Facile access to 3,5-dihalogenated pyrazoles by sydnone cycloaddition and their versatile functionalization by Pd-catalyzed cross-coupling processes

Article abstract of DOI:10.1002/ejoc.201100119

The 1,3-dipolar cycloaddition of diversely N-substituted 4-iodosydnones with 3-halopropiolates produces easily separable mixtures of dihalogenated pyrazolylcarboxylic esters at a preparative scale level, with the 3,5-dihalogenopyrazole regioisomers always predominating. Further decarboxylation of the major isomers provided the corresponding 3,5-dihalogenopyrazoles with a free C-4 position. These were found to be valuable scaffolds for the elaboration of unsymmetrically 1,3,5-trisubstituted pyrazole derivatives by site-selective Pd-catalyzed cross-coupling reactions. Notably, the flexible and site-selective introduction of different (hetero)aryl, vinyl, or alkyl substituents at the C-5 and C-3 positions of the pyrazole core could be achieved through sequential Suzuki-type reactions with various boron compounds. Copyright

Full text of DOI:10.1002/ejoc.201100119

FULL PAPER
DOI: 10.1002/ejoc.201100119
Facile Access to 3,5-Dihalogenated Pyrazoles by Sydnone Cycloaddition and
their Versatile Functionalization by Pd-Catalyzed Cross-Coupling Processes
Thierry Delaunay,[a] Mazen Es-Sayed,[b] Jean-Pierre Vors,[b] Nuno Monteiro,*[a] and
Geneviève Balme*[a]
Keywords: Nitrogen heterocycles / Polyhalides / Alkynes / Cycloaddition / Cross-coupling
The 1,3-dipolar cycloaddition of diversely N-substituted 4-
iodosydnones with 3-halopropiolates produces easily separa-
ble mixtures of dihalogenated pyrazolylcarboxylic esters at a
catalyzed cross-coupling reactions. Notably, the flexible and
site-selective introduction of different (hetero)aryl, vinyl, or
alkyl substituents at the C-5 and C-3 positions of the pyrazole
preparative scale level, with the 3,5-dihalogenopyrazole re- core could be achieved through sequential Suzuki-type reac-
gioisomers always predominating. Further decarboxylation
of the major isomers provided the corresponding 3,5-dihalo-
genopyrazoles with a free C-4 position. These were found to
be valuable scaffolds for the elaboration of unsymmetrically
1,3,5-trisubstituted pyrazole derivatives by site-selective Pd-
tions with various boron compounds. Furthermore, the Su-
zuki coupling sequence could be amenable to a one-pot pro-
cedure that enables rapid generation of the targeted com-
pounds.
azole nucleus of biologically relevant derivatives may also
incorporate halogen atoms. Recently, we became interested
Introduction
Multiple aryl- and heteroaryl-substituted heterocycles in exploring new flexible synthetic routes to 1,3,5-trisubsti-
are high-value targets in the pharmaceutical and agrochem- tuted pyrazoles that would allow rapid production of di-
ical industries. While there exist a plethora of methods to verse arrays of analogues for biological evaluation with a
access such compounds, one strategy that provides the high particular emphasis on (hetero)aromatic derivatives. For
levels of flexibility needed in library elaboration procedures this purpose we identified N-substituted 3,5-dihalogenated
is the sequential, site-selective installation of the aryl or pyrazoles as highly attractive intermediates because of their
heteroaryl groups onto polyhalogenated heterocycles inherent potential for diversification by established cross-
through metal-catalyzed cross-coupling processes with or- coupling processes. Surprisingly, a search of the literature
ganometallic reagents.[1,2] In this area, Suzuki-type reac- seemingly indicated that palladium-catalyzed coupling reac-
tions are particularly attractive, as they are largely unaffec- tions had not been previously investigated on such sub-
ted by the presence of water and allow not only (hetero)- strates, and therefore, no experimental data regarding the
aryl, but also vinyl and alkyl boron compounds, to partici- selectivities of the coupling were available. This lack of pre-
pate in the coupling process.[3]
cedence provided further impetus for us to explore this class
Pyrazole derivatives are important building blocks in or- of reactions. We naturally focused our attention on the use
ganic synthesis and have found numerous applications as of pyrazoles bearing distinguishable halides at C-3 and C-
pharmaceuticals and agrochemicals.[4] Among these, po- 5, as they would be normally considered as being the most
ly(hetero)aromatic pyrazoles are particularly important favorable candidates for highly selective cross-coupling re-
compounds with a broad spectrum of biological effects, in- actions. However, no practical and flexible approach to this
cluding kinase inhibitory,[5] estrogen receptor binding,[6] class of compounds was available from the literature, which
anti-inflammatory,[7] and herbicidal activities,[8] as illus- somehow reflected the difficulties inherent to selective halo-
trated in Figure 1. It is also of interest to note that the pyr- genations of the pyrazole core at the carbon atoms adjacent
to the nitrogen atom, most notably at C-3.[9] Within this
context, we envisioned that direct assembly of N-substituted
[a] Université Lyon 1; Institut de Chimie et Biochimie Moléculaires
pyrazoles bearing suitable halides at C-3 and C-5 would
normally be accessible by 1,3-dipolar cycloaddition of 4-
halosydnones 1 with 3-halopropiolates 2. 4-Halosydnones
are well-documented, readily available mesoionic com-
pounds that have been reported to cycloadd to alkynes ef-
ficiently to yield 5-halopyrazoles.[10] However, the participa-
tion of haloalkynes in this process had apparently not been
et Supramoléculaires (UMR 5246 du CNRS), CPE Lyon
43, Bd du 11 Novembre 1918, 69622 Villeurbanne, France
E-mail: balme@univ-lyon1.fr
monteiro@univ-lyon1.fr
[b] Bayer SAS, Bayer CropScience,
14 impasse Pierre Baizet, B. P. 9163, 69263 Lyon Cedex 09,
France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100119.
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previously investigated. 3-Halopropiolates appeared to be viously reported halogenation procedures (Scheme 2). p-
ideally suited for this purpose given the high reactivity of Methoxyphenyl- and benzyl-protected sydnones are of par-
alkynyl esters in sydnone cycloaddition.[11] Furthermore, ticular interest, should 1H-pyrazoles be desired.[14]
they are relatively stable, easily available compounds that
should ultimately allow access to pyrazole derivatives with
a free C-4 position upon decarboalkoxylation (Scheme 1).
Scheme 2.
1,3-Dipolar Cycloaddition: Access to 3,5-
Dihalogenopyrazole-4-carboxylates
With the halo compounds in hand, the viability of
haloalkynes participating in the sydnone 1,3-dipolar cyclo-
addition process was soon confirmed, and a representative
Figure 1. Some biologically active poly(hetero)aromatic pyrazoles.
experimental procedure is the following preparation of 3-
bromo-5-iodopyrazole 5a (Scheme 3). An equimolar mix-
ture of iodosydnone 1a and bromoalkyne 2b was heated
overnight in refluxing xylene. The reaction mixture was
then cooled and concentrated in vacuo to furnish a crude
3:1 mixture of regioisomeric dihalopyrazoles 5a and 6a. The
pyrazoles were easily separated by silica gel chromatog-
raphy eluting with cyclohexane/AcOEt, which furnished de-
sired pyrazole 5a in an acceptable 52% isolated yield. The
structure assignment was confirmed by comparison of the
NMR spectroscopic data of the corresponding dehaloge-
nated pyrazole 7, obtained by hydrogenolysis of 5a (50 mol-
% Pd/C, 30 bar H2, EtOH, 80 °C, 18 h, 39%) with the pre-
viously reported data.[15]
Scheme 1. Retrosynthetic analysis of 3,5-dihalopyrazoles.
In a previous report,[12] we demonstrated the viability of
this strategy by the synthesis of N-p-methoxyphenyl (PMP)
3-bromo-5-iodopyrazole as a valuable scaffold for the one-
pot preparation of dissymmetrical 3,5-(hetero)aromatic pyr-
azoles through successive Suzuki–Miyaura cross-coupling
reactions. The PMP protecting group offers additional op-
portunity to access NH-pyrazole derivatives. Because of our
interests in the synthesis of drug-like chemical collections
for biological screening, we have investigated further the
scope and limitations of the cycloaddition/cross-coupling
approach to polysubstituted pyrazoles. In this context, we
wish to disclose herein the results of our exploratory studies
toward 1,3,5-trisubstituted pyrazoles.
Results and Discussion
Scheme 3.
Preparation of 4-Halosydnones and 1-Haloalkynes
The scope of the reaction was then investigated by using
N-Substituted 4-halosydnones 1a–f[10] and ethyl halo- various combinations of halosydnones and haloalkynes.
propiolates 2a–c[13] were easily prepared following pre- The results are summarized in Table 1. The reaction toler-
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Functionalization of 3,5-Dihalogenated Pyrazoles
ates various substitution patterns of the sydnones at N-1, Although regioselectivities generally remained moderate
including alkyl, benzyl, and aryl substituents. Firstly, a (ratios 1.5:1 to 3:1), desired 3,5-dihalogenopyrazoles 5a–e
series of pairs of isomeric 3(4)-bromo-5-iodopyrazoles were were always isolated as the major compounds in satisfying
obtained in good to excellent combined yields (64–87%). yields (39–63%; Table 1, Entries 1–5). Importantly, the re-
actions may be performed on a 10-mmol preparative scale
without noticeable variations in yields. It is worth noting
Table 1. Cycloaddition of halosydnones with halopropiolates.[a]
that the size of the ester group had essentially no influence
on the regioselectivity (Table 1, Entry 6). Next, the method-
ology was successfully extended to the synthesis of diiodo-
pyrazoles, as illustrated with the synthesis of pyrazoles 5g
and 6g (Table 1, Entry 7). Finally, it was observed that our
model bromosydnone 1f was unstable under the reaction
conditions, which is consistent with prior observations in
the literature[16] and thus prevented access to isomeric 5-
bromo-3-iodopyrazole 5h (Table 1, Entry 8).
Dealkoxycarbonylation Step
N-Arylpyrazoles 5d–f underwent facile deethoxycarbon-
ylation in refluxing 50% aq. sulfuric acid to provide the
corresponding dihalogenopyrazoles 8a–c as the selected
candidates for site-selective cross-coupling reactions. Clean
and complete conversion of the starting materials was nor-
mally achieved within 30 min. However, it is important to
note that in the case of N-p-anisylpyrazoles, much longer
reaction times led to the production of undesired demethyl-
ated pyrazoles 8Ј (Scheme 4).
Scheme 4.
Pyrazole Functionalization by Suzuki-Type Cross-Coupling
Reactions
With these results in hand, we next focused our attention
on their application in C(sp2)–C(sp2) bond formation by
Pd-catalyzed cross-coupling reactions. We chose the reac-
tion of 8a and 8c with phenylboronic acid (1.1 equiv.) under
Suzuki-type conditions as our starting point for the evalu-
ation of the effectiveness and selectivity of the cross-cou-
pling reactions. As expected, the cross-coupling reaction
was shown to be highly selective for the C-5 position in the
case of 3-bromo-5-iodopyrazole 8a. Thus, under the opti-
mum set of reaction conditions [10 mol-% Pd(PPh3)4,
2 equiv. K3PO4, DMF/H2O (4:1), 50 °C, 2.5 h], 9a was
cleanly obtained as the only monocoupled product in 69%
isolated yield. In contrast, the reaction of 3,5-diiodopyr-
azole 8c proved nonselective under identical conditions, af-
fording inseparable mixtures of mono- and bis-arylated ad-
ducts (compounds 10a, 11, and 12 obtained in a 1:1:3 ratio
as determined by GC–MS; Scheme 5).[17]
[a] Reactions were conducted in boiling xylene. [b] Ratios of crude
reaction products as determined by 1H NMR spectroscopy.
[c] Combined isolated yields.
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Table 2. Monocoupling of 3-bromo-5-iodopyrazoles with various
boron compounds.
Scheme 5.
Accordingly, application of this strategy to a variety of
electron-poor and electron-rich arylboronic acids, as well as
to a series of heteroarylboronic acids, including 3(4)-pyr-
idyl-, 2(3)-furyl-, 2(3)-thienyl-, and 2-indolylboronic acids,
generally furnished the corresponding coupling products in
good to excellent yields (Table 2, Entries 1–17). The low
yields obtained in the synthesis of 9e and 9l (Table 2, En-
tries 5 and 12) was attributed to the poor stability of the
corresponding boronic acids under the reaction conditions.
It is interesting to note that 3-bromo-1-(4-fluorophenyl)-5-
(4-pyridinyl)pyrazole (9f) has been previously shown to
possess very potent anti-inflammatory properties.[7] In an
effort to further diversify and broaden the range of 5-
C(sp2)-functionalized 3-bromopyrazoles, it was shown that
isopropenyl boronic acid pinacol ester could be successfully
entered into the Suzuki–Miyaura coupling of 8a under the
previous reaction conditions to provide the corresponding
pyrazole derivative 9r in 77% isolated yield (Table 2, En-
try 18). The introduction of a cyclopropyl group to the pyr-
azole moiety was also attempted. The cyclopropyl group is
increasingly incorporated into pharmaceuticals and agro-
chemicals due to its particular spatial and electronic proper-
ties as well as its high metabolic stability.[18] Interestingly,
8b underwent selective cross-coupling with potassium cy-
clopropyl trifluoroborate (1.1 equiv.) at C-5 by using
Pd(OAc)2/RuPhos as a catalyst system[19] in aqueous tolu-
ene to give 5-cyclopropylpyrazole 9s in 45% isolated yield
(Table 2, Entry 19).
We then briefly investigated the reactivity of the remain-
ing halogen atom at C-3 of compounds 9 toward Pd-cata-
lyzed C–C bond-forming reactions. As illustrated by the
synthesis of pyrazoles 13a–d, Suzuki cross-coupling reac-
tions of bromine derivatives 9j,o with (hetero)aryl and alkyl
boron compounds proved very successful using the previous
reaction conditions at a slightly higher reaction tempera-
ture, thereby opening access to unsymmetrically 3,5-
bisfunctionalized pyrazoles (Table 3). The possibility of in-
troducing two different (hetero)aryl substituents at the C-
5 and C-3 positions of the pyrazole nucleus in a one-pot
sequential fashion was then investigated. Although one-pot
[a] Single runs conducted on 0.2-mmol scale. Conditions A:
Pd(PPh3)4 (10 mol-%), K3PO4 (2 equiv.), DMF/H2O (4:1), 50 °C,
2–3 h; conditions B: Pd(OAc)2 (10 mol-%), Ruphos (20 mol-%),
K3PO4 (3 equiv.), toluene/H2O (10:1), 100 °C, 6 h. [b] Reaction
conducted at 80 °C.
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Functionalization of 3,5-Dihalogenated Pyrazoles
double Suzuki–Miyaura cross-coupling reactions remain completion, as judged by TLC (ca. 2–3 h), the second bo-
rare, recent years have witnessed heightened efforts in this ronic acid (1.3 equiv.) was added, and the reaction was left
area[20] that also address important economical and envi- to stir overnight at 80 °C to afford the corresponding bis-
ronmental issues. Efficient processes should preferably cross-coupled pyrazole derivatives in satisfying yields. As
avoid the need for additional base, catalyst, or ligand to illustrated with the synthesis of 3-isopropenyl-5-(4-pyridyl)-
cross-couple the second boronic acid efficiently.
pyrazole 13l, the procedure allows different boron reagents
Table 4. One-pot Suzuki bis-coupling.[a]
Table 3. Suzuki coupling of 3-bromopyrazoles.[a]
[a] Single runs conducted on 0.2-mmol scale. Conditions A:
RB(OH)2 (1.3 equiv.), Pd(PPh3)4 (10 mol-%), K3PO4 (3 equiv.),
DMF/H2O (4:1), 80 °C, 18 h; conditions B: RBF3K (2 equiv.),
Pd(OAc)2 (10 mol-%), Ruphos (20 mol-%), K3PO4 (3 equiv.), tolu-
ene/H2O (10:1), 110 °C, 12 h.
Fortunately, a synthetic procedure based on the previous
set of reaction conditions and Pd catalyst could be estab-
lished for the rapid synthesis of a small array of 3,5-bis-
(heteroaromatic) pyrazoles that essentially only required a
temperature adjustment. Thus, the dihalogenopyrazoles
(1.0 equiv.) and a first boronic acid (1.1 equiv.) underwent
the Suzuki–Miyaura cross-coupling reaction under the pre-
vious conditions [10 mol-% Pd(PPh3)4, 2 equiv. of K3PO4,
DMF/H2O (4:1), 50 °C]. Once the reaction had reached
[a] Single runs conducted on 0.2-mmol scale. Conditions: R1B-
(OH)2 (1.1 equiv.), Pd(PPh3)4 (10 mol-%), K3PO4 (3 equiv.), DMF/
H2O (4:1), 50 °C, 3 h; then R2B(OH)2 (1.3 equiv.; or isopropenyl-
boronic acid pinacol ester), 80 °C, 18 h. [b] First coupling was per-
formed at 80 °C.
Scheme 6. Synthesis of symmetrically substituted pyrazoles.
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T. Delaunay, M. Es-Sayed, J.-P. Vors, N. Monteiro, G. Balme
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(i.e., boronic acid and pinacol ester) to take part in the pro- the C-5 and C-3 positions of the pyrazole core could be
cess (Table 4). achieved through sequential Suzuki-type reactions with
As illustrated in Scheme 6, symmetrically disubstituted various boron compounds. Furthermore, the Suzuki cou-
pyrazoles may also be easily accessed. It is worth men- pling sequence may be amenable to a one-pot procedure to
tioning that a high temperature, short-time microwave pro- enable rapid generation of targeted compounds. Overall, the
cedure may be used for the heating.
procedures introduced here allow rapid, practical, and
modular access to diversely functionalized pyrazole deriva-
tives from readily available substrates, and reagents and
should find broad applications in the preparation of chemi-
cal libraries of potentially biologically active compounds.
Pyrazole Functionalization by Sonogashira Cross-Coupling
Reactions
Next, the participation of dihalogenopyrazoles in the
Sonogashira cross-coupling process was also briefly ex-
plored given the high synthetic and biological value of acet-
ylenic pyrazoles.[21] For instance, 8a underwent cross-cou-
pling with 4-cyanophenylacetylene to give the correspond-
ing 3-alkynyl-furopyridinone 14 in 55% isolated yield
(Scheme 7).
Experimental Section
General Methods: All reactions were run under open atmosphere
by using commercial-grade solvents except for reactions catalyzed
by palladium, which were carried out under an argon atmosphere.
Analytical thin-layer chromatography (TLC) was carried out on
Merck silica 60/F-240 aluminum-backed plates. Visualization of the
developed chromatogram was done by UV absorbance. Flash
chromatography was performed by using Merck silica gel 60 (40–
63 μm). NMR spectra were recorded with either a 300 or 400 MHz
spectrometer in the indicated solvent. Chemical shifts (δ) are given
from TMS (δ = 0.00 ppm) in parts per million (ppm) with the resid-
ual signals of deuterated solvent used as standards [CDCl3: 1H
NMR δ = 7.26 ppm (s); 13C NMR δ = 77.0 ppm (t)]. Coupling
constants (J) are expressed in Hertz (Hz) and spin multiplicities are
given as s (singlet), d (doublet), dd (doublet of doublets), t (triplet),
m (multiplet), and br. (broad). Commercially available reagents
were used as purchased. Halosydnones 1a–f were prepared in three
steps from the corresponding N-arylglycines according to published
procedures.[10b,22] Haloalkynes 2a–c were obtained by silver-cata-
lyzed halogenation of ethyl or tert-butyl propiolates with N-bromo-
or N-iodosuccinimide.[23]
Scheme 7. Sonogashira cross-coupling.
PMP Protecting Group Removal: Access to 1-Unsubstituted
Pyrazoles
Finally, as illustrated with the synthesis of 15 (Scheme 8)
it was shown that N-PMP-pyrazoles may be easily depro-
tected with ceric ammonium nitrate, thus expanding the
synthetic potential of our strategy.
General Procedure for the Synthesis of Halopyrazoles 5 and 6: A
mixture of the selected halosydnone (11 mmol) and halopropiolate
(11 mmol) in xylene (10 mL) was heated at reflux overnight. The
reaction mixture was then cooled and concentrated in vacuo. The
residue was purified by column chromatography (silica gel, appro-
priate mixture of cyclohexane/AcOEt) to give, in a first fraction,
the 3,5-dihalogenopyrazole 5 and, in a second fraction, the iso-
meric 4,5-dihalogenopyrazole 6.
Ethyl 3-Bromo-5-iodo-1-phenyl-1H-pyrazole-4-carboxylate (5a):
1
Yield: 2.40 g (52%), white solid, m.p. 88 °C. H NMR (300 MHz,
CDCl3): δ = 1.41 (t, J = 7.2 Hz, 3 H, CH3), 4.39 (q, J = 7.1 Hz, 2
H, CH2), 7.42–7.51 (m, 5 H, arom.) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.6 (CH3), 61.5 (CH2), 91.1 (5-C), 119.0 (3-C), 127.4,
129.5, 130.3, 130.7 (arom.), 139.9 (4-C), 161.2 (CO) ppm. HRMS
(EI): calcd. for C12H10BrIN2O2 [M]+ 419.8970; found 419.8971.
Scheme 8. PMP protecting group removal.
Conclusions
Ethyl 3-Bromo-5-iodo-1-methyl-1H-pyrazole-4-carboxylate (5b):
Yield: 1.97 g (50%), white solid, m.p. 77 °C. H NMR (300 MHz,
The 1,3-dipolar cycloaddition of 4-halosydnones with 1-
haloalkynes opens straightforward access to 3,5-dihalopyr-
azoles of potential utility as scaffolds for drug discovery.
The somewhat modest regioselectivities achieved in this
process are compensated by repeatability, scalability, and
high global yields as well as by the ease of separation of the
regioisomers. These halo compounds proved to be valuable
substrates for the elaboration of unsymmetrically 3,5-sub-
stituted pyrazole derivatives by Pd-catalyzed cross-coupling
reactions. Notably, the flexible and site-selective introduc-
1
CDCl3): δ = 1.40 (t, J = 7.1 Hz, 3 H, CH3), 3.97 (s, 3 H, NCH3),
4.35 (q, J = 7.1 Hz, 2 H, CH2) ppm. 13C NMR (75 MHz, CDCl3):
δ = 14.5 (CH3), 41.5 (CH3), 61.2 (CH2), 91.0 (5-C), 117.7 (3-C),
128.8 (4-C), 161.0 (CO) ppm. HRMS (EI): calcd. for C7H8BrIN2O2
[M]+ 357.8814; found 357.8813.
Ethyl 1-Benzyl-3-bromo-5-iodo-1H-pyrazole-4-carboxylate (5c):
1
Yield: 1.86 g (39%), white solid, m.p. 92 °C. H NMR (300 MHz,
CDCl3): δ = 1.33 (t, J = 7.1 Hz, 3 H, CH3), 4.29 (q, J = 7.1 Hz, 2
H, CH2), 5.39 (s, 2 H, CH2), 7.18–7.28 (m, 5 H, arom.) ppm. 13C
tion of different (hetero)aryl, vinyl, or alkyl substituents at NMR (75 MHz, CDCl3): δ = 14.2 (CH3), 57.0 (CH2), 61.0 (CH2),
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Functionalization of 3,5-Dihalogenated Pyrazoles
90.3 (5-C), 117.8 (3-C), 127.7, 128.4, 128.9, 129.3, 134.8 (arom. + Ethyl 4-Bromo-1-(4-fluorophenyl)-5-iodo-1H-pyrazole-3-carboxylate
4-C), 160.8 (CO) ppm. HRMS (CI): calcd. for C13H13BrIN2O2 [M
(6d): Yield: 0.77 g (16%), white solid, m.p. 112 °C. 1H NMR
(300 MHz, CDCl3): δ = 1.37 (t, J = 7.1 Hz, 3 H, CH3), 4.45 (q, J
= 7.1 Hz, 2 H, CH2), 7.12–7.19 (m, 2 H, arom.), 7.42–7.48 (m, 2
H, arom.) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.3 (CH3), 61.7
(CH2), 92.6 (5-C), 108.2 (4-C), 116.1 (d, 2JC,F = 23.0 Hz), 128.6 (d,
3JC,F = 10.0 Hz), 136.1, 143.0 (arom. + 3-C), 160.2 (CO), 163.0 (d,
1JC,F = 250.8 Hz) ppm. HRMS (CI): calcd. for C12H9BrFIN2O2
[M + H]+ 438.8954; found 438.8954.
+ H]+ 434.9205; found 434.9205.
Ethyl 3-Bromo-1-(4-fluorophenyl)-5-iodo-1H-pyrazole-4-carboxylate
(5d): Yield: 2.31 g (48%), white solid, m.p. 116 °C. 1H NMR
(300 MHz, CDCl3): δ = 1.35 (t, J = 7.1 Hz, 3 H, CH3), 4.32 (q, J
= 7.1 Hz, 2 H, CH2), 7.09–7.15 (m, 2 H, arom.), 7.36–7.40 (m, 2
H, arom.) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1 (CH3), 61.0
(CH2), 91.4 (5-C), 116.0 (d, 2JC,F = 23.2 Hz), 118.6 (3-C), 128.9 (d,
4
3JC,F = 9.3 Hz), 130.2 (4-C), 135.5 (d, JC,F = 3.3 Hz), 160.5 (CO),
Ethyl
4-Bromo-5-iodo-1-(4-methoxyphenyl)-1H-pyrazole-3-carb-
1
1
162.8 (d, JC,F
= 250.8 Hz) ppm. HRMS (CI): calcd. for
oxylate (6e): Yield: 1.04 g (21%), white solid, m.p. 122–124 °C. H
NMR (400 MHz, CDCl3): δ = 1.39 (t, J = 7.1 Hz, 3 H, CH3), 3.84
(s, 3 H, OCH3), 4.41 (q, J = 7.1 Hz, 2 H, CH2), 6.96 (d, J = 8.7 Hz,
2 H, arom.), 7.36 (d, J = 8.7 Hz, 2 H, arom.) ppm. 13C NMR
(100 MHz, CDCl3): δ = 14.2 (CH3), 55.7 (OCH3), 61.6 (CH2), 93.0
(5-C), 107.8 (4-C), 114.2, 127.9, 133.2, 142.7 (arom. + 3-C), 160.5
(CO), 160.8 (CO) ppm. HRMS (ESI): calcd. for C13H13BrIN2O3
[M + H]+ 450.9147; found 450.9165.
C12H10BrFIN2O2 [M + H]+ 438.8954; found 438.8955.
Ethyl 3-Bromo-5-iodo-1-(4-methoxyphenyl)-1H-pyrazole-4-carb-
1
oxylate (5e): Yield: 3.12 g (63%), white solid, m.p. 120–121 °C. H
NMR (400 MHz, CDCl3): δ = 1.43 (t, J = 7.1 Hz, 3 H, CH3), 3.87
(s, 3 H, OCH3), 4.39 (q, J = 7.1 Hz, 2 H, CH2), 6.99 (d, J = 8.9 Hz,
2 H, arom.), 7.35 (d, J = 8.9 Hz, 2 H, arom.) ppm. 13C NMR
(100 MHz, CDCl3): δ = 14.2 (CH3), 55.7 (OCH3), 61.1 (CH2), 91.7
(5-C), 114.2 (arom.), 118.3 (3-C), 128.3, 130.0, 132.6 (arom. + 4-
C), 160.5 (CO), 160.9 (CO) ppm. HRMS (CI): calcd. for
C13H13BrIN2O3 [M + H]+ 450.9154; found 450.9155.
tert-Butyl
4-Bromo-5-iodo-1-(4-methoxyphenyl)-1H-pyrazole-3-
carboxylate (6f): Yield: 0.68 g (13%), white solid, m.p. 80–82 °C.
1H NMR (300 MHz, CDCl3): δ = 1.62 (s, 9 H, 3CH3), 3.87 (s, 3
H, OCH3), 6.97 (d, J = 8.8 Hz, 2 H, arom.), 7.39 (d, J = 8.8 Hz, 2
H, arom.) ppm. 13C NMR (75 MHz, CDCl3): δ = 28.4 (3CH3),
55.8 (OCH3), 83.0 (CMe3), 107.3 (4-C), 114.2, 128.0, 133.5, 144.1
(arom. + 3-C), 159.7 (CO), 160.5 (CO) ppm.
tert-Butyl
3-Bromo-5-iodo-1-(4-methoxyphenyl)-1H-pyrazole-4-
carboxylate (5f): Yield: 2.26 g (43%), white solid, m.p. 75–76 °C.
1H NMR (300 MHz, CDCl3): δ = 1.62 (s, 9 H, 3CH3), 3.87 (s, 3
H, OCH3), 6.97 (d, J = 8.8 Hz, 2 H, arom.), 7.32 (d, J = 8.8 Hz, 2
H, arom.) ppm. 13C NMR (75 MHz, CDCl3): δ = 28.5 (3CH3),
55.7 (OCH3), 82.6 (CMe3), 91.0 (5-C), 114.3 (arom.), 119.3 (3-C),
128.5, 130.0, 132.8, 144.5 (arom. + 4-C), 160.1 (CO), 160.6 (CO)
ppm.
Ethyl 4,5-Diiodo-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate
1
(6g): Yield: 1.53 g (28%), white solid, m.p. 138–145 °C. H NMR
(400 MHz, CDCl3): δ = 1.40 (t, J = 7.1 Hz, 3 H, CH3), 3.85 (s, 3
H, OCH3), 4.44 (q, J = 7.1 Hz, 2 H, CH2), 6.94 (d, J = 8.8 Hz, 2 H,
arom.), 7.35 (d, J = 8.8 Hz, 2 H, arom.) ppm. 13C NMR (100 MHz,
CDCl3): δ = 14.7 (CH3), 56.0 (OCH3), 62.1 (CH2), 100.2 (5-C),
114.5, 121.1, 128.4, 134.0, 146.3 (arom. + 3-C + 4-C), 160.9 (CO),
161.0 (CO) ppm. HRMS (EI): calcd. for C13H12I2N2O3 [M]+
497.8937; found 497.8938.
Ethyl 3,5-Diiodo-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylate
1
(5g): Yield: 3.18 g (58%), white solid, m.p. 140–141 °C. H NMR
(400 MHz, CDCl3): δ = 1.42 (t, J = 7.1 Hz, 3 H, CH3), 3.84 (s, 3
H, OCH3), 4.37 (q, J = 7.1 Hz, 2 H, CH2), 6.96 (d, J = 8.9 Hz, 2 H,
arom.), 7.35 (d, J = 8.9 Hz, 2 H, arom.) ppm. 13C NMR (100 MHz,
CDCl3): δ = 14.3 (CH3), 55.7 (OCH3), 61.1 (CH2), 90.7 (5-C), 100.4
(3-C), 114.2, 121.8, 128.4, 132.7 (arom. + 4-C), 160.5 (CO), 160.9
(CO) ppm. HRMS (EI): calcd. for C13H12I2N2O3 [M]+ 497.8937;
found 497.8936.
General Procedure for the Synthesis of Pyrazole 8a-c: A solution
of the selected ethyl 3-bromo-5-iodo-1H-pyrazole-4-carboxylate 5
(1.5 mmol) in 50% aqueous H2SO4 (20 mL) was heated at 180 °C
for 30 min. The reaction mixture was then cooled to room tempera-
ture, diluted with water (50 mL), and extracted with AcOEt
(3ϫ30 mL). The combined organic layers were dried with MgSO4
and concentrated in vacuo. The residue was purified by column
chromatography (silica gel, cyclohexane/AcOEt, 90:10).
Spectroscopic Data for the Isomeric 4,5-Dihalopyrazoles 6
Ethyl 4-Bromo-5-iodo-1-phenyl-1H-pyrazole-3-carboxylate (6a):
Yield: 0.74 g (16%), white solid, m.p. 108 °C. 1H NMR (300 MHz,
CDCl3): δ = 1.42 (t, J = 7.1 Hz, 3 H, CH3), 4.45 (q, J = 7.1 Hz, 2
H, CH2), 7.50 (s, 5 H, arom.) ppm. 13C NMR (75 MHz, CDCl3):
δ = 14.4 (CH3), 61.7 (CH2), 92.3 (5-C), 108.3 (4-C), 126.6, 129.2,
129.9, 140.1, 143.0 (arom. + 3-C), 160.4 (CO) ppm. HRMS (EI):
calcd. for C12H10BrIN2O2 [M]+ 419.8970; found 419.8970.
3-Bromo-5-iodo-1-(4-methoxyphenyl)-1H-pyrazole
(8a):
Yield:
0.37 g (65%), white solid, m.p. 102–104 °C. 1H NMR (400 MHz,
CDCl3): δ = 3.85 (s, 3 H, OCH3), 6.58 (s, 1 H, 4-H), 6.97 (d, J =
8.8 Hz, 2 H, arom.), 7.36 (d, J = 8.8 Hz, 2 H, arom.) ppm. 13C
NMR (100 MHz, CDCl3): δ = 55.7 (OCH3), 83.8 (5-C), 114.1,
118.9, 127.9, 129.2, 132.8, (arom. + 3-C + 4-C), 160.1 (CO) ppm.
HRMS (ESI): calcd. for C10H9BrIN2O [M + H]+ 378.8934; found
378.8943.
Ethyl 4-Bromo-5-iodo-1-methyl-1H-pyrazole-3-carboxylate (6b):
Yield: 1.46 g (37%), white solid, m.p. 102 °C. 1H NMR (300 MHz,
CDCl3): δ = 1.40 (t, J = 7.1 Hz, 3 H, CH3), 4.06 (s, 3 H, NCH3),
4.42 (q, J = 7.1 Hz, 2 H, CH2) ppm. 13C NMR (75 MHz, CDCl3):
δ = 14.7 (CH3), 42.4 (NCH3), 61.9 (CH2), 92.2 (5-C), 107.0 (4-C),
141.8 (3-C), 160.6 (CO) ppm. HRMS (EI): calcd. for C7H8BrIN2O2
[M]+ 357.8814; found 357.8814.
3-Bromo-1-(4-fluorophenyl)-5-iodo-1H-pyrazole (8b): Yield: 0.52 g
1
(95%), white solid, m.p. 101 °C. H NMR (300 MHz, CDCl3): δ =
6.61 (s, 1 H, 4-H), 7.14–7.19 (m, 2 H, arom.), 7.44–7.48 (m, 2 H,
arom.) ppm. 13C NMR (75 MHz, CDCl3): δ = 83.4 (5-C), 115.0 (d,
Ethyl 1-Benzyl-4-bromo-5-iodo-1H-pyrazole-3-carboxylate (6c):
3
2JC,F = 23.1 Hz), 119.5 (4-C), 128.4 (d, JC,F = 8.8 Hz), 129.8 (3-
1
Yield: 1.29 g (27%), white solid, m.p. 88 °C. H NMR (300 MHz,
4
1
C), 135.8 (d, JC,F = 2.8 Hz), 162.5 (d, JC,F = 250.3 Hz) ppm.
HRMS (CI): calcd. for C9H6BrFIN2 [M + H]+ 366.8743; found
366.8743.
CDCl3): δ = 1.40 (t, J = 7.1 Hz, 3 H, CH3), 4.43 (q, J = 7.1 Hz, 2
H, CH2), 5.53 (s, 2 H, CH2), 7.20–7.22 (m, 2 H, arom.), 7.30–7.32
(m, 3 H, arom.) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.4 (CH3),
58.1 (CH2), 61.6 (CH2), 91.4 (5-C), 107.3 (4-C), 127.6, 128.4, 128.9, 3,5-Diiodo-1-(4-methoxyphenyl)-1H-pyrazole (8c): Yield: 0.33 g
134.7, 142.1 (arom. + 3-C), 160.4 (CO) ppm. HRMS (CI): calcd.
(51%), white solid, m.p. 110–113 °C. 1H NMR (400 MHz, CDCl3):
δ = 3.85 (s, 3 H, CH3), 6.70 (s, 1 H, 4-H), 6.96 (d, J = 9.1 Hz, 2 H,
for C13H13BrIN2O2 [M + H]+ 434.9205; found 434.9203.
Eur. J. Org. Chem. 2011, 3837–3848
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3843

T. Delaunay, M. Es-Sayed, J.-P. Vors, N. Monteiro, G. Balme
FULL PAPER
arom.), 7.36 (d, J = 9.1 Hz, 2 H, arom.) ppm. 13C NMR (100 MHz,
CDCl3): δ = 56.0 (OCH3), 84.1 (5-C), 98.4 (3-C), 114.4, 125.0, (OCH3), 110.8 (4-C), 116.3 (d, JC,F = 23.6 Hz), 127.2 (d, JC,F
6.3 Hz, 2 H, arom.) ppm. 13C NMR (100 MHz, CDCl3): δ = 52.5
2
3
=
128.2, 133.1 (arom. + 4-C), 160.4 (CO) ppm. HRMS (EI): calcd.
8.8 Hz), 128.0, 128.7, 130.1, 130.6, 133.4 (arom. + 3-C), 135.3 (d,
1
for C10H8I2N2O [M]+ 425.8726; found 425.8726.
4JC,F = 3.3 Hz), 144.2 (5-C), 162.2 (d, JC,F = 249.2 Hz), 166.4
(C=O) ppm. HRMS (ESI): calcd. for C17H13BrFN2O2 [M + H]+
375.0139; found 375.0146.
Suzuki Cross-Coupling at C-5/Synthesis of 5-(Hetero)arylpyraz-
oles 9
3-Bromo-1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1H-pyr-
azole (9f): Yield: 54 mg (69%), yellow solid, m.p. 183–186 °C. H
NMR (400 MHz, CDCl3): δ = 3.06 (s, 3 H, CH3), 6.61 (s, 1 H, 4-
General Procedure for the Coupling of Boronic Acids and Boronic
Acid Pinacol Esters (Conditions A): In a glass tube fitted with a
Teflon screw seal, Pd(PPh3)4 (0.02 mmol), K3PO4 (0.40 mmol) and
the selected boronic acid (0.22 mmol) were added to a solution of
the selected 3-bromo-5-iodopyrazole 5 (0.20 mmol) in a degassed
mixture of DMF/H2O (4:1; 2 mL). The reactor was flushed with
argon, and the reaction mixture was left to stir at the indicated
temperature (50 or 80 °C) until complete consumption of the start-
ing material as judged by TLC (2–3 h). The reaction mixture was
then diluted with water (20 mL) and extracted with AcOEt
(2ϫ20 mL). The combined organic layers were dried with MgSO4
and concentrated in vacuo. The residue was purified by column
chromatography (silica gel, appropriate mixture of cyclohexane/Ac-
OEt).
1
H), 7.03–7.09 (m, 2 H, arom.), 7.21–7.26 (m, 2 H, arom.), 7.38 (d,
J = 8.5 Hz, 2 H, arom.), 7.88 (d, J = 8.5 Hz, 2 H, arom.) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 44.5 (CH3), 111.3 (4-C), 116.5 (d,
3
2JC,F = 23.6 Hz), 127.3 (d, JC,F = 8.8 Hz), 128.0, 128.1, 129.5,
4
134.4 (arom. + 3-C), 135.0 (d, JC,F = 3.3 Hz), 141.0, 143.2 (C-
1
SO2Me + 5-C), 162.2 (d, JC,F = 249.7 Hz) ppm. HRMS (ESI):
calcd. for C16H13BrFN2O2S [M + H]+ 394.9860; found 394.9869.
3-Bromo-1-(4-fluorophenyl)-5-(3-trifluorophenyl)-1H-pyrazole (9g):
1
Yield: 61 mg (79%), yellow oil, H NMR (400 MHz, CDCl3): δ =
6.59 (s, 1 H, 4-H), 7.03–7.07 (m, 2 H, arom.), 7.22–7.24 (m, 1 H,
arom.), 7.31–7.34 (m, 1 H, arom.), 7.42–7.49 (m, 2 H, arom.), 7.59–
7.61 (m, 2 H, arom.) ppm. 13C NMR (100 MHz, CDCl3): δ = 110.7
3-Bromo-1-(4-methoxyphenyl)-5-phenyl-1H-pyrazole (9a): Yield:
45 mg (69%), white solid, m.p. 80–82 °C. 1H NMR (400 MHz,
CDCl3): δ = 3.80 (s, 3 H, OCH3), 6.50 (s, 1 H, 4-H), 6.83 (d, J =
8.9 Hz, 2 H, arom.), 7.16–7.22 (m, 4 H, arom.), 7.30–7.38 (m, 3 H,
arom.) ppm. 13C NMR (100 MHz, CDCl3): δ = 55.6 (OCH3), 109.7
(4-C), 114.2, 126.8, 127.2, 128.7, 128.8, 128.9, 129.5, 132.7 (arom.
+ 3-C), 148.7 (5-C), 159.2 (CO) ppm. HRMS (ESI): calcd. for
C16H14BrN2O [M + H]+ 329.0284; found 329.0287.
2
1
(4-C), 116.3 (d, JC,F = 23.5 Hz), 123.7 (q, JC,F = 272 Hz, CF3),
3
3
3
125.5 (q, JC,F = 3.7 Hz), 125.8 (q, JC,F = 3.7 Hz), 127.3 (d, JC,F
= 8.8 Hz), 128.0, 129.4, 129.9, 131.9 (arom. + 3-C), 135.1 (d, JC,F
= 3.6 Hz), 143.7 (5-C), 162.2 (d, JC,F = 249.7 Hz, C-F) ppm.
4
1
3-Bromo-1-(4-fluorophenyl)-5-(furan-3-yl)-1H-pyrazole (9h): Yield:
1
50 mg (81%), yellow oil. H NMR (400 MHz, CDCl3): δ = 6.16 (s,
1 H, arom), 6.47 (s, 1 H, 4-H), 7.08–7.14 (m, 2 H, arom.), 7.23 (s,
1 H, arom.), 7.34–7.37 (m, 3 H, arom.) ppm. 13C NMR (100 MHz,
CDCl3): δ = 109.1, 109.9 (arom. + 4-C), 114.8 (3-C), 116.3 (d, 2JC,F
3-Bromo-1,5-bis(4-methoxyphenyl)-1H-pyrazole (9b): Yield: 67 mg
(94%), white solid, m.p. 130–132 °C. 1H NMR (400 MHz, CDCl3):
δ = 3.80 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3), 6.43 (s, 1 H, 4-H),
6.80–6.85 (m, 4 H, arom.), 7.11 (d, J = 8.7 Hz, 2 H, arom.), 7.19
(d, J = 8.9 Hz, 2 H, arom.) ppm. 13C NMR (100 MHz, CDCl3): δ
= 55.4 (OCH3), 55.6 (OCH3), 109.1 (4-C), 114.1, 114.2, 121.8,
126.8, 127.1, 130.1, 132.7 (arom. + 3-C), 145.0 (5-C), 159.1 (CO),
159.9 (CO) ppm. HRMS (CI): calcd. for C17H15BrN2O2 [M + H]+
359.0395; found 359.0395.
= 23.0 Hz), 127.7 (arom.), 127.8 (d, 3JC,F = 8.8 Hz), 135.6 (d, 4JC,F
1
= 3.29 Hz), 137.8 (5-C), 140.8, 143.6 (arom.), 162.5 (d, JC,F
=
249.2 Hz) ppm. HRMS (ESI): calcd. for C13H9BrFN2O [M + H]+
306.9877; found 306.9889.
3-Bromo-5-(furan-2-yl)-1-(4-methoxyphenyl)-1H-pyrazole
(9i):
Yield: 60 mg (95%), white solid, m.p. 85–87 °C. 1H NMR
(400 MHz, CDCl3): δ = 3.86 (s, 3 H, OCH3), 5.88 (d, J = 3.5 Hz,
1 H, arom.), 6.31 (dd, J = 1.8 and 3.5 Hz, 1 H, arom.), 6.65 (s, 1
H, 4-H), 6.95 (d, J = 8.8 Hz, 2 H, arom.), 7.31 (d, J = 8.8 Hz, 2 H,
arom.), 7.39 (d, J = 1.8 Hz, 1 H, arom.) ppm. 13C NMR (100 MHz,
CDCl3): δ = 55.7 (OCH3), 107.8 (4-C), 109.5, 111.4, 114.4 (arom.),
127.1 (3-C), 127.7, 132.6, 136.8, 143.0, 143.5 (arom.), 160.1 (CO)
ppm. HRMS (CI): calcd. for C14H11BrN2O2 [M + H]+ 319.0082;
found 319.0081.
3-Bromo-5-(4-fluorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole (9c):
Yield: 60 mg (87%), white solid, m.p. 108–112 °C. 1H NMR
(400 MHz, CDCl3): δ = 3.81 (s, 3 H, OCH3), 6.47 (s, 1 H, 4-H),
6.84 (d, J = 8.7 Hz, 2 H, arom.), 6.96–7.02 (m, 2 H, arom.), 7.15–
7.18 (m, 4 H, arom.) ppm. 13C NMR (100 MHz, CDCl3): δ = 55.6
2
(OCH3), 109.7 (4-C), 114.3 (arom.), 115.9 (d, JC,F = 21.9 Hz),
4
125.6 (d, JC,F = 3.3 Hz), 126.8, 127.2 (arom. + 3-C), 130.7 (d,
3JC,F = 8.8 Hz), 132.4, 144.2 (arom. + 5-C), 159.3 (CO), 163.9 (d,
1JC,F = 249.7 Hz) ppm. HRMS (EI): calcd. for C16H12BrFN2O
[M]+ 346.0117; found 346.0117.
3-Bromo-1-(4-methoxyphenyl)-5-(thiophen-2-yl)-1H-pyrazole (9j):
Yield: 61 mg (91%), white solid, m.p. 140–143 °C. 1H NMR
(400 MHz, CDCl3): δ = 3.81 (s, 3 H, OCH3), 6.52 (s, 1 H, 4-H),
6.80–6.92 (m, 4 H, arom.), 7.22–7.26 (m, 3 H, arom) ppm. 13C
NMR (100 MHz, CDCl3): δ = 55.7 (OCH3), 109.2 (4-C), 114.4,
127.1, 127.2, 127.5, 127.8, 128.0, 130.1, 132.2 (arom. + 3-C), 139.5
(5-C), 160.1 (CO) ppm. HRMS (CI): calcd. for C14H11BrN2OS [M
+ H]+ 334.9854; found 334.9855.
5-(Benzo[d][1,3]dioxol-5-yl)-3-bromo-1-(4-fluorophenyl)-1H-pyrazole
1
(9d): Yield: 58 mg (81%), white solid, m.p. 138–140 °C. H NMR
(400 MHz, CDCl3): δ = 6.01 (s, 2 H, OCH2O), 6.47 (s, 1 H, 4-H),
6.65–6.80 (m, 3 H, arom.), 7.04–7.10 (m, 2 H, arom.), 7.27–7.32
(m, 2 H, arom.) ppm. 13C NMR (100 MHz, CDCl3): δ = 101.6
2
(OCH2O), 108.7, 109.1, 110.0 (arom. + 4-C), 116.0 (d, JC,F
=
3
23.0 Hz), 122.8, 123.1 (arom.), 127.1 (d, JC,F = 8.8 Hz), 127.7 (3-
C), 135.5 (d, JC,F = 3.3 Hz), 145.0, 148.0, 148.4 (2CO + 5-C),
3-Bromo-1-(4-methoxyphenyl)-5-(thiophen-3-yl)-1H-pyrazole (9k):
Yield: 61 mg (91%), yellow solid, m.p. 112–114 °C. 1H NMR
(400 MHz, CDCl3): δ = 3.83 (s, 3 H, OCH3), 6.51 (s, 1 H, 4-H),
6.50–6.90 (m, 3 H, arom.), 7.04 (dd, J = 2.8, 1.1 Hz, 1 H, arom.),
4
1
160.9 (d, JC,F
= 248.0 Hz) ppm. HRMS (CI): calcd. for
C16H11BrFN2O2 [M + H]+ 360.9982; found 360.9994.
Methyl
(9e): Yield: 28 mg (38%), white solid, m.p. 75–76 °C. 1H NMR
4-[3-Bromo-1-(4-fluorophenyl)-1H-pyrazol-5-yl]benzoate 7.23–7.26 (m, 3 H, arom.) ppm. 13C NMR (100 MHz, CDCl3): δ
= 55.7 (OCH3), 108.9 (4-C), 114.4, 124.4, 126.9, 127.3, 127.1, 127.4,
(400 MHz, CDCl3): δ = 3.84 (s, 3 H, OCH3), 6.51 (s, 1 H, 4-H), 129.6, 132.7 (arom. + 3-C), 140.8 (5-C), 159.7 (CO) ppm. HRMS
6.93–6.99 (m, 2 H, arom.), 7.14–7.20 (m, 4 H, arom.), 7.91 (d, J = (EI): calcd. for C14H11BrN2OS [M]+ 333.9776; found 333.9777.
3844
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3837–3848

Functionalization of 3,5-Dihalogenated Pyrazoles
3-Bromo-5-[N-Boc-5-methoxyindol]-2-yl-1-(4-methoxyphenyl)-1H-
pyrazole (9l): Yield: 30 mg (30%), yellow solid, m.p. 117–119 °C.
1.84 (s, 3 H, CH3), 5.03 (s, 1 H, =CH2), 5.19 (s, 1 H, =CH2), 6.34
(s, 1 H, 4-H), 7.08–7.14 (m, 2 H, arom.), 7.38–7.42 (m, 2 H, arom.)
1H NMR (400 MHz, CDCl3): δ = 1.31 (s, 9 H, 3CH3), 3.74 (s, 3 ppm. 13C NMR (75 MHz, CDCl3): δ = 22.3 (CH3), 109.5 (4-C),
H, OCH3), 3.85 (s, 3 H, OCH3), 6.49, 6.64 (2s, 2 H, 4-C + arom.), 116.2 (d, 2JC,F = 23.1 Hz), 119.6 (=CH2), 126.8 (d, 3JC,F = 8.8 Hz),
4
6.75 (d, J = 9.1 Hz, 2 H, arom.), 6.98 (dd, J = 9.1 and 2.5 Hz, 1
H, arom.), 7.06 (d, J = 2.3 Hz, 1 H, arom.), 7.21 (d, J = 9.1 Hz, 2
H, arom.), 8.05 (d, J = 9.1 Hz, 1 H, arom.) ppm. 13C NMR
(100 MHz, CDCl3): δ = 27.9 (3CH3), 55.6 (OCH3), 55.8 (OCH3),
84.3 (CMe3), 103.2 (4-C), 111.8, 113.3, 114.2, 114.8, 116.9, 124.0,
126.5, 127.3, 129.3, 131.8, 133.0 (arom. + 3-C), 137.6 (5-C), 149.1
(CO), 156.3 (CO), 158.7 (CO) ppm. HRMS (EI): calcd. for
C24H24BrN3O4 [M]+ 497.0949; found 497.0950.
127.3, 133.1 (C-Me + 3-C), 136.2 (d, JC,F = 3.3 Hz), 146.6 (5-C),
1
162.2 (d, JC,F = 248.6 Hz) ppm. HRMS (ESI): calcd. for
C12H11BrFN2 [M + H]+ 281.0084; found 280.0096.
Procedure for the Coupling of Potassium Cyclopropyltrifluoroborate
(Conditions B): In a glass tube fitted with a Teflon screw seal,
Pd(OAc)2 (0.02 mmol), RuPhos (0.04 mmol), K3PO4 (0.60 mmol),
and the potassium trifluoroborate (0.22 mmol) were added to a
solution of pyrazole 8b (0.20 mmol) in a degassed mixture of tolu-
ene/H2O (10:1; 2 mL). The reactor was flushed with argon, and the
reaction mixture was left to stir at 100 °C for 6 h. The reaction
mixture was then diluted with water (20 mL) and extracted with
AcOEt (2ϫ20 mL). The combined organic layers were dried with
MgSO4 and concentrated in vacuo. The residue was purified by
column chromatography (silica gel, appropriate mixture of cyclo-
hexane/AcOEt) to afford 3-bromo-5-cyclopropyl-1-(4-fluo-
rophenyl)-1H-pyrazole (9s). Yield: 25 mg (45%), oil. 1H NMR
(400 MHz, CDCl3): δ = 0.74–0.78 (m, 2 H, CHCpr), 0.96–1.03 (m,
2 H, CHCpr), 2.01–2.25 (m, 1 H, CHCpr), 5.97 (s, 1 H, 4-H), 7.12–
7.18 (m, 2 H, arom.), 7.52–7.57 (m, 2 H, arom.) ppm. 13C NMR
(100 MHz, CDCl3): δ = 7.6 (CH2), 9.1 (CH), 105.7 (4-C), 116.1 (d,
3-[3-Bromo-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]pyridine
(9m):
Yield: 55 mg (83%), white solid, m.p. 70–72 °C. 1H NMR
(400 MHz, CDCl3): δ = 3.80 (s, 3 H, OCH3), 6.57 (s, 1 H, 4-H),
6.85 (d, J = 8.7 Hz, 2 H, arom.), 7.17 (d, J = 8.9 Hz, 2 H, arom.),
7.18–7.26 (m, 1 H, arom.), 7.43 (d, J = 7.9 Hz, 1 H, arom.), 8.52
(s, 1 H, arom.), 8.55 (d, J = 4.5 Hz, 1 H, arom.) ppm. 13C NMR
(100 MHz, CDCl3): δ = 55.6 (OCH3), 110.2 (4-C), 114.5, 123.4,
125.7, 127.0, 127.4, 132.0, 135.9, 141.9 (arom. + 3-C + 5-C), 149.4,
149.9 (arom.), 159.6 (CO) ppm. HRMS (EI): calcd. for
C15H12BrN3O [M]+ 329.0164; found 329.0164.
4-[3-Bromo-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]pyridine
(9n):
Yield: 45 mg (69%), white solid, m.p. 88–92 °C. 1H NMR
(400 MHz, CDCl3): δ = 3.82 (s, 3 H, OCH3), 6.62 (s, 1 H, 4-H),
6.87 (d, J = 8.8 Hz, 2 H, arom.), 7.07 (d, J = 5.8 Hz, 2 H, arom.),
7.18 (d, J = 8.8 Hz, 2 H, arom.), 8.55 (d, J = 3.5 Hz, 2 H, arom.)
ppm. 13C NMR (100 MHz, CDCl3): δ = 55.6 (OCH3), 110.5 (4-C),
114.5, 122.6, 126.9, 127.5, 132.0, 136.8, 142.3 (arom. + 3-C + 5-C),
150.3 (arom.), 159.8 (CO) ppm. HRMS (EI): calcd. for
C15H12BrN2O2 [M]+ 329.0164; found 329.0164.
3
2JC,F = 22.7 Hz), 126.8 (d, JC,F = 8.1 Hz), 127.2 (3-C), 135.5 (d,
1
4JC,F = 3.7 Hz), 148.4 (5-C), 162.1 (d, JC,F = 248.0 Hz) ppm.
HRMS (ESI): calcd. for C12H11BrFN2 [M + H]+ 281.0084; found
281.0091.
Suzuki Cross-Coupling at C-3/Synthesis of Pyrazoles 13a-d
General Procedure for the Introduction of (Hetero)aromatic Groups
(Conditions A): In a glass tube fitted with a Teflon screw seal,
Pd(PPh3)4 (0.02 mmol), K3PO4 (0.40 mmol), and the selected bo-
ronic acid (0.26 mmol) were added to a solution of the 3-bromopyr-
azole (0.20 mmol) in a degassed mixture of DMF/H2O (4:1; 2 mL).
The reactor was flushed with argon, and the reaction mixture was
left to stir at 80 °C for 18 h. The reaction mixture was then diluted
with water (20 mL) and extracted with AcOEt (2ϫ20 mL). The
combined organic layers were dried with MgSO4 and concentrated
in vacuo. The residue was purified by column chromatography (sil-
ica gel, appropriate mixture of cyclohexane/AcOEt).
4-[3-Bromo-1-(4-fluorophenyl)-1H-pyrazol-5-yl]pyridine (9o): Yield:
41 mg (64%), white solid, m.p. 88–92 °C. 1H NMR (400 MHz,
CDCl3): δ = 6.64 (s, 1 H, 4-H), 7.05–7.10 (m, 4 H, arom.), 7.23–
7.27 (m, 2 H, arom.), 8.58 (d, J = 6.1 Hz, 2 H, arom.) ppm. 13C
2
NMR (75 MHz, CDCl3): δ = 111.2 (4-C), 116.5 (d, JC,F
=
3
23.5 Hz), 122.7 (arom.), 127.3 (d, JC,F = 8.8 Hz), 128.1 (3-C),
135.0 (d, 4JC,F = 2.9 Hz), 136.6, 142.5 (arom. + 5-C), 150.5 (arom.),
1
162.4 (d, JC,F
= 249.4 Hz) ppm. HRMS (EI): calcd. for
C14H9BrFN3 [M]+ 316.9964; found 316.9965.
4-{1-(4-Fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-
yl}pyridine (13a): Yield: 51 mg (65%), white solid, m.p. 192–198 °C.
1H NMR (400 MHz, CDCl3): δ = 3.09 (s, 3 H, CH3), 7.02 (s, 1 H,
4-H), 7.10–7.17 (m, 4 H, arom.), 7.35–7.37 (m, 2 H, arom.), 7.80
(d, J = 8.3 Hz, 2 H, arom.), 8.09 (d, J = 8.3 Hz, 2 H, arom.), 8.62
(br. s, 2 H, arom.) ppm. 13C NMR (100 MHz, CDCl3): δ = 44.7
4-[3-Bromo-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-2-chloropyridine
(9p): Yield: 27 mg (51%), white solid, m.p. 96–100 °C. 1H NMR
(400 MHz, CDCl3): δ = 3.83 (s, 3 H, OCH3), 6.64 (s, 1 H, 4-H),
6.88–6.93 (m, 3 H, arom.), 7.16–7.26 (m, 3 H, arom.), 8.29 (d, J =
5.0 Hz, 1 H, arom.) ppm. 13C NMR (100 MHz, CDCl3): δ = 55.7
(OCH3), 111.0 (4-C), 114.7, 121.3, 123.1, 126.9, 127.6, 131.7, 139.7,
141.0 (arom. + 3-C + 5-C), 150.1, 152.2 (arom.), 160.0 (CO) ppm.
HRMS (CI): calcd. for C15H12BrClN3O [M + H]+ 363.9852; found
263.9852.
2
(CH3), 106.6 (4-C), 116.5 (d, JC,F = 22.7 Hz), 126.5, 127.3, 127.4,
128.1 (arom.), 135.6 (d, 4JC,F = 2.9 Hz), 137.4, 137.9, 140.0, 142.4,
1
150.4, 150.5 (arom. + 3-C + 5-C), 162.4 (d, JC,F = 249 Hz) ppm.
HRMS (EI): calcd. for C21H17FN3O2S [M + H]+ 394.1026; found
394.1029.
4-[3-Bromo-1-(4-fluorophenyl)-1H-pyrazol-5-yl]-2-chloropyridine
1
(9q): Yield: 38 mg (54%), white solid, m.p. 102–104 °C. H NMR
3-[1-(4-Methoxyphenyl)-5-thiophen-2-yl-1H-pyrazol-3-yl]pyridine
1
(400 MHz, CDCl3): δ = 6.74 (s, 1 H, 4-H), 6.99 (dd, J = 5.2 and
1.4 Hz, 2 H, arom.), 7.17–7.36 (m, 5 H, arom.), 8.39 (d, J = 5.2 Hz,
1 H, arom.) ppm. 13C NMR (100 MHz, CDCl3): δ = 111.5 (4-C),
(13b): Yield: 51 mg (77%), white solid, m.p. 150–153 °C. H NMR
(400 MHz, CDCl3): δ = 3.86 (s, 3 H, OCH3), 6.87–7.97 (m, 5 H,
arom.), 7.27–7.38 (m, 4 H, arom.), 8.19 (d, J = 7.9 Hz, 1 H, arom.),
8.58 (br. s, 1 H, arom.), 9.10 (br. s, 1 H, arom.) ppm. 13C NMR
(100 MHz, CDCl3): δ = 55.7 (OCH3), 104.2 (4-C), 114.5, 126.8,
127.4, 127.5, 127.9, 131.1, 132.8, 133.1, 139.1, 147.3, 148.7, 149.1
(arom. + 3-C + 5-C), 160.0 (CO) ppm. HRMS (EI): calcd. for
C19H15N3OS [M]+ 333.0936; found 333.0932.
2
3
116.5 (d, JC,F = 23.1 Hz), 121.3, 123.1 (arom.), 127.3 (d, JC,F
=
4
8.8 Hz), 128.2 (3-C), 134.7 (d, JC,F = 3.3 Hz), 139.4, 141.1 (arom.
1
+ 5-C), 150.2, 152.3 (arom.), 162.5 (d, JC,F = 250.3 Hz) ppm.
HRMS (EI): calcd. for C14H8BrClFN3 [M]+ 350.9574; found
350.9573.
3-Bromo-1-(4-fluorophenyl)-5-(prop-1-en-2-yl)-1H-pyrazole
Yield: 43 mg (77%), yellow oil. H NMR (400 MHz, CDCl3): δ = tions B): In a glass tube fitted with a Teflon screw seal, Pd(OAc)2
(9r): General Procedure for the Introduction of Alkyl Groups (Condi-
1
Eur. J. Org. Chem. 2011, 3837–3848
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3845

T. Delaunay, M. Es-Sayed, J.-P. Vors, N. Monteiro, G. Balme
FULL PAPER
(0.02 mmol), RuPhos (0.04 mmol), K3PO4 (0.60 mmol), and the
selected potassium trifluoroborate (0.40 mmol) were added to a
solution of the 3-bromopyrazole (0.20 mmol) in a degassed mixture
of toluene/H2O (10:1; 2 mL). The reactor was flushed with argon,
and the reaction mixture was left to stir at 110 °C for 12 h. The
reaction mixture was then diluted with water (20 mL) and extracted
with AcOEt (2ϫ20 mL). The combined organic layers were dried
with MgSO4 and concentrated in vacuo. The residue was purified
by column chromatography (silica gel, appropriate mixture of cy-
clohexane/AcOEt).
3-(4-Fluorophenyl)-5-(furan-2-yl)-1-(4-methoxyphenyl)-1H-pyrazole
(13f): Yield: 48 mg (72%), orange solid, m.p. 114–116 °C. 1H NMR
(400 MHz, CDCl3): δ = 3.88 (s, 3 H, OCH3), 5.89 (d, J = 3.0 Hz,
1 H, arom.), 6.33 (dd, J = 3.3 and 1.8 Hz, 1 H, arom.), 6.92 (s, 1
H, 4-H), 6.99 (d, J = 8.8 Hz, 2 H, arom.), 7.10 (m, 2 H, arom.),
7.39 (d, J = 8.8 Hz, 2 H, arom.), 7.42 (d, J = 1.3 Hz, 1 H, arom.),
7.85 (dd, J = 8.8 and 5.5 Hz, 2 H, arom.) ppm. 13C NMR
(100 MHz, CDCl3): δ = 55.7 (OCH3), 102.5 (4-C), 108.8, 111.4,
114.5 (arom.), 115.6 (d, 2JC,F = 22.0 Hz), 127.6 (d, 3JC,F = 8.1 Hz),
127.8 (arom.), 129.3 (d, 4JC,F = 3.7 Hz), 133.4, 136.3, 142.6, 144.7,
151.0 (arom.), 160.0 (CO), 162.9 (d, 1JC,F = 246.0 Hz) ppm. HRMS
(EI): calcd. for C20H15FN2O2 [M]+ 334.1118; found 334.1114.
4-[3-Cyclopropyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl]pyridine (13c):
1
Yield: 41 mg (74%), yellow oil. H NMR (400 MHz, CDCl3): δ =
1-(4-Methoxyphenyl)-3-(thiophen-2-yl)-5-[3-(trifluoromethyl)-
phenyl]-1H-pyrazole (13g): Yield: 42 mg (52 %), colorless oil. H
0.83 (m, 2 H, CHCpr), 1.00 (m, 2 H, CHCpr), 2.02 (m, 1 H, CHCpr),
6.29 (s, 1 H, 4-H), 7.03–7.07 (m, 4 H, arom.), 7.22–7.24 (m, 2 H,
1
arom.), 8.53 (d, J = 4.3 Hz, 2 H, arom.) ppm. 13C NMR (100 MHz,
NMR (400 MHz, CDCl3): δ = 3.82 (s, 3 H, OCH3), 6.77 (s, 1 H,
4-H), 6.88 (d, J = 9.1 Hz, 2 H, arom.), 7.09 (dd, J = 5.0, 3.5 Hz, 1
H, arom.), 7.25 (d, J = 9.1 Hz, 2 H, arom.), 7.28 (dd, J = 5.4,
1.0 Hz, 1 H, arom.), 7.35–7.44 (m, 3 H, arom.), 7.55–7.58 (m, 2 H,
arom.) ppm. 13C NMR (100 MHz, CDCl3): δ = 55.7 (OCH3), 105.1
2
CDCl3): δ = 8.3 (CH2), 9.2 (CH), 105.4 (4-C), 116.2 (d, JC,F
=
3
22.7 Hz), 122.6 (arom.), 127.2 (d, JC,F = 8.8 Hz), 135.9, 138.0,
140.9, 150.2, 156.6 (arom. + 3-C + 5-C), 161.9 (d, 1JC,F = 248.0 Hz)
ppm. HRMS (CI): calcd. for C17H15FN3 [M + H]+ 280.1250; found
280.1250.
1
(4-C), 114.5 (arom.), 123.9 (q, JC,F = 272.0 Hz, CF3), 124.3
3
3
(arom.), 125.1 (q, JC,F = 3.7 Hz), 125.1 (arom.), 125.5 (q, JC,F
=
4-[1-(4-Fluorophenyl)-3-methyl-1H-pyrazol-5-yl]pyridine
(13d):
2
4.4 Hz), 127.1, 127.7, 129.1 (arom.), 131.2 (q, JC,F = 32.3 Hz),
131.9, 132.8, 136.1, 142.9, 147.4 (arom.), 159.4 (CO) ppm. HRMS
(EI): calcd. for C21H15F3N2OS [M]+ 400.0857; found 400.0857.
Yield: 36 mg (71%), white solid, m.p. 122–126 °C. 1H NMR
(400 MHz, CDCl3): δ = 2.38 (s, 3 H, CH3), 6.43 (s, 1 H, 4-H), 7.03–
7.08 (m, 4 H, arom.), 7.22–7.27 (m, 2 H, arom.), 8.53 (d, J =
6.0 Hz, 2 H, arom.) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.6
(CH3), 108.7 (4-C), 127.3 (d, 2JC,F = 23.5 Hz), 122.7 (arom.), 127.2
1-{4-[5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]phen-
yl}ethanone (13h): Yield: 64 mg (80 %), white solid, m.p. 130–
1
3
4
132 °C. H NMR (400 MHz, CDCl3): δ = 2.61 (s, 3 H, CH3), 3.81
(d, JC,F = 8.1 Hz), 135.9 (d, JC,F = 2.9 Hz), 137.9, 141.1, 150.1,
1
(s, 3 H, OCH3), 6.84 (s, 1 H, 4-H), 6.87 (d, J = 8.8 Hz, 2 H, arom.),
7.17 (d, J = 8.6 Hz, 2 H, arom.), 7.29–7.33 (m, 4 H, arom.), 7.96–
8.01 (m, 4 H, arom.) ppm. 13C NMR (100 MHz, CDCl3): δ = 26.8
(CH3), 55.6 (OCH3), 105.3 (4-C), 114.4, 125.8, 126.9, 128.8, 128.9,
129.0, 129.8, 130.0, 133.0, 134.6, 136.5, 137.6, 143.6, 150.6 (arom.),
159.3 (CO), 197.8 (C=O) ppm. HRMS (EI): calcd. for
C24H19ClN2O2 [M]+ 402.1135; found 402.1135.
150.2 (arom. + 3-C + 5-C), 162.0 (d, JC,F = 248.0 Hz) ppm.
HRMS (CI): calcd. for C15H13FN3 [M + H]+ 254.1094; found
254.1095.
General Procedure for the Sequential Suzuki Cross-couplings at C-
5 and C-3: Synthesis of Pyrazoles 13a,b and 13e-l: In a glass tube
fitted with a Teflon screw seal, Pd(PPh3)4 (0.02 mmol), K3PO4
(0.60 mmol), and the selected boronic acid (0.22 mmol) were added
to a solution of the 3-bromo-5-iodopyrazole (0.20 mmol) in a de-
gassed mixture of DMF/H2O (4:1, 2 mL). The reactor was flushed
with argon, and the reaction mixture was left to stir at the indicated
temperature (50 or 80 °C) for 3 h. The second boron compound
(0.26 mmol) was then added, and the reaction mixture was left to
stir overnight at 80 °C. Water (20 mL) was added, and the reaction
mixture was extracted with AcOEt (2ϫ20 mL). The combined or-
ganic layers were dried with MgSO4 and concentrated in vacuo.
The residue was purified by column chromatography (silica gel,
appropriate mixture of cyclohexane/AcOEt) to afford the corre-
sponding 3,5-disubstituted pyrazole.
4-[3-(4-Fluorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]pyridine
1
(13i): Yield: 44 mg (62%), white solid, m.p. 127–129 °C. H NMR
(400 MHz, CDCl3): δ = 3.88 (s, 3 H, OCH3), 6.92–6.97 (m, 3 H, 4-
H + arom.), 7.15–7.20 (m, 4 H, arom.), 7.29–7.32 (m, 2 H, arom.),
7.88–7.93 (m, 2 H, arom.), 8.60 (s, 2 H, arom.) ppm. 13C NMR
(100 MHz, CDCl3): δ = 55.7 (OCH3), 105.3 (4-C), 114.6 (arom.),
2
3
115.7 (d, JC,F = 21.3 Hz), 122.7, 126.9 (arom.), 127.6 (d, JC,F
=
8.1 Hz), 132.8, 138.0, 141.7, 149.9, 151.3 (arom.), 159.6 (CO), 163.0
1
(d, JC,F = 288.6 Hz) ppm. HRMS (ESI): calcd. for C21H17FN3O
[M + H]+ 346.1363; found 356.1356.
3-[3-(4-Fluorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]pyridine
(13j): Yield: 58 mg (84 %), colorless oil. 1H NMR (400 MHz,
CDCl3): δ = 3.86 (s, 3 H, OCH3), 6.87 (s, 1 H, 4-H), 6.93 (d, J =
8.8 Hz, 2 H, arom.), 7.13–7.18 (m, 2 H, arom.), 7.28–7.31 (m, 3 H,
arom.), 7.58 (d, J = 8.1 Hz, 1 H, arom.), 7.91 (dd, J = 5.5 and
2.0 Hz, 1 H, arom.), 8.63 (d, J = 4.0 Hz, 1 H, arom.), 8.67 (s, 1 H,
arom.) ppm. 13C NMR (100 MHz, CDCl3): δ = 55.6 (OCH3), 105.0
13a: 51 mg (65%). Analytical data were identical to those described
above.
13b: 36 mg (54%). Analytical data were identical to those described
above.
Methyl
4-[3-(Furan-2-yl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-
2
(4-C), 114.5 (arom.), 115.7 (d, JC,F = 22.0 Hz), 123.6, 127.0
benzoate (13e): Yield: 22 mg (30%), orange solid, m.p. 140–143 °C.
1H NMR (400 MHz, CDCl3): δ = 3.82 (s, 3 H, OCH3), 3.91 (s, 3
H, OCH3), 6.49 (dd, J = 3.3 and 1.8 Hz, 1 H, arom.), 6.77 (d, J =
3.3 Hz, 1 H, arom.), 6.81 (s, 1 H, 4-H), 6.86 (d, J = 9.1 Hz, 2 H,
arom.), 7.23 (d, J = 9.1 Hz, 2 H, arom.), 7.25 (d, J = 8.4 Hz, 2 H,
3
4
(arom.), 127.6 (d, JC,F = 8.1 Hz), 129.1 (d, JC,F = 2.9 Hz), 132.7,
1
136.2, 141.0, 148.7, 151.2 (arom.), 159.4 (CO), 162.9 (d, JC,F
=
246.5 Hz) ppm. HRMS (CI): calcd. for C21H17FN3O [M + H]+
346.1356; found 346.1355.
arom.), 7.49 (d, J = 1.8 Hz, 1 H, arom.), 7.97 (d, J = 8.4 Hz, 2 H, 3-(1,3-Benzodioxol-5-yl)-1-(4-methoxyphenyl)-5(-furan-2-yl)-1H-pyr-
arom.) ppm. 13C NMR (100 MHz, CDCl3): δ = 52.4 (OCH3), 55.6 azole (13k): Yield: 44 mg (61%), orange solid, m.p. 109–111 °C. 1H
(OCH3), 105.0, 106.5, 111.5, 114.4, 127.1, 128.7, 129.9, 133.0, NMR (400 MHz, CDCl3): δ = 3.87 (s, 3 H, OCH3), 5.90 (d, J =
134.7, 142.3, 143.2, 144.6, 148.5 (arom.), 159.4 (CO), 166.7 (CO)
ppm. HRMS (EI): calcd. for C22H18N2O4 [M]+ 374.1267; found
374.1266.
3.0 Hz, 1 H, arom.), 5.98 (s, 2 H, OCH2O), 6.32 (dd, J = 3.4 and
1.9 Hz, 1 H, arom.), 6.84–6.88 (m, 2 H, 4-H + arom.), 6.97 (d, J =
8.8 Hz, 2 H, arom.), 7.36–7.42 (m, 5 H, arom.) ppm. 13C NMR
3846
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3837–3848

Functionalization of 3,5-Dihalogenated Pyrazoles
(100 MHz, CDCl3): δ = 55.7 (OCH3), 101.2 (OCH2O), 102.4 (4-C),
106.6, 108.6, 108.7, 111.4, 114.4, 119.7, 127.4, 127.7, 133.5, 136.1,
142.5, 144.8 (arom.), 147.6, 148.1, 151.6 (arom. + 2CO), 159.8 (CO)
ppm. HRMS (EI): calcd. for C22H18N2O4 [M]+ 361.1188; found
361.1188.
tube fitted with a Teflon screw seal. The reactor was flushed with
argon, and the reaction mixture was left to stir at 80 °C for 2.5 h,
after which time it was diluted with water (20 mL) and extracted
with AcOEt (2ϫ20 mL). The combined organic layers were dried
with MgSO4 and concentrated in vacuo. The residue was purified
by column chromatography (silica gel, appropriate mixture of cy-
clohexane/AcOEt) to afford 14 (41 mg, 55%) as a white solid. M.p.
189–192 °C. 1H NMR (300 MHz, CDCl3): δ = 3.87 (s, 3 H, OCH3),
6.69 (s, 1 H, 4-H), 6.99 (d, J = 8.6 Hz, 2 H, arom.), 7.48 (d, J =
8.6 Hz, 2 H, arom.), 7.60–7.64 (m, 4 H, arom.) ppm. 13C NMR
(75 MHz, CDCl3): δ = 55.7 (OCH3), 81.3, 95.3 (2Cϵ), 112.7, 114.2
(arom.), 114.7 (4-C), 118.3 (CN), 125.3, 125.9, 126.5, 126.8, 132.1,
132.4 (arom.), 159.6 (CO) ppm. HRMS (CI): calcd. for
C19H13BrN3O [M + H]+ 378.0243; found 378.0243.
4-[1-(4-Fluorophenyl)-3-(1-methylethenyl)-1H-pyrazol-5-yl]pyridine
(13l): Yield: 37 mg (67%), yellow oil. 1H NMR (400 MHz, CDCl3):
δ = 2.29 (s, 3 H, CH3), 5.27 (s, 1 H, =CH2), 5.71 (s, 1 H, =CH2),
6.84 (s, 1 H, 4-H), 7.13–7.18 (m, 2 H, arom.), 7.26 (br. s, 2 H,
arom.), 7.35–7.39 (m, 2 H, arom.), 8.83 (br. s, 2 H, arom.) ppm.
13C NMR (100 MHz, CDCl3): δ = 20.3 (CH3), 105.8 (4-C), 113.4
(=CH2), 116.3 (d, 2JC,F = 22.8 Hz), 127.3 (d, 3JC,F = 8.8 Hz), 135.9
4
(d, JC,F = 3.7 Hz), 136.5, 137.8, 149.8, 153.8 (arom. + C-Me),
1
162.1 (d, JC,F
= 248.7 Hz) ppm. HRMS (CI): calcd. for
C17H15FN3 [M + H]+ 280.1250; found 280.1251.
Removal of the PMP Protecting Group for the Synthesis of 3-[3-(4-
Fluorophenyl)-1H-pyrazol-5-yl]pyridine (15): A stirred, cooled solu-
tion (ice bath) of PMP-protected pyrazole 13i (0.2 mmol) in a mix-
ture of MeCN/H2O (4:1, 5 mL) was treated dropwise with a cooled
aqueous solution (3 mL) of ceric ammonium nitrate (1.0 mmol),
and stirring was continued for 1 h at 0 °C and then 4 h at room
temperature. The reaction mixture was then diluted with water
(20 mL), and the organic solvent was removed under reduced pres-
sure. The remaining aqueous solution was extracted with CH2Cl2
(3ϫ20 mL). The combined organic extracts were washed with satu-
rated aqueous NaHCO3 (2ϫ15 mL), dried with anhydrous
MgSO4, and concentrated in vacuo to give 15 (27 mg, 56%) as a
white solid. M.p. 195–196 °C. 1H NMR (400 MHz, CDCl3): δ =
6.82 (s, 1 H, 4-H), 7.08–7.12 (m, 2 H, arom.), 7.32 (dd, J = 7.8 and
4.8 Hz, 1 H, arom.), 7.64 (dd, J = 8.8 and 5.3 Hz, 2 H, arom.),
8.03 (d, J = 7.8 Hz, 1 H, arom.), 8.56 (d, J = 3.5 Hz, 1 H, arom.),
9.01 (s, 1 H, arom.) ppm. 13C NMR (100 MHz, CDCl3): δ = 100.5
(4-C), 116.2 (d, 2JC,F = 22.0 Hz), 123.9, 126.7, 127.0 (arom.), 127.6
Synthesis of Symmetrically Substituted Pyrazoles 13m,n
3,5-Bis-cyclopropyl-1-(4-fluoro)phenyl-1H-pyrazole (13m): In a glass
tube fitted with a Teflon screw seal, Pd(OAc)2 (0.02 mmol), RuPhos
(0.04 mmol), K3PO4 (0.60 mmol), and potassium cyclopropyltrifl-
uoroborate (0.60 mmol) were added to a solution of 3-bromo-5-
iodopyrazole 8b (0.20 mmol) in a degassed mixture of toluene/H2O
(10:1; 2 mL). The reactor was flushed with argon, and the reaction
mixture was left to stir at 110 °C for 18 h. The reaction mixture
was then diluted with water (20 mL) and extracted with AcOEt
(2ϫ20 mL). The combined organic layers were dried with MgSO4
and concentrated in vacuo. The residue was purified by column
chromatography (silica gel, appropriate mixture of cyclohexane/Ac-
OEt) to give 13m (27 mg, 56%) as a yellow oil. 1H NMR
(300 MHz, CDCl3): δ = 0.69–0.74 (m, 4 H, CHCpr), 0.89–0.95 (m,
4 H, CHCpr), 1.65–1.74 (m, 1 H, CHCpr), 1.88–1.97 (m, 1 H,
CHCpr), 5.60 (s, 1 H, 4-H), 7.09–7.15 (m, 2 H, arom.), 7.53–7.58
(m, 2 H, arom.) ppm. 13C NMR (75 MHz, CDCl3): δ = 7.8, 8.0,
8.8, 9.3 (CCpr), 99.3 (4-C), 115.8 (d, 2JC,F = 22.5 Hz), 126.5 (d, 3JC,F
= 8.8 Hz), 136.5 (d, 4JC,F = 2.7 Hz), 146.6, 155.2 (3-C + 5-C), 161.6
(d, 1JC,F = 246.4 Hz) ppm. HRMS (ESI): calcd. for C15H16FN2 [M
+ H]+ 243.1292; found 243.1302.
3
(d, JC,F = 8.1 Hz), 128.6, 133.1, 147.1, 149.2 (arom.), 163.0 (d,
1JC,F = 248.7 Hz) ppm. HRMS (CI): calcd. for C14H11FN3 [M +
H]+ 240.0937; found 240.0937.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra for new compounds.
3,5-Bis-isoprenyl-1-(4-fluoro)phenyl-1H-pyrazole (13n): Pd(PPh3)4
(0.02 mmol), K3PO4 (0.60 mmol), isopropenylboronic acid pinacol
ester (0.6 mmol), and 3-bromo-5-iodopyrazole 8b (0.20 mmol) were
filled into an appropriate small microwave process vial containing
a degassed mixture of DMF/H2O (4:1, 2 mL). The vial was flushed
with argon, sealed with a Teflon septum, and placed into a Biotage
Initiator microwave cavity. After irradiation at 140 °C for 20 min
and subsequent cooling, the reaction mixture was diluted with
water (20 mL) and extracted with AcOEt (2ϫ20 mL). The com-
bined organic layers were dried with MgSO4 and concentrated in
vacuo. The residue was purified by column chromatography (silica
gel, appropriate mixture of cyclohexane/AcOEt) to give 13n
Acknowledgments
This research was assisted financially by a grant to T.D. from Bayer
CropScience.
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(32.5 mg, 65%) as a yellow oil. H NMR (400 MHz, CDCl3): δ =
1.87 (s, 3 H, CH3), 2.17 (s, 3 H, CH3), 4.99, 5.11, 5.14, 5.55 (4s,
=CH2), 6.46 (s, 1 H, 4-H), 7.08–7.13 (m, 2 H, arom.), 7.43–7.47
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2
(CH3), 20.6 (CH3), 104.1 (4-C), 112.7 (=CH2), 116.0 (d, JC,F
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3
22.7 Hz), 118.3 (=CH2), 126.9 (d, JC,F = 8.1 Hz), 134.2, 136.9 (2
4
C-Me), 137.0 (d, JC,F = 2.9 Hz), 145.4, 153.0 (3-C + 5-C), 161.94
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+ H]+ 243.1292; found 243.1297.
Sonogashira Cross-Coupling at C-5 for the Synthesis of 4-{[3-
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3-Bromo-5-iodopyrazole 8a (0.2 mmol), the alkyne (0.24 mmol),
PdCl2(PPh3)2 (0.01 mmol), and CuI (0.01 mmol) were dissolved in
a mixture of degassed MeCN (1 mL) and TEA (2 mL) in a glass
Eur. J. Org. Chem. 2011, 3837–3848
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3847

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Received: January 27, 2011
Published Online: March 16, 2011
3848
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3837–3848