Palladium-catalyzed phosphonylation of pyrazoles substituted by electron-withdrawing groups

Article abstract of DOI:10.1016/j.tet.2015.03.099

Abstract A series of bromopyrazoles substituted by electron-withdrawing groups such as an ester, a trifluoromethyl group or a cyano group was involved in Pd-catalyzed phosphonylation. Moderate to good yields were obtained in the corresponding phosphonylat

Full text of DOI:10.1016/j.tet.2015.03.099

Accepted Manuscript
Palladium-Catalyzed Phosphonylation of Pyrazoles Substituted by Electron-
Withdrawing Groups
Qi Huang, Gaël Tran, Domingo Gomez Pardo, Tomoki Tsuchiya, Stefan Hillebrand,
Jean-Pierre Vors, Janine Cossy
PII:
S0040-4020(15)00439-1
10.1016/j.tet.2015.03.099
TET 26581
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 9 January 2015
Revised Date: 6 March 2015
Accepted Date: 26 March 2015
Please cite this article as: Huang Q, Tran G, Pardo DG, Tsuchiya T, Hillebrand S, Vors J-P, Cossy
J, Palladium-Catalyzed Phosphonylation of Pyrazoles Substituted by Electron-Withdrawing Groups,
Tetrahedron (2015), doi: 10.1016/j.tet.2015.03.099.
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ACCEPTED MANUSCRIPT
Palladium-Catalyzed Phosphonylation of Pyrazoles
Substituted by Electron-Withdrawing Groups
a
a
a
b
b
b
Qi Huang, Gaël Tran, Domingo Gomez Pardo, Tomoki Tsuchiya, Stefan Hillebrand, Jean-Pierre Vors, and
*a
Janine Cossy
a
Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI),
ESPCI ParisTech, UMR 8231, PSL Research University
1
0 rue Vauquelin, 75231 Paris Cedex 05, France
janine.cossy@espci.fr
b
Bayer S.A.S.-CRLD,
1
4, impasse Pierre Baizet, CS 99163, 69263 Lyon Cedex 09, France
A series of bromopyrazoles substituted by electron-withdrawing groups such as an ester, a trifluoromethyl
group or a cyano group were used in Pd-catalyzed phosphonylation. Moderate to good yields were obtained in
the corresponding phosphonylated pyrazoles.
Keywords: Pyrazoles, phosphonylation, palladium catalysis
1
. Introduction
Substituted pyrazoles are important heterocycles as they display a broad range of biological activities and are
extensively used in agrochemical and pharmaceutical applications. For example, rimonabant, an anorectic
1
2
3
4
antiobesity product, fipronil, an insecticide, tebufenpyrad, an acaricide, or viagra are commercially available
5
6
(
Figure 1). In addition, pyrazoles can serve as optical brighteners, U.V. stabilizers, ligands in coordinating
7
8
compounds, and building blocks in supramolecular assemblies.
Figure 1. Selected examples of bioactive pyrazoles.
1

ACCEPTED MANUSCRIPT
We were interested in the synthesis of pyrazoles bearing a phosphonyl substituent, as it is known that the
9
introduction of such substituents can modulate the properties of biologically active compounds.
Phosphonylated pyrazoles have mainly been synthesized by [3+2]-cycloadditions or ring-closure of acyclic
1
0
phosphorus-containing compounds, and numerous publications related to these methods have been reported.
However, these methods can suffer from a lack of regio-control depending on the substitution pattern of the
pyrazoles, and in addition the synthesis of the corresponding phosphonylated starting materials is needed. By
contrast, the phosphonylation of a preformed pyrazole ring offers significant advantages in terms of regiocontrol
and availability of the starting materials, although the majority of the reported methods is not general due to the
1
0
use of PCl and related P-Cl intermediates. Indeed, the commercial availability of these intermediates is poor,
3
and their use is usually not compatible with electron-poor pyrazoles. To overcome this issue, and based on
1
1,12
seminal reports,
we recently reported that C3-, C4- or C5-halogenopyrazoles can be phosphonylated by H-
phosphonates, H-phosphinates or secondary phosphine oxides using a Pd(OAc) /XantPhos catalytic system
2
1
3
(
Scheme 1). This method proved to be robust and general, providing access to a wide range of compounds
which would have required lengthy routes using others methods.
Scheme 1. Previous work on palladium-catalyzed phosphonylation of pyrazoles.
In this paper, we would like to report that this method can also be applied to pyrazoles bearing electron-
withdrawing groups, and that the reactivity of such pyrazoles is strongly dependant on stereoelectronic and
complexation effects.
2
. Results and Discussion
2

ACCEPTED MANUSCRIPT
Bromopyrazole ester 1a was chosen as the model substrate, and the N-SEM protecting group was chosen due
to its robustness, which allows the use of a wide range of conditions. Pyrazole 1a was involved in the
phosphonylation with diethyl phosphite 2a using the reaction conditions that have been previously reported for
non-functionalized pyrazoles [Pd(OAc) (10 mol %), XantPhos (20 mol %), KOAc (10 mol %), Et N (1.8
2
3
equiv)] (Table 1, entry 1). Under these conditions, the desired product 3a was obtained in a modest 30% yield,
1
the dehalogenated starting material being the main side-product (25% yield established by H NMR from the
crude reaction mixture). In a parallel study, we observed that the presence of diethyl phosphite and Et N alone
3
triggered the dehalogenation of 1a, and that this reaction was efficiently inhibited when Et N was replaced by
3
iPr NEt. However, when the coupling reaction of 1a and 2a was realized in the presence of iPr NEt, no
2
2
significant improvement in the yield of 3a was observed (Table 1, entry 2). A screening of polar aprotic solvents
(
(
Table 1, entries 3−5), hydrocarbon (Table 1, entries 6−8), dioxane (Table 1, entry 9) or halogenated solvants
Table 1, entry 10) was performed, but none of them were better than THF.
Table 1. Solvent screening.
entry
solvent
THF
base
Et N
yield
30%
32%
0%
10%
0%
22%
1
2
3
4
5
6
3
THF
DMSO
MeCN
DMA
iPr NEt
2
iPr NEt
2
iPr NEt
2
iPr NEt
2
Toluene
iPr NEt
2
Toluene/
DME (10:1)
7
iPr NEt
8%
2
8
9
1
PhCF3
Dioxane
CCl4
iPr NEt
17%
5%
0%
2
iPr NEt
2
0
iPr NEt
2
The screening of different palladium catalysts such as Pd(OAc) , Pd(OPiv) , Pd(MeCN) (BF ), Pd(PPh ) ,
2
2
4
4
3 4
monodentate phosphines [(2-furyl) P, t-BuXPhos, tetramethyl t-BuXPhos] as well as bidentate phosphines
3
(
XantPhos, dppf, binap, dppp), revealed that XantPhos was the only suitable ligand for the phosphonylation of
1
a, and that the different screened palladium catalysts performed similarly well (Table 2, entries 7−9)
Table 2. Catalyst and ligand screening.
3

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entry
1
cat.
ligand
yield
0%
Tetramethyl
t-BuXPhos
Pd(OAc)2
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
t-BuXPhos
(2-Furyl)3P
dppp
0%
0%
0%
0%
0%
29%
30%
25%
Binap
-
Pd(OAc)2
Pd(OPiv)2
XantPhos
XantPhos
XantPhos
Pd(MeCN) (BF )
4
4 2
As changing the catalytic system did not significantly improve the yields in 3a, we decided to investigate
other substrates. Therefore, bromopyrazoles 1b−f were involved in the phosphonylation using diethyl phosphite
as the coupling partner (Table 3), and it seems that when a bromine atom is present at C3, the Pd-catalyzed
phosphonylation led to the corresponding pyrazole in good yields, whatever the position of the ester group
(
Table 3, entries 2 and 3). On the contrary, when a bromine atom is present at C4 or C5, the yields in the
phosphonylated pyrazoles were moderate to poor (Table 3, entries 1, 4−6). In all cases, the reactions were run
until full consumption of diethyl phosphite 2a, and the principal side-product of the reaction was the
dehalogenated starting materials 1a-f. However, the observed amounts of dehalogenated starting materials did
not seem to be correlated to the yields in phosphonylated pyrazoles, and it is therefore more likely that the
moderate yields are due to the competitive degradation of the phosphite 2a.
Table 3. Influence of the substituent positions.
OEt
Pd(OAc) (10 mol %)
XantPhos (20 mol %)
2
P
OEt
Br
O
O
P
EtO
EtO C
N +
EtO C
N
2
EtO
2
H
KOAc (10 mol %)
N
N
iPr NEt (1.8 equiv)
2
SEM
a-f
SEM
3a-f
THF, 70-100 °C
1
2a
entry
1
1a-f
product
3a (32%)
2
3b (52%)
4

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3
4
5
3c (61%)
3d (29%)
3e (37%)
6
3f (0%)
Different phosphorous derivatives were also involved in the coupling reaction with pyrazoles 1a−c, and the
results are summarized in Table 4. When the stereoelectronic properties of the phosphonylidene derivatives were
changed, two different cases were noticed: when pyrazoles 1a and 1c were involved in the cross-coupling, the
nature of the phosphorous derivative did not seem to have a strong influence on the yields of the coupling
products (Table 4, entries 1−2 and 5−6). On the contrary, when pyrazole 1b was involved in the cross-coupling
with H-phosphinates or secondary phosphine oxides, the yield in 4 dropped dramatically (Table 4, entries 3−4).
Table 4. Influence of the phosphorous donor.
entry
1a-c
2b-d
product
O
P
iPrO
4a (29%)
1
H
iPrO
2
b
2
3
4
4b (29%)
4c (25%)
4d (11%)
5

ACCEPTED MANUSCRIPT
5
6
4e (52%)
4f (28%)
In metal-catalyzed reactions, and particularly with heteroatom-containing substrates, complexation effects can
be detrimental to the success of the reaction. In order to investigate these effects, trifluoromethyl- and cyano-
pyrazoles 5 and 6 were involved in the phosphonylation (Table 5). Good to excellent yields in the desired cross-
coupling products were obtained, regardless of the phosphorous donors, which is in contrast to the results
previously reported (Table 3, entries 3 and 5). Although the trifluoromethyl- and cyano- groups also vary from
the ester group by their electron-withdrawing force, the important differences in reactivity between the
trifluoromethyl-, cyano- and ester-substituted pyrazoles are suggestive of complexation effects.
Table 5. Influence of the nature of the substituents.
entry
5-6
2a-e
product
1
7a (83%)
2
3
7b (90%)
7c (57%)
4
7d (47%)
5
6
7
8a (81%)
8b (75%)
8c (58%)
6

ACCEPTED MANUSCRIPT
In terms of mechanistic studies, a solid basis has been provided over the years since the seminal work
1
1,14
by Hirao et al.,
and further refinement has recently been proposed by Stawinski et al. when KOAc is used as
1
3
an additive (Scheme 2). After initial formation of the anionic species A from Pd(OAc) and XantPhos,
2
intermediate B is formed by oxidative addition, and a phosphine ligand is then displaced by an oxygen atom of
the adjacent acetate. The generated species C coordinates a phosphonylidene nucleophile, and a subsequent
deprotonation leads to species D from which reductive elimination occurs.
Scheme 2. Proposed catalytic cycle.
In considering this catalytic cycle, the results presented in Table 3 and 4 suggest that the rate determining step
in the catalytic cycle is related to the substitution pattern of the pyrazoles. With pyrazoles 1a and 1c, the
oxidative addition is probably determinant as the yield in the cross-coupling products is not influenced by the
nature of the phosphorous derivatives. By contrast, the ligand displacement or the reductive elimination are
crucial with pyrazole 1b as the yield ranges from 11% to 52% depending on the nature of the phosphorous
partner.
In conclusion, a series of bromopyrazoles substituted by electron-withdrawing groups such as an ester, a
trifluoromethyl or a cyano group were involved in a palladium-catalyzed cross-coupling with different
phosphorus derivatives. Moderate to good yields were obtained depending on the electron-withdrawing group
and its relative position to the bromine atom, which suggests that multiple stereoelectronic and complexation
effects can influence the phosphonylation yields. As a general rule, the use of an electron-withdrawing group
which would not lead to the formation of a chelating system seems to be beneficial to the cross-coupling, as well
as a 1,3-relative relationship between the bromine and the electron-withdrawing group.
7

ACCEPTED MANUSCRIPT
3
3
. Experimental Section
.1. General Experimental. All reactions were carried out under an argon atmosphere unless otherwise
specified. Flasks were oven-dried at 120 °C and cooled under argon prior to use. THF was distilled over
sodium/benzophenone. Diisopropylethylamine was distilled over CaH2 and stored under argon. Diethyl
phosphite was purchased from Sigma-Aldrich, dried over Na SO and distilled prior to use. All other reagents
2
4
and solvents were used as obtained from Sigma-Aldrich without further purification unless otherwise specified.
Flash column chromatographies were carried out by using silica gel (pore size 60 Å, 230 mesh). TLC were
performed on silica gel plate (Merck 60F254) and visualized either with a UV lamp (254 nm) or by treatment
with an aqueous potassium permanganate solution (KMnO /K CO /AcOH) and subsequent heating. Infrared
4
2
3
TM
–1 1
(
IR) spectra were recorded on a Bruker TENSOR 27 (IRFT), wave numbers are indicated in cm . H-NMR
spectra were recorded on a Bruker Avance 400 at 400 MHz. The chemical shifts δ are reported in ppm relative to
tetramethylsilane. Residual CHCl (δ = 7.26 ppm) was used as internal reference unless otherwise specified.
3
H
The multiplicity and shape of signals are designated by the following abbreviations: s = singlet, d = doublet, t =
triplet, q = quartet, quin = quintet, m = multiplet, br = broad. Coupling constants J are reported in Hertz (Hz).
1
3
C-NMR spectra were recorded on a Bruker Avance 400 at 100 MHz. The chemical shifts δ are reported in ppm
relative to tetramethylsilane. CDCl (δ = 77.16 ppm, triplet) was used as internal reference unless otherwise
3
C
specified. The multiplicity and shape of signals are designated by the following abbreviations: d = doublet, q =
quartet. Coupling constants J are reported in Hertz (Hz). High resolution mass spectra (HRMS) were realized at
the Organic Spectrochemistry Center at the Université Pierre et Marie Curie. No HRMS peaks could be found
for intermediate compounds 5 and 6, presumably due to their degradation. However, the rest of the analysis were
consistent with the assigned structures, and the products resulting from the cross-coupling of 5 and 6 were
entirely characterized. Most of the products were obtained as oils, most likely due to the aliphatic nature of the
SEM- protecting group.
3
.3. Synthesis of starting materials 1a-f, 2e, 5 and 6
15
Ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate
To a suspension of sodium hydride (60% in oil, 1.10 g, 27.5 mmol, 1.6 equiv) in dry THF (40 mL), at 0 °C, was
added a solution of ethyl 4-pyrazolecarboxylate (2.47 g, 17.6 mmol, 1.0 equiv) in dry THF (10 mL). The
resulting purple suspension was stirred at rt for 3 h. A solution of SEM-Cl (3.75 mL, 21.2 mmol, 1.2 equiv) in
8

ACCEPTED MANUSCRIPT
dry THF (10 mL) was then added dropwise at 0 °C. The resulting solution was allowed to warm up to rt and
stirred for 3 h. Water was added, and the aqueous phase was extracted 4 times with EtOAc. The combined
organic layers were dried over anhydrous Na SO , filtered and concentrated in vacuo to give a yellow oil.
2
4
Purification by flash column chromatography on silica gel (EtOAc/PE = 10:90) led to the desired product ethyl
1
-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate as a colorless oil (4.66 g, 17.23 mmol, 98%
1
yield). H-NMR (CDCl , 400 MHz): δ 8.06 (d, J = 0.6 Hz, 1H), 7.94 (d, J = 0.6 Hz, 1H), 5.43 (s, 2H), 4.31 (q, J
3
=
7.1 Hz, 2H), 3.62 – 3.52 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H), 0.95 – 0.86 (m, 2H), -0.02 (s, 9H).
Ethyl 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate (1a)
To a solution of ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate (4.66 g, 17.2 mmol, 1
equiv) in dry THF (47 mL), at −30 °C, was added dropwise a 1.0 M solution of TMPMgCl•LiCl (21.0 mL, 21.0
mmol, 1.22 equiv) in THF/toluene. The resulting mixture was stirred at −30 °C for 2 h and a solution of 1,2-
dibromotetrachloroethane (7.41 g, 22.7 mmol, 1.32 equiv) in dry THF (20 mL) was then added dropwise at −30
°C. The reaction mixture was stirred at this temperature for 4 h, and then allowed to warm up to rt and stirred for
1
2 h. Aqueous saturated NaHCO was added to the reaction mixture, and the aqueous phase was extracted 4
3
times with EtOAc. The combined organic layers were dried over anhydrous Na SO , filtered and concentrated in
2
4
vacuo to give a brown suspension. Purification by flash column chromatography on silica gel (EtOAc/PE = 5:95)
led to the desired product 1a as a pale yellow oil (4.31g, 12.34 mmol, 72% yield).
1
IR (neat): 2953, 2897, 1720, 1537, 1407, 1395, 1373, 1244, 1209, 1101, 1079, 1040, 976, 858, 833. H-NMR
(
CDCl , 400 MHz): δ 7.99 (s, 1H), 5.53 (s, 2H), 4.33 (q, J = 7.1 Hz, 2H), 3.66–3.56 (m, 2H), 1.37 (t, J = 7.1 Hz,
3
1
3
3
H), 0.96−0.86 (m, 2H), −0.03 (s, 9H). C-NMR (CDCl , 100 MHz): δ 161.9 (C), 142.6 (CH), 118.5 (C), 115.0
3
+
(
C), 78.9 (CH ), 67.4 (CH ), 60.7 (CH ), 17.9 (CH ), 14.4 (CH ), −1.3 (CH ). HRMS (ESI+): [M+H] calculated
2
2
2
2
3
3
for C H BrN O Si: 349.0578 and 351.0557. Found: 349.0580 and 351.0558.
1
2
22
2
3
Ethyl 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate (1b)
aThe reaction was performed in an oven-dried vial. To a solution of 1a (648 mg, 1.86 mmol, 1.0 equiv) in
anhydrous MeCN (2.0 mL) was added SEM-Cl (33 µL, 0.186 mmol, 0.1 equiv). The vial was sealed with a
teflon-lined cap and stirred at 95 °C for 26 h. The reaction mixture was evaporated to give a yellow solid.
Purification by flash column chromatography (EtOAc/PE = 5:95) led to the desired product 1b as a colorless oil
(
481 mg, 1.38 mmol, 74% yield). IR (neat): 3127, 2953, 2897, 1718, 1536, 1406, 1248, 1211, 1094, 1057, 857,
1
8
1
33. H-NMR (CDCl , 400 MHz): δ 8.02 (s, 1H), 5.38 (s, 2H), 4.32 (q, J = 7.1 Hz, 2H), 3.62−3.57 (m, 2H),
3
13
.36 (t, J = 7.1 Hz, 3H), 0.94−0.89 (m, 2H), −0.02 (s, 9H). C-NMR (CDCl , 100 MHz): δ 161.6 (C), 135.0
3
9

ACCEPTED MANUSCRIPT
(
CH), 128.2 (C), 115.2 (C), 81.2 (CH ), 67.8 (CH ), 60.8 (CH ), 17.9 (CH ), 14.4 (CH ), −1.3 (CH ). HRMS
2
2
2
2
3
3
+
(
ESI+): [M+Na] calculated for C H BrN NaO Si: 371.0397 and 373.0377. Found: 371.0399 and 373.0377.
12 21 2 3
16
1
-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazole
To a suspension of sodium hydride (3.96 g, 99 mmol, 1.5 equiv) in dry THF (50 mL), at 0 °C, was added a
solution of 1H-pyrazole (4.50 g, 66.1 mmol, 1 equiv) in dry THF (20 mL). The resulting suspension was stirred
at rt for 2 h. The solution was then cooled down to 0 °C and a solution of SEM-Cl (12.9 mL, 72.7 mmol, 1.1
equiv) in dry THF (23 mL) was added dropwise. The solution was then allowed to warm up to rt and stirred
overnight. Water was added, and the aqueous phase was extracted 4 times with EtOAc. The combined organic
phases were dried over anhydrous Na SO , filtered and concentrated in vacuo to give a pale yellow oil.
2
4
Purification by flash column chromatography (EtOAc/PE = 15:85) led to the desired product 1-((2-
1
(
trimethylsilyl)ethoxy)methyl)-1H-pyrazole as a colorless oil (12.4 g, 62.7 mmol, 95% yield). H NMR (400
MHz, CDCl ): δ 7.56 (br, d, J = 2.4 Hz, 1H), 7.55 (br, d, J = 1.6 Hz, 1H), 6.33 (br, t, J = 2.1 Hz, 1H), 5.44 (s,
3
2
H), 3.58 – 3.49 (m, 2H), 0.95 – 0.78 (m, 2H), −0.03 (s, 9H).
-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole
13
5
To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (3.00 g, 15.1 mmol, 1 equiv) in dry THF (30
mL), at 0 °C, was added dropwise a 1.0 M solution of TMPMgCl•LiCl (18.0 mL, 18.0 mmol, 1.2 equiv) in
THF/toluene. The resulting mixture was allowed to warm up to rt and the completion of the deprotonation was
checked by GC/MS analysis of reaction aliquots quenched with I . The solution was then cooled down to 0 °C,
2
and a solution of 1,2-dibromotetrachloroethane (5.91 g, 18.2 mmol, 1.2 equiv) in THF (12 mL) was added
dropwise. The resulting solution was then allowed to warm up to rt and stirred overnight. Aqueous saturated
NaHCO was added to the reaction mixture and the aqueous phase was extracted 4 times with EtOAc. The
3
organic phase was collected and dried over anhydrous Na SO , filtered and concentrated in vacuo to give a
2
4
brown oil. Purification by flash column chromatography (EtOAc/PE = 5:95 to 15:85) led to the desired product
5
-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole as a pale yellow oil (3.60 g, 13.2 mmol, 88% yield).
1
H NMR (400 MHz, CDCl ): δ 7.53 (d, J = 1.9 Hz, 1H), 6.35 (d, J = 1.9 Hz, 1H), 5.49 (s, 2H), 3.72 – 3.11 (m,
3
2
H), 1.09 – 0.73 (m, 2H), −0.03 (s, 9H).
3
-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole
The reaction was performed in an oven-dried vial. To
trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.34 g, 4.84 mmol, 1.0 equiv) in anhydrous MeCN (2.0 mL) was
added SEM-Cl (85 µL, 0.48 mmol, 0.1 equiv). The vial was sealed with a teflon-lined cap and stirred at 95 °C
a
solution of 5-bromo-1-((2-
(
1
0

ACCEPTED MANUSCRIPT
for 24 h. The reaction mixture was evaporated to give a yellow oil. Purification by flash column chromatography
(
EtOAc/PE = 5:95 to 10:90) led to the desired product 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-
pyrazole as a colorless oil (1.10 g, 3.80 mmol, 78% yield). IR (neat): 2953, 2896, 1501, 1360, 1297, 1248,
1
1
095, 952, 857, 833,745. H-NMR (CDCl , 400 MHz): δ 7.46 (d, J = 2.4 Hz, 1H), 6.35 (d, J = 2.4 Hz, 1H), 5.37
3
13
(
s, 2H), 3.59−3.55 (m, 2H), 0.92−0.87 (m, 2H), −0.02 (s, 9H). C-NMR (CDCl , 100 MHz): δ 131.6 (CH),
3
+
1
26.6 (C), 109.9 (CH), 80.6 (CH ), 67.2 (CH ), 17.9 (CH ), −1.3 (CH ). HRMS (ESI+): [M+Na] calculated for
2
2
2
3
C H BrN NaOSi: 299.0186 and 301.0165. Found: 299.0189 and 301.1411.
9
17
2
Ethyl 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate (1c)
To a solution of 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (417 mg, 1.51 mmol, 1 equiv) in
dry THF (3 mL) was added dropwise a 1.0 M solution of TMPMgCl•LiCl (1.80 mL, 1.80 mmol, 1.2 equiv) in
THF/toluene. The resulting mixture was allowed to warm up to rt and the completion of the deprotonation was
checked by GC/MS analysis of reaction aliquots quenched with I . The solution was then cooled down to −30
2
°C, and a solution of ethyl cyanoformate (158 µL, 1.59 mmol, 1.1 equiv) in THF (2.0 mL) was added dropwise.
The reaction was stirred at −30 °C for 3 h, allowed to warm up to rt and stirred at this temperature for 12 h.
Aqueous saturated NaHCO was added to the reaction mixture, and the aqueous phase was extracted 3 times
3
with EtOAc. The combined organic layers were dried over anhydrous Na SO , filtered and concentrated in vacuo
2
4
to give a brown oil. Purification by flash column chromatography (EtOAc/PE = 5:95) led to the desired product
1
9
3
1
c as a pale yellow oil (454 mg, 1.30 mmol, 86% yield). IR (neat): 2953, 2897, 1729, 1368, 1339, 1240, 1078,
1
61, 858, 834, 764, 743. H-NMR (CDCl , 400 MHz): δ 6.89 (s, 1H), 5.79 (s, 2H), 4.36 (q, J = 7.1 Hz, 2H),
3
13
.62−3.58 (m, 2H), 1.37 (t, J = 7.1 Hz, 3H), 0.91−0.87 (m, 2H), −0.04 (s, 9H). C-NMR (CDCl , 100 MHz): δ
3
58.4 (C), 134.8 (C), 125.9 (C), 114.8 (CH), 79.6 (CH ), 67.2 (CH ), 61.8 (CH ), 17.8 (CH ), 14.3 (CH ), −1.3
2
2
2
2
3
+
(
CH ). HRMS (ESI+): [M+Na] calculated for C H BrN NaO Si: 371.0397 and 373.0377. Found: 371.0399
3 12 21 2 3
and 373.0378.
Ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate
To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.48 g, 12.5 mmol, 1 equiv) in dry THF (13
mL), at 0 °C, was added dropwise a 1.0 M solution of TMPMgCl•LiCl (15.0 mL, 15.0 mmol, 1.2 equiv) in
THF/toluene. The resulting mixture was allowed to warm up to rt and the completion of the deprotonation was
checked by GC/MS analysis of reaction aliquots quenched with I . A solution of ethyl cyanoformate (1.61 mL,
2
1
6.3 mmol, 1.3 equiv) in dry THF (8 mL) was then added dropwise at −30 °C, the reaction mixture was stirred
for 1.5 h, and then allowed to warm up to rt and stirred for 1 h. Aqueous saturated NaHCO was added to the
3
1
1

ACCEPTED MANUSCRIPT
reaction mixture, and the aqueous phase was extracted 4 times with EtOAc. The combined organic layers were
dried over anhydrous Na SO , filtered and concentrated in vacuo to give a dark brown oil. Purification by flash
2
4
column chromatography (EtOAc/PE
= 5:95 to 10:90) led to the desired product ethyl 1-((2-
(
trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate as a pale yellow oil (2.20 g, 8.12 mmol, 65% yield).
1
IR (neat): 2953, 2898, 1725, 1521, 1466, 1312, 1246, 1116, 1085, 1020, 858. H-NMR (CDCl , 400 MHz): δ
3
7
.54 (d, J = 1.9 Hz, 1H), 6.90 (d, J = 1.9 Hz, 1H), 5.86 (s, 2H), 4.36 (q, J = 7.1 Hz, 2H), 3.60−3.56 (m, 2H), 1.38
13
(
t, J = 7.1 Hz, 3H), 0.91−0.87 (m, 2H), −0.05 (s, 9H). C-NMR (CDCl , 100 MHz): δ 159.6 (C), 138.9 (CH),
3
1
33.0 (C), 112.6 (CH), 79.3 (CH ), 66.9 (CH ), 61.3 (CH ), 17.9 (CH ), 14.4 (CH ), −1.4 (CH ). HRMS (ESI+):
2 2 2 2 3 3
+
[
M+Na] calculated for C H N NaO Si: 293.1292. Found: 293.1294.
12 22 2 3
Ethyl 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate (1d)
Under argon, at −30 °C, to a solution of ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate
(
(
1.66 g, 6.13 mmol, 1.0 equiv) in dry THF (18 mL) was added dropwise a 1.0 M solution of TMPMgCl•LiCl
7.40 mL, 7.40 mmol, 1.2 equiv) in THF/toluene. The resulting mixture was stirred at −30 °C for 5.5 h. A
solution of 1,2-dibromotetrachloroethane (2.63 g, 8.09 mmol, 1.3 equiv) in dry THF (6 mL) was added dropwise
at −30 °C, the reaction mixture was stirred for 4 h, and then allowed to warm up to rt and stirred for 12 h.
Aqueous saturated NaHCO was added to the reaction mixture, aqueous phase was extracted 4 times with
3
EtOAc. The combined organic layers were dried over anhydrous Na SO , filtered and concentrated in vacuo to
2
4
give a dark brown oil. Purification by flash column chromatography (EtOAc/PE = 1:99, then repurified with
CH Cl /toluene = 15:85 to 30:70) to give 1d as a colorless oil (211 mg, 0.60 mmol, 10% yield) (the main product
2
2
of the reaction was 1c, which was isolated in 28% yield). IR (neat): 2953, 2897, 1724, 1509, 1440, 1367, 1306,
1
1
2
247, 1086, 1024, 975, 834, 751. H-NMR (CDCl , 400 MHz): δ 7.56 (s, 1H), 5.81 (s, 2H), 4.42 (q, J = 7.1 Hz,
3
13
H), 3.56−3.52 (m, 2H), 1.42 (t, J = 7.1 Hz, 3H), 0.90−0.86 (m, 2H), −0.04 (s, 9H). C-NMR (CDCl , 100
3
MHz): δ 158.8 (C), 141.0 (CH), 130.8 (C), 100.9 (C), 80.8 (CH ), 67.1 (CH ), 61.9 (CH ), 17.8 (CH ), 14.2
2
2
2
2
+
(
CH ), −1.4 (CH ). HRMS (ESI+): [M+Na] calculated for C H BrN NaO Si: 371.0397 and 373.0377. Found:
3 3 12 21 2 3
3
71.0399 and 373.0377.
Ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate
To a suspension of sodium hydride (60% in oil, 0.45 g, 11.3 mmol, 1.6 equiv) in dry THF (16 mL) was added a
solution of ethyl 1H-pyrazole-3-carboxylate (1.00 g, 7.14 mmol, 1.0 equiv) in dry THF (16 mL). The resulting
dark brown solution was stirred at rt for 3 h. A solution of SEM-Cl (1.52 mL, 8.56 mmol, 1.2 equiv) in dry THF
(
6 mL) was then added dropwise at 0 °C. The solution was then allowed to warm up to rt and stirred overnight.
1
2

ACCEPTED MANUSCRIPT
Water was added to the reaction mixture, aqueous phase was extracted 4 times with EtOAc. The combined
organic layers were dried over anhydrous Na SO , filtered and concentrated in vacuo to give a dark red oil.
2
4
Purification by flash column chromatography (Et O/CH Cl = 0:100 to 5:95) led to the desired product ethyl
2
2
2
1
-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate as a light orange oil (1.22 g, 4.50 mmol, 63%
1
yield). IR (neat): 2954, 2897, 1720, 1469, 1370, 1213, 1149, 1095, 1043, 1023, 858, 834, 761. H-NMR
(
CDCl , 400 MHz): δ 7.61 (d, J = 2.4 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 5.51 (s, 2H), 4.42 (q, J = 7.1 Hz, 2H),
3
13
3
.59−3.54 (m, 2H), 1.40 (t, J = 7.1 Hz, 3H), 0.92−0.88 (m, 2H), −0.03 (s, 9H). C-NMR (δ, ppm) (CDCl , 100
3
MHz): δ 162.2 (C), 143.9 (C), 130.4 (CH), 109.8 (CH), 80.9 (CH ), 67.0 (CH ), 60.9 (CH ), 17.7 (CH ), 14.3
2
2
2
2
+
(
CH ), −1.5 (CH ). HRMS (ESI+): [M+Na] calculated for C H N NaO Si: 293.1292. Found: 293.1290.
3 3 12 22 2 3
Ethyl 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (1e)
To a solution of ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (237 mg, 0.876 mmol, 1
equiv) in dry THF (2.6 mL), at −30 °C, was added dropwise a 1.0 M solution of TMPMgCl•LiCl (1 mL, 1
mmol, 1.14 equiv) in THF/toluene. The resulting mixture was stirred at −30 °C for 6 h. A solution of 1,2-
dibromotetrachloroethane (371 mg, 1.14 mmol, 1.3 equiv) in dry THF (1 mL) was then added dropwise at −30
°C, and the reaction mixture was stirred overnight at −30 °C, then allowed to warm up to rt and stirred at rt for 9
h. Aqueous saturated NaHCO was added to the reaction mixture, and the aqueous phase was extracted 4 times
3
with EtOAc. The combined organic layers were dried over anhydrous Na SO , filtered and concentrated in vacuo
2
4
to give an orange suspension. Purification by flash column chromatography (EtOAc/PE = 5:95 to 15:85) led to
the desired product 1e as a yellow oil (46 mg, 0.13 mmol, 15% yield). IR (neat): 2953, 1721, 1463, 1412, 1384,
1
1
4
307, 1248, 1092, 1046, 1019, 914, 858, 775, 749. H-NMR (CDCl , 400 MHz): δ 6.88 (s, 1H), 5.56 (s, 2H),
3
13
.41 (q, J = 7.1 Hz, 2H), 3.64−3.60 (m, 2H), 1.39 (t, J = 7.1 Hz, 3H), 0.92−0.88 (m, 2H), −0.03 (s, 9H). C-
NMR (CDCl , 100 MHz): δ 161.6 (C), 144.8 (C), 114.6 (C), 112.4 (CH), 79.4 (CH ), 67.3 (CH ), 61.5 (CH ),
3
2
2
2
+
1
3
7.9 (CH ), 14.5 (CH ), −1.3 (CH ). HRMS (ESI+): [M+Na] calculated for C H BrN NaO Si: 371.0397 and
2 3 3 12 21 2 3
73.0377. Found: 371.0402 and 373.0377.
Ethyl 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (1f)
Under air, to a solution of ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (685 mg, 2.53
mmol, 1.0 equiv) in CHCl (0.7 mL), at 0°C, was added a solution of Br (0.14 mL, 2.73 mmol, 1.08 equiv) in
3
2
CHCl (0.1 mL) and the red-brown mixture was stirred at 0 °C for 3.5 h. The reaction solution was diluted with
3
CHCl , quenched by Na S O and washed with aqueous saturated NaHCO and then brine. The organic phase
3
2
2
3
3
1
3

ACCEPTED MANUSCRIPT
was dried over anhydrous Na SO , filtered and concentrated in vacuo to give a brown oil. Purification by flash
2
4
column chromatography (EtOAc/PE = 15:85, repurified with Et O/toluene = 15:85) led to the desired product 1f
2
as a pale yellow oil (87 mg, 0.25 mmol, 10% yield). IR (neat): 3125, 2953, 2897, 1725, 1463, 1352, 1324, 1211,
1
1
2
093, 1042, 1011, 915, 858, 834. H-NMR (CDCl , 400 MHz): δ 7.69 (s, 1H), 5.46 (s, 2H), 4.43 (q, J = 7.1 Hz,
3
13
H), 3.58−3.54 (m, 2H), 1.41 (t, J = 7.1 Hz, 3H), 0.93−0.88 (m, 2H), −0.02 (s, 9H). C-NMR (CDCl , 100
3
MHz): δ 161.2 (C), 140.8 (C), 131.9 (CH), 97.7 (C), 81.8 (CH ), 67.7 (CH ), 61.5 (CH ), 17.9 (CH ), 14.4
2
2
2
2
+
(
CH ), −1.3 (CH ). HRMS (ESI+): [M+Na] calculated for C H BrN NaO Si: 371.0397 and 373.0377. Found:
3 3 12 21 2 3
3
71.0402 and 373.0378.
1
3
Cyclopropyl(phenyl) phosphine oxide (2e)
At –78 °C, to a 1.0 M solution of cyclopropylmagnesium bromide (12.5 mL, 12.5 mmol, 2.1 equiv) in 2-methyl-
tetrahydrofuran was added a solution of ethyl phenylphosphinate (1.00 g, 5.88 mmol, 1.0 equiv) in THF (6 mL)
dropwise. The resulting yellow solution was stirred at –78 °C for 40 min. An aqueous saturated NH Cl solution
4
(
6 mL) was then added, and the resulting slurry was allowed to warm up to rt. Water was then added (50 mL),
the aqueous phase was washed 2 times with petroleum ether (2 x 30 mL), and then extracted 3 times with CHCl3
3 x 50 mL). The combined halogenated phases were dried over anhydrous Na SO , and concentrated in vacuo to
(
2
4
give a colorless oil. Distillation in vacuo using a Kugelrohr apparatus (90 °C, 0.5 mbar) led to the desired
1
product 2e as a colorless oil (590 mg, 3.55 mmol, 60% yield). H-NMR (400MHz, CDCl ): δ 7.72 (ddd, J =
3
1
3.2, 8.1, 1.3 Hz, 2H), 7.58–7.43 (m, 3H), 7.31 (dd, J = 480.0, 2.2 Hz, 1H), 1.11–0.87 (m, 5H).
3
-(Trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole
To a suspension of sodium hydride (60% in oil, 0.97 g, 24.3 mmol, 1.5 equiv) in dry THF (30 mL), at 0 °C, was
added a solution of 3-(trifluoromethyl)pyrazole (2.20 g, 16.2 mmol, 1.0 equiv) in dry THF (10 mL). The
resulting suspension was stirred at rt for 2 hours. The reaction solution was then cooled down to 0 °C and a
solution of SEM-Cl (3.46 mL, 19.5 mmol, 1.2 equiv) in dry THF (10 mL) was added dropwise. The solution
gradually turned yellow and was allowed to warm up to rt and stirred for 3 h. Aqueous saturated NaHCO was
3
added to the reaction mixture and the aqueous phase was extracted 4 times with EtOAc. The combined organic
layers were dried over anhydrous Na SO , filtered and concentrated in vacuo to give a colorless oil. Purification
2
4
by flash column chromatography (EtOAc/PE = 10:90) led to the desired product 3-(trifluoromethyl)-1-((2-
(
trimethylsilyl)ethoxy)methyl)-1H-pyrazole as a colorless oil (1.69 g, 6.34 mmol, 39% yield). IR (neat): 2957,
1
2
900, 1490, 1341, 1252, 1228, 1172, 1133, 1102, 967, 860, 836, 771, 756. H-NMR (CDCl , 400 MHz): δ 7.62
3
13
(
m, 1H), 6.60 (br, d, J = 2.4 Hz, 1H), 5.47 (s, 2H), 3.60−3.56 (m, 2H), 0.95−0.83 (m, 2H), −0.03 (s, 9H). C-
1
4

ACCEPTED MANUSCRIPT
NMR (CDCl , 100 MHz): δ 143.0 (dapp, J = 38.0 Hz), 130.8 (CH), 121.3 (C, dapp, J = 269 Hz), 105.6 (CH, dapp
,
3
J = 2 Hz), 80.9 (CH ), 67.41 (CH ), 17.8 (CH ), −1.4 (CH ). HRMS (ESI+): no peak found (see General
2
2
3
3
Experimental).
-Bromo-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (5)
5
To a solution of 3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (856 mg, 3.22 mmol, 1
equiv) in dry THF (6 mL), at 0 °C, was added dropwise a 1.0 M solution of TMPMgCl•LiCl (3.60 mL, 3.60
mmol, 1.1 equiv) in THF/toluene. The resulting mixture was stirred at 0 °C for 3 h and the completion of the
deprotonation was checked by GC/MS analysis of reaction aliquots quenched with I . A solution of 1,2-
2
dibromotetrachloroethane (1.27 g, 3.9 mmol, 1.2 equiv) in dry THF (2 mL) was then added dropwise at 0 °C,
and the reaction mixture was allowed to warm up to rt and stirred for 4.5 h. Aqueous saturated NaHCO was
3
added to the reaction mixture, and the aqueous phase was extracted 4 times with EtOAc. The combined organic
phases were dried over anhydrous Na SO , filtered and concentrated in vacuo to give a brown oil. Purification by
2
4
flash column chromatography (PE) led to the desired product 5 as a light yellow oil (717 mg, 2.08 mmol, 65%
yield). IR (neat): 2955, 2898, 1468, 1421, 1396, 1367, 1249, 1211, 1172, 1120, 1091, 1052, 1028, 969, 913,
1
8
9
58. H-NMR (CDCl , 400 MHz): δ 6.63 (s, 1H), 5.53 (s, 2H), 3.65−3.61 (m, 2H), 0.92−0.88 (m, 2H), −0.02 (s,
3
1
3
H). C-NMR (CDCl , 100 MHz): δ 143.8 (C, q, J = 39 Hz), 120.6 (C, q, J = 269 Hz), 114.9 (C), 108.2 (CH,
3
dapp, J = 2 Hz), 79.1 (CH ), 67.4 (CH ), 17.7 (CH ), −1.5 (CH ). HRMS (ESI+): no peak found (see General
2
2
2
3
Experimental).
-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile (6)
3
To a solution of 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.08 g, 3.9 mmol, 1.0 equiv) in dry
THF (7.6 mL), at 0°C, was added dropwise a 1.0 M solution of TMPMgCl•LiCl (4.70 mL, 4.70 mmol, 1.2
equiv) in THF/toluene. The solution was then stirred at rt for 8 h. The solution was cooled down to −15 °C and a
solution of p-toluene sulfonyl cyanide (847 mg, 4.67 mmol, 1.2 equiv) in THF (4.0 mL) was added dropwise.
The reaction was stirred overnight at −15 °C and then at rt for 0.5 h. Aqueous saturated NaHCO was added to
3
the reaction mixture, and the aqueous phase was extracted 4 times with EtOAc. The combined organic phases
were dried over anhydrous Na SO , filtered and concentrated in vacuo to give a brown suspension. Purification
2
4
by flash column chromatography (EtOAc/PE = 5:95 to 10:90) led to the desired product 6 as a colorless oil (1.02
g, 3.38 mmol, 87% yield). IR (neat): 3143, 2953, 2897, 2239, 1509, 1360, 1297, 1248, 1092, 961, 858, 834,
1
7
61. H-NMR (CDCl , 400 MHz): δ 6.86 (s, 1H), 5.55 (s, 2H), 3.66−3.62 (m, 2H), 0.96−0.91 (m, 2H), -0.01 (s,
3
1
5

ACCEPTED MANUSCRIPT
1
3
9
H). C-NMR (CDCl , 100 MHz): δ 126.8 (C), 117.2 (CH), 116.9 (C), 109.0 (C), 80.1 (CH ), 68.1 (CH ), 17.7
3 2 2
(
CH ), −1.3 (CH ). HRMS (ESI+): no peak found (see General Experimental).
2 3
3
.5. General procedure for the cross-couplings of bromopyrazoles with phosphonylidenes
Pd(OAc)2 (10 mol %), XantPhos (20 mol %), and KOAc (10 mol %), bromopyrazole (1.5 equiv) were weighted
in a microwave vial, which was then sealed and flushed with argon. THF (c = 0.25 M) and DIPEA (1.8 equiv)
were then added through the septum and the resulting suspension was stirred for 20 min at 70 °C. The
phosphonylidene (1.0 equiv) was then added through the septum, and the reaction mixture was stirred at 70 °C
and the temperature was increased to 100 °C if necessary until completion of the reaction, as determined by
TLC. The reaction mixture was then diluted with EtOAc, an aqueous saturated NaHCO solution was added, the
3
layers were separated, and the aqueous phase was extracted 3 more times with EtOAc. The combined organic
phases were then dried over anhydrous Na SO , and concentrated in vacuo. Purification by flash column
2
4
chromatography on silica gel led to the desired cross-coupling products.
Ethyl 5-(diethoxyphosphoryl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate
(3a).
Pyrazole 1a (262 mg, 0.75 mmol) and diethyl phosphite 2a (64 µL, 0.5 mmol) were reacted together according
to the general procedure. After 25 h, TLC showed full consumption of 2a. Purification by flash column
chromatography on silica gel (EtOAc/CH Cl = 90:10) led to the desired product 3a as a pale yellow oil (65 mg,
2
2
0
8
4
2
.16 mmol, 32% yield). IR (neat): υmax 2982, 2954, 1735, 1716, 1524, 1379, 1250, 1207, 1114, 1091, 1020,
1
35, 750. H-NMR (CDCl , 400 MHz): δ 7.97 (d, J = 1.3 Hz, 1H), 5.94 (s, 2H), 4.32 (q, J = 7.1 Hz, 2H),
3
.29−4.10 (m, 4H), 3.62−3.56 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H), 1.32 (td, J = 7.1, 0.7 Hz, 6H), 0.93−0.86 (m,
1
3
H), −0.03 (s, 9H). C-NMR (CDCl , 100 MHz): δ 162.0 (C), 141.5 (CH, d, J = 14 Hz), 133.1 (C, d, J = 208
3
Hz), 122.0 (C, d, J = 16 Hz), 80.7 (CH ), 67.1 (CH ), 63.5 (CH , d, J = 5 Hz), 61.0 (CH ), 18.0 (CH ), 16.4 (CH ,
2
2
2
2
2
3
+
d, J = 7 Hz), 14.4 (CH ), −1.3 (CH ). HRMS (ESI+): [M+H] calculated for C H N O PSi: 407.1762. Found:
3
3
17 31
2
6
4
07.1758.
Ethyl
3-(diethoxyphosphoryl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate
(3b).
Pyrazole 1b (112 mg, 0.321 mmol) and diethyl phosphite 2a (27 µL, 0.211 mmol) were reacted together
according to the general procedure. After 6 h, TLC showed full consumption of 2a. Purification by flash column
chromatography on silica gel (EtOAc/PE = 20:80 to 100:0) led to the desired product 3b as a pale yellow oil (45
mg, 0.11 mmol, 52% yield). IR (neat): υmax 2981, 2954, 2904, 1725, 1248, 1225, 1085, 1053, 1024, 971, 858,
1
8
35, 752. H-NMR (CDCl , 400 MHz): δ 8.15 (d, J = 1.9 Hz, 1H), 5.48 (s, 2H), 4.38−4.19 (m, 6H), 3.61−3.55
3
13
(
m, 2H), 1.39−1.33 (m, 9H), 0.95−0.88 (m, 2H), −0.02 (s, 9H). C-NMR (CDCl , 100 MHz): δ 161.6 (C),
3
1
6

ACCEPTED MANUSCRIPT
1
43.2 (C, d, J = 231 Hz), 134.7 (CH, d, J = 8 Hz), 119.8 (C, d, J = 21 Hz), 81.2 (CH ), 67.8 (CH ), 63.2 (CH , d,
2
2
2
+
J = 6 Hz), 61.0 (CH ), 17.9 (CH ), 16.5 (CH , d, J = 7 Hz), 14.4 (CH ), −1.3 (CH ). HRMS (ESI+): [M+Na]
2
2
3
3
3
calculated for C H N NaO PSi: 429.1581. Found: 429.1584.
1
6
31
2
6
Ethyl
3-(diethoxyphosphoryl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate
(3c).
Pyrazole 1c (130 mg, 0.374 mmol) and diethyl phosphite 2a (32 µL, 0.250 mmol) were reacted together
according to the general procedure. After 2 h, TLC showed full consumption of 2a. Purification by flash column
chromatography on silica gel (EtOAc/PE = 60:40) led to the desired product 3c as a pale yellow oil (61 mg, 0.15
1
mmol, 61% yield). IR (neat): υmax 2982, 2954, 2904, 1729, 1244, 1081, 1052, 1020, 970, 835, 769, 749. H-
NMR (CDCl , 400 MHz): δ 7.32 (d, J = 1.4 Hz, 1H), 5.91 (s, 2H), 4.37 (q, J = 7.1 Hz, 2H), 4.26−4.10 (m, 4H),
3
3
.63−3.55 (m, 2H), 1.37 (t, J = 7.1 Hz, 3H), 1.34 (td, J = 7.1, 0.5 Hz, 6H), 0.90−0.86 (m, 2H), −0.06 (s, 9H).
1
3
C-NMR (CDCl , 100 MHz): δ 158.9 (C), 141.7 (C, d, J = 232 Hz), 134.0 (C, d, J = 10 Hz), 118.0 (CH, d, J =
3
2
3 Hz), 80.2 (CH ), 67.3 (CH ), 62.9 (CH , d, J = 6 Hz), 61.7 (CH ), 17.9 (CH ), 16.4 (CH , d, J = 6 Hz), 14.3
2
2
2
2
2
3
+
(
CH ), −1.4 (CH ). HRMS (ESI+): [M+Na] calculated for C H N NaO PSi: 429.1581. Found: 429.1580.
3 3 16 31 2 6
Ethyl
4-(diethoxyphosphoryl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate
(3d)
Pyrazole 1d (110 mg, 0.315 mmol) and diethyl phosphite 2a (27 µL, 0.211 mmol) were reacted together
according to the general procedure. After 23 h, TLC showed full consumption of 2a. Purification by flash
column chromatography on silica gel (EtOAc/PE = 10:90 to 100:0) led to the desired product 3d as an orange oil
(
65 mg, 0.061 mmol, 29% yield). IR (neat): υmax 2982, 2954, 2903, 1729, 1519, 1311, 1249, 1092, 1055, 1021,
1
9
4
2
67, 859, 791. H-NMR (CDCl , 400 MHz): δ 7.82 (d, J = 1.4 Hz, 1H), 5.83 (s, 2H), 4.43 (q, J = 7.1 Hz, 2H),
3
.23−4.04 (m, 4H), 3.60−3.56 (m, 2H), 1.43 (t, J = 7.2 Hz, 3H), 1.34 (td, J = 7.1, 0.5 Hz, 6H), 0.93−0.84 (m,
1
3
H), −0.05 (s, 9H). C-NMR (CDCl , 100 MHz): δ 158.8 (C), 144.1 (CH, d, J = 11 Hz), 135.9 (C, d, J = 22
3
Hz), 113.0 (C, d, J = 217 Hz), 80.1 (CH ), 67.4 (CH ), 62.5−62.4 (3CH ), 17.9 (CH ), 16.5 (CH , d, J = 7 Hz),
2
2
2
2
3
+
1
4.1 (CH ), −1.4 (CH ). HRMS (ESI+): [M+Na] calculated for C H N NaO PSi: 429.1581. Found: 429.1585.
3 3 16 31 2 6
Ethyl
5-(diethoxyphosphoryl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate
(3e).
Pyrazole 1e (95 mg, 0.272 mmol) and diethyl phosphite 2a (23 µL, 0.180 mmol) were reacted together according
to the general procedure. After 22 h at 70 °C, TLC showed that 2a was not fully consumed, so the temperature
was increased to 100 °C and the reaction mixture was stirred at this temperature for 6 h. Purification by flash
column chromatography on silica gel (EtOAc/PE = 10:90 to 100:0) led to the desired product 3e as a yellow oil
(
27 mg, 0.066 mmol, 37% yield). IR (neat): υmax 2982, 2954, 1740, 1723, 1509, 1446, 1390, 1369, 1250, 1206,
1
1
090, 1016, 975, 859, 835. H-NMR (Acetone-d6, 400 MHz): δ 7.19 (d, J = 2.5 Hz, 1H), 5.77 (s, 2H), 4.34 (q,
1
7

ACCEPTED MANUSCRIPT
J = 7.1 Hz, 2H), 4.26−4.06 (m, 4H), 3.70−3.66 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H), 1.33 (td, J = 7.2, 0.4 Hz, 6H),
1
3
0
1
1
.93−0.89 (m, 2H), −0.01 (s, 9H). C-NMR (Acetone-d6, 100 MHz): δ 161.9 (C), 144.2 (C, d, J = 16 Hz),
34.8 (C, d, J = 210 Hz), 118.3 (CH, d, J = 17 Hz), 81.0 (CH ), 67.6 (CH ), 63.8 (CH , d, J = 5 Hz), 61.4 (CH ),
2
2
2
2
+
8.2 (CH ), 16.5 (CH , d, J = 6 Hz), 14.6 (CH ), −1.4 (CH ). HRMS (ESI+): [M+Na] calculated for
2
3
3
3
C H N NaO PSi: 429.1581. Found: 429.1583.
1
6
31
2
6
Ethyl 5-(diisopropoxyphosphoryl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate (4a).
Pyrazole 1a (266 mg, 0.76 mmol) and diisopropyl phosphite 2b (84 µL, 0.504 mmol) were reacted together
according to the general procedure. After 22 h at 70 °C, TLC showed full consumption of 2b. Purification by
flash column chromatography on silica gel (EtOAc/PE = 15:85) led to the desired product 4a as a white oil (63
mg, 0.145 mmol, 29% yield). IR (neat): υmax 2980, 2954, 1736, 1715, 1524, 1376, 1251, 1206, 1093, 990, 834,
1
7
4
52. H NMR (400 MHz, CDCl ) δ 7.96 (d, J = 1.2 Hz, 1H), 5.98 (s, 2H), 4.78 (dhept, J = 7.9, 6.2 Hz, 2H),
3
.31 (q, J = 7.1 Hz, 2H), 3.65 – 3.54 (m, 2H), 1.37 (d, J = 6.2 Hz, 6H), 1.35 （t, J = 7.1 Hz, 3H), 1.21 (d, J =
1
3
6
1
.2 Hz, 6H), 0.92 – 0.85 (m, 2H), −0.04 (s, 9H). C-NMR (CDCl , 100 MHz): δ 162.1 (C), 141.6 (CH, d, J =
3
4 Hz), 134.2 (C, d, J = 207 Hz), 121.7 (C, d, J = 15 Hz), 80.6 (CH ), 72.4 (CH, d, J = 5 Hz), 67.0 (CH ), 60.8
2
2
(
[
CH ), 24.1 (CH , d, J = 5 Hz), 23.7 (CH , d, J = 5 Hz), 18.0 (CH ), 14.4 (CH ), −1.3 (CH ). HRMS (ESI+):
2 3 3 2 3 3
+
M+Na] calculated for C H N NaO PSi: 457.1894. Found: 457.1896.
1
8
35
2
6
Ethyl 5-(ethoxy(phenyl)phosphoryl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate (4b).
Pyrazole 1a (263 mg, 0.734 mmol) and ethyl phenylphosphinate 2c (81 µL, 0.505 mmol) were reacted together
according to the general procedure. After 25 h, TLC showed full consumption of 2c. Purification by flash
column chromatography on silica gel (EtOAc/Toluene = 20:80) led to the desired product 4b as a pale yellow oil
(
65 mg, 0.148 mmol, 29% yield). IR (neat): υmax 2953, 2899, 1730, 1520, 1439, 1377, 1235, 1206, 1107, 1026,
1
9
7
4
3
62, 859, 749. H-NMR (CDCl , 400 MHz): δ 8.03–7.95 (m, 2H), 7.93 (d, J = 1.1 Hz, 1H), 7.51 (m, 1H),
3
.44−7.39 (m, 2H), 6.32 (d, J = 9.9 Hz, 1H), 5.78 (d, J = 9.9 Hz, 1H), 4.21 (m, 1H), 4.18 (q, J = 7.1 Hz, 2H),
.08 (m, 1H), 3.49 (ddd, J = 11.3, 9.6, 5.7 Hz, 1H), 3.39 (ddd, J = 11.3, 9.6, 5.7 Hz, 1H), 1.35 (t, J = 7.1 Hz,
H), 1.23 (t, J = 7.1 Hz, 3H), 0.81 (ddd, J = 13.8, 11.3, 5.7 Hz, 1H), 0.67 (ddd, J = 13.8, 11.3, 5.7 Hz, 1H), −0.09
1
3
(
(
9H). C-NMR (CDCl , 100 MHz): δ 162.0 (C), 141.3 (CH, d, J = 12 Hz), 135.1 (C, d, J = 138 Hz), 132.7
3
CH, d, J = 3 Hz), 131.8 (CH, d, J = 11 Hz), 130.9 (C, d, J = 156 Hz), 128.3 (CH, d, J = 15 Hz), 121.9 (C, d, J =
,
1
4 Hz), 81.1 (CH ), 66.8 (CH ), 62.2 (CH d, J = 6 Hz), 60.9 (CH ), 17.8 (CH ), 16.4 (CH , d, J = 7 Hz), 14.2
2
2
2
2
2
3
+
(
CH ), −1.4 (CH ). HRMS (ESI+): [M+H] calculated for C H N O PSi: 439.1813. Found: 439.1814.
3 3 20 32 2 5
1
8

ACCEPTED MANUSCRIPT
Ethyl 3-(ethoxy(phenyl)phosphoryl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate (4c).
Pyrazole 1b (109 mg, 0.312 mmol) and ethyl phenylphosphinate 2c (32 µL, 0.212 mmol) were reacted together
according to the general procedure. After 6 h at 70 °C, TLC showed that 2c was not fully consumed, so the
temperature was increased to 100 °C and the reaction mixture was stirred at this temperature for 15 h.
Purification by flash column chromatography on silica gel (EtOAc/PE = 10:90 to 100:0) led to the desired
product 4c as a pale yellow oil (23 mg, 0.052 mmol, 25% yield). IR (neat): υmax 2953, 2900, 1723, 1531, 1439,
1
1
1
7
0
220, 1125, 1080, 1027, 955, 858, 835, 773, 748, 723, 694. H-NMR (CDCl , 400 MHz): δ 8.14 (d, J = 1.4 Hz,
3
H), 7.87 (ddd, J = 13.3, 8.3, 1.2 Hz, 2H), 7.50 (m, 1H), 7.46−7.38 (m, 2H), 5.48 (s, 2H), 4.34−4.22 (pentapp, J =
.2 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 3.62−3.52 (m, 2H), 1.37 (t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H),
1
3
.94−0.86 (m, 2H), −0.03 (s, 9H). C-NMR (CDCl , 100 MHz): δ 161.6 (C), 145.6 (C, d, J = 164 Hz), 135.0
3
(
CH, d, J = 6 Hz), 132.2 (CH), 131.9 (CH, d, J = 11 Hz), 131.5 (C, d, J = 153 Hz), 128.2 (CH, d, J = 14 Hz),
1
20.1 (C, d, J = 19 Hz), 81.1 (CH ), 67.7 (CH ), 62.1 (CH , d, J = 6 Hz), 60.8 (CH ), 17.9 (CH ), 16.6 (CH , d, J
2 2 2 2 2 3
+
=
6 Hz), 14.2 (CH ), −1.3 (CH ). HRMS (ESI+): [M+Na] calculated for C H N NaO PSi: 461.1632. Found:
3 3 20 31 2 5
4
61.1634.
Ethyl
3-(diphenylphosphoryl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate
(4d).
Pyrazole 1b (105 mg, 0.301 mmol) and diphenyl phosphine oxide 2d (40 mg, 0.198 mmol) were reacted together
according to the general procedure. After 38 h at 70 °C, TLC showed that 2d was not fully consumed, so the
temperature was increased to 100 °C and the reaction mixture was stirred at this temperature for 48 h.
Purification by flash column chromatography on silica gel (EtOAc/CH Cl = 60:40 to 100:0) led to the desired
2
2
product 4d as a yellow solid (10 mg, 0.021 mmol, 11% yield).
IR (neat): υmax 2953, 1719, 1532, 1438, 1384, 1247, 1197, 1076, 835. H-NMR (CDCl , 400 MHz): δ H NMR
1
1
3
(
400 MHz, CDCl ) δ 8.24 (d, J = 0.9 Hz, 1H), 7.76–7.69 (m, 4H), 7.55 – 7.48 (m, 2H), 7.47 – 7.39 (m, 4H), 5.39
3
(
s, 2H), 4.03 (q, J = 7.1 Hz, 2H), 3.54 – 3.47 (m, 2H), 0.99 (t, J = 7.1 Hz, 3H), 0.91 – 0.84 (m, 2H),  0.04 (s,
1
3
9
H). C-NMR (CDCl , 100 MHz): 161.7 (C), 146.8 (C, d, J = 129 Hz), 135.4 (CH, d, J = 5 Hz), 132.8 (C, d, J
3
=
112 Hz), 131.8 (CH, d, J = 10 Hz), 131.7 (CH), 128.21 (CH, d, J = 13Hz), 120.9 (C, d, J = 16 Hz), 81.0 (CH2),
+
6
7.7 (CH ), 60.8 (CH ), 17.8 (CH ), 13.8 (CH ), −1.3 (CH ). HRMS (ESI+): [M+H] calculated for
2
2
2
3
3
C H N O PSi: 471.1863. Found: 471.1862.
2
5
31
2
4
Ethyl 3-(ethoxy(phenyl)phosphoryl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate (4e).
Pyrazole 1c (106 mg, 0.303 mmol) and ethyl phenylphosphinate 2c (32 µL, 0.202 mmol) were reacted together
1
9

ACCEPTED MANUSCRIPT
according to the general procedure. After 2 h at 70 °C, TLC showed full consumption of 2c. Purification by flash
column chromatography on silica gel (EtOAc/PE = 60:40 to 100:0) led to the desired product 4e as a grey oil (46
mg, 0.10 mmol, 52% yield). IR (neat): υmax 2980, 2953, 2900, 1728, 1305, 1236, 1124, 1096, 1080, 1027, 952,
1
8
58, 771. H-NMR (CDCl , 400 MHz): δ 7.94−7.88 (m, 2H), 7.53 (m, 1H), 7.49−7.41 (m, 2H), 7.37 (d, J = 1.2
3
Hz, 1H), 5.90 (d, J = 10.2 Hz, 1H), 5.87 (d, J = 10.2 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 4.21−4.11 (m, 2H),
13
3
.55−3.51 (m, 2H), 1.38 (t, J = 7.2 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H), 0.86−0.82 (m, 2H), −0.10 (s, 9H). C-
NMR (CDCl , 100 MHz): δ 158.9 (C), 144.8 (C, d, J = 171 Hz), 134.0 (C, d, J = 8.1 Hz), 132.6 (CH, d, J = 3
3
Hz), 131.8 (CH, d, J = 10 Hz), 130.9 (C, d, J = 146 Hz), 128.6 (CH, d, J = 14 Hz), 118.2 (CH, d, J = 20 Hz),
8
0.2 (CH ), 67.2 (CH ), 61.9 (CH , d, J = 6 Hz), 61.7 (CH ), 17.8 (CH ), 16.6 (CH , d, J = 7 Hz), 14.3 (CH ),
2
2
2
2
2
3
3
+
−
1.4 (CH ). HRMS (ESI+): [M+Na] calculated for C H N NaO PSi: 461.1632. Found: 461.1636.
3 20 31 2 5
Ethyl
3-(diphenylphosphoryl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate
(4f).
Pyrazole 1c (125 mg, 0.359 mmol) and diphenylphosphine oxide 2d (48 mg, 0.238 mmol) were reacted together
according to the general procedure. After 6 h, TLC showed full consumption of 2d. Purification by flash column
chromatography on silica gel (EtOAc/PE = 50:50) led to the desired product 4f as a yellow oil (54 mg, 0.11
1
mmol, 48% yield). IR (neat): υmax 2952, 1727, 1438, 1303, 1244, 1201, 1120, 1094, 1079, 857, 748. H-NMR
(
CDCl , 400 MHz): δ 7.85−7.76 (m, 4H), 7.57-7.50 (m, 2H), 7.49−7.42 (m, 5H), 5.90 (s, 2H), 4.35 (q, J = 7.1
3
13
Hz, 2H), 3.56−3.52 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H), 0.88−0.84 (m, 2H), −0.09 (s, 9H). C-NMR (CDCl , 100
3
MHz): δ 159.0 (C), 145.9 (C, d, J = 132 Hz), 134.1 (C, d, J = 7 Hz), 132.5 (C, d, J = 109 Hz), 132.2 (CH, d, J =
3
6
4
Hz), 131.8 (CH, d, J = 10 Hz), 128.6 (CH, d, J = 13 Hz), 118.6 (CH, d, J = 18 Hz), 80.2 (CH ), 67.3 (CH ),
2 2
+
1.7 (CH ), 17.8 (CH ), 14.3 (CH ), −1.4 (CH ). HRMS (ESI+): [M+Na] calculated for C H N NaO PSi:
2
2
3
3
24 31
2
4
93.1683. Found: 493.1684.
(3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)phosphonate
Diethyl
(7a).
Pyrazole 5 (330 mg, 0.956 mmol) and diethyl phosphite 2a (81 µL, 0.633 mmol) were reacted together
according to the general procedure. After 3 h, TLC showed full consumption of 2a. Purification by flash column
chromatography on silica gel (EtOAc/toluene = 20:80) led to the desired product 7a as a yellow oil (212 mg,
0
1
3
.527 mmol, 83% yield). IR (neat): υmax 2984, 2955, 2902, 1530, 1456, 1370, 1252, 1210, 1171, 1133, 1092,
1
017, 973, 835, 756. H-NMR (CDCl , 400 MHz): 7.01 (d, J = 2.4 Hz, 1H), 5.73 (s, 2H), 4.29–4.10 (m, 4H),
3
13
.68–3.60 (m, 2H), 1.37 (td, J = 7.1, 0.6 Hz, 6H), 0.93–0.84 (m, 2H), −0.02 (s, 9H). C-NMR (CDCl , 100
3
MHz): δ 142.3 (C, qd, J = 39, 17 Hz), 134.0 (C, d, J = 214 Hz), 120.8 (C, q, J = 269 Hz), 113.9 (CH, ddapp, J =
2
0

ACCEPTED MANUSCRIPT
1
8, 2 Hz), 80.3 (CH ), 67.4 (CH ), 63.5 (CH , d, J = 6 Hz), 17.8 (CH ), 16.3 (CH , d, J = 7 Hz), −1.5 (CH ).
2
2
2
2
3
3
+
HRMS (ESI+): [M+Na] calculated for C H F N NaO PSi: 425.1244. Found: 425.1243.
1
4
26
3
2
4
Ethyl phenyl(3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)phosphinate (7b).
Pyrazole 5 (112 mg, 0.324 mmol) and ethyl phenylphosphinate 2c (35 µL, 0.218 mmol) were reacted together
according to the general procedure. After 9 h, TLC showed full consumption of 2c. Purification by flash column
chromatography on silica gel (Et O/toluene = 35:65) led to the desired product 7b as a yellow oil (85 mg, 0.20
2
mmol, 90% yield). IR (neat): υmax 2954, 2901, 1527, 1440, 1240, 1209, 1170, 1128, 1091, 1023, 974, 834, 693.
1
H-NMR (CDCl , 400 MHz): δ 7.89−7.78 (m, 2H), 7.58 (m, 1H), 7.53−7.44 (m, 2H), 6.91 (d, J = 2.0 Hz, 1H),
3
5
3
1
.91 (d, J = 10.3 Hz, 1H), 5.61 (d, J = 10.3 Hz, 1H), 4.27−4.11 (m, 2H), 3.41 (ddd, J = 11.1, 9.7, 5.8 Hz, 1H),
.30 (ddd, J = 11.2, 9.7, 5.6 Hz, 1H), 1.40 (t, J =7.1, 3H), 0.68 (ddd, J = 13.8, 11.2, 5.8 Hz, 1H), 0.52 (ddd, J =
1
3
3.8, 11.1, 5.6 Hz, 1H), −0.11 (s, 9H). C-NMR (CDCl , 100 MHz): δ 142.2 (C, qd, J = 39, 14 Hz), 136.8 (C,
3
d, J = 150 Hz), 133.1 (CH, d, J = 3 Hz), 131.9 (CH, d, J = 11 Hz), 130.1 (C, d, J = 150 Hz), 128.9 (CH, d, J = 14
Hz), 120.9 (C, q, J = 269 Hz), 113.5 (CH, d, J = 18 Hz), 80.5 (CH ), 67.0 (CH ), 62.4 (CH , d, J = 6 Hz), 17.5
2
2
2
+
(
CH ), 16.6 (CH , d, J = 7 Hz), −1.5 (CH ). HRMS (ESI+): [M+Na] calculated for C H F N NaO PSi:
2 3 3 18 26 3 2 3
4
57.1295. Found: 457.1298.
Diphenyl(3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)phosphine oxide (7c).
Pyrazole 5 (132 mg, 0.384 mmol) and diphenylphosphine oxide 2d (52 mg, 0.255 mmol) were reacted together
according to the general procedure. After 9 h, TLC showed full consumption of 2d. Purification by flash column
chromatography on silica gel (Et O/toluene = 30:70) led to the desired product 7c as a yellow oil (68 mg, 0.15
2
1
mmol, 57% yield). IR (neat): υmax 2953, 2897, 1526, 1438, 1249, 1208, 1170, 1120, 973, 834, 693. H-NMR
(
CDCl , 400 MHz): δ 7.71−7.63 (m, 4H), 7.66−7.55 (m, 2H), 7.53−7.46 (m, 4H), 6.35 (d, J = 2.1 Hz, 1H), 5.78
3
13
(
s, 2H), 3.30−3.26 (m, 2H), 0.48−0.43 (m, 2H), −0.14 (s, 9H). C-NMR (CDCl , 100 MHz): δ 141.9 (C, qd, J =
3
3
1
9, 13 Hz), 137.6 (C, d, J = 108 Hz), 132.9 (CH, broad), 131.7 (CH, d, J = 11 Hz), 131.0 (C, d, J = 112 Hz),
28.9 (CH, d, J = 13 Hz), 120.8 (C, q, J = 269 Hz), 114.4 (CH, d, J = 16 Hz), 80.8 (CH ), 66.9 (CH ), 17.3
2
2
+
(
CH ), −1.6 (CH ). HRMS (ESI+): [M+Na] calculated for C H F N NaO PSi: 489.1346. Found: 489.1347.
2 3 22 26 3 2 2
Cyclopropyl(phenyl)(3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)phosphine
oxide (7d) Pyrazole 5 (101 mg, 0.293 mmol) and cyclopropylphenylphosphine oxide 2e (35 mg, 0.211 mmol)
were reacted together according to the general procedure. After 23 h, TLC showed full consumption of 2e.
Purification by flash column chromatography on silica gel (Et O/toluene = 35:65) led to the desired product 7d
2
as a yellow oil (43 mg, 0.10 mmol, 47% yield). IR (neat): υmax 2953, 2916, 1528, 1249, 1216, 1172, 1123, 1106,
2
1

ACCEPTED MANUSCRIPT
1
1
6
1
1
1
1
087, 973, 932, 895, 763. H-NMR (CDCl , 400 MHz): δ 7.76−7.70 (m, 2H), 7.57 (m, 1H), 7.52−7.47 (m, 2H),
3
.91 (d, J = 1.8 Hz, 1H), 5.75 (d, J = 10.4 Hz, 1H), 5.58 (d, J = 10.4 Hz, 1H), 3.40 (ddd, J = 11.1, 9.6, 5.9 Hz,
H), 3.30 (ddd, J = 11.1, 9.6, 5.6 Hz, 1H), 1.38 (m, 1H), 1.18−0.95 (m, 4H), 0.64 (ddd, J = 13.8, 11.1, 5.9 Hz,
13
H), 0.51 (ddd, J = 13.8, 11.1, 5.6 Hz, 1H), −0.11 (s, 9H). C-NMR (CDCl , 100 MHz): δ 142.2 (C, qd, J = 39,
3
3 Hz), 138.6 (C, d, J = 106 Hz), 132.6 (CH, d, J = 3 Hz), 131.8 (C, d, J = 112 Hz), 130.9 (CH, d, J = 10 Hz),
28.9 (CH, d, J = 13 Hz), 121.0 (C, q, J = 269 Hz), 112.8 (CH, d, J = 14 Hz), 80.5 (CH ), 67.0 (CH ), 17.5
2
2
(
[
CH ), 8.3 (CH, d, J = 112 Hz), 3.7 (CH , d, J = 5 Hz), 3.4 (CH , d, J = 4 Hz), −1.5 (CH ). HRMS (ESI+):
2 2 2 3
+
M+Na] calculated for C H F N NaO PSi: 453.1346. Found: 453.1347.
1
9
26
3
2
2
Diethyl (5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)phosphonate (8a). Pyrazole 6 (101
mg, 0.293 mmol) and diethyl phosphite 2a (36 µL, 0.282 mmol) were reacted together according to the general
procedure. After 5 h, TLC showed full consumption of 2a. Purification by flash column chromatography on
silica gel (EtOAc/PE = 10:100 to 100:0) led to the desired product 8a as an orange oil (82 mg, 0.23 mmol, 81%
1
yield). IR (neat): υmax 2983, 2954, 2901, 2240, 1393, 1299, 1249, 1095, 1051, 1019, 972, 858, 835, 762. H-
NMR (Acetone-d6, 400 MHz): δ 7.49 (d, J = 1.5 Hz, 1H), 5.76 (s, 2H), 4.23−4.07 (m, 4H), 3.72−3.65 (m, 2H),
13
1
.30 (td, J = 7.1, 0.5 Hz, 6H), 0.97−0.90 (m, 2H), −0.02 (s, 9H). C-NMR (Acetone-d6, 100 MHz): δ 144.7 (C,
d, J = 230 Hz), 121.1 (CH, d, J = 23 Hz), 116.9 (C, d, J = 11 Hz), 110.3 (C), 81.2 (CH ), 68.2 (CH ), 63.4 (CH ,
2
2
2
+
d, J = 6 Hz), 18.1 (CH ), 16.6 (CH , d, J = 6 Hz), −1.4 (CH ). HRMS (ESI+): [M+Na] calculated for
2
3
3
C H N NaO PSi: 382.1322. Found: 382.1326.
1
4
26
3
4
Ethyl (5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)(phenyl)phosphinate (8b) Pyrazole 6
123 mg, 0.409 mmol) and ethyl phenylphosphinate 2c (44 µL, 0.273 mmol) were reacted together according to
(
the general procedure. After 5 h, TLC showed full consumption of 2c. Purification by flash column
chromatography on silica gel (EtOAc/PE = 10:100 to 100:0) led to the desired product 8b as a yellow oil (80 mg,
0
.20 mmol, 75% yield). IR (neat): υmax 2953, 2899, 2239, 1439, 1297, 1234, 1124, 1093, 1025, 953, 858, 751.
1
H-NMR (CDCl , 400 MHz): δ 7.93−7.86 (m, 2H), 7.56 (m, 1H), 7.51−7.43 (m, 2H), 7.31 (d, J = 1.2 Hz, 1H),
3
5
.63 (s, 2H), 4.23−4.09 (m, 2H), 3.61−3.53 (m, 2H), 1.37 (t, J = 7.1 Hz, 3H), 0.94−0.84 (m, 2H), −0.07 (s, 9H).
1
3
C-NMR (CDCl , 100 MHz): δ 146.9 (C, d, J = 169 Hz), 133.0 (CH, d, J = 3 Hz), 131.9 (CH, d, J = 10 Hz),
3
1
8
30.1 (C, d, J = 145 Hz), 128.8 (CH, d, J = 14 Hz), 120.3 (CH, d, J = 20 Hz), 116.2 (C, d, J = 9 Hz), 109.5 (C),
0.4 (CH ), 68.1 (CH ), 62.1 (CH , d, J = 6 Hz), 17.7 (CH ), 16.6 (CH , d, J = 6 Hz), −1.4 (CH ). HRMS
2
2
2
2
3
3
+
(
ESI+): [M+Na] calculated for C H N NaO PSi: 414.1373. Found: 414.1376.
18 26 3 3
2
2

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3
-(Diphenylphosphoryl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile (8c). Pyrazole 6
(
117 mg, 0.388 mmol) and diphenylphosphine oxide 2d (52 mg, 0.258 mmol) were reacted together according to
the general procedure. After 23 h, TLC showed full consumption of 2d. Purification by flash column
chromatography on silica gel (EtOAc/PE = 10:100 to 100:0) led to the desired product 8c as a yellow oil (63 mg,
0
.15 mmol, 58% yield). IR (neat): υmax 2952, 2896, 2238, 1438, 1296, 1248, 1200, 1118, 1093, 980, 834, 752.
1
H-NMR (CDCl , 400 MHz): δ 7.82−7.73 (m, 4H), 7.60−7.52 (m, 2H), 7.50−7.43 (m, 4H), 7.37 (d, J = 1.5 Hz,
3
13
1
H), 5.64 (s, 2H), 3.65−3.50 (m, 2H), 0.98−0.76 (m, 2H), −0.06 (s, 9H). C-NMR (CDCl , 100 MHz): δ 148.2
3
(
C, d, J = 129 Hz), 132.5 (CH, d, J = 3 Hz), 131.758 (CH, d, J = 10 Hz), 131.755 (C, d, J = 109 Hz), 128.7 (CH,
d, J = 13 Hz), 120.9 (CH, d, J = 18 Hz), 116.4 (C, d, J = 8 Hz), 109.5 (C), 80.4 (CH ), 68.1 (CH ), 17.7 (CH ),
2
2
2
+
−
1.4 (CH ). HRMS (ESI+): [M+Na] calculated for C H N NaO PSi: 446.1424. Found: 446.1426.
3 22 26 3 2
Associated Content
1
13
The H and C NMR for compounds 1a−f, 2e, 3a−e, 4a−f, 5, 6 , 7a−d and 8a−c are provided in the supporting
information. This material is available free of charge via the internet at http://www.sciencedirect.com.
Author Information
E-mail: janine.cossy@espci.fr. Fax: (+33)140794660. Tel: (+33)140794429.
Acknowledgments
Financial support and a PhD grant (G.T.) from Bayer S.A.S. is gratefully acknowledged.
1
Van Gaal, L. F.; Rissanen, A. M.; Scheen, A. J.; Ziegler, O.; Rössner, S. Lancet 2005, 365,
1
389.
2
Terçariol, P. R. G.; Godinho, A. F. Pest. Biochem. Physiol. 2011, 99, 221.
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Terrett, N. K.; Bell, A. S.; Brown, D.; Ellis, P. Bioorg. Med. Chem. Lett. 1996, 6, 1819.
Dorlars, A.; Schellhammer, C.-W.; Schroeder, J. Angew. Chem. Int. Ed. 1975, 14, 665.
Catalán, J.; Fabero, F.; Claramunt, R. M.; Santa Maria, M. D.; Foces-Foces, M. C.;
3
4
5
6
Hernández Cano, F.; Martínez-Ripoll, M.; Elguero, J.; Sastre, R. J. Am. Chem. Soc. 1992,
1
14, 5039.
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Olguín, J.; Brooker, S. Coord. Chem. Rev. 2011, 255, 203.
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Westheimer, F. H. Science 1987, 235, 1173.
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9
1
0
a) Ali, T. E.; Abdel-Kariem, S. M. Heterocycles 2012, 85, 2073. and references cited
therein. b) Conti, P.; Pinto, A.; Tamborini, L.; Rizzo, V.; De Micheli, C. Tetrahedron 2007,
6
3, 5554.
1
1
For seminal reports by Hirao, see: a) Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T.;
Tetrahedron Lett. 1980, 21, 3595. b) Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T.;
Synthesis 1981, 56. c) Hirao, T.; Masunaga, T.; Yamada, N.; Ohshiro, Y.; Agawa, T.; Bull.
Chem. Soc. Jpn. 1982, 53, 909.
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a) Kalek, M.; Stawinski, J. Organometallics 2007, 26, 5840. b) Kalek, M.; Jezowska, M.;
Stawinski, J. Adv. Synth. Catal. 2009, 351, 3207.
1
3
Tran, G.; Gomez Pardo, D.; Tsuchiya, T.; Hillebrand, S.; Vors, J.-P.; Cossy, J. Org. Lett.,
013, 15, 5550.
2
1
4
a) Kohler, M. C.; Grimes, T. V.; Wang, X.; Cundari, T. R.; Stockland, R. A.
Organometallics 2009, 28, 1193. and references therein. b) Han, L. B.; Mirzaei, F.; Zhao, C.
Q.; Tanaka, M. J. Am. Chem. Soc. 2000, 122, 5407. c) Deprele, S.; Montchamp, J. L. J. Am.
Chem. Soc. 2002, 124, 9386. d) Berger, O.; Petit, C.; Deal, E. L.; Montchamp, J.-L. Adv.
Synth. Catal. 2013, 355, 1361.
1
1
5
6
Fugina, N.; Holzer, W.; Wasicky, M. Heterocycles 1992, 34, 303.
Despotopoulou, C.; Klier, L.; Knochel, P. Org. Lett. 2009, 11, 3326.
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Palladium-Catalyzed Phosphonylation of
Substituted Pyrazoles
a
a
b
b
b
Qi Huang, Gaël Tran, Tomoki Tsuchiya, Jean-Pierre Vors, Stefan Hillebrand,
a
*a
Domingo Gomez Pardo and Janine Cossy
a
Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI),
ESPCI ParisTech, UMR 8231, PSL Research University
1
0 rue Vauquelin, 75231 Paris Cedex 05, France
janine.cossy@espci.fr
b
Bayer S.A.S.-CRLD,
1
4, impasse Pierre Baizet, CS 99163, 69263 Lyon Cedex 09, France
Supporting Information
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