A simple new hydrazine-free synthesis of methyl 1,4,5-trisubstituted 1H-pyrazole-3-carboxylates

Article abstract of DOI:10.1007/s00706-013-0962-2

Conditions for successful syntheses of polysubstituted pyrazole-3- carboxylates have been found. The methodology consists in mixing equimolar amounts of diazonium tetrafluoroborates and enaminoesters in presence of sodium acetate. 1-Methylpyrrolidone has

Full text of DOI:10.1007/s00706-013-0962-2

Monatsh Chem (2013) 144:1013–1019
DOI 10.1007/s00706-013-0962-2
ORIGINAL PAPER
A simple new hydrazine-free synthesis of methyl
1,4,5-trisubstituted 1H-pyrazole-3-carboxylates
•
Bretislav Broz Zdenka Padelkova
•
ˇ
ˇ
ˇ
Valerio Bertolasi Petr Simunek
ˇ
´
ˇ
•
˚
Received: 4 December 2012 / Accepted: 5 March 2013 / Published online: 15 May 2013
Ó Springer-Verlag Wien 2013
Abstract Conditions for successful syntheses of poly-
substituted pyrazole-3-carboxylates have been found. The
methodology consists in mixing equimolar amounts of
diazonium tetrafluoroborates and enaminoesters in pres-
ence of sodium acetate. 1-Methylpyrrolidone has appeared
to be the solvent of choice. The compounds prepared have
been characterized by means of nuclear magnetic reso-
nance (NMR) spectroscopy, elemental analysis, and in two
cases, also by X-ray diffraction. The advantage of the
methodology is a simple implementation without necessity
of working under inert atmosphere. The presence of other
functional groups enables further synthetic transformations
of the products.
Introduction
Compounds containing pyrazole motif are relatively rare in
nature. Among some exceptions rank withasomnine, iso-
lated from the Indian plant Withania somnifera [1], or
pyrazomycines that are very efficient antivirotics and an-
tineoplastics, isolated from Streptomyces candidus [2].
Pyrazole derivatives have found broad applications as
either pharmaceutics [3] [e.g., nonsteroidal anti-inflam-
matory drugs (NSAIDs), antivirotics, antineoplastics, etc.]
or pesticides [4]. Synthesis of pyrazoles attracts great
attention and is the subject of many reviews; for some of
them see [5–12]. Probably the most widespread method for
construction of the pyrazole skeleton is the reaction of 1,3-
difunctional compounds with hydrazine derivatives. The
drawbacks of this methodology are, on the one hand, the
substantial toxicity of some hydrazines and, on the other
hand, the possibility of the formation of regioisomers in
case of using unsymmetrical starting compounds.
Keywords NMR spectroscopy Á Diazonium salts Á
X-ray structure determination Á Enaminoesters Á
Heterocycles
A few years ago we published a simple new method for
synthesis of polysubstituted pyrazoles from b-enaminones
[13] using diazonium salts as nitrogen source. This method
is generally safer, as the risk upon working with stabilized
diazonium salts is sometimes lower in comparison with
hydrazines. Another advantage of the methodology is its
regioselectivity. Only 3-acyl derivatives have been hitherto
isolated (Scheme 1). As arylhydrazines are usually pre-
pared from the corresponding diazonium salts, the
methodology also shortens the synthesis. Later we suc-
cessfully used the methodology for synthesis of some
fluorinated pyrazoles [14].
ˇ
ˇ
˚
B. Broz Á P. Simunek (&)
Faculty of Chemical Technology, Institute of Organic Chemistry
´
and Technology, University of Pardubice, Studentska 573,
532 10 Pardubice, Czech Republic
e-mail: petr.simunek@upce.cz
ˇ
´
Z. Padelkova
Department of General and Inorganic Chemistry, Faculty
of Chemical Technology, University of Pardubice,
´
Studentska 573, 532 10 Pardubice, Czech Republic
The products of the reaction represent, due to the pres-
ence of both carbonyl and amino group, useful precursors
for further synthetic transformations. In addition to that, the
above-mentioned protocol has considerable potential for
V. Bertolasi
Dipartimento di Scienze Chimiche e Farmaceutiche,
`
Centro di Strutturistica Diffrattometrica, Universita di Ferrara,
Via L. Borsari 46, 441 00 Ferrara, Italy
123

ˇ
B. Broz et al.
1014
Scheme 1
NHR2
N
O
O
NHR2
AcONa
R1
R1
ArN2 BF4
+
R
CH2Cl2, r.t.
R
N
Ar
R = Et, Ph, cycloPr
R1 = Me, Ph
R2 = H, Me, subst. Ph
Scheme 2
O
NH2
NH4OAc
CH3
MeOH, r.t.
MeO
1d
O
NR1R2
O
O
R
Zn(OAc)2
MeO
+ R1R2NH
R
MgSO4
CH2Cl2, r.t.
MeO
1a R = Me, R1 = Me, R2 = H
1b R = Me, R1, R2 = morpholine-1-yl
1c R = COOMe, R1 = Me, R2 = H
R = Me, COOMe
extension to other polarized ethylenes (enaminoesters, e-
naminoamides, enaminonitriles, etc.), which would enable
access to other pyrazole derivatives. The goal of the
present work is to find conditions for transformation of
enaminoesters to the corresponding pyrazoles.
‘‘Experimental’’). Upon an attempt to prepare diester 2g,
application of sodium acetate failed, but success was
achieved using tripotassium phosphate as the base.
The structure of the prepared compounds was confirmed
1
using H and 13C NMR spectroscopy, elemental analysis,
and in case of derivatives 2b and 2e also by means of X-ray
diffraction (Figs. 1–3).
Results and discussion
ORTEP [16] views of compounds 2b and 2e are shown
in Figs. 1 and 3. Compound 2b crystallizes in the ortho-
rhombic space group P212121 with four molecules within
the unit cell without intermolecular hydrogen bonding.
Only the intramolecular N(1)–H(1)ÁÁÁO(2) contact is pres-
ent, along with other short contacts forming a three-
dimensional (3D) structure (Fig. 2). In the molecule of 2b,
the interatomic angles within the central heterocyclic ring
confirm that this ring is planar. The arrangement of the
substituents of this ring led to self-assembly of the mole-
cules, producing a helical superstructure in the solid state
with chiral properties similar to, for example, in helicenes.
Although a high degree of conjugation is observed through
the molecule, C2–C3 and C1–N3 bonds are attributed as
the multiple ones [17]. Direct comparison of the structure of
2b with recently obtained structures of compounds with the
same central ring (1-(4-methoxyphenyl)-4-(methylamino)-
5-phenyl-1H-pyrazol-3-yl(phenyl)methanones [13]) could
be made, with the exception that these structures do not
reveal atropoisomerism. Similar structures of different het-
erocycles also exist [18–22].
The starting enaminoesters 1a–1c were prepared by adop-
tion of the method published by Vohra et al. [15]; the
derivative 1d with primary amino group was prepared
using ammonium acetate as ammonia source (Scheme 2).
Enaminoester 1b is very unstable and undergoes decom-
position even under cooling; hence, the crude reaction
mixture was, after structure elucidation by NMR, used for
the next step without further purification.
As the starting point we used the conditions successfully
applied for synthesis of 1-aryl-4-(substituted amino)-5-acyl-
1H-pyrazoles [13] (CH2Cl2, 2 eq. of diazonium salt, 6 eq. of
AcONa). Only low yield (25 %) of pyrazole 2a was isolated
after time-consuming work-up of the reaction mixture.
Upon gradual change of the reaction parameters (base,
solvent, and ratio of starting components), it was found that
the key factor was solvent selection. 1-Methylpyrrolidone
(NMP) turned out to be the most convenient one. Appli-
cation of this solvent led to successful synthesis of
derivatives 2a–2d in moderate to low yields (Scheme 3,
123

A simple new hydrazine-free synthesis
1015
Scheme 3
NR1R2
N2 BF4
O
O
NR1R2
R
Base
R
MeO
+
MeO
N
N
NMP, r.t.
1a-1d
X
X = Me, OMe, F, NO2
2a-2g
X
2a R = Me, R1 = Me, R2 = H, X = Me
2b R = Me, R1 = Me, R2 = H, X = NO2
2c R = Me, R1 = Me, R2 = H, X = F
2d R = Me, R1, R2 = morpholine-1-yl, X = Me
2e R = Me, R1, R2 = morpholine-1-yl, X = OMe
2f R = Me, R1, R2 = H, X = Me
2g R = COOMe, R1 = Me, R2 = H, X = Me
Fig. 1 Molecular structure of
2b (ORTEP 50 % probability
level) with H-bonding
interaction [N(1)–H(1)ÁÁÁO(2),
˚
2.875(3) A]
Conclusions
The method described here extends the synthetic arsenal
for construction of the pyrazole moiety. Its extension to
other polarized ethylenes is currently under research.
Enaminoesters turned out to be much more challenging
substrates for synthesis of pyrazoles by reaction with dia-
zonium salts than corresponding enaminoketones. Upon
gradual optimization, conditions for successful synthesis of
polysubstituted pyrazole carboxylates were found. The
advantage of the protocol is a simple implementation
without the demand to work under inert atmosphere or to
use hydrazine derivatives. Only pyrazole-3-carboxylates
were isolated. Enaminoesters having primary as well as
secondary or tertiary amino groups were successfully used.
The method is applicable for diazonium salts bearing both
electron-donating and electron-withdrawing groups. A
certain drawback of the method is the moderate to low
yield.
Experimental
Diazonium tetrafluoroborates were freshly prepared before
use by standard procedures (dissolving the appropriate ani-
line in dilute hydrochloric acid, adding sodium nitrite
solution, and subsequent treatment of the formed diazonium
chloride by aqueous sodium tetrafluoroborate) and dried
in vacuo. NMR spectra were measured in CDCl3 at labora-
tory temperature using a Bruker AVANCE 400 spectrometer
operating at 400.13 MHz (1H), 376.46 MHz (19F), and
100.62 MHz (13C). The 1H NMR spectra were calibrated on
123

ˇ
B. Broz et al.
1016
Fig. 2 Supramolecular
architecture of 2b, view along
the b-axis
Crystallography
X-ray data were collected on a Nonius Kappa charge-
coupled device (CCD) diffractometer with Mo Ka radiation
˚
(k = 0.71073 A), a graphite monochromator, and the /
and v scan mode. Data for orange single crystal of 2b were
obtained at 150 K using an Oxford Cryostream low-tem-
perature device and for compound 2e at laboratory
temperature (295 K). Data reductions were performed with
DENZO-SMN [24]. The absorption was corrected by
integration methods [25]. The structures were solved by
direct methods (SIR92 [26] for 2b or SIR97 [28] for 2e)
and refined by full matrix least-squares based on F2
(SHELXL97) [27]. Hydrogen atoms were mostly localized
on a difference Fourier map; however, to ensure uniformity
of treatment of crystal, all hydrogens were recalculated into
idealized positions (riding model) and assigned tempera-
ture factors Hiso(H) = 1.2Ueq (pivot atom) or 1.5Ueq for
˚
the methyl moiety with C–H = 0.96 and 0.93 A for methyl
and hydrogen atoms in aromatic ring, respectively. The
hydrogen atom of N–H group was placed according to
appropriate maxima on Fourier difference map.
Fig. 3 ORTEP view of 2e showing the thermal ellipsoids at 30 %
level of probability
Crystallographic data for structural analysis have been
deposited with the Cambridge Crystallographic Data Centre,
CCDC 913069 for 2b and CCDC 900893 for 2e. Copies of
this information may be obtained, free of charge, from The
Director, CCDC, 12 Union Road, Cambridge CB2 1EY, UK
(fax: ? 44(0)-1223-336033; e-mail: deposit@ccdc.cam.ac.
uk or via http://www.ccdc.cam.ac.uk/conts/retrieving.html).
tetramethylsilane (TMS, d = 0.0 ppm). The 13C NMR
spectra were measured in the standard way and by attached
proton test (APT) pulse sequence, and calibrated on the
central signal of the solvent multiplet (d = 77.16 ppm). 19
F
NMR spectra were measured using Waltz-16 proton
decoupling and were standardized against fluorobenzene as
the secondary external standard (d = -113.1 against CFCl3
as primary standard [23]). Elemental analyses were per-
formed on a Flash 2000 CHNS elemental analyzer. Melting
points were measured on a Kofler hot-stage microscope
(Boetius PHMK 80/2644).
General procedure for preparation of enaminoesters
1a–1c
An appropriate b-ketoester (30 mmol), 0.33 g zinc acetate
dihydrate (1.5 mmol, 5 mol %), and 0.72 g anhydrous
123

A simple new hydrazine-free synthesis
1017
MgSO4 (6 mmol, 20 mol %) were added into a flask equip-
ped with a calcium chloride drying tube and suspended in
40 cm3 dichloromethane. A corresponding amine (30 mmol)
was then added in one portion, and the reaction mixture was
stirred at room temperature for 16 h. Subsequently, another
portion of 0.72 g MgSO4 was added into the mixture and the
suspension was stirred for 2 days. Solid compounds were
then filtered off, and the filtrate was evaporated in vacuo to
give products 1a–1c. All products were used in next steps
without further purification unless otherwise stated.
added to a dried flask equipped with a calcium chloride
drying tube. The mixture was then ice-cooled, and an
appropriate benzenediazonium tetrafluoroborate (4 mmol)
was added stepwise (during 20 min). The reaction tem-
perature was then spontaneously raised to laboratory value,
and the mixture was stirred for 4 days. Subsequently, the
reaction mixture was diluted with 25 cm3 ethyl acetate and
filtered through CeliteÒ. The clear filtrate was extracted
with 20 cm3 50 % brine, 20 cm3 water, and concd. brine
(2 9 20 cm3). The organic layer was dried over Na2SO4
and evaporated in vacuo. The crude product was suspended
in 10 cm3 diluted (1:1) aqueous HCl and was well shaken.
Undissolved solids were filtered off, and the filtrate was
extracted with diethyl ether (4 9 10 cm3). The aqueous
phase was then neutralized with solid NaHCO3. Precipi-
tated products 2a, 2b, and 2d were collected by filtration;
compounds 2c and 2e–2g were isolated by extraction with
dichloromethane (2 9 20 cm3), drying of the organic layer
over Na2SO4, and evaporating in vacuo. The resulting oils
solidified on standing.
Methyl 3-(methylamino)pent-2-enoate (1a)
Prepared from methyl 3-oxopentanoate and 8 M ethanolic
solution of methylamine. Yellow oily compound, 92 %
1
yield. H NMR (400.13 MHz): d = 8.51 (br s, 1H), 4.48
(s, 1H), 3.62 (s, 3H), 2.91 (d, J = 5.3 Hz, 3H), 2.23 (q,
J = 7.5 Hz, 2H), 1.14 (t, J = 7.5 Hz, 3H) ppm.
Methyl 3-(morpholin-4-yl)pent-2-enoate (1b)
Methyl 5-methyl-4-(methylamino)-1-(4-methylphenyl)-1H-
pyrazole-3-carboxylate (2a, C14H17N3O2)
Prepared from methyl 3-oxopentanoate and morpholine.
An unstable brown oily compound was obtained, which
was used immediately for the next reaction step.
1
Light-yellow solid; yield 49 %; m.p.: 80–85 °C; H NMR
(400.13 MHz): d = 7.28–7.32 (m, 2H), 7.23–7.28 (m, 2H),
4.42 (br s, 1H), 3.92 (s, 3H), 2.90 (s, 3H), 2.40 (s, 3H), 2.31
(s, 3H) ppm; 13C NMR (100.62 MHz): d = 164.6, 138.5,
136.9, 136.6, 131.6, 129.7, 127.2, 125.4, 51.7, 35.0, 21.2,
11.6 ppm.
Dimethyl 3-(methylamino)pent-2-enedioate (1c)
Prepared from dimethyl 3-oxopentanedioate and 8 M eth-
anolic solution of methylamine. The isolated yellow oil
crystallized using an ultrasonic bath. The crude product
was washed thoroughly with diethyl ether, and the resulting
white solid 1c was isolated in 62 % yield. M.p.: 83–88 °C
(Ref. [29] 83–90 °C).
Methyl 5-methyl-4-(methylamino)-1-(4-nitrophenyl)-1H-
pyrazole-3-carboxylate (2b, C13H14N4O4)
Red solid; yield 46 %; m.p.: 154–156 °C; 1H NMR
(400.13 MHz): d = 8.33–8.39 (m, 2H), 7.60–7.72 (m,
2H), 4.69 (br s, 1H), 3.95 (s, 3H), 2.94 (s, 3H), 2.44 (s, 3H)
ppm; 13C NMR (100.62 MHz): d = 164.2, 146.9, 144.2,
137.9, 133.5, 126.6, 125.3, 124.8, 52.0, 34.9, 12.2 ppm.
Crystallographic data for 2b: C13H14N4O4, M = 290.28,
Methyl 3-aminopent-2-enoate (1d)
Methyl 3-oxopentanoate (2.5 cm3, 20 mmol) was intro-
duced under argon atmosphere to the clear solution of
7.71 g ammonium acetate (100 mmol) in 25 cm3 methanol
and stirred at room temperature for 3 days. The solvent was
then evaporated in vacuo, and 30 cm3 chloroform was
added. The resulting solid was then filtered off and washed
with chloroform (2 9 15 cm3). The combined filtrate was
washed with 15 cm3 water and 15 cm3 brine, dried over
Na2SO4, and evaporated in vacuo to give 1d (2.25 g) as
yellow oil in 87 % yield. The 1H NMR spectrum was
found to agree with the one described in Ref. [30].
˚
orthorhombic, space group P212121, a = 7.4490(4) A,
˚
˚
b = 11.6130(7) A, c = 15.5131(10) A, b = 90°, Z = 4,
V = 1341.96(14) A , Dc = 1.437 g cm-3; hmax = 27.49°;
3
˚
3,035 independent reflections measured, 2,294 reflections
observed with I [ 2r(I), 190 parameters, S = 1.184, R1
(obs. data) = 0.0536, wR2 (all data) = 0.0956.
˚
Selected interatomic distances (A) and angles (°): C1–
C2 1.418(3), C2–C3 1.376(4), C3–N2 1.390(3), N2–N3
1.344(3), C1–N3 1.340(3), O1–C10 1.333(3), O2–C10
1.211(3), C2–N1 1.387(3), N1–C12 1.451(3), C7–N4
1.468(3), N4–O3 1.228(3), N4–O4 1.224(3); C1–C2–C3
105.2(2), C2–C3–N2 105.1(2), C3–N2–N3 113.7(2), N2–
N3–C1 103.68(19), N3–C1–C2 112.3(2), C1–C2–N1
125.5(2), C2–N1–C12 121.4(2), C1–C10–O2 123.0(2),
N3–C1–C10 122.6(2), O1–C10–O2 123.0(3), C7–N4–O3
118.6(2), O3–N4–O4 123.4(2).
General procedure for preparation of pyrazoles 2a–2g
The corresponding enaminoester 1a–1d (2 mmol), 0.98 g
sodium acetate (12 mmol), and 5 cm3 dry NMP were
123

ˇ
B. Broz et al.
1018
Methyl 1-(4-fluorophenyl)-5-methyl-4-(methylamino)-1H-
pyrazole-3-carboxylate (2c, C13H14FN3O2)
Dimethyl 4-(methylamino)-1-(4-methylphenyl)-1H-
pyrazole-3,5-dicarboxylate (2g, C15H17N3O4)
The isolated compound was purified by column chroma-
tography (silica gel/AcOEt) and obtained as yellow solid in
41 % yield. M.p.: 94–98 °C; 1H NMR (400.13 MHz):
d = 7.42–7.49 (m, 2H), 7.14–7.18 (m, 2H), 4.72 (br s, 1H),
3.93 (s, 3H), 2.91 (s, 3H), 2.31 (s, 3H) ppm; 13C NMR
Enaminoester 1c (373 mg, 2 mmol), 1.27 g tripotassium
phosphate (6 mmol), and 5 cm3 dry NMP were added to a
dried flask equipped with a calcium chloride drying tube.
The mixture was then ice-cooled and 826 mg 4-meth-
ylbenzenediazonium tetrafluoroborate (4 mmol) was added
stepwise (during 15 min). The reaction temperature was
then spontaneously raised to r.t. and the mixture was stirred
for 2 days. Subsequently, the reaction mixture was diluted
with 25 cm3 ethyl acetate and filtered through CeliteÒ. The
clear filtrate was extracted with 20 cm3 50 % brine, 20 cm3
water, and concd. brine (2 9 20 cm3). The organic layer
was dried over Na2SO4 and evaporated in vacuo. The crude
product was purified by column chromatography (silica
gel/AcOEt) and obtained as brown-yellow solid in 26 %
yield. M.p.: 114–116 °C; 1H NMR (400.13 MHz):
d = 7.23–7.27 (m, 2H), 7.19–7.23 (m, 2H), 3.93 (s, 3H),
3.70 (s, 3H), 3.04 (s, 3H), 2.40 (s, 3H) ppm; 13C NMR
(100.62 MHz): d = 163.6, 160.4, 143.6, 139.0, 138.6,
130.8, 129.3, 125.6, 119.3, 52.2, 51.8, 34.4, 21.4 ppm.
1
(100.62 MHz): d = 164.4, 162.3 (d, JCF = 249.0 Hz),
4
136.8, 135.4 (d, JCF = 3.3 Hz), 131.9, 127.4 (d,
3JCF = 8.8 Hz), 127.1, 116.1 (d, 2JCF = 22.7 Hz),
51.7, 34.9, 11.5 ppm; 19F NMR (376.46 MHz):
d = -112.4 ppm.
Methyl 5-methyl-1-(4-methylphenyl)-4-(morpholin-4-yl)-
1H-pyrazole-3-carboxylate (2d, C17H21N3O3)
1
Brown-red solid; yield 23 %; m.p.: 98–104 °C; H NMR
(400.13 MHz): d = 7.29–7.34 (m, 2H), 7.24–7.29 (m, 2H),
3.94 (s, 3H), 3.86–3.77 (m, 4H), 3.17–3.08 (m, 4H), 2.41
(s, 3H), 2.26 (s, 3H) ppm; 13C NMR (100.62 MHz):
d = 163.1, 138.7, 138.6, 137.1, 137.0, 135.0, 129.8, 125.2,
68.1, 52.1, 51.5, 21.3, 10.6 ppm.
Methyl 1-(4-methoxyphenyl)-5-methyl-4-(morpholin-4-yl)-
1H-pyrazole-3-carboxylate (2e, C17H21N3O4)
References
The isolated compound was purified by column chroma-
tography (silica gel/AcOEt) and obtained as brown-red
solid in 15 % yield. M.p.: 121–126 °C; 1H NMR
(400.13 MHz): d = 7.31–7.37 (m, 1H), 6.94–7.00 (m,
1H), 3.93 (s, 1H), 3.86 (s, 2H), 3.79–3.83 (m, 2H),
3.10–3.17 (m, 2H), 2.24 (s, 1H) ppm; 13C NMR
(100.62 MHz): d = 163.0, 159.7, 138.5, 137.2, 134.8,
132.6, 126.8, 114.3, 68.1, 55.7, 52.1, 51.6, 10.5 ppm.
Crystallographic data for 2e: C17H21N3O4; M = 331.37,
¨
1. Schroter HB, Neumann D, Katritzky AR, Swinbourne FJ (1966)
Tetrahedron 22:2895
2. Doyle Daves G, Cheng CC (1976) In: Ellis GP, West GB (eds)
Progress in Medicinal Chemistry, vol 13. North-Holland,
Amsterdam, p 327
3. Orth RE (1968) J Pharm Sci 57:537
4. Lamberth C (2007) Heterocycles 71:1467
5. Stanovnik B, Svete J (2002) In: Neier R (ed) Science of Syn-
thesis, vol 12. Thieme, Stuttgart, p 15
6. Schmidt A, Dreger A (2011) Curr Org Chem 15:1423
7. Schmidt A, Dreger A (2011) Curr Org Chem 15:2897
˚
triclinic, space group P-1, a = 5.9674(2) A, b =
˚
˚
´
8. Fustero S, Simon-Fuentes A, Sanz-Cervera JF (2009) Org Prep
Proced Int 41:253
10.3939(3) A, c = 14.7099(5) A, a = 102.623(1)°, b =
3
˚
92.262(1)°, c = 103.969(2)°, V = 859.88(5) A , Z = 2,
9. Elguero J (1996) In: Katritzky AR, Scriven EFV (eds) Compre-
hensive Heterocyclic Chemistry II, vol 3. Elsevier, Oxford
10. Makino K, Kim HS, Kurasawa Y (1999) J Heterocycl Chem
36:321
11. Fustero S, Sanchez-Rosello M, Barrio P, Simon-Fuentes A (2011)
Chem Rev 111:6984
12. Bekhit AA, Hymete A, Bekhit AEA, Damtew A, Aboul-Enein
HY (2010) Mini-Rev Med Chem 10:1014
ˇ
13. Simunek P, Svobodova M, Bertolasi V, Machacek V (2008)
Dc = 1.280 g cm-3
;
hmax = 28.0°; 4,093 independent
reflections measured, 3,153 reflections observed with
I [ 2r(I), 220 parameters, S = 1.044, R1 (obs. data) =
0.0645, wR2 (all data) = 0.1858.
˚
Selected interatomic distances (A): C1–C2 = 1.420(2),
C1–N2 = 1.339(2), C2–C3 = 1.383(2), N1–C3 = 1.362(2),
N1–N2 = 1.349(2).
´
´ˇ
˚
Synthesis 2008(11):1761–1766
ˇ
Methyl 4-amino-5-methyl-1-(4-methylphenyl)-1H-
pyrazole-3-carboxylate (2f, C13H15N3O2)
´ ´ˇ
˚
14. Simunek P, Svobodova M, Machacek V (2009) J Heterocycl
Chem 46:650
15. Vohra RK, Renaud JL, Bruneau C (2005) Collect Czech Chem
Commun 70:1943
16. Burnett MN, Johnson CK (1996) ORTEP III, Report ORNL-
6895. Oak Ridge National Laboratory, Oak Ridge
17. Allen FH, Kennard O, Watson DG, Brammer L, Orpen AG,
Taylor R (1987) J Chem Soc Perkin Trans 2:S1
18. Gieren A, Lamm V (1982) Acta Crystallogr Sect B 38:844
19. El-Abadelah MM, Sabri SS, Khanfar MA, Voelter W, Maichle-
Moessmer C (1999) Z Naturforsch B 54:1323
The isolated compound was purified by column chroma-
tography (silica gel/AcOEt) and obtained as orange solid in
14 % yield. M.p.: 88–92 °C; 1H NMR (400.13 MHz):
d = 7.28–7.33 (m, 2H), 7.22–7.28 (m, 2H), 3.94 (s, 3H),
2.41 (s, 3H), 2.18 (s, 3H) ppm; 13C NMR (100.62 MHz):
d = 164.5, 138.5, 137.0, 132.2, 130.8, 129.8, 125.3, 125.1,
51.8, 21.3, 10.0 ppm.
123

A simple new hydrazine-free synthesis
1019
20. Boyd M, Atwell GJ, Denny WA (1993) Acta Crystallogr Sect C
49:1429
21. Brady T, Khang V, Barber JR, Chung Ng S, Zhou Y (2009)
Tetrahedron Lett 50:6223
26. Altomare A, Cascarano G, Giacovazzo C, Guagliardi A (1994) J
Appl Crystal 27:1045
¨
27. Sheldrick GM (2008) SHELXL-97. University of Gottingen,
¨
Gottingen
22. Ibrahim HM, Behbehani H, Makhseed S, Elnagdi MH (2011)
Molecules 16:3723
23. Berger S, Braun S, Kalinowski HO (1997) NMR Spectroscopy of
the Non-metallic Elements. Wiley, Chichester
24. Otwinowski Z, Minor W (1997) Processing of X-ray diffraction
data collected in oscillation mode. In: Carter CW, Sweet RM
(eds) Methods in Enzymology, vol 276, part A. London
pp 307–326
25. Coppens P (1970) In: Ahmed FR, Hall SR, Huber CP (eds)
Crystallographic Computing. Munksgaard, Copenhagen, p 255
28. Altomare A, Burla MC, Camalli M, Cascarano GL, Giacovazzo
C, Guagliardi A, Moliterni AGG, Polidori G, Spagna R (1999) J
Appl Crystallogr 32:115
29. Augustine RL, Bellina RF, Gustavsen AJ (1968) J Org Chem
33:1287
30. Ohashi T, Oguro Y, Tanaka T, Shiokawa Z, Tanaka Y, Shibata S,
Sato Y, Yamakawa H, Hattori H, Yamamoto Y, Kondo S, Mi-
yamoto M, Nishihara M, Ishimura Y, Tojo H, Baba A, Sasaki S
(2012) Bioorg Med Chem 20:5507
123