Regioselective synthesis of 3-carbo-5-phosphonylpyrazoles through a one-pot Claisen-Schmidt/1,3-dipolar cycloaddition/oxidation sequence

Article abstract of DOI:10.1002/ejoc.201100167

A one-pot reaction involving an aldehyde, a methyl ketone, and the Bestmann-Ohira reagent has been developed for the synthesis of variously substituted 3-carbo-5-phosphonylpyrazoles. Our synthetic methodology features a domino Claisen-Schmidt/1,3-dipolar cycloaddition/oxidation sequence, which leads to the target compounds in excellent yields. We further demonstrated that this unprecedented sequence could also be combined with a copper-catalyzed azide-alkyne cycloaddition in a one-pot, four-step cascade process generating five new bonds and two heterocyclic rings. Copyright

Full text of DOI:10.1002/ejoc.201100167

FULL PAPER
DOI: 10.1002/ejoc.201100167
Regioselective Synthesis of 3-Carbo-5-phosphonylpyrazoles through a One-Pot
Claisen–Schmidt/1,3-Dipolar Cycloaddition/Oxidation Sequence
Anthony R. Martin,[a] Kishor Mohanan,[a] Loic Toupet,[b] Jean-Jacques Vasseur,[a] and
Michael Smietana*[a]
Keywords: Click chemistry / Cycloaddition / Heterocycles / Multicomponent reactions / Synthetic methods /
Organophosphorus compounds
A one-pot reaction involving an aldehyde, a methyl ketone,
and the Bestmann–Ohira reagent has been developed for the
which leads to the target compounds in excellent yields. We
further demonstrated that this unprecedented sequence
synthesis of variously substituted 3-carbo-5-phosphonylpyraz- could also be combined with a copper-catalyzed azide–
oles. Our synthetic methodology features a domino Claisen–
alkyne cycloaddition in a one-pot, four-step cascade process
generating five new bonds and two heterocyclic rings.
Schmidt/1,3-dipolar
cycloaddition/oxidation
sequence,
Introduction
Dimethyl (1-diazo-2-oxopropyl)phosphonate (1; Best-
mann–Ohira reagent, BOR) is a valuable reagent that al-
lows a one-carbon chain homologation of an aldehyde into
a terminal alkyne under mild reaction conditions. Readily
Figure 1. Dimethyl (1-diazo-2-oxopropyl)phosphonate (1; BOR)
prepared from commercially available precursors, this rea- and dimethyl (diazomethyl)phosphonate (2).
gent is the outcome of a story that began in the early 1970s
with the discovery by Seyferth and co-workers of dimethyl
(diazomethyl)phosphonate (2; Figure 1).[1] Over the years,
Recently, the BOR has found new applications in organic
Colvin et al.[2] demonstrated the ability of 2 to transform synthesis as a cycloaddition partner for the synthesis of
carbonyl compounds into the corresponding acetylenic de- phosphonyloxazoles[9] and -pyrazoles.[10] This latter class of
rivatives, while Gilbert and Weerasooriya[3] extended the compounds is particularly attractive, because appropriately
scope of the reaction and studied its mechanism. Neverthe- functionalized pyrazoles have emerged as enzyme inhibi-
less, 2 was still not easily accessible, requiring five steps tors, fungicides, and insecticides.[11] The pyrazole scaffold is
from the starting phthalimide, and stability issues prevented also found in best-selling drugs such as Celebrex, Viagra,
many groups from using it. A major breakthrough was and Acomplia. In the multitude of existing methods avail-
made when Ohira found that the anion of 2 could be gener- able for the synthesis of pyrazole derivatives, classical ap-
ated in situ by treatment of 1 under mild basic conditions.[4] proaches are based on either the condensation of hydrazine
A few years later, Bestmann and co-workers examined in on 1,3-dicarbonyl compounds or on the cycloaddition of
more detail the reactivity of 1 and described major improve- 1,3-dipoles to triple bonds.[12] Due to the decisive role
ments in its synthesis.[5] Since then, the so-called Bestmann– played by the C–P bond in isosteric, biologically active
Ohira reagent has been used as an efficient alternative to phosphate analogues,[13] the synthesis of phosphonylpyra-
the Corey–Fuchs procedure.[6] The BOR-based homologa- zoles has attracted considerable attention over the years.
tion of aldehydes has been used on many sensitive sub- Hence, the development of a synthetic route towards 5-
strates, including modified nucleosides and amino acids,[7] phosphonylpyrazoles involving the reaction of the BOR
and many one-pot procedures rely on its versatility.[8]
with aryl- or heteroaryl nitroalkenes[10] was welcomed and
provided an efficient alternative to the previously reported
methodologies, which were often limited by the number of
steps and the harsh conditions required.[14]
In this context, we recently described a new multicompo-
nent reaction (MCR) that allowed the regioselective synthe-
sis of phosphonylpyrazoles 3 by combining an aldehyde, a
cyano acid derivative, and the BOR (Scheme 1).[15] Based
on a domino Knoevenagel condensation/formal 1,3-dipolar
[a] Institut des Biomolécules Max Mousseron (IBMM) UMR 5247
CNRS – Université Montpellier 1 et Université Montpellier 2,
Place Eugène Bataillon, 34095 Montpellier, France
E-mail: msmietana@univ-montp2.fr
[b] Institut de Physique (IPR), UMR 6521 CNRS – Université de
Rennes 1,
35042 Rennes, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100167.
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Regioselective Synthesis of 3-Carbo-5-phosphonylpyrazoles
cycloaddition sequence, this process afforded 5-phosphon- Table 1. Base screening and optimization of the reaction condi-
tions.
ylpyrazole scaffolds through the formation of two C–C
bonds and one C–N bond (Scheme 1). This study provided
the first example of an MCR featuring the BOR, thus pav-
ing the way for new applications in diversity-oriented syn-
thesis.
Entry
Base
Temp. [°C]
Time [h]
Yield [%][a]
1
2
3
4
5
6
7
8
9
piperidine
TEA
DIEA
K2CO3
KOH
piperidine
TEA
DIEA
K2CO3
NaOH
KOH
r.t.
r.t.
r.t.
r.t.
r.t.
60
60
60
60
60
60
4
4
4
4
4
4
4
4
4
2
2
–
–
–
20
35
–
–
–
35
90
95
Scheme 1. Three-component synthesis of phosphonylpyrazoles.[15]
In a continuation of our work, we sought to extend the
scope and applications of the BOR to a diverse array of 3-
substituted 5-phosphonyl heterocycles. Herein, we wish to
report a novel one-pot, sequential, multicomponent, re-
gioselective synthesis of 3-carbo-5-phosphonylpyrazoles
based on a domino Claisen–Schmidt/1,3-dipolar cycload-
dition/oxidation sequence.
10
11
[a] Isolated yield.
with 2 equiv. of BOR, because it was observed that some
decomposition of the BOR might occur over time. Surpris-
ingly, instead of the expected pyrazoline, we observed the
exclusive formation of phosphonylpyrazole 3a. The struc-
ture, as well as the regioselectively of the process, was
eventually secured by spectroscopic and crystallographic
Results and Discussion
Because the Claisen–Schmidt condensation offers an ef- analyses (Scheme 2).[16] This result was unexpected, because
ficient way to synthesize enones under alcoholic alkaline the reaction of α,β-unsaturated ketones with diazo com-
conditions, we envisioned that it would be possible to com- pounds usually leads to pyrazolines,[17] which are then read-
bine this approach with a 1,3-dipolar cycloaddition in a ily converted into pyrazoles through an oxidative dehydro-
one-pot sequential process. The significance of the present genation in the presence of an oxidizing agent.[18] It is worth
protocol relies on the possibility of building α,β-unsatu- noting that in our previously reported Knoevenagel con-
rated ketone intermediates starting from a methyl ketone densation/formal 1,3-dipolar cycloaddition sequence,[15] the
and an aldehyde, and on the ability of these intermediates aromatization was promoted by the elimination of hydrogen
to act as dipolarophiles in the presence of the BOR. Aceto- cyanide. In contrast, in the present process, although there
phenone and p-bromobenzaldehyde were selected as model is no leaving group, the pyrazoline could not be isolated
substrates to establish optimum experimental conditions for regardless of whether the reaction was carried out under air
the formation of the corresponding chalcone. Because the or nitrogen. Whereas spontaneous air oxidation of pyraz-
dimethyl (diazomethyl)phosphonate anion of 2 is generated olines is not frequently encountered in the literature, a few
under mild reaction conditions (MeOH/K2CO3), we con- reports indicate that such oxidation might take place de-
ducted a base screen; the results are summarized in Table 1. pending on the nature of the substituents on the resulting
Interestingly, organic bases failed to catalyze the formation pyrazoles.[19] We thus suspected that oxidation of the phos-
of the expected chalcone, whereas inorganic bases gave bet- phonylpyrazoline to the corresponding pyrazole proceeded
ter results, particularly KOH, which, upon heating at 60 °C upon exposure to air during the workup. A control experi-
in MeOH, afforded the desired compound in 95% yield ment was performed with cyclopentanone and p-bro-
within 2 h (Table 1, Entry 11). With these results in hand, mobenzaldyde. This should lead to a bis(pyrazoline), which
we next explored the use of the BOR in the conversion of is not able to be oxidized. Although the bis(α,β-unsaturated
the resulting α,β-unsaturated ketones into the correspond- ketone) was observed, we were not able to identify any cy-
ing phosphonylpyrazolines through a cycloaddition reac- cloaddition products. An unprecedented one-pot Claisen–
tion. This sequential process is particularly challenging due Schmidt/1,3-dipolar cycloaddition/oxidation sequence was
to the inherent reactivity of the BOR in the presence of therefore unveiled. We further demonstrated that this one-
aldehydes.
pot sequential process compared favorably with the two-
Our initial attempt was carried out with acetophenone step procedure. Indeed, whereas the two-step protocol af-
and p-bromobenzaldehyde. After complete conversion of forded phosphonylpyrazole 3a in 70% yield after two puri-
the starting materials into the corresponding α,β-unsatu- fication steps, and required almost 2 d of bench work, the
rated ketone as determined by TLC, the BOR was added one-pot sequential process generated 3a with 77% yield in
to the reaction mixture. Optimum conditions were obtained 10 h, purification included.
Eur. J. Org. Chem. 2011, 3184–3190
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M. Smietana et al.
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Table 2. Three-component, sequential synthesis of 3-oxo-5-phos-
phonylpyrazoles.
Entry
R1
R2
3
Yield [%][a]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4-Br-C6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
77
71
67
61
70
91
70
70
81
65
71
30
65
65
4-MeO-C6H4
3-MeO-C6H4
4-(HCϵC)-C6H4
4-O2N-C6H4
2-thiophenyl
4-Br-C6H4
4-O2N-C6H4
2-thiophenyl
4-Br-C6H4
2,4-Cl2-C6H3
Ph
Scheme 2. One-pot access to phosphonylpyrazoles and X-ray struc-
ture of 3a.[16]
4-MeO-C6H4
4-MeO-C6H4
4-MeO-C6H4
N-Me-pyrrol-2-yl
N-Me-pyrrol-2-yl
tBu
With these initial results in hand, we then investigated
the scope of this unique one-pot sequence; the results are
4-O2N-C6H4
tBu
summarized in Table 2. Interestingly, α,β-unsaturated [a] Isolated yield.
ketone formation was usually complete within 1–3 h,
whereas the cycloaddition at room temperature required 6–
12 h unless otherwise specified. A survey of the scope with
regards to the aldehyde component revealed that aromatic
hyde and 1 leads to the formation of phosphonylpyrazole
3h in good yield (Table 2, Entry 8), we found that p-nitro-
acetophenone was too reactive under these reaction condi-
tions, leading mostly to autocondensation products (data
not shown). These results suggest that fine-tuning of the
pKa value of the α-proton is essential. Interestingly, the pyr-
azole formation reaction also proceeds smoothly with het-
erocyclic methyl ketones. Nevertheless, as observed with
acetophenone, ortho substituents are not well tolerated, be-
cause, in the presence of 2,4-dichlorobenzaldeyde, the corre-
sponding phosphonylpyrazole 3m is obtained with only
30% yield (Table 2, Entries 11 and 12). Finally, we demon-
strated that sterically hindered aliphatic methyl ketones
were also good substrates for this one-pot sequential pro-
cess (Table 2, Entries 13 and 14).
On the basis of these results, a plausible mechanism ac-
counting for this novel three-component sequential reaction
is devised in Scheme 3. The first step would be the forma-
tion of α,β-unsaturated ketone A, which would be attacked
by the dimethyl (diazomethyl)phosphonate anion B. We as-
sume a stepwise cycloaddition based on a Michael-type 1,4-
addition leading to intermediate C. An intramolecular cycli-
zation would then proceed to afford the highly reactive in-
termediate pyrazoline D, which would then undergo an O2-
promoted oxidative aromatization to furnish, after tauto-
merization, the pyrazole product 3.
or heteroaromatic aldehydes were needed to afford the cor-
responding pyrazoles in good to excellent yields (Table 2).
In addition, we noticed significant electronic effects, be-
cause faster reactions and higher yields were observed with
arenecarbaldehydes bearing electron-withdrawing groups.
In contrast, the reactions of aldehydes substituted with elec-
tron-donating groups were slightly more sluggish and less
efficient (Table 2, Entries 1–5). Similarly, steric effects were
found to play a decisive role in the formation of the target
phosphonylpyrazoles. Whereas p-, m-, or o-methoxybenzal-
dehydes reacted with acetophenone to give the correspond-
ing α,β-unsaturated ketone intermediates (TLC monitor-
ing), we observed that after adding 1, the cycloaddition
only took place with the less constrained structures
(Table 2, Entries 3 and 4). Indeed, in the case of o-methoxy-
benzaldehyde, the corresponding chalcone was recovered
mostly unreacted. This result suggested that hindered α,β-
unsaturated ketones are not reactive enough to lead to the
expected phosphonylpyrazoles. It is worth noting that the
reaction using 2-thiophenecarbaldehyde together with ace-
tophenone also provided good yields of the desired pyr-
azoles under the optimized reaction conditions (Table 2,
Entry 7).
We next examined the scope of the reaction with regard
to the methyl ketone component. The electronic properties
of the substituents also appeared to be a dominant factor
controlling the reactivity. This is not unexpected, because
The prospect of discovering compounds with pharmaco-
the rate-determining step of the reaction is proportional to logical activity prompted us to combine this one-pot se-
the concentration of the enolate anion, which, in turn, quence of two divergent reaction pathways with click chem-
should be dependent upon the acidity of the α-proton of istry. As shown in Scheme 4, 4-ethynylbenzaldehyde was se-
the substituted acetophenone. For example, whereas the re- quentially submitted to the optimized reaction conditions.
action of p-methoxyacetophenone with p-bromobenzalde- Treatment of the phosphonylpyrazole intermediate 3e with
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Eur. J. Org. Chem. 2011, 3184–3190

Regioselective Synthesis of 3-Carbo-5-phosphonylpyrazoles
Scheme 3. Proposed mechanism for the three-component sequential process.
Scheme 4. One-pot, sequential MCR/CuAAC.
5Ј-azidothymidine through a copper-catalyzed azide–alkyne
1,3-dipolar cycloaddition (CuAAC) gave the thymidine–
Conclusions
pyrazol 4a with 61% yield and 85% atom economy
We have developed a general and straightforward pro-
(Path a).[20] Alternatively, 3e reacts quickly with 1-azidoglu- cedure for the regioselective preparation of 3-carbo-5-phos-
copyranose, leading to phosphonylpyrazole 4b with 55% phonylpyrazoles. Based on an unprecedented Claisen–
yield and 82% atom economy (Path b). In each case, the Schmidt/1,3-dipolar cycloaddition/oxidation sequence,
cascade sequence generates five new bonds and two hetero- these results broaden the emerging role of the BOR as a
cyclic rings in a one-pot fashion, thus further demonstrat- 1,3-dipolar precursor in one-pot reactions. Moreover, this
ing the versatility of the BOR. Moreover, because chemical sequence has been efficiently coupled to a CuAAC reaction
processes are expected to maximize the formation of the for the rapid synthesis of potential biologically active com-
target products, the BOR is significantly more atom-eco- pounds. Given the importance played by substituted pyr-
nomical when used as a cycloaddition partner than as a azoles in the pharmaceutical and agrochemical industry,
homologation reagent.[21]
and in light of the considerable challenges faced by re-
Eur. J. Org. Chem. 2011, 3184–3190
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M. Smietana et al.
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53.6, 55.4, 113.6, 122.7, 128.2, 130.6, 131.4, 133.1, 137.2, 159.5,
188.7 ppm. 31P NMR (CDCl3, 121 MHz): δ = 9.51 ppm. HRMS
(ESI): calcd. for C19H20N2O5P [M + H]+ 387.1110; found 387.1106.
searchers to develop sustainable chemical processes, the
readily available starting materials, combined with the rapid
one-pot assembly of this complex scaffold, should be useful
in drug discovery.
Dimethyl
[5-Benzoyl-4-(3-methoxyphenyl)-1H-pyrazol-3-yl]phos-
phonate (3d): Colorless solid (94 mg, 61% yield). M.p. 156–158 °C.
1H NMR (CDCl3, 300 MHz): δ = 3.64 (s, 3 H, OCH3), 3.68 (s, 3
H, OCH3), 3.72 (s, 3 H, Ar-OCH3), 6.79–6.82 (m, 1 H, ArH), 6.91–
6.93 (m, 2 H, ArH), 7.18 (t, J = 8.1 Hz, 1 H, ArH), 7.32 (t, J =
7.6 Hz, 2 H, ArH), 7.46 (t, J = 7.4 Hz, 1 H, ArH), 7.92 (d, J =
7.5 Hz, 2 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 53.5,
53.6, 55.3, 113.9, 115.6, 122.6, 128.2, 129.0, 130.3, 130.5, 131.9,
133.2, 137.1, 159.1, 188.5 ppm. 31P NMR (CDCl3, 121 MHz): δ =
9.31 ppm. HRMS (ESI): calcd. for C19H20N2O5P [M + H]+
387.1110; found 387.1116.
Experimental Section
General Remarks: All reactions were conducted in oven-dried glass-
ware. Methanol was distilled from sodium and benzophenone. Di-
methyl (oxopropyl)phosphonate was purchased from Alfa Aesar
and used as received for the synthesis of the Bestmann–Ohira rea-
gent.[4,5] All other reagents were purchased from local suppliers and
used without purification. All reactions were monitored by TLC;
visualization was effected with UV and/or by developing in iodine.
Chromatography refers to open column chromatography on silica
gel (Merck, 40–63 μm). Melting points were recorded with a Bibby
Stuart Scientific SMP3 melting point apparatus. NMR spectra
were recorded with a Bruker DRX-300 MHz spectrometer at 300
(1H), 75 (13C), and 121 MHz (31P) at 298°K. Chemical shifts are
reported in δ units (ppm) relative to the solvent residual peak as
internal standard (1H and 13C) and H3PO4 as external standard for
31P NMR measurements. High-resolution mass spectra (ESI+) were
recorded with a Micromass apparatus.
Dimethyl [5-Benzoyl-4-(4-ethynylphenyl)-1H-pyrazol-3-yl]phosphon-
1
ate (3e): Colorless solid (106 mg, 70% yield). M.p. 196–199 °C. H
NMR (CDCl3, 300 MHz): δ = 3.08 (s, 1 H, ϵCH), 3.65 (s, 3 H,
OCH3), 3.69 (s, 3 H, OCH3), 7.30–7.52 (m, 7 H, ArH), 7.94 (d, J
= 6.0 Hz, 2 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 53.6,
53.7, 78.1, 83.6, 122.0, 128.4, 128.6, 130.2, 130.6, 131.4, 131.9,
133.4, 137.0, 188.2 ppm. 31P NMR (CDCl3, 121 MHz): δ =
8.76 ppm. HRMS (ESI): calcd. for C20H18N2O4P [M + H]+
381.1004; found 381.1006.
Dimethyl [5-Benzoyl-4-(4-nitrophenyl)-1H-pyrazol-3-yl]phosphonate
(3f): Yellowish solid (146 mg, 91% yield). M.p. 180–183 °C. 1H
NMR (CDCl3, 300 MHz): δ = 3.72 (s, 3 H, OCH3), 3.75 (s, 3 H,
OCH3), 7.36–7.41 (m, 2 H, ArH), 7.52–7.58 (m, 3 H, ArH), 8.00
(d, J = 7.3 Hz, 2 H, ArH), 8.19 (d, J = 8.8 Hz, 2 H, ArH) ppm.
13C NMR (CDCl3, 75 MHz): δ = 53.7, 53.8, 123.1, 128.4, 128.7,
130.6, 131.0, 133.6, 136.8, 138.1, 147.5, 188.0 ppm. 31P NMR
(CDCl3, 121 MHz): δ = 8.05 ppm. HRMS (ESI): calcd. for
C18H17N3O6P [M + H]+ 402.0855; found 402.0849.
General Procedure for the Synthesis of Pyrazoles 3a–n: To a solution
of aldehyde (0.4 mmol) and ketone (0.8 mmol) in MeOH (5 mL),
was added powdered KOH (2 mmol), and the reaction mixture was
stirred at 55 °C for 1–3 h. When the starting aldehyde was com-
pletely converted into the intermediate chalcone (TLC monitoring),
the Bestmann–Ohira reagent (0.8 mmol) diluted with MeOH
(1 mL) was added at room temperature, and stirring was continued
until completion of the reaction (2–16 h; TLC monitoring). The
solvent was then evaporated, and the crude product was dissolved
in ethyl acetate (50 mL), washed with saturated ammonium chlo-
ride (1ϫ 20 mL), and brine (1ϫ 20 mL). The organic layer was
dried with anhydrous sodium sulfate, filtered, and concentrated un-
der reduced pressure. The crude residue was finally purified by col-
umn chromatography (acetone/CH2Cl2, 0–30%) to afford the de-
sired product.
Dimethyl [5-Benzoyl-4-(thiophen-2-yl)-1H-pyrazol-3-ylphosphonate]
(3g): Colorless solid (101 mg, 70% yield). M.p. 124–126 °C. 1H
NMR (CDCl3, 300 MHz): δ = 3.72 (s, 3 H, OCH3), 3.75 (s, 3 H,
OCH3), 6.98–7.01 (m, 1 H, ArH), 7.18–7.20 (m, 1 H, ArH), 7.31–
7.40 (m, 3 H, ArH), 7.52 (t, J = 7.3 Hz, 1 H, ArH), 7.98 (d, J =
7.2 Hz, 2 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 53.7,
53.8, 122.7, 123.0, 127.0, 127.3, 128.3, 129.5, 130.6, 133.3, 137.1,
188.5 ppm. 31P NMR (CDCl3, 121 MHz): δ = 8.53 ppm. HRMS
(ESI): calcd. for C16H16N2O4PS [M + H]+ 363.0568; found
363.0566.
Dimethyl [5-Benzoyl-4-(4-bromophenyl)-1H-pyrazol-3-yl]phosphon-
ate (3a): Colorless crystals (133 mg, 77% yield). M.p. 214–216 °C.
1H NMR (CDCl3, 300 MHz): δ = 3.66 (s, 3 H, OCH3), 3.70 (s, 3
H, OCH3), 7.22–7.25 (m, 2 H, ArH), 7.34–7.53 (m, 5 H, ArH),
7.95 (d, J = 7.3 Hz, 2 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz):
δ = 53.6, 53.7, 122.6, 128.4, 129.7, 130.6, 131.3, 131.8, 133.4, 137.0,
188.3 ppm. 31P NMR (CDCl3, 121 MHz): δ = 8.73 ppm. HRMS
(ESI): calcd. for C18H17BrN2O4P [M + H]+ 435.0109; found
435.0103.
Dimethyl [4-(4-Bromophenyl)-5-(4-methoxybenzoyl)-1H-pyrazol-3-
yl]phosphonate (3h): Colorless solid (130 mg, 70% yield). M.p. 179–
180 °C. 1H NMR (CDCl3, 300 MHz): δ = 3.65 (s, 3 H, OCH3),
3.69 (s, 3 H, OCH3), 3.80 (s, 3 H, Ar-OCH3), 6.83 (d, J = 7.6 Hz,
2 H, ArH), 7.24 (s, 2 H, ArH), 7.42 (d, J = 6.9 Hz, 2 H, ArH),
7.96 (d, J = 7.4 Hz, 2 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz):
δ = 53.6, 53.7, 55.7, 113.7, 122.4, 129.0, 129.3, 129.8, 129.9, 131.3,
131.8, 133.1, 147.2, 164.0, 186.8 ppm. 31P NMR (CDCl3,
121 MHz): δ = 8.89 ppm. HRMS (ESI): calcd. for C19H19BrN2O5P
[M + H]+ 465.0215; found 465.0207.
Dimethyl (5-Benzoyl-4-phenyl-1H-pyrazol-3-yl)phosphonate (3b):
Colorless solid (101 mg, 71% yield). M.p. 154–156 °C. 1H NMR
(CDCl3, 300 MHz): δ = 3.64 (s, 3 H, OCH3), 3.68 (s, 3 H, OCH3),
7.28–7.39 (m, 7 H, ArH), 7.47 (t, J = 7.4 Hz, 1 H, ArH), 7.95 (d,
J = 7.4 Hz, 2 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 53.5,
53.6, 128.0, 128.1, 128.2, 130.1, 130.5, 130.6, 130.7, 133.1, 137.1,
188.5 ppm. 31P NMR (CDCl3, 121 MHz): δ = 9.06 ppm. HRMS
(ESI): calcd. for C18H18N2O4P [M + H]+ 357.1004; found 357.1001.
Dimethyl [5-(4-Methoxybenzoyl)-4-(4-nitrophenyl)-1H-pyrazol-3-yl]-
phosphonate (3i): Pale-yellow solid (139 mg, 81% yield). M.p. 108–
110 °C. 1H NMR (CDCl3, 300 MHz): δ = 3.68 (s, 3 H, OCH3),
3.72 (s, 3 H, OCH3), 3.79 (s, 3 H, Ar-OCH3), 6.84 (d, J = 8.7 Hz,
2 H, ArH), 7.54 (d, J = 8.9 Hz, 2 H, ArH), 7.99 (d, J = 8.7 Hz, 2
H, ArH), 8.15 (d, J = 8.9 Hz, 2 H, ArH) ppm. 13C NMR (CDCl3,
75 MHz): δ = 53.7, 53.8, 55.6, 113.7, 123.2, 128.0, 128.3, 129.5,
Dimethyl
[5-Benzoyl-4-(4-methoxyphenyl)-1H-pyrazol-3-yl]phos-
phonate (3c): Colorless solid (103 mg, 67% yield). M.p. 187–190 °C.
1H NMR (CDCl3, 300 MHz): δ = 3.66 (s, 3 H, OCH3), 3.70 (s, 3
H, OCH3), 3.79 (s, 3 H, Ar-OCH3), 6.84 (d, J = 8.7 Hz, 2 H, ArH), 131.0, 133.1, 138.2, 147.4, 186.3 ppm. 31P NMR (CDCl3,
7.28–7.38 (m, 4 H, ArH), 7.49 (t, J = 7.4 Hz, 1 H, ArH), 7.95 (d, 121 MHz): δ = 8.51 ppm. HRMS (ESI): calcd. for C19H19N3O7P
J = 7.2 Hz, 2 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 53.5,
[M + H]+ 432.0961; found 432.0945.
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Eur. J. Org. Chem. 2011, 3184–3190

Regioselective Synthesis of 3-Carbo-5-phosphonylpyrazoles
Dimethyl [5-(4-Methoxybenzoyl)-4-(thiophen-2-yl)-1H-pyrazol-3-yl]-
phosphonate (3j): Pale-yellow solid (102 mg, 65% yield). M.p. 117–
Dimethyl (5-Benzoyl-4-{4-[1-(2Ј,5Ј-dideoxythymidin-5Ј-yl)-1H-1,2,3-
triazol-4-yl]phenyl}-1H-pyrazol-3-yl)phosphonate(4a): Colorless so-
1
120 °C. 1H NMR (CDCl3, 300 MHz): δ = 3.68 (s, 3 H, OCH3), lid (158 mg, 61% yield). M.p. 220–223 °C. H NMR ([D6]DMSO,
3.72 (s, 3 H, OCH3), 3.77 (s, 3 H, Ar-OCH3), 6.82 (d, J = 8.9 Hz, 300 MHz): δ = 1.70 [s, 3 H, CH3(thymine)], 2.14–2.19 (m, 2 H, 2Ј-
2 H, ArH), 6.95 (dd, J = 5.1, 3.6 Hz, 1 H, ArH), 7.16 (dd, J = 3.5,
1.1 Hz, 1 H, ArH), 7.26 (dd, J = 5.1, 1.0 Hz, 1 H, ArH), 7.95 (d,
J = 8.7 Hz, 2 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 53.6,
53.7, 55.5, 113.6, 122.2, 122.4, 126.9, 127.0, 129.2, 129.8, 130.4,
H and 2"-H), 3.40–3.43 (m, 2 H, OH and NH), 3.60 (s, 3 H,
OCH3), 3.64 (s, 3 H, OCH3), 4.12–4.17 (m, 1 H, 4Ј-H), 4.33–4.34
(m, 1 H, 3Ј-H), 4.70 (dd, J = 6.5, 14.4 Hz, 1 H, 5Ј-H), 4.79 (dd, J
= 4.5, 14.4 Hz, 1 H, 5ЈЈ-H), 6.21 (t, J = 6.9 Hz, 1 H, 1Ј-H), 7.24 (s,
132.9, 163.9, 186.9 ppm. 31P NMR (CDCl3, 121 MHz): δ = 1 H, 6-H), 7.38–7.47 (m, 4 H, ArH), 7.56–7.60 (m, 1 H, ArH),
9.13 ppm. HRMS (ESI): calcd. for C17H18N2O5PS [M + H]+
393.0674; found 393.0665.
7.78–7.86 (m, 4 H, ArH), 8.59 (s, 1 H, Htriazole), 11.32 (s, 1 H,
NHpyrazole) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 12.0, 38.0,
51.2, 53.1, 53.1, 54.9, 70.6, 83.8, 83.9, 110.0, 122.4, 124.5, 128.3,
129.8, 130.0, 130.5, 133.2, 136.0, 146.1, 150.5, 163.7 ppm. 31P
NMR ([D6]DMSO, 121 MHz): δ = 9.31 ppm. HRMS (ESI): calcd.
for C30H31N7O8P [M + H]+ 648.1972; found 648.1988.
Dimethyl [4-(4-Bromophenyl)-5-(1-methyl-1H-pyrrol-2-ylcarbonyl)-
1H-pyrazol-3-yl]phosphonate (3k): Colorless crystalline solid
(124 mg, 71% yield). M.p. 172–175 °C. 1H NMR (CDCl3,
300 MHz): δ = 3.65 (s, 3 H, OCH3), 3.69 (s, 3 H, OCH3), 3.92 (s,
3 H, NCH3), 6.09 (dd, J = 2.4, 4.1 Hz, 1 H, ArH), 6.82–6.88 (m,
1 H, ArH), 7.01–7.06 (m, 1 H, ArH), 7.24–7.30 (m, 2 H, ArH),
7.43–7.49 (m, 2 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ =
37.8, 53.5, 53.6, 108.8, 122.3, 124.4, 128.1, 128.4, 130.1, 130.7,
131.3, 131.7, 132.6, 177.5 ppm. 31P NMR (CDCl3, 121 MHz): δ
= 9.20 ppm. HRMS (ESI): calcd. for C17H18BrN3O4P [M + H]+
438.0218; found 438.0219.
Dimethyl {5-Benzoyl-4-[4-(1-β-D-glucopyranosyl-1H-1,2,3-triazol-4-
yl)phenyl]-1H-pyrazol-3-yl}phosphonate (4b): Colorless solid
(129 mg, 55% yield). M.p. 122–124 °C. 1H NMR (MeOD,
300 MHz): δ = 3.54–3.61 (m, 2 H, HGluc), 3.68–3.77 (m, 1 H,
HGluc), 3.80 (d, J = 3.1 Hz, 3 H, OCH3), 3.84 (d, J = 3.2 Hz, 3 H,
OCH3), 3.88–3.99 (m, 2 H, HGluc), 4.28 (dd, J = 3.9, 7.8 Hz, 1 H,
HGluc), 5.66 (d, J = 9.2 Hz, 1 H, HGluc), 7.33–7.44 (m, 4 H, ArH),
7.53 (t, J = 7.9 Hz, 1 H, ArH), 7.77–7.80 (m, 2 H, ArH), 8.03–8.12
(m, 2 H, ArH), 8.51 (d, J = 1.2 Hz, 1 H, Htriazole) ppm. 13C NMR
(MeOD, 75 MHz): δ = 54.6, 54.7, 62.5, 71.0, 74.2, 78.5, 81.2, 89.8,
121.7, 127.4, 129.2, 129.7, 131.0, 131.2, 133.7, 138.7, 142.4, 142.6,
148.5, 150.3, 150.4, 188.5 ppm. 31P NMR (MeOD, 121 MHz): δ =
8.41 ppm. HRMS (ESI): calcd. for C26H29N5O9P [M + H]+
586.1709; found 586.1683.
Dimethyl [4-(2,4-Dichlorophenyl)-3-(1-methyl-1H-pyrrol-2-ylcarb-
onyl)-1H-pyrazol-5-yl]phosphonate (3l): Colorless solid (52 mg, 30%
yield). M.p. 186–188 °C. 1H NMR (CDCl3, 300 MHz): δ = 3.68 (d,
J = 11.8 Hz, 3 H, OCH3), 3.75 (d, J = 11.7 Hz, 3 H, OCH3), 3.92
(s, 3 H, NCH3), 6.14 (dd, J = 2.4, 4.0 Hz, 1 H, ArH), 6.87–6.88
(m, 1 H, ArH), 7.29–7.36 (m, 3 H, ArH), 7.44 (d, J = 1.8 Hz, 1 H,
ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 37.7, 53.5, 53.8,
108.7, 124.0, 125.5, 125.7, 126.9, 129.3, 129.6, 130.2, 132.3, 132.7,
134.7, 134.9, 176.8 ppm. 31P NMR (CDCl3, 121 MHz): δ =
8.58 ppm. HRMS (ESI): calcd. for C17H17Cl2N3O4P [M + H]+
432.0961; found 432.0945.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H, 13C, and 31P NMR spectra for all reported com-
pounds.
Acknowledgments
Dimethyl [4-Phenyl-5-pivaloyl-1H-pyrazol-3-yl]phosphonate (3m):
Colorless solid (87 mg, 65% yield). M.p. 139–141 °C. 1H NMR
(CDCl3, 300 MHz): δ = 1.32 [s, 9 H, (CH3)3C], 3.60 (s, 3 H, OCH3),
3.65 (s, 3 H, OCH3), 7.25–7.37 (m, 5 H, ArH) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 27.3, 45.0, 53.5, 53.6, 127.9, 128.0, 129.9,
130.6, 131.5, 147.6, 147.9, 202.4 ppm. 31P NMR (CDCl3,
121 MHz): δ = 9.09 ppm. HRMS (ESI): calcd. for C16H22N2O4P
[M + H]+ 337.1317; found 337.1302.
L’Université de Montpellier 2 (K. M.), the Ministère de l’Enseigne-
ment Supérieur et de la Recherche (MESR) (A. R. M.) and the
Centre National de la Recherche Scientifique (CNRS) are grate-
fully acknowledged for financial support.
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Received: February 4, 2011
Published Online: April 27, 2011
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Eur. J. Org. Chem. 2011, 3184–3190