5-Iodo-3-ethoxypyrazoles: An entry point to new chemical entities

Article abstract of DOI:10.1002/chem.200903442

Our program, which has focused on the preparation of new pyrazole derivatives, has led us to report here an original and simplified preparation of ethyl 3-ethoxy-lW-pyrazole-4-carboxylate. This is based on the reaction of hydrazine monohydrochloride and diethyl 2-(ethoxymethylene)malonate. Further transformations of this key compound allowed the preparation of the two possible iodinated isomers, namely, 3-ethoxy-4-iodo- and 3-ethoxy-5-iodo-1H-pyrazole. These compounds have opened the way to a quick access to many original pyrazole series. As an illustration, we report here on the selectivity of N-arylation, by using the Lam and Cham method, the C4- and C5-arylation of some of these 3-ethoxy-pyrazole derivatives by using the Suzuki-Miyaura reaction, and C5-benzylation reactions by means of the Negishi reaction. This was followed by hydrolysis of the ethoxy group, which led to the corresponding pyrazol-3-one derivatives. As a conclusion of this work, we conducted an investigation into the regiochemistry of the condensation between diethyl 2-(ethoxymethylene) malonate and the hydrochloride salts of methyl, benzyl, or phenyl hydrazine.

Full text of DOI:10.1002/chem.200903442

FULL PAPER
DOI: 10.1002/chem.200903442
5-Iodo-3-Ethoxypyrazoles: An Entry Point to New Chemical Entities
Sandrine Guillou and Yves L. Janin*[a]
Abstract: Our program, which has fo-
cused on the preparation of new pyra-
zole derivatives, has led us to report
here an original and simplified prepa-
ration of ethyl 3-ethoxy-1H-pyrazole-4-
carboxylate. This is based on the reac-
tion of hydrazine monohydrochloride
and diethyl 2-(ethoxymethylene)malo-
nate. Further transformations of this
key compound allowed the preparation
of the two possible iodinated isomers,
namely, 3-ethoxy-4-iodo- and 3-ethoxy-
5-iodo-1H-pyrazole. These compounds
have opened the way to a quick access
to many original pyrazole series. As an
illustration, we report here on the se-
lectivity of N-arylation, by using the
Lam and Cham method, the C4- and
C5-arylation of some of these 3-ethoxy-
pyrazole derivatives by using the
Suzuki–Miyaura reaction, and C5-ben-
zylation reactions by means of the Ne-
gishi reaction. This was followed by hy-
drolysis of the ethoxy group, which led
to the corresponding pyrazol-3-one de-
rivatives. As a conclusion of this work,
we conducted an investigation into the
regiochemistry of the condensation be-
tween diethyl 2-(ethoxymethylene)mal-
onate and the hydrochloride salts of
methyl, benzyl, or phenyl hydrazine.
Keywords: arylation · heterocycles ·
organic synthesis
pyrazoles
· palladium ·
Introduction
related structures were patented for their serine/threonine
and tyrosine kinase inhibition properties.[3] Even more re-
cently, derivatives such as 3 were reported as inhibitors of
prion accumulation,[4] whereas 4-benzoyl analogues, such as
4, are able to inhibit Mycobacterium tuberculosis growth.[5]
Thus, the core pyrazol-3-one structure (5) with at least three
potential nucleophilic centers (the two nitrogen atoms and
one oxygen atom) and two carbon atoms is still an attractive
heterocyclic entity. Many of its reactive centers may lend
themselves to chemical transformations with a potential for
“quick” chemical diversity attainable in few reaction steps.
This number of reactive centers, although desirable for
chemical diversity, does force protection and deprotection
steps to ensure a reaction regioselectivity. In the case of the
pyrazol-3-ones, this is a problem as the protection steps
themselves also face this issue of regioselectivity, alkylation
of such entities may[6] or may not[7] be selective. From N-
aryl or N-alkyl hydrazines, the age-old Knorr reaction[8] pro-
vides a fairly selective access to many N1-subtituted pyra-
zol-5-ones. On the other hand, as we have recently report-
ed,[9] the isomeric N1-subtituted pyrazol-3-ones are less easy
to prepare. This aspect is illustrated by a chemical database
survey. Out of the 76790 compounds featuring a pyrazolone
moiety ever reported, some 66103 are N1-aryl (or alkyl)
pyrazol-5-ones, but “only” 4563 are the isomeric N1-aryl (or
alkyl) pyrazol-3-ones.
The pyrazole ring system and more precisely the 3- or 5-
“oxo” derivatives cannot be considered as an original scaf-
fold as many derivatives have been reported for their bio-
logical activities.[1] For instance, the analgesic N1-phenyl-pyr-
azol-5-one antipyrine (1) was first prepared as early as
1892.[2] More than one hundred years after, compound 2 and
[a] S. Guillou, Y. L. Janin
Institut Pasteur, URA 2128 CNRS-Institut Pasteur
28 rue du Dr. Roux, 75724 Paris cedex 15 (France)
Fax : (+33)145688404
E-mail: yves.janin@pasteur.fr
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4669

Results and Discussion
amino)methylene]malonate (7b)[10b] and hydrazine dihydro-
ACHTUNGTRENNUNG
chloride. On the other hand, a lesser amount of 3-ethoxypyr-
azole (10) was obtained from ethyl 3-(dimethylamino)acry-
late (traces) or ethylpropiolate (7%). Moreover, under the
same reaction conditions, a small quantity of the corre-
sponding 3-methoxypyrazole was isolated when starting
from methyl 3-methoxyacrylate. In any case, an acid hydro-
We have recently reported a study on the N-alkylation/-ary-
lation selectivity of 5-substituted 3-alkoxypyrazoles.[9] How-
ever, an equivalent work on 5-unsubstituted 3-alkoxy pyra-
zoles, such as 6, was not so easy to design as only two
papers describe the direct O-alkylation of 5 or further chem-
ical transformations.[10] It is only quite recently that the
problem of selective oxygen protection of compound 5 was
breached. As depicted in Scheme 1, a patent[11] describes the
AHCTUNGTREGlNNNU ysis of the ester moiety of compound 8 also leads to its de-
carboxylation and thus to compound 10 in a 38% yield from
7a. From compounds 8 and 10, further transformations al-
lowed the preparation of the two iodo-bearing derivatives
11 and 12. Although the synthesis of compound 11 could be
said to be trouble-free, many attempts were made to pre-
pare the 5-halogenated alkoxypyrazole 12. This compound is
of much interest as it avoids the nitrogen methylation re-
quired for a butyl lithium based halogenation strategy re-
ported in a related case.[15] With this goal in mind we pre-
pared compound 12a from 8 in a 60% yield by using N-io-
dosuccinimide in boiling cyclohexane. The 5-brominated ho-
mologue 12b was also prepared by using N-bromosuccini-
mide although in only a 47% yield. A related process (N-
iodosuccinimide in hot DMF) was actually reported for the
5-iodination of two 3-carboxyethyl-bearing pyrazoles.[16] As
heating is necessary for these reactions to proceed, we sug-
gest a 1–2-migration reaction of a halogenated intermediate,
from either C4 or N1, to C5 of the pyrazole nucleus. Such a
mechanism suggests a stabilization effect of the ester moiety
of 8, which is in effect acting as a pyrazole C4 protecting
group. This is all the more true as an acid (or a basic) hy-
drolysis of 12a leads to a subsequent decarboxylation and
thus to 67% (or 76%) of the stable 5-iodopyrazole 13.
To illustrate the diversity attainable from compounds 8
and 10–13, a few chemical transformations were studied.
Scheme 2 depicts the copper-based N-phenylation of these
compounds by using phenylboronic acid.[9,17] From 8, a 92%
yield of the N1-phenylation product 14a along with 7% of
its isomer 15a were obtained. The latter isomer is actually
the only one that had been partially reported previously.[18]
The N-phenylation of the 4-iodo-bearing compound 11 gave
71% of the N1-phenylation product 14b and only traces of
15b. On the other hand, this reaction proceeded with a
lesser selectivity from compound 12a as the N-phenyl deriv-
ative 14c was obtained in a 60% yield along with 26% of
15c. A similar result was observed from 12b, which led to
compounds 14d and 15d in 54 and 13% yield, respectively.
In addition, from compound 10, isomers 14e and 15e are
obtained in 56 and 20% yield, respectively. Arylation of
compound 13 also proceeded well; however, we could not
separate the 1:3 mixture of the corresponding isomeric prod-
ucts. A remarkable phenomenon took place if the arylation
of 12a was run under an inert atmosphere. The 1H NMR
spectra and the LCMS monitoring of the reaction mixture
pointed out the occurrence of the expected derivative 14c
along with a substantial amount of the reduced derivative
14a. As far as we know, such copper-caused halide reduction
in an oxygen-deprived medium at room temperature has not
been reported previously. The closest observation is proba-
Scheme 1. i) for 7a: NH2NH2, HCl, EtOH, reflux; ii) HCl 6n reflux or
NaOH, ethanol 20%, 1708C, MW; iii) I2, NaI, K2CO3, EtOH, H2O; iv) N-
iodosuccinimide or N-bromosuccinimide, cyclohexane, reflux.
generalization of processes[12] involving either a transient N-
carboxylation or -acetylation prior to a, then selective, O-al-
kylation. We wish to report here an alternative that shunts
these three steps (the synthesis of the pyrazol-3-one, its tran-
sient N-protection, followed by its selective O-alkylation) as
we prepared the readily O-protected ethyl 3-ethoxy-1H-pyr-
azole-4-carboxylate (8) in one step. This was achieved from
diethyl 2-(ethoxymethylene)malonate (7a) in a 41% yield
by means of its condensation with hydrazine hydrochloride
in boiling ethanol. The alternative reaction product, the
known ethyl 3-hydroxy-1H-pyrazole-4-carboxylate 9, is also
isolated in a 37% yield and is actually the sole compound
obtained when using hydrazine hydrate.[12a,13] Surprisingly,
this synthetic pathway has no precedent, although the reac-
tion mechanism is likely to be related to the one-step syn-
thesis of C5-substituted-3-alkoxypyrazoles from alkylacetoa-
cetates that we improved recently.[7] This reaction turns out
to proceed in a similar 42% yield from diethyl 2-[(dimethyl-
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5-Iodo-3-Ethoxypyrazoles
FULL PAPER
product corresponding to the isomer 14e. A partial (as the
evolving hydrogen iodide poisons the catalyst) palladium-
catalyzed reduction of compound 14b also gave a small
amount of the isomer 14e. Under these reduction condi-
tions, the bromine-bearing compound 14d led to the isomer
14a. Moreover, as is shown below, further chemistry by
using compound 14c and 14d gave the same reaction prod-
uct thus completing the structure assignment of all the N-
phenyl derivatives described here.
Following this N-arylation study, we focused on pyrazoles
C4 and C5-phenylation reactions. The recently reported pal-
ladium-catalyzed decarboxylative aryl–aryl coupling[22] led
us to attempt such a reaction on 4-carboxylic acid bearing
pyrazoles. We also put to good use a microwave (MW)
oven, which greatly reduced the heating time. From acid 18,
readily obtained by the saponification of compound 8
(Scheme 3), the N-phenylated compound 14e, resulting
Scheme 2. i) PhB(OH)2, CuACHTNUGTRNEUNG(OAc)2, pyridine, 4 ꢁ molecular sieves,
CH2Cl2, air 258C; ii) HBr/AcOH 1408C; iii) NaOH, EtOH, H2O, reflux;
iv) MeSO3H, toluene reflux; v) NH3, HCOOH, ethanol Pd/C reflux.
bly the CuI-mediated reductive cross-coupling of aromatic
nitroso derivatives with arylboronates reported recently.[19]
Of related interest is the copper-catalyzed reaction between
O-acetylated oximes and arylboronates in the presence of
copper that leads to a reductive amination yielding N-aryl-
ACHTUNGTRENNUNG
imines,[20] whereas the occurrence of O-aryloxime ethers is
Scheme 3. i) KOH, EtOH, H2O, reflux; ii) PhBr, Pd
throline, K2CO3, 3 ꢁ molecular sieves, N-methylpyrrolidone (NMP),
2108C MW; iii) PhB(OH)2, [PdCl2A(dppf)] (dppf=1,1’-bis(diphenylphos-
phino)ferrocene), Cs2CO3, PrOH/H2O 1208C MW; iv) MeSO3H, toluene
reflux.
ACHTUNGRTEN(NNUG OAc)2, CuI, phenan-
described when using free oximes.[21] In our case, this halo-
gen reduction readily takes place on a large scale run if the
reaction medium is insufficiently aired. Concerning the
structure assignments of these products, as long distance cor-
relation or NOE-based NMR spectroscopic experiments
were of little use, they were ascertained beyond any doubt
by further transformations of the separated isomers. As de-
picted in Scheme 2, an exhaustive acid hydrolysis of 14a and
CTHUNGTRENNUNG
from an Ullmann/Buchwald–Hartwig reaction,[23] was the
only product isolated (in a 41% yield). From acid 17, the ex-
pected C4-arylation product 19 was isolated, although in
only an 8% yield. On the other hand, a far better 72%
yield of 19 was obtained from the 4-iodinated isomer 14b by
using the more conventional Suzuki–Miyaura aryl–aryl cross
coupling reaction. The duration of this coupling reaction
was greatly shortened by the use of the [1,1’-bis(diphenyl-
phosphino)ferrocene] dichloropalladium as a precatalyst[24]
1
15a led to compounds 16a and 16b. The H and 13C NMR
spectra of 16b in deuterated chloroform pointed out the oc-
currence of a methylene component only compatible with
the mesomeric form 16b drawn in Scheme 2. The saponifica-
tion of the ester function of compound 14a gave the acid 17,
which upon heating in the presence of an equivalent amount
of methanesulfonic acid gave 56% of a decarboxylation
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Y. L. Janin and S. Guillou
and a microwave oven. The use of these aryl–aryl coupling
conditions successfully led to the C5 phenyl derivatives 20
and 21, from compounds 12a and 14c in 75 and 74% yield,
respectively. Very similar results were obtained from the 5-
bromo homologues 12b and 14d (giving 73 or 62% yields of
compounds 20 and 21, respectively). However, attempts to
achieve a direct C5-arylation of compound 13 led to an in-
separable mixture of the arylation product, unreacted com-
pound, and some reduced materials. A similar observation
was made in the course of C4-arylation trials of compound
11 reminiscent of our earlier observations.[24a] Further work
on these specific cases is underway and will be reported
elsewhere. To complete this initial synthetic exploration, we
undertook the removal of the carboxyl moiety of com-
pounds 20 and 21. In the case of 20, this was achieved by
using strongly basic conditions leading to the known com-
pound 22 in 86% yield.[7] From ester 21, a two-step se-
quence was used leading first to acid 23, which then under-
went an acid-catalyzed decarboxylation giving the known
compound 24[25] in a 68% overall yield.
reaction conditions, we could only isolate 34% of compound
26 (instead of the highly optimistic 81% reported[26]) along
with 27% of the previously unreported 3-ethoxypyrazole de-
rivative 27. These results are thus in conformity with what
we observed from the reaction of many b-ketoesters and hy-
drazine hydrochloride.[7] Decarboxylation of compound 27
led to the 5-benzyl derivative 28 and this compound could
also be obtained in a more convergent fashion by means of
the Negishi reaction between compound 13 and benzylzinc-
bromide in a 63% yield. As mentioned above, the deprotec-
tion of these 3-alkoxypyrazoles derivatives to give the corre-
sponding pyrazol-3-ones was usually performed in a sealed
tube flushed with argon by using 33% hydrobromic acid in
acetic acid at 1408C. The complete ether cleavage of com-
pound 19 to give the 1,4-diphenylpyrazol-3-one 29 or the hy-
drolysis of the 1,5-diphenylderivatives 21 and 24 to give
compound 30 were achieved in a maximum of 5 h at this
temperature. A related heating time was required to fully
hydrolyze the carboxyl-bearing compound 20 into 5-phenyl-
pyrazol-3-one (31). On the other hand, hydrolysis of the
ethoxy moieties of the 5-phenylpyrazole 22 or the 5-benzyl
homologue 28, leading to compounds 31 and 32, respective-
ly, took 23 h of heating time to be completed.
Our attention was then drawn to a report claiming that
the condensation between phenylacetylmalonate 25 and hy-
drazine hydrochloride gives exclusively the corresponding
pyrazol-3-ones 26.[26] In light of all our results with b-ke-
toesters,[7] we reinvestigated this work. Compound 25
(Scheme 4) was prepared by using the reported magnesium-
based condensation between diethylmalonate and phenyla-
cetyl chloride.[27] In our hands, from 25, under the described
As a conclusion of this report, we also studied the regio-
chemistry of the condensation between the ethoxymethyle-
nemalonate 7a and phenyl, benzyl, or methyl hydrazine hy-
drochloride. Aside from the expected pyrazolones, this led
to the separable pair of isomers of 3 and 5-ethoxypyrazoles
derivatives. As depicted in Scheme 5, from phenyl hydrazine
Scheme 5. i) NH2NH2, HCl, EtOH, reflux.
hydrochloride, a small 1.9% of the 1-phenyl-3-ethoxy pyra-
zole derivative 14a could be isolated and 22% of the 1-
phenyl-5-ethoxy pyrazole isomer 15a. From benzyl hydra-
zine hydrochloride, the amount of 1-benzyl-3-ethoxy pyra-
zole isomer 33a rose to 5.7%, whereas the 1-benzyl-5-
ethoxy pyrazole derivative 34a was isolated in a 22% yield.
Interestingly, from methylhydrazine hydrochloride, no regio-
selectivity was observed as the isomers 33b and 34b were
both isolated in 17% yields. Their structural assignments
1
was fairly easy as H–13C NMR long distance correlations,
from the methylenes of compounds 33a and 34a or from
the methyls of compounds 33b and 34b, provided unambig-
uous evidence. Furthermore, we also searched for ethoxy-
bearing isoxazoles arising from the reaction between 7a and
hydroxylamine hydrochloride. However, contrary to a previ-
Scheme 4. i) NH2NH2, HCl, EtOH, reflux; ii) NaOH, H2O/EtOH, 1108C;
iii) PhCH2ZnBr, [PdCl2ACHTUNGTRENNUNG(dppf)], THF, 858C; iv) EtOH, reflux.
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5-Iodo-3-Ethoxypyrazoles
FULL PAPER
ous case,[7] heating was necessary for any reaction to pro-
ceed and no 3- nor 5-ethoxyisoxazole derivatives could be
detected in the reaction mixture.
Ethyl 3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (9): M.p. 1858C
(lit.:[34] 1808C); 1H NMR (400 MHz, [D6]DMSO, TMS): d=1.23 (t, 3J=
7.1 Hz, 3H), 4.15 (q, 3J=7.1 Hz, 2H), 7.90 (brs, 1H), 10.20 ppm (brs,
1H); 13C NMR (100 MHz, [D6]DMSO, TMS, D1 set to 10 s): d=19.6,
64.1, 102.2, 139.5 (br), 165.2 (br), 168.0 ppm.
Preparation of 3-ethoxy-1H-pyrazole (10): By starting from diethylethox-
ymethylenemalonate (38.9 g, 0.179 mol), the protocol described above
for the preparation of 8 was followed and the residue was dispersed in
6n hydrochloric acid (100 mL). This mixture was heated to reflux until
the end of the carbon dioxide evolution (4 h in the present case). The
aqueous phase was diluted in water, slowly made basic by the addition of
sodium hydrogencarbonate, saturated with sodium chloride, and then ex-
tracted with ethyl acetate four times. The organic phase was washed with
a 1n solution of sodium hydrogencarbonate once, with brine once, dried
over sodium sulfate, and concentrated to dryness to yield compound 10
as an oil (7.77 g, 38%). 1H NMR (400 MHz, CDCl3, TMS): d=1.43 (t,
3J=7.0 Hz, 3H), 4.23 (q, 3J=7.0 Hz, 2H), 5.74 (d, 3J=2.5 Hz, 1H), 7.37
(d, 3J=2.5 Hz, 1H), 9.40 ppm (brs, 1H); 13C NMR (100 MHz, CDCl3,
TMS): d=14.9, 64.9, 90.3, 130.2, 167.7 ppm; HRMS: m/z: calcd for
C5H8N2O+H: 113.0715; found: 113.0788.
Conclusion
These very few transformations utilizing the now available
5-iodo-bearing 3-ethoxypyrazoles pave the way to the syn-
thesis of many original chemical libraries.[28] Most of them
do have the great advantage of providing fairly elaborate
structures in just a few synthetic steps. Amongst their poten-
tial interest, we can mention the reported antimicrobial ac-
tivity of pyrazole-featuring compounds[13,25b,29] that fit our
current interest in the design of original antimycobacteri-
als.[30] The relatively easy synthesis of various analogues of
many other pyrazoles of biological interest can also be envi-
sioned. One could also mention analogues of HSP90 inhibi-
tors,[31] HIV-1 protease inhibitors,[32] and pyrazoles useful for
crop protection or with a potentially interesting biological
effect.[1] We hope that, because of the flexibility of their
chemistry, these alkoxypyrazoles may become useful in frag-
ment-based approaches in drug discovery.[33]
Preparation of 3-ethoxy-4-iodo-1H-pyrazole (11): Compound 10 (8.37 g,
0.074 mol), sodium iodide (11.2 g, 0.082 mol), and potassium carbonate
(40 g, 0.289 mol) were dissolved in water (400 mL) and ethanol (100 mL).
To this solution was added iodine (28.5 g, 0.112 mol). The resulting sus-
pension was stirred for 90 min, decolorized (if necessary) with sodium bi-
sulfate, and diluted with brine (400 mL). The resulting mixture was fil-
tered, washed with water, and dried under vacuum while heating at 708C
in a large Petri dish to sublimate the iodoform sometimes forming in this
reaction to yield compound 11 as an off-white solid (16.2 g, 91%). M.p.
1148C; 1H NMR (400 MHz, CDCl3, TMS): d=1.44 (t, 3J=7.1 Hz, 3H),
4.31 (q, 3J=7.1 Hz, 2H), 7.42 (s, 1H), 9.35 ppm (brs, 1H); 13C NMR
(100 MHz, CDCl3, TMS): d=14.8, 44.2, 65.5, 134.3, 163.2 ppm; HRMS:
m/z: calcd for C5H7N2OI+H: 238.9681; found: 238.9722.
Experimental Section
General: A Biotage initiator 2 microwave oven was used for reactions re-
quiring microwave irradiations. The 1H and 13C NMR spectra were re-
corded on a Bruker Avance 400 spectrometer at 400 and 100 MHz, re-
spectively. Shifts (d) are given in ppm with respect to the TMS signal and
coupling constants (J) are given in Hertz. Column chromatography was
performed either with Merck silica gel 60 (0.035–0.070 mm) or neutral
alumina containing a suitable proportion of water, by using a solvent
pump operating at a pressure between 2 and 7 bar (25–50 mLminÀ1) and
an automated collecting system driven by a UV detector set to 254 nm
unless stated otherwise (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 on the top of the column. The low resolution mass spec-
tra were obtained on an Agilent 1100 series LCMSD system by using an
atmospheric electrospray ionization system and the HRMS were ob-
tained by using a Waters Micromass Q-Tof with an electrospray ion
source.
Preparation of compounds 12a and 12b: Compound
4.02 mmol) and N-iodosuccinimide (0.94 g, 4.22 mmol) or N-bromosuc-
AHCTUNGERTGcNNUN inimide (0.75 g, 4.22 mmol) were refluxed in cyclohexane (50 mL) for
8 (0.74 g,
24 h or 30 min. The resulting suspension was dissolved in ethyl acetate
and then decolorized with a solution of sodium sulfite. The organic layer
was washed with brine, dried over sodium sulfate, and concentrated to
dryness. The residue was purified by chromatography over silica gel (di-
chloromethane/ethanol 98:2) to yield compound 12a (0.75 g, 60%) or
12b (0.5 g, 47%). On a small scale (3 g of compound 8), the iodo-bearing
derivative 12a was also prepared in similar yield by using a microwave
oven (45 min of heating at 1508C).
Ethyl 5-iodo-3-ethoxy-1H-pyrazole-4-carboxylate (12a): Obtained as an
1
oil that slowly solidified; m.p. 1128C; H NMR (400 MHz, CDCl3, TMS):
d=1.36 (t, 3J=7.0 Hz, 3H), 1.39 (t, 3J=7.0 Hz, 3H), 4.31 ppm (m, 4H);
13C NMR (100 MHz, CDCl3, TMS): d=14.2, 14.6, 60.4, 65.5, 87.0, 103.6,
161.9, 162.0 ppm; HRMS: m/z: calcd for C8H11IN2O3 +H: 332.9712;
found: 332.9722.
Preparation of compounds 8 and 9: Diethylethoxymethylenemalonate
(37.4 g, 0.172 mol) and hydrazine hydrochloride (12.2 g, 0.178 mol) was
refluxed in ethanol (500 mL) for 16 h. The solvent was removed under re-
duced pressure, then the residue was dispersed in water (500 mL) and
slowly made basic by the addition of solid sodium hydrogencarbonate.
The aqueous phase was extracted with dichloromethane; this organic
phase was washed with a saturated solution of sodium hydrogencarbon-
ate three times, dried over sodium sulfate, and concentrated to dryness to
yield compound 8 as an oil that solidified very slowly (13.2 g, 41%). The
aqueous phase was cautiously made acidic with concentrated hydrochlo-
ric acid, then saturated with sodium chloride, and the resulting precipi-
tate was filtered, washed with water, and dried under vacuum while heat-
ing at 608C to yield compound 9 (10 g, 37%) as a white powder.
Ethyl 5-bromo-3-ethoxy-1H-pyrazole-4-carboxylate (12b): White crystals;
m.p. 908C; 1H NMR (400 MHz, CDCl3, TMS): d=1.40 (t, 3J=7.0 Hz,
3H), 1.48 (t, 3J=7.0 Hz, 3H), 4.33 (m, 4H), 9.50 ppm (brs, 1H);
13C NMR (100 MHz, CDCl3, TMS, D1 set to 10 s): d=14.2, 14.5, 60.4,
65.7, 99.0, 119.5 (br), 161.6 (br), 162.0 ppm; HRMS: m/z: calcd for
C8H11BrN2O3 +H: 263.0031; found: 263.0049.
Preparation of 3-ethoxy-5-iodo-1H-pyrazole (13): Compound 12a (0.99 g,
3.2 mmol) was dispersed in 6n hydrochloric acid (20 mL) and heated to
reflux for 4 h. The aqueous phase was diluted in water, slowly made basic
by the addition of concentrated ammonia, and extracted with ethyl ace-
tate four times. The organic phase was washed with brine once, dried
over sodium sulfate, and concentrated to dryness to yield compound 13
as an oil that crystallized very slowly (0.52 g, 67%). M.p. <508C;
1H NMR (400 MHz, CDCl3, TMS): d=1.40 (t, 3J=7.0 Hz, 3H), 4.18 (q,
3J=7.0 Hz, 2H), 5.85 (s, 1H), 6.90 ppm (brs, 1H); 13C NMR (100 MHz,
CDCl3, TMS): d=14.7, 65.7, 83.3, 98.4, 162.4 ppm; HRMS: m/z: calcd for
C5H7IN2IO+H: 238.9681; found: 238.9621. Alternatively, compound 12a
(1.27 g, 4.09 mmol), sodium hydroxide (0.70 g, 13.4 mmol) in ethanol
Ethyl 3-ethoxy-1H-pyrazole-4-carboxylate (8): M.p. <508C; 1H NMR
3
3
(400 MHz, CDCl3, TMS): d=1.35 (t, J=7.1 Hz, 3H), 1.46 (t, J=7.1 Hz,
3H), 4.30 (q, 3J=7.1 Hz, 2H), 4.36 (q, 3J=7.1 Hz, 2H), 7.89 (s, 1H),
11.4 ppm (brs, 1H); 13C NMR (100 MHz, CDCl3, TMS): d=14.3, 14.5,
60.1, 65.3, 99.0, 134.0, 162.3, 163.8 ppm; HRMS: m/z: calcd for
C8H12N2O3 +H: 185.0926; found: 185.0971.
Chem. Eur. J. 2010, 16, 4669 – 4677
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4673

Y. L. Janin and S. Guillou
(8 mL), and water (2 mL) were heated in a microwave oven at 1508C for
3 min. The resulting mixture was dispersed in water and extracted with
ethyl acetate. The organic layer was then washed with brine, dried over
magnesium sulfate, and concentrated to dryness with a high-vacuum
pump to yield compound 13 (0.74 g, 76%) as described above.
led, in this order, to compound 15d (13%) and then its isomer 14d
(54%).
Ethyl 5-bromo-3-ethoxy-1-phenyl-1H-pyrazole-4-carboxylate (14d): Oil;
1H NMR (400 MHz, CDCl3, TMS): d=1.37 (t, 3J=7.0 Hz, 3H), 1.46 (t,
3J=7.0 Hz, 3H), 4.37 (m, 4H), 7.46 ppm (m, 5H); 13C NMR (100 MHz,
CDCl3, TMS): d=14.3, 14.6, 60.4, 65.0, 101.3, 118.4, 126.2, 128.9, 129.0,
138.5, 161.8, 162.7 ppm; HRMS: m/z: calcd for C14H15N2O379Br+Na:
361.0164; found: 361.0184.
General procedure for the N-arylation of compounds 8, and 10–12a,b:
The pyrazole derivative (5.43 mmol), benzeneboronic acid (0.73 g,
5.97 mmol), pyridine (0.88 mL, 10.9 mmol, dried over 4 ꢁ molecular
sieves), 4 ꢁ molecular sieves (2 g), and copper(II) acetate hydrate
(1.62 g, 8.15 mmol) were dispersed in dichloromethane (100 mL). The
suspension was stirred in open air for 48 h. After concentration to dry-
ness, the residue was absorbed on a small amount of silica gel and puri-
fied as described below for each pair of isomers.
Ethyl 3-bromo-5-ethoxy-1-phenyl-1H-pyrazole-4-carboxylate (15d): Oil;
1H NMR (400 MHz, CDCl3, TMS): d=1.29 (t, 3J=7.0 Hz, 3H), 1.44 (t,
3J=7.0 Hz, 3H), 4.28 (q, 3J=7.0 Hz, 2H), 4.38 (q, 3J=7.0 Hz, 2H), 7.37
(m, 1H), 7.46 (m, 2H), 7.66 ppm (m, 2H); 13C NMR (100 MHz, CDCl3,
TMS): d=14.3, 15.2, 60.6, 72.8, 101.4, 123.2, 128.1, 128.8, 129.1, 137.1,
155.1, 161.2 ppm; HRMS: m/z: calcd for C14H15N2O379Br+Na: 361.0164;
found: 361.0172.
Compounds 14a and 15a: From compound 8, chromatography over silica
gel (cyclohexane/ethyl acetate 8:1) led in this order to compound 15a
and then compound 14a (92%). The fraction containing 15a had to be
further purified by a second chromatography over neutral alumina con-
taining 1.5% water (cyclohexane/ethyl acetate 9:1) to yield pure 15a
(7%).
Compounds 14e and 15e: From compound 10, chromatography over
neutral alumina containing 1.5% water (cyclohexane/dichloromethane
9:1 and then 2:1) led, in this order, to compound 14e (56%) and its
isomer 15e (20%).
Ethyl 3-ethoxy-1-phenyl-1H-pyrazole-4-carboxylate (14a): Solid; m.p.
788C (cyclohexane); 1H NMR (400 MHz, CDCl3, TMS): d=1.38 (t, 3J=
7.1 Hz, 3H), 1.51 (t, 3J=7.1 Hz, 3H), 4.33 (q, 3J=7.1 Hz, 2H), 4.46 (q,
3J=7.1 Hz, 2H), 7.30 (m, 1H), 7.46 (m, 2H), 7.65 (m, 2H), 8.25 ppm (s,
1H); 13C NMR (100 MHz, CDCl3, TMS): d=14.4, 14.7, 60.1, 65.4, 102.2,
118.5, 126.6, 129.5, 131.1, 139.3, 162.5, 162.7 ppm; HRMS: m/z: calcd for
C14H16N2O3 +H: 261.1239; found: 261.1275.
Ethyl 3-ethoxy-1-phenyl-1H-pyrazole (14e): Oil; 1H NMR (400 MHz,
CDCl3, TMS): d=1.46 (t, 3J=7.0 Hz, 3H), 4.33 (q, 3J=7.0 Hz, 2H), 5.90
(d, 3J=2.5 Hz, 1H), 7.23 (m, 1H), 7.42 (m, 2H), 7.63 (m, 2H), 7.74 ppm
(d, 3J=2.5 Hz, 1H); 13C NMR (100 MHz, CDCl3, TMS): d=14.8, 64.9,
93.7, 117.8, 125.2, 125.5, 129.3, 140.2, 164.5 ppm; HRMS: m/z: calcd for
C11H12N2O+H: 189.1028; found: 189.1061.
1
Ethyl 5-ethoxy-1-phenyl-1H-pyrazole (15e): Obtained as an oil; H NMR
3
3
Ethyl 5-ethoxy-1-phenyl-1H-pyrazole-4-carboxylate (15a): Oil; 1H NMR
(400 MHz, CDCl3, TMS): d=1.47 (t, J=7.1 Hz, 3H), 4.19 (q, J=7.1 Hz,
2H), 5.67 (d, 3J=1.7 Hz, 1H), 7.28 (m, 1H), 7.42 (m, 2H), 7.51 (d, 3J=
1.7 Hz, 1H), 7.77 ppm (m, 2H); 13C NMR (100 MHz, CDCl3, TMS): d=
14.6, 67.9, 86.2, 122.0, 126.2, 128.8, 138.8, 139.6, 154.6 ppm; HRMS: m/z:
calcd for C11H12N2O+H: 189.1028; found: 189.0971.
3
3
(400 MHz, CDCl3, TMS): d=1.31 (t, J=7.1 Hz, 3H), 1.37 (t, J=7.1 Hz,
3H), 4.32 (q, 3J=7.1 Hz, 2H), 4.42 (q, 3J=7.1 Hz, 2H), 7.34 (m, 1H),
7.46 (m, 2H), 7.67 (m, 2H), 7.94 ppm (s, 1H); 13C NMR (100 MHz,
CDCl3, TMS): d=15.7, 16.5, 61.4, 73.4, 102.3, 124.5, 128.8, 130.2, 139.2,
143.2, 156.1, 163.6 ppm; HRMS: m/z: calcd for C14H16N2O3 +H:
261.1239; found: 261.1272.
Acid hydrolysis of compounds 14a and 15a: In a 60 mL round-bottomed
thick glass tube fitted with a PTFE-faced screw-cap, the considered pyra-
zole (1 mmol) was degassed with argon and 33% hydrogen bromide in
acetic acid (1.5 mL) was then added. The tube was closed tightly and
heated at 1408C for 4 h. The resulting solution was cooled, diluted in
water and extracted with ethyl acetate. The organic layer was washed
with brine, dried over sodium sulfate, and concentrated to dryness. The
resulting residues were purified in both cases by chromatography over
silica gel (dichloromethane/ethanol 97:3) to yield compounds 16a or 16b
as described below.
Compounds 14b and 15b: From compound 11, chromatography over
silica gel (cyclohexane/dichloromethane 8:2) led, in this order, to com-
pound 14b (71%) and its isomer 15b (1.5%).
3-Ethoxy-4-iodo-1-phenyl-1H-pyrazole (14b): Oil; 1H NMR (400 MHz,
CDCl3, TMS): d=1.48 (t, 3J=7.0 Hz, 3H), 4.42 (q, 3J=7.0 Hz, 2H), 7.24
(m, 1H), 7.43 (m, 2H), 7.58 (m, 2H), 7.79 ppm (s, 1H); 13C NMR
(100 MHz, CDCl3, TMS): d=14.7, 47.0, 65.6, 117.7, 125.7, 129.4, 131.8,
139.8, 163.7 ppm; HRMS: m/z: calcd for C11H11N2OI+H: 314.9995;
found: 315.0037.
5-Ethoxy-4-iodo-1-phenyl-1H-pyrazole (15b): Oil; 1H NMR (400 MHz,
CDCl3, TMS): d=1.32 (t, 3J=7.0 Hz, 3H), 4.21 (q, 3J=7.0 Hz, 2H), 7.34
(m, 1H), 7.47 (m, 2H), 7.54 (s, 1H), 7.68 ppm (m, 2H); 13C NMR
(100 MHz, CDCl3, TMS): d=15.3, 45.3, 71.2, 122.4, 127.2, 129.0, 138.4,
144.2, 153.2 ppm; HRMS: m/z: calcd for C11H11N2OI+H: 314.9995;
found: 315.0053.
1-Phenyl-1H-pyrazol-3ACTHNUGRTNEUNG(2H)one (16a): White powder; yield: 81%; m.p.
1588C (lit.:[35] 1568C); 1H NMR (400 MHz, [D6]DMSO, TMS): d=5.80
(d, 3J=2.5 Hz, 1H), 7.18 (m, 1H), 7.47 (m, 2H), 7.67 (m, 2H), 8.20 (d,
3J=2.5 Hz, 1H), 10.18 ppm (brs, 1H); 13C NMR (100 MHz, [D6]DMSO,
TMS): d=94.3, 116.7, 124.5, 128.3, 129.3, 139.8, 162.6 ppm; HRMS: m/z:
calcd for C9H8N2O+H: 161.0715; found: 161.0793.
1-Phenyl-1H-pyrazol-5ACTHNUTRGNEUG(N 4H)one (16b): Obtained as an oil which solidi-
fied; yield: 71%; m.p. 1208C (dec., lit.:[36] 1188C); 1H NMR (400 MHz,
CDCl3, TMS): d=3.51 (d, 3J=1.2 Hz, 1H), 7.21 (m, 1H), 7.43 (m, 2H),
7.49 (t, 1H, J=1.2), 7.88 ppm (m, 2H); 13C NMR (100 MHz, CDCl3,
TMS): d=40.9, 119.0, 125.4, 128.9, 137.9, 146.8, 169.9 ppm; HRMS: m/z:
calcd for C9H8N2O+H: 161.0715; found: 161.0799.
Compounds 14c and 15c: From compound 12a, chromatography over
neutral alumina containing 1.5% water (cyclohexane/ethyl acetate 96:4)
led, in this order, to compound 15c (26%) and then compound 14c
(60%).
Ethyl 5-iodo-3-ethoxy-1-phenyl-1H-pyrazole-4-carboxylate (14c): Solid;
m.p. 808C; 1.40 (t, 3J=7.0 Hz, 3H), 1.45 (t, 3J=7.0 Hz, 3H), 4.37 (m,
4H), 7.48 ppm (m, 5H); 13C NMR (100 MHz, CDCl3, TMS): d=14.2,
14.6, 60.3, 65.1, 90.2, 105.4, 127.1, 128.9, 129.1, 140.1, 161.9, 163.8 ppm;
HRMS: m/z: calcd for C14H15N2O3I+Na: 409.0025; found: 409.0036.
Preparation of 3-ethoxy-1-phenyl-1H-pyrazole-4-carboxylic acid (17):
Ester 14a (0.5 g, 1.92 mmol) was refluxed in a mixture of water/ethanol
1:1 (20 mL) containing sodium hydroxide (0.3 g, 7.5 mmol) for 1 h. The
resulting solution was diluted in water, made acidic with 2n hydrochloric
acid, and the resulting precipitate was filtered, washed with water, and
dried under vacuum to yield compound 17 as a white powder (0.38 g,
85%). M.p. 1728C (lit.:[37] 2168C); 1H NMR (400 MHz, [D6]DMSO,
TMS): d=1.37 (t, 3J=7.1 Hz, 3H), 4.33 (q, 3J=7.1 Hz, 2H), 7.32 (m,
1H), 7.48 (m, 2H), 7.85 (m, 2H), 8.20 ppm (s, 1H); 13C NMR (100 MHz,
[D6]DMSO, TMS): d=15.0, 65.1, 102.6, 118.4, 126.8, 129.9, 133.2, 139.3,
162.4, 163.3 ppm; HRMS: m/z: calcd for C12H12N2O3 +H: 233.0926;
found: 233.0973.
Ethyl 3-iodo-5-ethoxy-1-phenyl-1H-pyrazole-4-carboxylate (15c): Oil;
1H NMR (400 MHz, CDCl3, TMS): d=1.28 (t, 3J=7.1 Hz, 3H), 1.43 (t,
3J=7.1 Hz, 3H), 4.27 (q, 3J=7.1 Hz, 2H), 4.38 (q, 3J=7.1 Hz, 2H), 7.39
(m, 1H), 7.46 (m, 2H), 7.65 ppm (m, 2H); 13C NMR (100 MHz, CDCl3,
TMS): d=14.3, 15.2, 60.5, 72.7, 99.9, 104.7, 123.2, 128.3, 128.8, 137.1,
154.7, 161.2 ppm; HRMS: m/z: calcd for C14H15N2O3I+Na: 409.0025;
found: 409.0026.
Compounds 14d and 15d: From compound 12b, chromatography over
neutral alumina containing 1.5% water (cyclohexane/ethyl acetate 97:3)
Preparation of 3-ethoxy-1,5-diphenyl-1H-pyrazole-4-carboxylic acid (23):
The protocol used for the preparation of compound 17 was used from 21
4674
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Chem. Eur. J. 2010, 16, 4669 – 4677

5-Iodo-3-Ethoxypyrazoles
FULL PAPER
to yield compound 23 as a white powder (94% yield). M.p. 2118C;
1H NMR (400 MHz, [D6]DMSO, TMS): d=1.38 (t, 3J=7.1 Hz, 3H), 4.32
(q, 3J=7.1 Hz, 2H), 7.15 (m, 2H), 7.30 ppm (m, 8H); 13C NMR
(100 MHz, [D6]DMSO, TMS): d=14.7, 64.3, 99.8, 125.4, 127.5, 127.8,
128.7, 128.8, 129.4, 130.3, 138.8, 146.3, 161.7, 163.0 ppm; HRMS: m/z:
calcd for C18H16N2O3 +H: 309.1239; found: 309.1239.
d=1.17 (t, 3J=7.0 Hz, 3H), 1.36 (t, 3J=7.0 Hz, 3H), 4.16 (q, 3J=7.0 Hz,
2H), 4.21 (q, 3J=7.0 Hz, 2H), 7.38 (m, 3H), 7.51 (m, 2H), 10.74 ppm
(brs, 1H); 13C NMR (100 MHz, CDCl3, TMS): d=14.0, 14.6, 59.8, 65.0,
96.8, 128.1, 129.0, 129.3, 129.5, 147.3, 163.2, 163.3 ppm; HRMS: m/z:
calcd for C14H16N2O3 +H: 261.1239; found: 261.1228.
Preparation of ethyl 3-ethoxy-1,5-diphenyl-1H-pyrazole-4-carboxylate
(21): This compound was obtained from compound 14c, by using the pro-
cedure described for 20, as an oil that slowly solidified in 75% yield after
a purification by chromatography over silica gel (dichloromethane/etha-
nol 99:1). M.p. 1118C; 1H NMR (400 MHz, CDCl3, TMS): d=1.22 (t,
3J=7.0 Hz, 3H), 1.31 (t, 3J=7.0 Hz, 3H), 4.15 (q, 3J=7.0 Hz, 2H), 4.48
(q, 3J=7.0 Hz, 2H), 7.28 ppm (m, 10H); 13C NMR (100 MHz, CDCl3,
TMS): d=13.9, 14.8, 59.7, 65.1, 100.1, 125.1, 127.2, 127.9, 128.7, 128.9,
129.8, 130.4, 139.2, 144.4, 162.7, 162.8 ppm; HRMS: m/z: calcd for
C20H20N2O3 +H: 337.1552; found: 337.1545.
Preparation of 3-ethoxy-1H-pyrazole-4-carboxylic acid (18): Compound 8
(1 g, 5.43 mmol) was heated to reflux in 1n sodium hydroxide solution
(11 mL) for 1 h (a shorter time is likely to be better) and upon acidifica-
tion the precipitate was filtered, washed with water, and dried under
vacuum to yield 18 as a white powder (0.62 g, 58%). M.p. 2508C (dec.);
1H NMR (400 MHz, [D6]DMSO, TMS): d=1.30 (t, 3J=7.0 Hz, 3H), 4.20
(q, 3J=7.0 Hz, 2H), 7.98 (s, 1H), 11.8 (brs, 1H), 12.5 ppm (brs, 1H);
13C NMR (100 MHz, [D6]DMSO, TMS): d=14.6, 64.0, 98.5, 134.3, 161.4,
163.4 ppm; HRMS: m/z: calcd for C6H8N2O3 +H: 157.0613; found:
157.0600.
Preparation of compounds 26 and 27: Compound 25 was prepared as de-
scribed from diethylmalonate (5 g, 0.312 mol).[26] However, despite re-
peated trials, in our hands, the batches prepared still contained 12 mol%
of ethyl phenylacetate and 12 mol% of unreacted diethyl malonate. The
batches were used without further purification. Thus, such a batch and
hydrazine hydrochloride (0.032 mol, 2.2 g) were dissolved in ethanol
(150 mL) and heated to reflux for 6 h. The resulting suspension was con-
centrated to dryness, dispersed in water, made basic with solid sodium
hydrogenocarbonate, and extracted with ethyl acetate (400 mL). The or-
ganic layer was washed with a saturated solution of sodium hydrogeno-
carbonate, washed with brine, and then dried over sodium sulfate. The
mixture was then concentrated to dryness and the residue purified by
chromatography (dichloromethane/ethanol 97.5:2.5 to 95:5) to yield, in
this order, compound 27 (2.30 g, 27% from the starting diethyl malonate)
and then the known[26] compound 26 (1.08 g, 13.8% from the starting di-
ethyl malonate). An additional amount of compound 26 (1.5 g, 20.2%
from the starting diethyl malonate) was obtained by acidification of the
aqueous phase with concentrated hydrochloric acid and then filtration of
the resulting precipitate, which was washed with water and dried under
vacuum.
Preparation of 3-ethoxy-1,4-diphenyl-1H-pyrazole (19): In a 10 mL Biot-
age-adapted tube, compound 17 (0.11 g, 0.47 mmol), bromobenzene
(0.068 mL, 0.64 mmol), potassium carbonate (0.078 g, 0.57 mmol), copper
iodide (0.009 g, 0.047 mmol), phenanthroline (0.013 mg, 0.071 mmol), and
4 A molecular sieves (0.02 g) were dispersed in N-methylpyrolidinone
(4 mL). The oxygen was removed by a slow stream of argon and palladi-
um acetate (5 mg, 0.023 mmol) was then added before sealing the tube.
This tube was heated in the microwave oven for 40 min at 2108C. The re-
sulting suspension was concentrated to dryness under high vacuum. The
residue was dispersed in water and extracted with ethyl acetate. The or-
ganic phase was washed with water, dried over sodium sulfate, and con-
centrated to dryness. The residue was purified by chromatography over
silica gel (cyclohexane/dichloromethane 95:5) to yield compound 19 as a
solid (0.010 g, 8%). M.p. 618C; 1H NMR (400 MHz, CDCl3, TMS): d=
1.58 (t, 3J=7.0 Hz, 3H), 4.55 (q, 3J=7.0 Hz, 2H), 7.27 (m, 2H), 7.48 (m,
4H), 7.70 (m, 2H), 7.81 (m, 2H), 8.04 ppm (s, 1H); 13C NMR (100 MHz,
CDCl3, TMS): d=15.0, 65.0, 109.9, 117.7, 124.4, 125.2, 126.1 (two signals),
128.6, 129.4, 131.8, 140.1, 161.4 ppm; HRMS: m/z: calcd for C17H16N2O+
H: 265.1341; found: 265.1365.
Ethyl 5-benzyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (26): Ana-
Note: As mentioned in the text, under these reaction conditions, the N-
phenylated derivative 14a described above was obtained in a 41% yield
from acid 18.
lytical data are identical with those reported.[26]
Ethyl 3-ethoxy-5-benzyl-1H-pyrazole-4-carboxylate (27): M.p. 1038C;
1H NMR (400 MHz, CDCl3, TMS): d=1.22 (t, 3J=7.0 Hz, 3H), 1.31 (t,
3J=7.0 Hz, 3H), 4.18 (m, 6H), 7.20 (m, 5H), 8.70 ppm (brs, 1H);
13C NMR (100 MHz, CDCl3, TMS): d=14.3, 14.6, 32.7, 59.8, 64.9, 97.0,
127.2, 128.9, 129.0, 135.9, 147.6, 163.1, 163.4 ppm; HRMS: m/z: calcd for
C15H18N2O3 +H: 275.1396; found: 275.1360.
Preparation of 3-ethoxy-5-phenyl-1H-pyrazole (22): Compound 20
(0.08 g, 0.30 mmol) and sodium hydroxide (1 g, 25 mmol) were heated to
reflux in a mixture of water (4 mL) and ethanol (2 mL) for 12 h. The so-
lution was extracted with ethyl acetate, dried over sodium sulfate, and
concentrated to dryness to yield 22 (0.05 g, 86%). This compound was
identical to a sample we have previously prepared.[7]
Preparation of 5-benzyl-3-ethoxy-1H-pyrazole (28)
Preparation of 3-ethoxy-1,5-diphenyl-1H-pyrazole (24): Acid 23 (0.08 g,
0.25 mmol) and methanesulfonic acid (0.016 mL, 0.25 mmol) were re-
fluxed in toluene (20 mL) for 2 h. The solution was washed with a satu-
rated sodium hydrogencarbonate solution, dried over sodium sulfate, and
concentrated to dryness to yield compound 24 as an oil (0.05 g, 73%).
1H NMR (400 MHz, CDCl3, TMS): d=1.46 (t, 3J=7.1 Hz, 3H), 4.34 (q,
3J=7.1 Hz, 2H), 5.97 (s, 1H), 7.27 ppm (m, 10H); 13C NMR (100 MHz,
CDCl3, TMS): d=14.9, 64.7, 93.7, 124.9, 126.7, 128.3, 128.4, 128.7, 128.8,
130.7, 140.1, 144.1, 163.5 ppm; HRMS: m/z: calcd for C17H16N2O+H:
265.1341; found: 265.1286.
By decarboxylation of 27: In a Teflon flask, compound 27 (1.32 g, 4.81
mol) was dispersed in a mixture of water/ethanol 1:2 (45 mL) containing
sodium hydroxide (5 g, 0.12 mol). This was heated at 1108C under an
inert atmosphere for 16 h and then diluted in water. The aqueous phase
was extracted with dichloromethane, the organic layer was washed with
brine, dried over sodium sulfate, and concentrated to dryness to yield
compound 28 as described below (0.83 g, 85%).
Alternative preparation of 28 by a Negishi reaction: In a glass tube seala-
ble with a teflon-coated joint, compound 13 (0.35 g, 1.49 mmol) was de-
gassed with argon.
A 0.5m solution of benzylzincbromide in THF
Representative aryl–aryl coupling procedure, preparation of ethyl 3-
(4.47 mmol, 9 mL) was added, followed by [1,1’-bis(diphenylphosphino)-
ferrocene] dichloropalladium complexed with dichloromethane (0.06 g,
0.074 mmol). This mixture was sealed and heated at 858C for 6 h by
using an oil bath. After cooling to room temperature, the resulting mix-
ture was diluted in ethyl acetate, washed with a 0.25n solution of potassi-
um sodium tartrate twice and water once, dried over sodium sulfate, and
concentrated to dryness. The residue was purified by chromatography
over silica gel (dichloromethane/ethanol 99:1) to yield compound 28
(0.19 g, 63%) as colorless crystals. M.p. 968C; 1H NMR (400 MHz,
CDCl3, TMS): d=1.38 (t, 3J=7.1 Hz, 3H), 3.96 (s, 2H), 4.17 (q, 3J=
7.1 Hz, 2H), 5.54 (s, 1H), 7.28 ppm (m, 5H); 13C NMR (100 MHz,
CDCl3, TMS): d=14.8, 32.8, 65.0, 89.6, 126.9, 128.7, 128.8, 137.2, 144.5,
163.2 ppm; HRMS: m/z: calcd for C12H14N2O+H: 203.1184; found:
203.1135.
ethoxy-5-phenyl-1H-pyrazole-4-carboxylate (20): In
a 10 mL biotage-
adapted tube, compound 13 (0.10 g, 0.34 mmol), phenyl boronic acid
(0.054 g, 0.442 mmol), and cesium carbonate (0.28 g, 0.847 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 [1,1’-bis(diphenylphosphino)-
ferrocene] dichloropalladium complexed with dichloromethane
(0.057 mmol) was then added before sealing the tube. This was heated in
the microwave oven for 30 min at 1208C. The resulting suspension was
diluted in water and extracted with dichloromethane. The organic layer
was washed with brine, dried over sodium sulfate, and concentrated to
dryness. The residue was purified by a chromatography over silica gel (di-
chloromethane/ethanol 99:1) to yield compound 20 as an oil that slowly
solidified (0.065 g, 73%). M.p. 958C; 1H NMR (400 MHz, CDCl3, TMS):
Chem. Eur. J. 2010, 16, 4669 – 4677
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4675

Y. L. Janin and S. Guillou
Preparation of 1,4-diphenyl-1H-pyrazol-3(2H)one (29): In
a
60 mL
Ethyl 5-ethoxy-1-methyl-1H-pyrazole-4-carboxylate (34b): Oil; yield:
17% after chromatography over neutral alumina containing 1.5% water
(cyclohexane/ethyl acetate 95:5 to 4:1); 1H NMR (400 MHz, CDCl3,
round-bottomed thick glass tube fitted with a PTFE-faced screw-cap, the
ethoxypyrazole 19 (0.1 g, 1 mmol) was degassed with argon. Following
this, 33% hydrogen bromide in acetic acid (1.0 mL) was added, the tube
was tightly closed and was heated at 1408C for 4 h. The resulting reaction
mixture then precipitated in water to give compound 29 (0.074 g, 83%)
3
TMS): d=1.35 (t, 3J=7.1 Hz, 3H), 1.41 (t, J=7.0 Hz, 3H), 3.68 (s, 3H),
4.27 (q, 3J=7.1 Hz, 2H), 4.48 (q, 3J=7.0 Hz, 2H), 7.76 ppm (s, 1H);
13C NMR (100 MHz, CDCl3, TMS): d=14.4, 15.4, 34.1, 59.9, 71.6, 99.3,
140.7, 154.7, 162.4 ppm; HRMS: m/z: calcd for C9H14N2O3 +H: 199.1083;
found: 199.1001.
as
a
white powder. M.p. 1958C (lit.: 202[38] or 2058C[39]); 1H NMR
(400 MHz, [D6]DMSO, TMS): d=7.17 (m, 2H), 7.43 (m, 2H), 7.39 (m,
2H), 7.47 (m, 2H), 7.77 (m, 4H), 8.76 (s, 1H), 10.93 ppm (brs, 1H);
13C NMR (100 MHz, [D6]DMSO, TMS): d=109.0, 117.2, 125.3, 125.9,
126.0, 126.1, 128.9, 129.9, 132.4, 140.0, 160.4 ppm; HRMS: m/z: calcd for
C15H12N2O+H: 237.1028; found: 237.1043.
Acknowledgements
Preparation of 1,5-diphenyl-1H-pyrazol-3(2H)one (30): In
a 60 mL
round-bottomed thick glass tube fitted with a PTFE-faced screw-cap, a
mixture of compound 21 (0.062 g, 0.23 mmol) was degassed with argon.
Following this, 33% hydrogen bromide in acetic acid (1.0 mL) was
added, the tube was tightly closed and was heated at 1408C for 5 h. The
resulting suspension was dissolved in ethanol, concentrated to dryness,
made basic with ethanolic ammonia, and concentrated to dryness again.
The residue was purified by chromatography over silica gel (dichlorome-
thane/ethanol 97:3) to yield compound 30 (0.045 g, 81%) as a white
powder. M.p. >2508C (lit.:[40] 2578C); 1H NMR (400 MHz, [D6]DMSO,
TMS): d=5.94 (s, 1H), 7.15–7.42 (m, 10H), 10.19 ppm (brs, 1H);
13C NMR (100 MHz, [D6]DMSO, TMS): d=94.3, 124.5, 126.5, 128.28,
128.31, 128.5, 128.8, 130.4, 139.9, 143.1, 161.7 ppm; HRMS: m/z: calcd for
C15H12N2O+H: 237.1028; found: 237.0966.
This work was supported by the Medicen initiative (Chemical Library
Project, grant of the Rꢂgion Ile de France no. I 06-222/R and I 09-1739/
R, which included a fellowship for S.G.). Dr. D. Larzul and Dr. E. Bisag-
ni are also acknowledged for their interest and support.
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Ethyl 1-benzyl-3-ethoxy-1H-pyrazole-4-carboxylate (33a): Oil; yield:
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Published online: March 23, 2010
Chem. Eur. J. 2010, 16, 4669 – 4677
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4677