Efficient syntheses of some versatile 3,5-bifunctional pyrazole building blocks

Article abstract of DOI:10.1055/s-2008-1032180

A series of convenient synthetic procedures are reported for pyrazole derivatives with carbonyl or ester groups in the 3- and 5-positions and variable substitution pattern at C4 and at the functional side arms. All compounds have been characterized by ¹H and ¹³C NMR spectroscopy, elemental analyses, and mass spectrometry. In addition, the structures of several pyrazole derivatives have been determined by single crystal X-ray diffraction, which provides insight into the effect of functional side arms on the hydrogen-bonded supramolecular motifs of NH-pyrazoles. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032180

800
PAPER
Efficient Syntheses of Some Versatile 3,5-Bifunctional Pyrazole Building
Blocks
S
ynthese
s
of 3,5-B
n
ifunctional
Pn
yrazoles a Sachse,a Larysa Penkova,b Gilles Noël,a Sebastian Dechert,a Oleg A. Varzatskii,c Igor O. Fritsky,*b Franc
Meyer*a
a
Institut für Anorganische Chemie, Georg-August-Universität Göttingen, Tammannstraße 4, 37077 Göttingen, Germany
Fax +49(551)393063; E-mail: franc.meyer@chemie.uni-goettingen.de
Department of Chemistry, Kiev National Taras Shevchenko University, Vladimirskaya Street 64, 01033 Kiev, Ukraine
b
Fax +380(44)2393393; E-mail: ifritsky@univ.kiev.ua
Vernadskii Institute of General and Inorganic Chemistry, 32/34 Palladin Avenue, 03680 Kiev-142, Ukraine
c
Received 15 November 2007; revised 27 November 2007
O
O
O
O
O
O
Abstract: A series of convenient synthetic procedures are reported
for pyrazole derivatives with carbonyl or ester groups in the 3- and
5-positions and variable substitution pattern at C4 and at the func-
tional side arms. All compounds have been characterized by 1H and
13C NMR spectroscopy, elemental analyses, and mass spectrome-
try. In addition, the structures of several pyrazole derivatives have
been determined by single crystal X-ray diffraction, which provides
insight into the effect of functional side arms on the hydrogen-
bonded supramolecular motifs of NH-pyrazoles.
Cl
Cl
MeO
OMe
N
NH
N
NH
N
NH
A
B
C
Figure 1 Established 3,5-bifunctionalized pyrazole synthons.
stituted pyrazoles.7,8 Established pyrazole building blocks
include dialdehyde A9 and diacid dichloride B10 as well as
diester C11 (Figure1), all of which have proven useful for
the preparation of, for example, macrocycles and multi-
dentate ligand scaffolds incorporating one or more pyra-
zole moieties.3
Key words: pyrazoles, N-heterocycles, X-ray crystal structure, H-
bonding
Pyrazoles are considered as extremely versatile building
blocks in organic chemistry.1 They constitute key frag-
ments in active pharmaceutical and agrochemical ingredi-
ents, which have found widespread use as ligands for
transition-metal complexes.2,3 Decoration of the pyrazole
core often requires the attachment of functional substitu-
ents at the 3- and 5-positions of the heterocycle, which can
then be further manipulated. Recent examples of valuable
3,5-difunctionalized pyrazoles comprise aminopyrazole
derivatives as nonpeptidic templates capable of recogniz-
ing β-sheet structures,4 and compartmental pyrazole/
imine ligand scaffolds that form binuclear Pd and Ni com-
plexes for catalytic olefin polymerization.5
In order to broaden the scope of these systems, we set out
to develop efficient syntheses for a variety of new 1H-
pyrazole derivatives related to A–C with carbonyl or ester
groups in the 3- and 5-positions, but with different substi-
tution pattern both at the pyrazole-C4 position and the
side arm carbonyl functions. For the synthetic approaches
it was aimed to avoid toxic hydrazine or its derivatives.
Finally, it was deemed interesting to study the solid-state
structures of such pyrazole synthons that are decorated
with functional groups, since the presence of multiple H-
bonding donor and acceptor sites may give rise to com-
plex aggregation patterns, distinct from those of simple
pyrazoles.12 The new compounds reported here are col-
lected in Table1.
The most common methods for the preparation of pyra-
zoles are the reaction of hydrazines with β-dicarbonyl
compounds, and 1,3-dipolar cycloadditions of diazo com-
pounds onto triple bonds.6 The former process, usually
considered to be the best and most versatile method, in-
volves the double condensation of 1,3-diketones with hy-
drazine or its derivates. While this works well for simple
pyrazoles bearing various alkyl or aryl substituents in the
3- and 5-positions, however, most electrophilic functional
groups such as aldehydes, nitriles, esters, and alkyl ha-
lides do not survive such transformation. On the other
hand, there is a paucity of 3,5-bifunctional pyrazole com-
pounds that would allow facile subsequent derivatization.
These should be amenable via high-yielding and straight-
forward syntheses, which is particularly true for N-unsub-
The potassium salt of pyrazole-3,5-dicarboxylic acid D as
well as the diester C are readily accessible from commer-
cially available 3,5-dimethylpyrazole by oxidation with
KMnO4 and subsequent esterification using MeOH and
gaseous HCl.11 We found that treatment of D with MeLi
in THF directly gave 3,5-diacetylpyrazole (1) in 60%
yield (Scheme1). While the low solubility of the starting
material D in THF or diethyl ether apparently has a detri-
mental effect on the yield, this method still represents an
improvement over the two procedures reported previously
for 1, one of which has not been optimized and gives only
a mixture of products.13 In order to open the potential for
substituting at C4 via, for example, Pd-catalyzed cross-
coupling reactions, 4-iodo-1H-pyrazole-3,5-dicarboxylic
acid dimethyl ester (2) was prepared in 95% yield by the
reaction of C with I2 in the presence of ammonium ceri-
um(IV) nitrate, following a procedure developed by
Rodríguez-Franco.14
SYNTHESIS 2008, No. 5, pp 0800–0806
x
x
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x
x
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Advanced online publication: 18.02.2008
DOI: 10.1055/s-2008-1032180; Art ID: Z26107SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Syntheses of 3,5-Bifunctional Pyrazoles
801
O
O
O
O
O
O
Table 1 3,5-Bifunctional Pyrazoles Prepared
H2SO4
NaNO2
H2SO4
Zn
O
R2
O
E
NO
NH2
R1
R3
N
NH
NaNO2
O
O
O
Product
R1
Me
R2
H
I
R3
NaOH
O
1
Me
OMe
Me
OMe
H
E
N
NH
N
N
2
OMe
Me
OMe
H
3
F
37%
3
Me
Ph
Ph
Ph
Me
Ph
Scheme 2 Original synthesis of 3; the yield given is the overall
5
yield for four steps (which may vary; see text).
7
O
Ph
O
O
8
Ph
Ph
O
Ph
OMe
N2
9
Me
Me
OH
Ph
MeO
OMe
MeO
N
NH
4
10
G
70%
Br2
2 d
Ph
N
N
NH
Ph
O
O
KMnO4
O
LiAlH4
HO
OH
MeO
OMe
O
O
O
N
NH
N NH
MeLi
6
5
KO
OH
NH
N NH
70%
93%
1
60%
D
MnO2
MeOH, HCl
O
Ph
O
O
I
O
O
O
(NH4)2Ce(NO3)6
I2
H
H
MeO
OMe
NH
MeO
OMe
N
NH
N
N NH
7
2
C
57%
95%
Scheme 3 Synthetic route to 4-phenyl-1H-pyrazole-3,5-dicarbalde-
hyde (7).
Scheme 1 Synthesis of pyrazole derivatives 1 and 2.
SO2N3
The 3,5-diacetylpyrazole (1) represents a modification of
A with acetyl instead of formyl groups as side arms. The
fully methylated derivative 3 can be prepared according to
a procedure reported by Wolff in 1902 (Scheme2).15
However, this method proved to be quite unreliable, since
the 4-acetyl-5-methyl[1,2,3]oxadiazole F is rather unsta-
ble and its yield is often very low. A better synthesis of 3
has been developed here (see below).
O
O
O
O
Et3N
+
R1
R1
R1
R1
N2
O
O
K2CO3
R2
R3
3 R1 = R2 = R3 = Me
8 R1 = R2 = R3 = Ph
9 R1 = R2 = Me
85%
26%
41%
R2
A four-step procedure has been followed to introduce a
single phenyl group at the pyrazole-C4. 4-Phenyl-1H-
pyrazole-3,5-dicarbaldehyde (7) was synthesized from
methyl diazoacetate via modification of a procedure re-
ported by Buchner and co-workers in 1902 (Scheme3).16
Dipolar cycloaddition of diazoglycine methyl ester with
the methyl ester of cinnamic acid forms pyrazoline 4.
Pyrazolines have often been described as fairly unstable
compounds that are not easy to purify and handle, but 4
can be isolated in 70% yield after recrystallization from
diethyl ether at –30 °C. Oxidation with bromine then af-
fords the pyrazole diester 5, and subsequent reduction
O
O
R3
R1
N
NH
R
3 = OEt
10 R1 = Me
2 = R3 = Ph
OH
40%
R
Scheme 4 New synthetic route to 3,5-dicarbonyl-1H-pyrazoles
with variable substitution pattern; overall yields for two steps.
with LiAlH4 gives dialcohol 6. Reoxidation with MnO2
then leads to the sought-after product 7. The final step
Synthesis 2008, No. 5, 800–806 © Thieme Stuttgart · New York

802
A. Sachse et al.
PAPER
Figure 4 View of the hydrogen bond structure of 2. Selected atom
distances (Å) and angles (°): N1···N2¢ 2.890(2), N1···O4¢ 3.200(2);
N1–H1···N2¢ 148(2), N1–H1···O4¢ 127(3). Symmetry transformations
used to generate equivalent atoms: (¢) –1/2+x, 3/2–y, 1–z; (¢¢) 1/2+x,
3/2–y, 1–z.
Figure 2 View of the hydrogen-bond structure of 8. Selected atom
distances (Å) and angles (°): N1···N2¢ 2.841(2); N1–H1···N2¢ 167(2).
Symmetry transformations used to generate equivalent atoms: (¢) y,
1–x, 2–z; (¢¢) 1–y, x, 2–z.
Figure 5 View of the hydrogen bond structure of 5. Selected atom
distances (Å) and angles (°): N1···N2¢ 3.120(2), N1···O4¢ 3.084(2);
N1–H1···N2¢ 146(2), N1–H1···O4¢ 138(2). Symmetry transformations
used to generate equivalent atoms: (¢) –1/2+x, 3/2–y, –z; (¢¢) 1/2+x,
3/2–y, –z.
Figure 3 ORTEP plot (30% probability thermal ellipsoids) of the
cationic part of 5. For the sake of clarity, most hydrogen atoms have
been omitted.
proceeds only to 57%, giving a modest overall yield of
26% for the combined four steps.
While 13C NMR spectra of all 3,5-disubstituted pyrazoles
usually show a single broad resonance for the C3/5 atoms
of the heterocycle due to fast NH tautomerism, two broad
signals are observed for 6 at 140.0 and 149.0 ppm. In ad-
dition, 13C resonances for the side arm methylene groups
are significantly broadened, suggesting that tautomerism
is slowed down in this particular compound. Involvement
of the side arm hydroxyl groups in hydrogen bonding in-
teractions might be assumed as a likely reason.
An alternative synthetic route was developed to provide a
more general approach towards 3,5-dicarbonyl pyrazoles
with variable substitution pattern (Scheme4). Diazotiza-
tion of a β-diketone with p-toluenesulfonyl azide and sub-
sequent treatment with a second equivalent of β-diketone,
which may be the same or different from the first one, pro-
vides a series of trisubstituted pyrazoles, with R1, R2 and
R3 depending on the b-diketones.
Figure 6 ORTEP plot (30% probability thermal ellipsoids) of the
cationic part of 6⋅HCl. For the sake of clarity, most hydrogen atoms
have been omitted.
served when using ethyl acetoacetate as an unsymmetric
β-diketone in the second step, and pure 5-acetyl-4-meth-
yl-1H-pyrazole-3-carboxylic acid (9) is conveniently iso-
lated in 41% yield from the reaction mixture. This implies
hydrolysis of the ester moiety under the reaction condi-
tions to give a carboxylic acid function in the product.
For 3, this method is a significant improvement over the
laborious synthesis described above (Scheme2). Com-
pound 3 and the triphenyl derivative 8 are obtained in 85%
and 26% yield, respectively. High regioselectivity is ob-
Synthesis 2008, No. 5, 800–806 © Thieme Stuttgart · New York

PAPER
Syntheses of 3,5-Bifunctional Pyrazoles
803
Table 2 Crystal Data and Refinement Details for Compounds 2, 5, 6, and 8
2
5
6
8
+
Formula
C7H7IN2O4
C13H12N2O4
C11H12N2O2, C11H13N2O2 ,
Br–, 0.5 CH4O, 0.5 H2O
C23H16N2O2, 0.5 C3H6O
Mr
310.05
260.25
514.40
381.42
crystal size [mm]
crystal system
space group
a [Å]
0.49 × 0.04 × 0.04
orthorhombic
P212121 (No. 19)
4.5086(2)
12.6705(6)
17.1726(10)
90
0.47 × 0.34 × 0.31
orthorhombic
P212121 (No. 19)
6.2569(3)
14.1156(9)
14.5255(8)
90
0.30 × 0.21 × 0.11
triclinic
0.48 × 0.37 × 0.25
tetragonal
I4 (No. 82)
12.9187(5)
12.9187(5)
24.7001(13)
90
P1 (No. 2)
9.4338(14)
9.7537(13)
13.6894(18)
101.433(11)
108.673(11)
100.573(11)
1127.5(3)
2
b [Å]
c [Å]
α [°]
β [°]
90
90
90
γ [°]
90
90
90
V [Å3]
981.01(9)
4
1282.89(12)
4
4122.3(3)
8
Z
ρ
calcd. [g cm–3]
2.099
1.347
1.515
1.229
F(000)
592
544
532
1600
µ [mm–1]
3.255
0.102
1.866
0.080
Tmax/Tmin
0.9181/0.4158
–5 to 4, 16, 21
2.00–26.94
9592
–
0.8213/0.7027
–11 to 10, 11, –16 to 15
2.21–24.82
7117
–
hkl range
–8 to 7, 18, 18
2.01–27.35
25226
16, 16, 31
1.65–27.42
31940
θ range [°]
measured refl.
unique refl. [Rint]
observed refl. (I>2σ(I))
ref. param./ restraints
goodness-of-fit
Abs. structure param.
R1, wR2 [I>2σ(I)]
R1, wR2 (all data)
resid. el. dens. [e Å–3]
2128 [0.0405]
2035
2897 [0.0490]
2285
2248 [0.0658]
1234
4678 [0.0503]
4082
133/0
178/0
293/3
267/5
1.013
1.028
1.165
1.007
–0.029(17)
0.0151, 0.0373
0.0165, 0.0378
0.249/–0.709
0.3(13)
–
0.5(12)
0.0408, 0.1115
0.0516, 0.1165
0.182/–0.187
0.1053, 0.2958
0.1638, 0.3402
0.618/–0.732
0.0413, 0.1109
0.0476, 0.1144
0.411/–0.300
The variety of synthetic procedures shown in Schemes1– catemers.17 A relationship between the size of C-substitu-
4 now provides convenient access to differently substitut- ents attached to the heterocycle and the aggregation pat-
ed 3,5-dicarbonyl pyrazoles, which should prove valuable terns has been proposed,12 and neural networks as well as
synthons for subsequent transformations.
theoretical methods have been used in order to predict the
secondary structures.19,20 Since those previous studies
have mostly focused on NH-pyrazoles with purely alkyl
or aryl substituents, it appeared interesting to investigate
the effect of functional groups that might act as hydrogen
bond donor or acceptor, such as the appended carbonyl
and hydroxyl groups of the present NH-pyrazole deriva-
tives.
The solid-state structures of N-unsubstituted pyrazoles
have received considerable attention over the last years, in
particular their hydrogen-bonded supramolecular
arrangements12,17 and their annular tautomerism.18 At
least five different structural motifs are known to exist,
comprising of dimers, trimers, tetramers, hexamers, and
Synthesis 2008, No. 5, 800–806 © Thieme Stuttgart · New York

804
A. Sachse et al.
PAPER
mL), washed with aq Na2CO3 (2 × 50 mL), and dried (MgSO4). The
pure product was obtained as a white solid; yield: 0.40 g (60%); mp
146 °C.
X-ray crystallographic studies were performed on crystal-
line compounds 2, 5, 6⋅HBr and 8, and the results are pre-
sented in Figures2–6. Compound 8 that bears benzoyl
groups in the 3- and 5-positions features the common S4-
symmetric tetrameric arrangement with intermolecular
N–H···N hydrogen bonds, without any involvement of the
side arm carbonyl groups. Compounds 2 and 5 both have
methyl ester groups but differ in their C4 substituents,
which is iodine in 2 versus a phenyl group in 5. Molecular
structures of 2 and 5 emphasizing the H-bonding patterns
IR (KBr): 3433, 3296, 3206, 3126, 3001, 2919, 1668, 1602, 1561,
1497, 1567, 1430, 1375,1306, 1261, 1236,1220, 1205, 1140, 1097,
1016, 999, 962, 946, 867, 796, 705, 661, 622, 531, 507, 483 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.59 (s, 6 H, CH3), 7.29 (s, 1 H,
CHpz4), 11.42 (br, 1 H, NH).
13C NMR (125 MHz, CDCl3): d = 26.8 (CH3), 108.9 (Cpz4), 147.5
(br, Cpz3/5), 191.3 (C=O).
are provided in Figures4 and5. In both cases infinite zig- MS (EI, 70 eV): m/z (%) = 152 (51, [M]+), 137 (100, [M – Me]+).
HRMS-(ESI–): m/z calcd for C7H7N2O2 [M – H]–: 151.05130;
found: 151.05129.
zag chains of pyrazole ester molecules are formed via in-
termolecular N–H···N linkages. Further interactions with
the ester oxygen atoms can be taken into account, but
these are clearly weaker in 2 [d(N1···O4¢) = 3.200(2) Å]
than in 5 [d(N1···O4¢) = 3.084(2) Å]. Interestingly, a
stronger involvement of the side arm acceptor induces a
significant lengthening of the N1···N2¢ distances
[2.890(2) Å in 2 versus 3.120(2) Å in 5]. The crystallo-
graphic analysis of 6⋅HBr confirms the identity of the di-
alcohol (Figure6). However, due to twinning and disorder
the quality of the structure determination is rather low,
which precludes a detailed discussion of metric parame-
ters.
4-Iodo-1H-pyrazole-3,5-dicarboxylic Acid Dimethyl Ester (2)
A solution of the hydrochloride salt of 1H-pyrazole-3,5-dicarboxy-
lic acid dimethyl ester (3.7 g, 17 mmol), I2 (5.5 g, 22 mmol), and
(NH4)2Ce(NO3)6 (10.0 g, 19 mmol) in MeCN (500 mL) was heated
to reflux for 3 d. After evaporation of the solvent and addition of
EtOAc (300 mL), the excess of I2 was destroyed by adding a 5% aq
Na2S2O3 solution. The mixture was washed with brine (50 mL),
dried (MgSO4), and the solvent evaporated. The crude product was
finally recrystallized from CHCl3 to give pure 2; yield: 5.0 g (95%);
white solid; mp 157 °C.
IR (KBr): 3444, 3196, 3050, 2958, 2009, 1951, 1878, 1739, 1533,
1467, 1420, 1376, 1283, 1246, 1201, 1173, 1060, 1019, 940, 816,
776, 633, 569, 506 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.97 (s, 6 H, CH3), 8.48 (br, 1 H,
NH).
In summary, we have developed or improved a variety of
straightforward synthetic procedures that make available
pyrazole derivatives with carbonyl or ester functions in
the 3- and 5-positions and different backbone substituents.
These compounds will serve as valuable starting materials
for new pyrazole-based ligands, receptors, etc. Solid-state
structures of some of the functionalized pyrazoles reveal
a subtle interplay between intra- and intermolecular H-
bonding in their supramolecular arrangements.
13C NMR (125 MHz, CDCl3): d = 52.6 (CH3), 65.3 (Cpz4), 141.1
(Cpz3/5), 159.8 (C=O).
MS (EI, 70 eV): m/z (%) = 310 (100, [M]+), 279 (67, [M – OMe]+),
Anal. Calcd for C7H7IN2O4: C, 27.10; H, 2.28; N, 9.04. Found: C,
27.38; H, 2.46; N, 8.88.
3,5-Diacetyl-4-methyl-1H-pyrazole (3)
Melting points/decomposition temperatures were determined with
an OptiMelt system (Stanford Research Systems, Inc.) using open
A solution of diazoacetylacetone (25 g, 0.20 mol) in MeOH (100
mL) was added to a solution of acetylacetone (20 g, 0.20 mol) and
K2CO3 (55 g, 0.40 mol) in MeOH (100 mL) at r.t. The mixture was
stirred for 2 h, and H2O (200 mL) was then added. After removal of
MeOH under reduced pressure, the pH was adjusted to 2 by the slow
addition of aq 12 M HCl. The resulting solid was separated by fil-
tration and recrystallized from CH2Cl2; yield: 28 g (85%); white sol-
id; mp 113 °C.
1
capillaries; values are uncorrected. H and 13C NMR spectra were
recorded on a Bruker Avance 500, a Bruker Avance 300, or a Bruk-
er 200 spectrometer. 13C resonances were obtained with broad-band
1
proton decoupling, spectra were recorded at 298 K. H NMR and
13C NMR chemical shifts were referenced internally to solvent sig-
nals. Mass spectra were recorded using a Finnigan MAT 95 (EI) or
Bruker APEX IV (HRMS, ESI). IR spectra from KBr peletts were
recorded on a Digilab Excalibur Series FTS 3000 spectrometer. El-
emental analyses were performed by the analytical laboratory of the
Institut of Inorganic Chemistry, University of Göttingen using a
Heraeus CHN-O-RAPID instrument or an Elementar vario EL III
instrument. All reagents were purchased from commercial sources
and employed without further treatment. 1H-Pyrazole-3,5-dicar-
boxylic acid dimethyl ester C,11 pyrazole-3,5-dicarboxylic acid mo-
IR (KBr): 3293, 3013, 2925, 1690, 1648, 1570, 1544, 1484, 1434,
1411, 1395, 1354, 1303, 1243, 1206, 1188, 1057, 1014, 980, 936,
803, 687, 561, 545, 486 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.59 (s, 6 H, O=CCH3), 2.62 (s, 3
H, CH3pz4).
13C NMR (125 MHz, CDCl3): d = 10.3 (CH3pz4), 28.4 (O=CCH3),
121.8 (Cpz4), 156.0 (Cpz3,5), 195.1 (O=CCH3).
nopotassium
salt
D,11
methyl
diazoacetate
G,21
MS (EI, 70 eV): m/z (%) = 166 (100, [M]+), 151 (95, [M – Me]+).
diazoacetylacetone,22 and 2-diazo-1,3-diphenylpropane-1,3-dione22
were prepared according to literature methods.
Anal. Calcd for C32H16N2O2: C, 57.82; H, 6.07; N, 16.86. Found: C,
57.75; H, 6.00; N, 16.78.
3,5-Diacetyl-1H-pyrazole (1)
4-Phenyl-4,5-Dihydro-1H-pyrazole-3,5-dicarboxylic Acid
Dimethyl Ester (4)
To a –78 °C cold suspension of the monopotassium salt of pyrazole-
3,5-dicarboxylic acid (1.0 g, 5.2 mmol) in THF (200 mL) was added
dropwise MeLi in Et2O (1.6 M, 16 mmol). After stirring for 1 h at
–78 °C, the suspension was allowed to warm to r.t. and stirring was
continued for 2 d. Unreacted MeLi was carefully hydrolyzed with
H2O. The resulting suspension was extracted with CH2Cl2 (2 × 100
A mixture of diazoacetic acid methyl ester (6.0 g, 0.06 mol) and
methyl cinnamate (9.7 g, 0.06 mol) was kept between 60 and 90 °C
for 18 h (heating rate 5 °C per 30 min). The crude product was re-
crystallized from Et2O at –30 °C; yield: 10.9 g (70%); white solid;
mp 106 °C.
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PAPER
Syntheses of 3,5-Bifunctional Pyrazoles
805
IR (KBr): 3446, 3308, 3066, 3028, 3004, 2954, 2846, 2089, 2020,
1955, 1732, 1694, 1601, 1532, 1494, 1445, 1416, 1349, 1258, 1204,
1153, 1114, 1047, 1013, 973, 908, 893, 870, 827, 793, 773, 750,
700, 621, 611, 525, 492, 474 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.73 (s, 3 H, CH3), 3.81 (s, 3 H,
CH3), 4.31 (d, J = 3.8 Hz, 1 H, CH), 4.65 (d, J = 3.8 Hz, 1 H, CH),
7.19–7.32 (m, 5 H, ArH).
4-Phenyl-1H-pyrazole-3,5-dicarbaldehyde (7)
A suspension of 6 (2.5 g, 17 mmol) and MnO2 (4.8 g, 170 mmol) in
1,2-dimethoxyethane (500 mL) was heated to reflux for 4 h. After
hot filtration over Celite, washing with hot MeOH (100 mL), and
evaporation of the solvent, the crude product was recrystallized
from light petroleum (bp 40–60 °C); yield: 1.9 g (57%); light brown
solid; mp 60 °C.
IR (KBr): 3384, 3245, 3059, 2954, 2856, 2360, 2340, 1699, 1609,
1493, 1436, 1398, 1289, 1204, 1158, 1067, 1016, 930, 868, 770,
698, 537 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 7.38–7.61 (m, 5 H, ArH), 9.82
(s, 2 H, O=CH), 14.99 (br, 1 H, NH).
13C NMR (125 MHz, DMSO-d6): d = 124.2 (Cpz4), 128.0 (CH, Ar-
p), 128.2 (CH, Ar-o), 130.4 (CH, Ar-m), 136.2 (C, Ar-i), 143.3
(Cpz3/5), 183.8 (C=O).
13C NMR (125 MHz, CDCl3): d = 52.2 (OCH3), 53.0 (OCH3), 53.4
(CH), 69.9 (CH), 127.1 (CH, Ar-p), 127.9 (CH, Ar-o), 129.1 (CH,
Ar-m), 138.8 (C, Ar-i), 145.2 (N=C), 161.8 (=CC=O), 171.4
(HCC=O).
MS (EI, 70 eV): m/z (%) = 262 (18, [M]+), 231 (7, [M – OMe]+),
203 (100, [M – MeOC=O]+), 171 (83, [M – MeOC=O, –MeO]+),
159 (30, [M – MeOC=O, –MeOC]+), 144 (11, [M – 2MeOC=O]+).
Anal. Calcd for C13H14N2O4: C, 59.52; H, 5.38; N, 10.68. Found: C,
59.26; H, 5.47; N, 10.49.
MS (EI, 70 eV): m/z (%) = 200 (100, [M]+).
HRMS (ESI–): m/z calcd for C11H9N2O2 [M + H]+: 201.06584;
found: 201.06585.
4-Phenyl-1H-pyrazole-3,5-dicarboxylic Acid Dimethyl Ester (5)
Br2 (14.7 g, 0.092 mol) was added dropwise to a cooled solution of
4-phenyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylic acid dimethyl
ester (22.0 g, 0.084 mol) in CHCl3 (250 mL). After stirring for 2 d,
the solution was washed with aq Na2S2O3 to eliminate the excess of
Br2. Extraction with CHCl3 (2 × 200 mL), drying (Na2SO4), and
evaporation of the solvent leads to the pure product; yield: 20.3 g
(93%); white solid; mp 130 °C.
3,5-Dibenzoyl-4-phenyl-1H-pyrazole (8)
To a solution of 1,3-diphenylpropane-1,3-dione (3.2 g, 14 mmol) in
MeOH (200 mL) were added 2-diazo-1,3-diphenylpropane-1,3-di-
one (4.7 g, 19 mmol) and K2CO3 (3.9 g, 28 mmol). After stirring for
2 d at r.t. were added H2O (50 mL) and HCl (10 mL). The organic
phase was extracted with Et2O (2 × 150 mL), and the combined
Et2O phases were washed with H2O (2 × 100 mL), dried (MgSO4),
and the solvent was evaporated. The crude product was purified by
chromatography on silica gel (hexane–EtOAc, 7:1, DC 3:1) and re-
crystallized from acetone; yield: 1.3 g (26%); white solid; mp
154 °C.
IR (KBr): 3447, 3264, 3065, 3008, 2957, 1964, 1894, 1746,1729,
1582, 1561, 1508, 1459, 1441, 1416, 1381, 1280, 1226, 1195, 1172,
1144, 1077, 1019, 1009, 942, 821, 801, 781, 766, 749, 699, 684,
646, 611, 509, 476 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.82 (s, 6 H, CH3), 7.32–7.43 (m,
5 H, ArH).
13C NMR (125 MHz, CDCl3): d = 52.2 (OCH3), 127.5 (CH, Ar-p),
128.0 (CH, Ar-o), 130.2 (CH, Ar-m), 130.3 (C, Ar-i), 138.0 (br,
Cpz3/5), 160.9 (C=O), Cpz4 was not observed.
IR (KBr): 3264, 3201, 3056, 1958, 1811, 1729, 1669, 1648, 1598,
1578, 1500, 1449, 1418, 1375, 1310, 1284, 1226, 1177, 1075, 1048,
1024, 1015, 1001, 911, 799, 769, 740, 691, 568, 524 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.01–7.81 (m, 15 H, ArH), 9.98
(br, 1 H, NH).
13C NMR (125 MHz, CDCl3): d = 127.3 (Cpz4), 127.4 (CH, Ar),
127.6 (CH, Ar), 127.9 (CH, Ar), 130.0 (CH, Ar), 130.3 (C, Ar),
130.5 (CH, Ar), 132.9 (CH, Ar), 136.4 (C, Ar), 143.6 (Cpz3/5), 188.0
(C=O).
MS (EI, 70 eV): m/z (%) = 260 (100, [M]+), 229 (27, [M – OMe]).
Anal. Calcd for C13H12N2O4: C, 59.98; H, 4.65; N, 10.77. Found:
C, 59.85; H, 4.67; N, 10.75.
3,5-Bis(hydroxymethyl)-4-phenyl-1H-pyrazole (6)
To a suspension of LiAlH4 (2.6 g, 69 mmol) in Et2O (250 mL) was
added dropwise a solution of 5 (3.4 g, 13 mmol) in THF (50 mL) at
–78 °C. After stirring at –78 °C for 2 h, the suspension was allowed
to warm to 0 °C and was carefully hydrolyzed with H2O. The sol-
vent was evaporated under reduced pressure and the residual solid
dissolved in MeOH (250 mL). Carbon monoxide was bubbled
through the suspension for 10 min, the mixture stirred overnight and
then filtered. The pure product was obtained after recrystallization
from MeOH; yield: 2.4 g (70%); white solid; mp 197 °C.
MS (EI, 70 eV): m/z (%) = 352 (100, [M]+).
Anal. Calcd for C32H16N2O2: C, 78.38; H, 4.58; N, 7.95. Found: C,
78.06; H, 4.56; N, 8.03.
5-Acetyl-4-methyl-1H-pyrazole-3-carboxylic Acid (9)
To a solution of ethyl acetoacetate (23.4 g, 0.18 mol) in MeOH (200
mL) were added diazoacetylacetone (22.8 g,0.18 mol) and K2CO3
(46.7 g, 0.36 mol). After stirring for 2 h at r.t., the solvent was par-
tially evaporated (to a volume of ca. 200 mL) and H2O (250 mL)
was added. The precipitate was dissolved in EtOH (150 mL) and
H2O (250 mL) was added. The pH was first adjusted to 11 by the
addition of aq KOH and then adjusted to 2 by the addition of aq 5
M HCl. The resulting pure product was collected by filtration and
washed with H2O (50 mL); yield: 12.4 g (41%); mp 115 °C.
IR (KBr): 3435, 2954, 2924, 2854, 2360, 2341, 1636, 1520, 1454,
1383, 1235, 1212, 1175, 1081, 1056, 1006, 922, 811, 783, 758, 704,
679, 557, 494 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 4.42 (s, 4 H, CH2), 4.81–5.38
(br, 2 H, OH), 7.38–7.55 (m, 5 H, ArH), 12.74 (s, 1 H, NH).
IR (KBr): 3721, 3290, 3012, 1666, 1650, 1392, 1225, 1188, 936,
13C NMR (125 MHz, DMSO-d6): d = 53.6 (br, CH2), 55.6 (br, CH2),
117.6 (Cpz4), 125.9 (CH, Ar-p), 128.3 (CH, Ar-o), 128.9 (CH, Ar-
m), 133.4 (C, Ar-i), 140.0 (br, Cpz3/5), 149.0 (br, Cpz5/3).
787, 671 cm–1.
1H NMR (300 MHz, CD3OD): δ = 2.55 (s, 6 H, CH3), 14.15 (s, 1 H,
NH).
MS (EI, 70 eV): m/z (%) = 204 (100, [M]+), 169 (18, M –
CH2OH]+).
13C NMR (125 MHz, DMSO-d6): δ = 9.6 (CH3pz4), 28.0 (CH3C=O),
120.4 (Cpz4), 148.7 (Cpz3/5), 175.8 (COOH), 190.5 (O=CCH3).
Anal. Calcd for (C11H12N2O2)2⋅HBr: C, 54.00; H, 5.15; N, 11.45.
Found: C, 54.17; H, 5.72; N, 11.48.
MS (EI, 70 eV): m/z (%) = 167 (100, [M – H]+).
Anal. Calcd for C7H8N2O3: C, 50.00; N, 16.66; H, 4.80. Found: C,
50.11; N, 16.56; H, 4.89.
Synthesis 2008, No. 5, 800–806 © Thieme Stuttgart · New York

806
A. Sachse et al.
PAPER
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5-Acetyl-4-phenyl-1H-pyrazole-3-yl-phenylmethanone (10)
To a solution of 1,3-diphenylpropane-1,3-dione (2.8 g, 13 mmol) in
MeOH (20 mL) were added a solution of diazoacetylacetone (1.6 g,
13 mmol) in MeOH (20mL) and solid K2CO3 (2.5 g, 18 mmol). Af-
ter stirring for 28 h at r.t., the solvent was partially evaporated (to a
volume of ca. 20 mL) and H2O (40 mL) was added. The pH was ad-
justed to 5 by the addition of aq 5 M HCl. The aqueous phase was
extracted with Et2O (2 × 25 mL), dried (MgSO4), and the solvent
evaporated under reduced pressure. The crude product was purified
by chromatography on silica gel (CH2Cl2–i-PrOH, 95:5, Rf = 0.30)
and (CHCl3–EtOAc, 98:2, Rf = 0.41); yield: 1.3 g (20%); light
brown solid; mp 130 °C.
IR (KBr): 3205, 1958, 1913, 1817, 1773, 1682, 1659, 1595, 1578,
1549, 1506, 1468, 1448, 1428, 1382, 1352, 1308, 1284, 1213, 1175,
1166, 1142, 1075, 1045, 1031, 1020, 1000, 957, 907, 809, 797, 772,
750, 706, 692, 663, 606, 562, 491, 414 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.28 (s, 3 H, CH3), 7.29–7.89 (m,
10 H, ArH), 9.52 (br, 1 H, NH).
13C NMR (125 MHz, CDCl3): d = 28.7 (CH3), 127.3 (Cpz4), 128.3
(CH-Ar), 128.4 (CH-Ar), 128.5 (CH-Ar), 130.4 (CH-Ar), 130.5
(CH-Ar), 131.1 (CH-Ar), 133.3 (C-Ar), 136.8 (C-Ar), 142.4 (Cpz3/5),
188.0 (PhC=O), 191.4 (CH3C=O).
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MS (EI, 70 eV): m/z (%) = 290 (100, [M]+), 275 (17, [M – Me]+).
Anal. Calcd for C32H16N2O2: C, 74.47; H, 4.86; N, 9.65. Found: C,
74.64; H, 5.13; N, 9.49.
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X-ray Crystal Structure Determination
X-ray data were collected on a STOE IPDS II diffractometer
(graphite monochromated Mo-Kα radiation, λ = 0.71073 Å) by use
of ω scans at r.t. (5, 6) or at –140 °C (2, 8) (Table2). The structures
were solved by direct methods and refined on F2 using all reflec-
tions with SHELX-97.23a,b The nonhydrogen atoms were refined
anisotropically, except those in disordered parts. Most hydrogen at-
oms were placed in calculated positions and assigned to an isotropic
displacement parameter of 0.08 Å2. Crystals of 6 are nonmerohe-
drally twinned (ratio of the two twin components approximately
60:40, twinlaw –1, 0, 0/0, –1, 0/–1.07, 0.74, 1) and the reflection
data for refinement were prepared using the program X-AREA.23c
One side-arm in 6 was found to be disordered about two positions
[occupancy factors 0.54(2)/0.46(2)] and was refined by using DFIX
(dC–O = 1.41 Å) restraints. Furthermore, H2O and MeOH (DFIX re-
straint, dC–O = 1.41 Å) solvent molecules are disordered about a cen-
ter of inversion and were refined with a fixed occupancy factor of
0.5. In 6a an acetone molecule is disordered about a two-fold rota-
tion axis and was refined a fixed occupancy factor of 0.5. DFIX
(dC–C = 1.51 Å, dC=O = 1.21 Å), SADI (dC···O) and FLAT restraints
were used to model the disorder. The positional and isotropic dis-
placement parameters of the nitrogen-bound hydrogen atoms in 5,
2, and 8 were refined without any restraints or constraints. Face-in-
dexed absorption corrections for 2 and 6 were performed numerical-
ly with the program X-RED.23d,24
2004, 69, 9085.
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Higueras, A. I.; Antequera, G. Tetrahedron Lett. 2001, 42,
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(23) (a) Sheldrick, G. M. SHELXL-97, Program for Crystal
Structure Refinement; University of Göttingen: Göttingen,
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Crystal Structure Solution; University of Göttingen:
Göttingen, 1997. (c) X-AREA; STOE & CIE GmbH:
Darmstadt, 2002. (d) X-RED; STOE & CIE GmbH:
Darmstadt, 2002.
(24) CCDC-664760 (2), CCDC-664761 (5), CCDC-664762 (6),
and CCDC-664763 (8) contain the supplementary
crystallographic data for this paper. These data can be
obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html [or from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44(1223)336033; E-mail: deposit@ccdc.cam.ac.uk].
Acknowledgment
The authors acknowledge financial support by NATO (grant No.
CBP.NUKR.CLG 982019) and the Fonds der Chemischen Indu-
strie. L.P. thanks the DAAD for a scholarship.
References
(1) Dvorak, C. A.; Rudolph, D. A.; Ma, S.; Carruthers, N. I.
J. Org. Chem. 2005, 70, 4188.
Synthesis 2008, No. 5, 800–806 © Thieme Stuttgart · New York