Q-Tof (ESI source).
211.0885.
1,4-Dibenzyl-5-methyl-1,2-dihydro-3H-pyrazol-3-one (7)
Note: long distance correlations between the benzyls 1H signals and
the 13C of the pyrazole ring established the regioselectivity of the N-
benzylation; mp 161 °C (cyclohexane).
1H NMR (CDCl3): d = 2.02 (s, 3 H), 3.69 (s, 2 H), 5.07 (s, 1 H),
7.14–7.16 (m, 2 H), 7.25–7.33 (m, 8 H).
13C NMR (CDCl3): d = 10.3, 28.4, 52.5, 102.7, 126.0, 127.3, 127.9,
128.6, 128.7, 129.1, 137.6, 138.2, 141.8, 160.6.
HRMS: m/z [M + Na] calcd for C18H18N2NaO: 301.1317; found:
301.1327.
Preparation of Compounds 5–8
In a 500-mL flask mounted with a CaCl2 guard, NaH (60% in oil,
1.23 g, 0.031 mol) was added to a soln of 5-methyl-1,2-dihydro-3H-
pyrazol-3-one (3c, 3 g, 0.031 mol) in anhyd DMF (75 mL; dried
over 4 Å molecular sieves). At the end of the gaseous evolution, the
soln was cooled to 0 °C with an ice bath and BnBr (3.7 mL, 0.031
mol) was added. The ice bath was removed and the resulting sus-
pension was stirred overnight. The DMF was removed under vacu-
um and the residue was dispersed in H2O (100 mL) and extracted
with EtOAc (3 × 50 mL). The combined organic layers were washed
4,4-Dibenzyl-5-methyl-2,4-dihydro-3H-pyrazol-3-one (8)29
Mp 202 °C (toluene) (Lit.29 204 °C).
1H NMR (CDCl3): d = 2.11 (s, 3 H), 2.98 (d, J = 13.6 Hz, 2 H), 3.29
(d, J = 13.6 Hz, 2 H), 7.15–7.28 (m, 10 H), 8.14 (s, 1 H).
13C NMR (CDCl3): d = 15.6, 41.4, 60.6, 127.6, 128.8, 129.6, 135.3,
161.7, 178.7.
Synthesis 2008, No. 21, 3504–3508 © Thieme Stuttgart · New York

PAPER
Preparation of 3-Alkoxypyrazoles
3-Ethoxy-5-phenyl-1H-pyrazole (10g)30
3507
HRMS: m/z [M + Na] calcd for C18H18N2NaO: 301.1317; found:
301.1322.
This compound was further purified using chromatography (silica
gel, CH2Cl2–EtOH, 98:2) to give a white solid. On a larger scale,
this chromatography was avoided as the residue could be recrystal-
lized (cyclohexane, 500 mL for 11 g of crude compound; long boil-
ing time required); mp 130 °C (Lit.30 126–128 °C).
1H NMR (CDCl3): d = 1.40 (t, J = 7.0 Hz, 3 H), 4.22 (q, J = 7.0 Hz,
2 H), 5.96 (s, 1 H), 7.36–7.44 (m, 3 H), 7.56–7.59 (m, 2 H), 9.9 (br
s, 1 H).
3-Alkoxy-1H-pyrazoles 4c, 5, 10b–10l and 11–12; General Pro-
cedure
The acetoacetate (0.01 mmol) and hydrazine hydrochloride (0.0105
mmol) were refluxed in the relevant solvent [1, 9e–l (EtOH, 60 mL),
9a, 9c (i-PrOH, 60 mL) or 9d (t-BuOH, 60 mL)] for 8 h. In the case
of the allyl acetoacetate 9m, the reaction was run at r.t. overnight in
i-PrOH. The solvent was removed under reduced pressure, the res-
idue was dispersed in CH2Cl2 (100 mL) and excess 1 M NaHCO3
soln (50 mL). The organic phase was washed with 1 M NaHCO3
soln (3 × 30 mL), dried (Na2SO4), and concentrated to dryness. The
resulting residue was either pure enough for analytical characteriza-
tion (>95% pure as seen by 1H NMR and LC/MS) or further purified
as described below.
13C NMR (CDCl3): d = 15.2, 65.4, 88.1, 125.7, 128.0, 129.3, 130.3,
145.3, 164.3.
HRMS: m/z [M + H] calcd for C11H13N2O: 189.1028; found:
189.1036.
3-Ethoxy-4,5,6,7-tetrahydro-1H-indazole (10h)
Mp 113 °C.
3-Ethoxy-5-methyl-1H-pyrazole (4c)30
1H NMR (CDCl3): d = 1.40 (t, J = 7.0 Hz, 3 H), 1.73–1.80 (m, 4 H),
2.37–2.40 (m, 2 H), 2.53–2.56 (m, 2 H), 4.26 (q, J = 7.0 Hz, 2 H).
13C NMR (CDCl3): d = 15.1, 19.2, 22.1, 22.9, 23.3, 64.4, 101.3,
141.2, 161.4.
Oil that solidified; mp 62 °C (Lit.30 67–68 °C).
1H NMR (CDCl3): d = 1.39 (t, J = 7.2 Hz, 3 H), 2.25 (s, 3 H), 4.17
(q, J = 7.2 Hz, 2 H), 5.48 (s, 1 H).
13C NMR (CDCl3): d = 12.0, 15.2, 65.0, 89.9, 141.2, 164.2.
HRMS: m/z [M + H] calcd for C9H15N2O: 167.1184; found:
167.1184.
3-(Benzyloxy)-5-methyl-1H-pyrazole (5)
This compound was further purified first using a high vacuum pump
to remove most of the BnOH present and then further purified by
chromatography (silica gel, CH2Cl2–EtOH, 98:2). The fraction ob-
tained slowly crystallized as described above.
3-Ethoxy-4-fluoro-5-methyl-1H-pyrazole (10i)
Recrystallization (cyclohexane) gave yellow crystals; mp 91 °C.
1H NMR (CDCl3): d = 1.42 (t, J = 7.0 Hz, 3 H), 2.22 (s, 3 H), 4.25
(q, J = 7.0 Hz, 2 H).
13C NMR (CDCl3): d = 8.9, 15.1, 65.4, 125.9 (d, J = 23.5 Hz), 134.1
(d, J = 237.8 Hz), 150.8 (d, J = 9.1 Hz).
3-Methoxy-5-methyl-1H-pyrazole (10b)8,31
Oil that solidified; mp 46 °C (Lit.8 49–50 °C).
1H NMR (CDCl3): d = 2.25 (s, 3 H), 3.88 (s, 3 H), 5.50 (s, 1 H).
13C NMR (CDCl3): d = 12.0, 56.5, 89.9, 141.3, 165.0.
HRMS: m/z [M + H] calcd for C6H10FN2O: 145.0777; found:
145.0783.
Ethyl 3-Ethoxy-4-methyl-1H-pyrazole-5-carboxylate (10j)
Chromatography (silica gel, CH2Cl2) gave white crystals; mp 95 °C.
3-Isopropoxy-5-methyl-1H-pyrazole (10c)
Oil.
1H NMR (CDCl3): d = 1.36–1.43 (m, 6 H), 2.14 (s, 3 H), 4.30 (q,
J = 7.0 Hz, 2 H), 4.37 (q, J = 7.0 Hz, 2 H), 10.7 (br s, 1 H).
1H NMR (CDCl3): d = 1.34 (d, J = 6.5 Hz, 6 H), 2.25 (s, 3 H), 4.65
(sept, J = 6.5 Hz, 1 H), 5.45 (s, 1 H).
13C NMR (CDCl3): d = 7.0, 14.2, 14.8, 61.0, 64.8, 105.5, 130.9,
160.3, 162.3.
13C NMR (CDCl3): d = 11.9, 22.6, 72.1, 90.3, 141.2, 163.2.
MS (EI): m/z (%) = 98 (100), 140 (5).
HRMS: m/z [M + H] calcd for C9H15N2O3: 199.1083; found:
199.1116.
HRMS could not be obtained as the compound readily loses its iso-
propyl moiety.
Ethyl 3-Ethoxy-1H-pyrazole-5-carboxylate (10k)
3-Ethoxy-4-ethyl-5-methyl-1H-pyrazole (10e)6
This compound was prepared from the sodium salt of diethyl 2-oxo-
succinate (9k) as follow: diethyl 2-oxosuccinate sodium salt (27.8
g, 0.132 mol; 95% pure) was dissolved in EtOH (300 mL) and H2O
(20 mL). To this was added NH2NH2·2 HCl (14.3 g, 0.136 mol) and
the suspension was stirred at r.t. overnight and then heated to reflux
for an additional 12 h. The solvent was removed under reduced
pressure; the residue was dispersed in H2O (400 mL) and made ba-
sic with the addition of small portion of solid NaHCO3. The aqueous
phase was extracted with EtOAc (5 × 50 mL), the combined organic
layers were dried (Na2SO4) and concentrated to dryness. The resi-
due was further purified by chromatography (silica gel, CH2Cl2–
EtOH, 97:3) to yield 10k (2.19 g, 9%) as a low melting solid.
White solid; mp 85 °C (Lit.6 86 °C).
1H NMR (CDCl3): d = 1.11 (t, J = 7.5 Hz, 3 H), 1.40 (t, J = 7.0 Hz,
3 H), 2.18 (s, 3 H), 2.33 (q, J = 7.5 Hz, 2 H), 4.24 (q, J = 7.0 Hz, 2
H), 8.5 (br s, 1 H).
13C NMR (CDCl3): d = 10.5, 15.0, 15.4, 15.43, 64.4, 104.8, 137.4,
162.7.
HRMS: m/z [M + H] calcd for C8H15N2O: 155.1184; found:
155.1188.
4-Benzyl-3-ethoxy-5-methyl-1H-pyrazole (10f)
White solid; mp 107 °C.
1H NMR (CDCl3): d = 1.38 (t, J = 6.7 Hz, 3 H), 2.11 (s, 3 H), 3.69
(s, 2 H), 4.25 (q, J = 6.7 Hz, 2 H), 7.18–7.29 (m, 5 H).
13C NMR (CDCl3): d = 10.7, 15.4, 28.0, 64.5, 102.4, 127.1, 128.6,
138.3, 141.6, 162.7.
1H NMR (CDCl3): d = 1.36–1.42 (m, 6 H), 4.26 (q, J = 7.0 Hz, 2 H),
4.38 (q, J = 7.0 Hz, 2 H), 6.22 (s, 1 H), 10.6 (br s, 1 H).
13C NMR (CDCl3): d = 14.2, 14.7, 61.4, 65.3, 93.2, 134.3, 159.6,
163.4.
HRMS: m/z [M + H] calcd for C8H13N2O3: 185.0926; found:
185.0980.
HRMS: m/z [M + H] calcd for C13H17N2O: 217.1341; found:
217.1387.
Synthesis 2008, No. 21, 3504–3508 © Thieme Stuttgart · New York

3508
S. Guillou et al.
PAPER
3-Ethoxy-5-(trifluoromethyl)-1H-pyrazole (10l)32
Oil that slowly crystallized.
(7) Maquestiau, A.; Van Haverbeke, Y.; Bruyere, A. Bull. Soc.
Chim. Belg. 1973, 82, 747.
(8) Arakawa, K.; Miyasaka, T.; Ochi, H. Chem. Pharm. Bull.
1974, 22, 207.
(9) Puar, M. S.; Funke, P. T.; Cohen, A. I. J. Pharm. Sci. 1978,
67, 850.
(10) Pilgram, K. J. Heterocycl. Chem. 1980, 17, 1413.
(11) Zefirov, N. S.; Kozhushkov, S. I.; Kuznetsova, T. S. Khim.
Geterotsikl. Soedin. 1983, 19, 801.
(12) Krohn, K.; Stenns, C. Arch. Pharm. (Weinheim, Ger.) 1989,
322, 351.
(13) Claramunt, R. M.; Sanz, D.; Lopez, C.; Jimenez, J. A.;
Jimeno, M. L.; Elguero, J.; Fruchier, A. Magn. Res. Chem.
1997, 35, 35.
(14) Batterjee, S. M. J. Text. Assoc. 2001, 62, 145.
(15) Martins, M. A. P.; Pereira, C. M. P.; Zimmermann, N. E. K.;
Moura, S.; Sinhorin, A. P.; Cunico, W.; Zanatta, N.;
Bonacorso, H. G.; Flores, A. C. F. Synthesis 2003, 2353.
(16) Bevk, D.; Svete, J.; Stanovnik, B. J. Heterocycl. Chem.
2005, 42, 1413.
1H NMR (CDCl3): d = 1.43 (t, J = 7.1 Hz, 3 H), 4.18 (q, J = 7.1 Hz,
2 H), 5.86 (d, 1 H), 11.3 (br s, 1 H).
13C NMR (CDCl3): d = 14.4, 67.4, 85.2, 120.0 (q, J = 267 Hz),
141.1 (m), 158.3.
3-(Allyloxy)-5-methyl-1H-pyrazole (10m)
Oil.
1H NMR (CDCl3): d = 2.25 (s, 3 H), 4.65–4.67 (m, 2 H), 5.25–5.28
(m, 1 H), 5.39 (dd, J = 1.6, 17.2 Hz, 1 H), 6.04–6.11 (m, 1 H), 8.9
(br s, 1 H).
13C NMR (CDCl3): d = 11.9, 70.1, 90.1, 117.8, 133.8, 141.3, 163.9.
HRMS: m/z [M + H] calcd for C7H11N2O: 139.0871; found:
139.0900.
5-Isopropoxy-1,3-dimethyl-1H-pyrazole (11)
Following the general procedure using MeNHNH2·HCl (1.05
equiv) and acetoacetate 9c gave 11 as an oil.
(17) Bau, B.; Hofmann, T.; Kloss, J.; Neunhoeffer, H. Sci.
Pharm. 1998, 66, 119.
1H NMR (CDCl3): d = 1.32 (d, J = 6.1 Hz, 6 H), 2.16 (s, 3 H), 3.53
(s, 3 H), 4.31 (sept, J = 6.1 Hz, 1 H), 5.26 (s, 1 H).
13C NMR (CDCl3): d = 14.7, 22.3, 33.5, 75.5, 85.5, 147.1, 154.3.
(18) Selwood, D. L.; Brummell, D. G.; Budworth, J.; Burtin, G.
E.; Campbell, R. O.; Chana, S. S.; Charles, I. G.; Fernandez,
P. A.; Glen, R. C.; Goggin, M. C.; Hobbs, A. J.; Kling, M.
R.; Liu, Q.; Madge, D. J.; Millerais, S.; Powell, K. L.;
Reynolds, K.; Spacey, G. D.; Stables, J. N.; Tatlock, M. A.;
Wheeler, K. A.; Wishart, G.; Woo, C.-K. J. Med. Chem.
2001, 44, 78.
Anal. Calcd for C8H14N2O: C, 14.55; H, 8.55; N, 33.94. Found: C,
14.61; H, 8.51; N, 33.97.
5-Isopropoxy-3-methylisoxazole (12)
(19) Zimmermann, D.; Janin, Y. L.; Brehm, L.; Bräuner-
Osborne, H.; Ebert, B.; Johansen, T. N.; Madsen, U.;
Krogsgaard-Larsen, P. Eur. J. Med. Chem. 1999, 34, 967.
(20) Janin, Y. L.; Huel, C.; Flad, G.; Thirot, S. Eur. J. Org. Chem.
2002, 1763.
(21) Genevois Borella, A.; Malleron, J. L.; Bouquerel, J.;
Doerflinger, G.; Bohme, A.; Touyer, G.; Sabuco, J. F.;
Terrier, C.; Mignani, S.; Evers, M. FR 2,862,647 Chem.
Abstr. 2005, 143, 7705p.
(22) Cottineau, B.; Toto, P.; Marot, C.; Pipaud, A.; Chenault, J.
Bioorg. Med. Chem. Lett. 2002, 12, 2105.
(23) Willson, T. S.; Henke, B. R.; Momtahen, T. M.; Garrison, D.
T.; Moore, L. B.; Geddie, N. G.; Baer, P. G. Bioorg. Med.
Chem. Lett. 1996, 6, 1047.
Isopropyl acetoacetate (2.7 g, 0.019 mol) was dissolved in anhyd i-
PrOH (30 mL, dried over 4A molecular sieves). To this was added
NH2OH·HCl (1.43 g, 0.02 mol) and the suspension was stirred at r.t.
for 48 h. The resulting soln was processed as described in the gen-
eral procedure and gave an oil that was further purified by chroma-
tography (silica gel, CH2Cl2) to give 12 (0.16 g, 6%) as an oil. Note:
if compound 12 was weakly detected by the UV monitor of the
chromatography apparatus set at 254 nm, on TLC, it was only visi-
ble using a spraying reagent (EtOH soln containing 2% phosphomo-
lybdic acid); Rf = 0.31 (CH2Cl2).
1H NMR (CDCl3): d = 1.41 (d, J = 6.2 Hz, 6 H), 2.21 (s, 3 H), 4.62
(sept, J = 6.2 Hz, 1 H), 5.03 (s, 1 H).
13C NMR (CDCl3): d = 12.8, 22.3, 76.6, 79.1, 162.5, 173.1.
15N NMR (CDCl3, ): d = –27.
(24) Rossiter, S.; Woo, C. K.; Hartzoulakis, B.; Wishart, G.;
Stanyer, L.; Labadie, J. W.; Selwood, D. L. J. Comb. Chem.
2004, 6, 385.
This compound was too volatile for HRMS analysis.
(25) Braibante, M. E. F.; Braibante, H. T. S.; de
Carvalho Tavares, L.; Rohte, S. F.; Costa, C. C.; Morel, A.
F.; Stüker, C. Z.; Burrow, R. A. Synthesis 2007, 2485.
(26) Khalil, A. K.; Hassan, M. A.; Mohamed, M. M.; El-Sayed,
A. M. Phosphorus, Sulfur Silicon Relat. Elem. 2005, 180,
479.
(27) Grünanger, P.; Vita-Finzi, P. In The Chemistry of
Heterocyclic Compounds, Vol. 49; Taylor, E. C., Ed.; John
Wiley & Sons: Chichester, 1991.
Acknowledgment
This work was supported by the Medicen initiative (Chemical Li-
brary Project; grant of the Région Ile de France n° I 06-222/R, as
well as a fellowship for S.G.). We thank Sanofi-Aventis as well as
Pfizer for donations of scientific equipment. Moreover, Dr. Emile
Bisagni is acknowledged for his interest and sound advices in this
work.
(28) v Auwers, K.; Niemeyer, F. J. Prakt. Chem. 1925, 110, 153.
(29) Singh, G.; Singh, D.; Ram, R. N. Tetrahedron Lett. 1981, 22,
2213.
(30) Ohta, T.; Fujisawa, H.; Nakai, Y.; Furukawa, I. Bull. Chem.
Soc. Jpn. 2000, 73, 1861.
(31) Rodríguez-Franco, M. I.; Dorronsoro, I.; Hernández-
Higueras, A. I.; Antequera, G. Tetrahedron Lett. 2001, 42,
863.
(32) Martins, M. A. P.; Cunico, W.; Brondani, S.; Peres, R. L.;
Zimmermann, N.; Rosa, F. A.; Fiss, G. F.; Zanatta, N.;
Bonacorso, H. G. Synthesis 2006, 1485.
References
(1) Varvounis, G.; Fiamegos, Y.; Pilidis, G. Adv. Heterocycl.
Chem. 2001, 80, 74.
(2) Stanovik, E.; Svete, J. In Science of Synthesis, Vol. 12;
Neier, R., Ed.; Georg Thieme Verlag: Stuttgart, 2002, 15.
(3) Knorr, L. Ber. Dtsch. Chem. Ges. 1895, 28, 706.
(4) Stolz, F. Ber. Dtsch. Chem. Ges. 1895, 28, 635.
(5) Wolff, L. Ber. Dtsch. Chem. Ges. 1904, 37, 2827.
(6) Backer, H. J.; Meijer, W. Recl. Trav. Chim. Pays-Bas 1926,
45, 428.
Synthesis 2008, No. 21, 3504–3508 © Thieme Stuttgart · New York