A study of Negishi cross-coupling reactions with benzylzinc halides to prepare original 3-ethoxypyrazoles

Article abstract of DOI:10.1055/s-0034-1379458

The Negishi palladium-catalyzed cross-coupling reaction between 3-ethoxy-4-iodo-1H-pyrazole and various benzylzinc halides was extensively studied. Using simplified, robust, and optimized reaction conditions, a series of electron-poor benzylzinc halides w

Full text of DOI:10.1055/s-0034-1379458

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 511–516
paper
511
E. P. Coutant, Y. L. Janin
Paper
Synthesis
A Study of Negishi Cross-Coupling Reactions with Benzylzinc
Halides To Prepare Original 3-Ethoxypyrazoles
Eloi P. Coutanta,b
Yves L. Janin*a,b
HN
N
HN
N
Negishi
reaction
HN
N
iodination
56–71%
OEt
I
OEt
OEt
50–81%
a Unité de Chimie et Biocatalyse, Département de Biologie
Structurale et Chimie, Institut Pasteur, 28 rue du Dr. Roux,
I
Ar
Ar
75724 Paris Cedex 15, France
yves.janin@pasteur.fr
+
3
3
1
(4
)
5
6
8
6
4
0
4
Ar = Ph, 2-ClC6H4, 3-ClC6H4, 4-ClC6H4, 2,4-Cl2C6H3, 3,4-Cl2C6H3
b Unité Mixte de Recherche 3523, Centre National de la
Recherche Scientifique, 28 rue du Dr. Roux, 75724 Paris Cedex
15, France
HN
N
Received: 01.10.2014
Accepted after revision: 24.10.2014
Published online: 21.11.2014
Negishi
reaction
ZnX
X
Zn
OEt
HN
+
DOI: 10.1055/s-0034-1379458; Art ID: ss-2014-z0604-op
Ar
Ar
I
1
2a–f
3
Abstract The Negishi palladium-catalyzed cross-coupling reaction be-
tween 3-ethoxy-4-iodo-1H-pyrazole and various benzylzinc halides was
extensively studied. Using simplified, robust, and optimized reaction
conditions, a series of electron-poor benzylzinc halides were prepared
and used to synthesize 4-benzyl-3-ethoxy-1H-pyrazoles derivatives.
From these, iodination on C5 of the pyrazole nucleus led to the corre-
sponding 4-benzyl-3-ethoxy-5-iodo-1H-pyrazoles, these are original
building blocks for the preparation of libraries of new chemical entities.
HN
N
N
I
OEt
OEt
NIS
Ar
Ar
4a–f
5a–f
Key words cross-coupling, heterocycles, palladium, zinc, benzylation
Ar = a Ph, b 2-ClC6H4, c 3-ClC6H4,
d 4-ClC6H4, e 2,4-Cl2C6H3, f 3,4-Cl2C6H3
Scheme 1 General synthetic pathway used
Over the course of the past decade, we have worked on
the design and optimization of synthetic accesses to new
chemical entities featuring an alkoxypyrazole component.
This has led us to report on many aspects of alkoxypyrazole
chemistry,1–9 and all the prepared compounds have been
assayed in our research facilities during the course of
screening campaigns against a number of infectious diseas-
es. In a few cases, the results of these screenings led us to
undertake additional iterations of synthesis and biological
evaluation. We wish to report here our efforts to use the
pathway depicted in Scheme 1 to prepare a set of 4-benzyl-
3-ethoxy-5-iodo-1H-pyrazoles 5a–f as building blocks for
the synthesis of chemical libraries of potential biological in-
terest.
A major improvement in the achievement of a repro-
ducible zinc insertion into a benzyl halide bond has been
the combined use of zinc dust, a solution of dry lithium
chloride in tetrahydrofuran, and two activation stages with
the successive addition of small amount of 1,2-dibro-
moethane and chlorotrimethylsilane before the addition of
the halogenated substrate.12–16 All these ‘tricks’, along with
hydrochloric acid treatment of the zinc, have previously
been used separately or in partial combination. Early re-
ports pointed out the benefit of using 1,2-dibromoethane17–19
or chlorotrimethylsilane20,21 for improving various reac-
tions and it has been reported that the latter reagent is not
only instrumental in removing the zinc-passivating layer
present on the surface of the metal but also in suppressing
the effect of lead traces present in the zinc used.22 The suc-
cessive addition of 1,2-dibromoethane and chlorotrimeth-
ylsilane to powdered zinc was then reported for its
activation.23,24 Additionally, the generation of the highly ac-
tive Rieke zinc25–28 by the reduction of zinc chloride with
lithium is also an excellent method for the preparation of a
The synthetic path chosen involved a Negishi10,11 car-
bon–carbon cross-coupling reaction between benzylzinc
halides 2a–f, prepared from the corresponding benzyl ha-
lides 1a–f, and the readily available 3-ethoxy-4-iodo-1H-
pyrazole (3)5 to give the 4-benzyl derivatives 4a–f. However,
it quickly became apparent that full studies of the zinc in-
sertion reaction as well as the Negishi cross-coupling step
were required.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 511–516

512
E. P. Coutant, Y. L. Janin
Paper
Synthesis
tetrahydrofuran suspension of finely divided zinc contain-
ing two equivalents of lithium chloride. The importance of
lithium chloride has been investigated and, based on mass
spectroscopy and NMR, a recent report describes the occur-
rence of lithium organozincate complexes LiRZnX2, which
provides an explanation for the improvement in the prepa-
ration and reactivity of organozinc halides.29
coupling step, few side compounds were observed. Along
with volatile 3-chlorotoluene, the expected reduced pyra-
zole 6 occurred in varying amounts. This is either due to the
acidic workup of the reaction in the presence of zinc, lead-
ing to a reduction of 3, or to the fact that, in the presence of
hydrochloric acid, such 4-iodopyrazoles are reduced, along
with the occurrence of iodine and/or iodine monochloride,
as we have previously reported.4 This observation was put
to good use as such treatment allows the removal of the
side products 3 and 6 from the reaction mixture prior to
chromatography. The bibenzyl derivative 7 was also expect-
ed as a side product due to the excess of benzylzinc chloride
In our hands, the preparation of benzylzinc bromide
(2a) was fairly permissive and robust (flame-dried inacti-
vated technical powdered Zn and LiCl, anhydrous THF, stir-
ring, 4 °C, 1 h). With a three-equivalent excess, this
benzylzinc bromide solution, along with a 1:2 premixed
mixture of palladium(II) acetate and 2-dicyclohexylphos-
phino-2',4',6'-triisopropylbiphenyl (XPhos) as the pre-cata-
lyst and heating at 50 °C for three hours, was used for the
Negishi cross-coupling reaction with 3-ethoxy-4-iodo-1H-
pyrazole (3). These conditions led to compound 4a in 70%
isolated yield. Interestingly, the use of PdCl2(dppf) at 50 °C
was not efficient and at 80 °C, only a 49% yield of compound
4a could be isolated. However, when applied to the prepa-
ration of compound 4b–f, these so far optimized conditions
generally failed. Accordingly, in order to prepare the ben-
zylzinc chlorides 2b–f efficiently, we adapted previously re-
ported conditions30–32 to the specific cases of the electron-
poor benzyl chlorides 1b–f, and compound 1c was selected
as a model substrate. Since optimizing the consecutive reac-
tion steps was a task with too many variables, first the
preparation of 3-chlorobenzylzinc chloride (2c) was stud-
ied and extensive use was made of a reported33 organozinc
halide iodometric titration to establish the yield of 2c, next
the ensuing Negishi cross-coupling step using 2c leading to
compound 4c was studied (Scheme 2). We found that this
titration method is impervious to the presence of zinc dust
in suspension in the samples titrated, even if the zinc has
undergone the various activation processes described be-
low. It appears that the expected discoloration of the iodine
solution by zinc alone is probably taking place so slowly
that it does not interfere with the titration of the organoz-
inc derivatives. After many experiments, we established
that, in contrast to the preparation of 2a, the preparation of
2c required the use of zinc dust, with an average size small-
er than 10 μm, in anhydrous tetrahydrofuran containing
flame-dried lithium chloride, and the two-stage activation
process (1,2-dibromoethane and chlorotrimethylsilane) fol-
lowed by heating the suspension at 70 °C for one hour. Re-
peated titration of the resulting mixture indicated yields
between 87–90% starting from benzyl chloride 1c. Interest-
ingly, higher titers (96–100%) of 3-chlorobenzylzinc chlo-
ride (2c) were always obtained when the zinc powder was
also flame-dried in the presence of the lithium chloride. At-
tempts to use coarser powdered zinc were less efficient.
Omitting the lithium chloride gave a lower yield, whereas
the two-stage activation process with chlorotrimethylsi-
lane and 1,2-dibromoethane was mandatory. In the course
of the study of the ensuing Negishi carbon–carbon cross-
1
added, H NMR and LC/MS analysis of the crude reaction
mixtures also showed the much less expected occurrence of
polybenzylated materials such as compound 8 (m/z =
327/329) and 9 (m/z = 417/419), which we could not prop-
erly purify. Since such side compounds are due to a palladi-
um insertion into a carbon–chlorine bond, we focused on
limiting the amount of benzylzinc halide, altering the na-
ture of the palladium ligands and/or the temperature of this
reaction. Trials with varying amounts of 3-chlorobenzylzinc
chloride (2c) indicated that two equivalents were optimum,
as some unreacted compound 3 was observed below this
amount. Higher quantities of 2c (3 equiv) led to more poly-
benzylated products. Of interest is the fact that adding
more 3-chlorobenzyl chloride (1c) in a coupling trial did
not result in an increase of the amount of polybenzylated
material but led to a sharp increase in the quantity of the
bibenzyl derivative 7. One of the most important observa-
tions, which came out of a rather long series of experi-
ments, was that the palladium-catalyzed cross-coupling
reactions leading to the polybenzylated products 8 and 9
took place even when some 4-iodopyrazole 3 was still pres-
ent in the reaction mixture. During experiments with
triphenylphosphine as the palladium ligand, it was neces-
sary to heat the reaction mixture to at least 50 °C for some
carbon–carbon coupling to proceed. On the other hand, the
use of XPhos as the ligand allowed us to lower the reaction
temperature: the coupling reaction proceeded well with 2%
of catalyst at 4 °C, but the reaction required three days.
Even if this low temperature led to a slightly lower amount
of the polybenzylated material, running the reaction at
room temperature for 24 hours with a 2% catalyst loading
was considered optimal and thus selected.
As shown in Table 1, we then used these conditions for
the synthesis of compounds 4b and 4d–f. As for the prepa-
ration of 2c, the benzylzinc chloride titer was always im-
proved when both the lithium chloride, and then the
mixture of zinc powder and lithium chloride were flame-
dried. From 2b and 2d, we then obtained acceptable yields
of the 4-benzyl derivatives 4b and 4d. However, two addi-
tional difficulties arose in the case of the preparation of
compounds 4e and 4f. First, despite initial experiments at
various temperatures, the reaction never reached comple-
tion as 4-iodopyrazole 3 was observed in the crude reaction
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 511–516

513
E. P. Coutant, Y. L. Janin
Paper
Synthesis
R
HN
N
Accordingly, and as depicted in Scheme 3, in a final at-
tempt to avoid the polybenzylation reaction in the case of
the preparation of compound 4f, we prepared the N-pro-
tected 4-iodopyrazole 10. This compound was then coupled
with a single equivalent of the 3,4-dichlorobenzylzinc chlo-
ride 2f at 50 °C and, following treatment with hydrochloric
acid to cleave the ethoxyethyl protecting group, this led to
the isolation of compound 4f in 63% yield containing less
than 3% of polybenzylated material. This experiment also
demonstrated that the free NH of the 4-iodopyrazole 3 is
the reason behind the requirement for two equivalents of
benzylzinc chloride in the Negishi reaction.
HN
N
Cl
ii
OEt
OEt
+
Cl
I
3
4c
1c R = Cl
2c R = ZnCl
i
HN
N
Cl
OEt
HN
N
Cl
( )n
OEt
+
+
8 n = 1
9 n = 2
6
7
HN
N
ZnCl
EtO
N
N
OEt
Cl
Cl
Cl
i, ii
Scheme 2 Reagents and conditions: (i) Zn powder (<10 μm, 2 equiv),
LiCl (2 equiv), THF, (activation by 1,2-dibromoethane and TMSCl), mi-
crowaves, 70 °C, 1 h; (ii) Pd(OAc)2–XPhos (1:2, 0.02 equiv), THF, r.t., 24 h.
+
OEt
Cl
Cl
63%
I
10
2f
4f
product in both cases. This led us to treat the reaction prod-
ucts with concentrated hydrochloric acid, to remove the
unreacted 4-iodopyrazole 3, before chromatography. More-
over, we observed the occurrence of greater quantities of
polybenzylated material in these two cases and although
we could isolate pure 4-benzyl derivative 4e in 50% yield, all
our purification attempts were unsuccessful in the case of
compound 4f.
HN
N
HN
N
iii
56–71%
I
OEt
OEt
Ar
Ar
4a–f
5a–f
Ar = a Ph, b 2-ClC6H4, c 3-ClC6H4,
d 4-ClC6H4, e 2,4-Cl2C6H3, f 3,4-Cl2C6H3
Scheme 3 Reagents and conditions: (i) Pd(OAc)2–XPhos (1:2, 0.02
equiv), THF, 50 °C, 3 h; (ii) 33% HCl; (iii) NIS (1.05 equiv), 1,2-dichlo-
roethane, reflux.
Table 1 Preparation of Compounds 4a–fa
HN
N
HN
N
X
ZnX
i
ii
OEt
OEt
+
Ar
Ar
Finally, compounds 4a–f were treated with N-iodosuc-
cinimide in refluxing dichloroethane to give smoothly,
without unexpected difficulties, the 5-iodinated building
blocks 5a–f in 56–71% yields.
I
Ar
1a–f
2a–f
3
4a–f
Product
X
Ar
Yield (%)
In conclusion, we hope that this unplanned, but neces-
sary, study of the Negishi coupling reaction to access 4-ben-
zylpyrazoles 4a–f is of more general interest, especially
since we avoided the use of a glove box or Schlenk appara-
tus when preparing the solutions of benzylzinc halides 2a–
f. In our experience, the iodometric titration was essential;
it allowed the determination of the amount of benzylzinc
chloride and thus reduced the multiplicity of factors in-
volved in the optimization of these syntheses. Interestingly,
an efficient palladium/ligand system was necessary for the
4-benzylation of 3-ethoxy-4-iodo-1H-pyrazole (3) to give
the chlorinated derivatives 4a–f, but this efficiency also re-
sulted in the undesired palladium insertion reaction into
the aryl chloride bond. To overcome this problem, we ex-
plored the lower limits of the reaction parameters, and a
room temperature reaction over one day was selected in
most cases. Following this study, we prepared the 5-iodin-
2b
2c
4d
70f
e
2a, 4a
2b, 4b
2c, 4c
2d, 4d
2e, 4e
2f, 4f
Br
Cl
Cl
Cl
Cl
Cl
Ph
–
88
100
96
98
96
95
2-ClC6H4
3-ClC6H4
4-ClC6H4
89
85
83
78
83
67
81
71
50
2,4-Cl2C6H3
3,4-Cl2C6H3
g
–
a Reaction conditions: 2a: (i) Zn powder (2 equiv), LiCl (2.5 equiv), THF, 4
°C, 1 h; (ii) Pd(OAc)2–XPhos (1:2, 0.02 equiv), THF, 50 °C, 3 h; 2b–f: (i) Zn
powder (<10 μm, 2 equiv), LiCl (2 equiv), THF, (activation by 1,2-dibro-
moethane and TMSCl), microwaves, 70 °C, 1 h; (ii) Pd(OAc)2–XPhos (1:2,
0.02 equiv), THF, r.t., 24 h.
b Determined by titration; no Zn drying.
c Determined by titration; with Zn drying.
d Using the flame-dried Zn for 2b–f.
e Not determined.
f From BnZnBr (3 equiv).
g Not isolated.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 511–516

514
E. P. Coutant, Y. L. Janin
Paper
Synthesis
ated building blocks 5a–f and we will report their transfor-
mations into chemical libraries of biological interest in due
course.
cated a titer of 3-chlorobenzylzinc chloride (2c) of 0.89 M (0.92 M
expected, 96% yield). Note: heating the reaction flask at 60 °C using an
oil bath (under an inert atmosphere) instead of a microwave oven for
the entire procedure did not lead to a significant change in the titer of
the solution. By following this procedure (or the one omitting flame-
drying the zinc) solutions of benzylzinc chloride 2b–f were obtained
with the titers listed in Table 1.
Reactions using microwave heating used a Biotage initiator 2 micro-
wave oven. 1H and 13C NMR spectra were recorded on a Bruker Avance
400 spectrometer at 400 MHz and 100 MHz, respectively, referenced
to TMS. Column chromatography was performed either on Merck sili-
ca gel 60 (0.035–0.070 mm) or neutral alumina using a solvent pump
and an automated collecting system driven by a UV detector set to
254 nm unless required otherwise. Sample deposition was carried
out by absorption of the mixture to be purified on a small amount of
the solid phase followed by its deposition on the top of the column.
LR-MS were obtained on an Agilent 1100 series LC/MSD system using
an atmospheric electrospray ionization system and HRMS were ob-
tained using a Waters Micromass Q-Tof with an electrospray ion
source. Anhyd THF used was purchased commercially. Note: some of
the 1H signals of the compounds described here are concentration de-
pendent (not only the broad pyrazole NH signal but also the OCH2CH3
signals).
4-(3-Chlorobenzyl)-3-ethoxy-1H-pyrazole (4c); Typical Procedure
for 4b–e
3-Ethoxy-4-iodo-1H-pyrazole (3, 0.53 g, 2.23 mmol, 1 equiv) and pre-
mixed Pd(OAc)2 and XPhos (1:2, 53 mg, 45 μmol, 0.02 equiv) were
dissolved in anhyd THF (5 mL) in an argon-flushed microwave reac-
tion vial. The mixture was allowed to stir for a few minutes and the
(non-centrifuged) solution of 0.89 M 3-chlorobenzylzinc chloride (2c,
5 mL) was added with a syringe. The resulting mixture was allowed to
stir for 24 h at r.t., and then diluted with EtOAc (100 mL). Excess 1 M
HCl (50 mL) was added and the mixture was stirred for a few min. The
organic layer was separated and washed with brine (30 mL), dried
(MgSO4), and concentrated in vacuo. The crude product was purified
by chromatography (silica gel, CH2Cl2–EtOH, 99:1) to give 4c (0.43 g,
81%) as a white powder; mp 86 °C.
4-Benzyl-3-ethoxy-1H-pyrazole (4a)
1H NMR (CDCl3): δ = 9.06 (s, 1 H), 7.27–7.12 (m, 4 H), 7.10 (s, 1 H),
4.28 (q, J = 7.0 Hz, 2 H), 3.71 (s, 2 H), 1.40 (t, J = 7.0 Hz, 3 H).
13C NMR (CDCl3): δ = 161.7, 143.1, 134.1, 129.5, 128.6, 128.5, 126.7,
LiCl (0.89 g, 21.0 mmol) was dried with a flame under high vacuum
then technical grade Zn powder (1.10 g, 16.8 mmol) was added. The
mixture was heated again under high vacuum then allowed to cool
under an argon atmosphere. Anhyd THF (10 mL) was added and the
suspension cooled to 0 °C with an ice bath. BnBr (1 mL, 8.4 mmol)
was then added and the mixture stirred for 1 h at 4 °C. Titration
showed 88% conversion of BnBr. 3-Ethoxy-4-iodo-1H-pyrazole (3,
0.45 g, 1.89 mmol) and premixed Pd(OAc)2 and XPhos (1:2; 0.11 g,
0.093 mmol) were weighted into another flask and it was flushed
with argon. The solution of 0.67 M BnZnBr (2a, 8.5 mL, 5.69 mmol)
was added and the mixture was stirred for 3 h at 50 °C using an oil
bath, and then diluted with EtOAc (100 mL). Excess 1 M HCl (50 mL)
was added and the mixture was stirred for a few minutes. The organic
layer was separated and washed with brine (30 mL), dried (MgSO4),
and concentrated in vacuo. The crude product was purified by chro-
matography (silica gel, CH2Cl2–EtOH, 99:1) to give 4a (0.27 g, 70%) as
an oil.
126.1, 104.7, 64.5, 28.1, 14.9.
HRMS: m/z [M
+ H] calcd for C12H14ClN2O: 237.0795; found:
237.0729.
4-(2-Chlorobenzyl)-3-ethoxy-1H-pyrazole (4b)
White crystals; yield: 0.73 g (67%); mp 68 °C.
1H NMR (CDCl3): 9.13 (s, 1 H), 7.38–7.34 (m, 1 H), 7.30–7.26 (m, 1 H),
7.22–7.15 (m, 2 H), 7.13 (s, 1 H), 4.28 (q, J = 7.1 Hz, 2 H), 3.84 (s, 2 H),
1.40 (t, J = 7.1 Hz, 3 H).
13C NMR (CDCl3): δ = 161.8, 138.6, 133.8, 130.5, 129.3, 128.8, 127.4,
126.7, 103.6, 64.5, 26.2, 14.9.
HRMS: m/z [M
+ H] calcd for C12H14ClN2O: 237.0795; found:
237.0722.
1H NMR (CDCl3): δ = 7.37–7.24 (m, 5 H), 7.07 (s, 1 H), 4.32 (q, J = 7.1
Hz, 2 H), 3.79 (s, 2 H), 1.44 (t, J = 7.1 Hz, 3 H).
13C NMR (CDCl3): δ = 161.5, 141.2, 128.8, 128.5, 128.4, 125.9, 105.1,
4-(4-Chlorobenzyl)-3-ethoxy-1H-pyrazole (4d)
White crystals; yield: 0.76 g (71%); mp 89 °C.
64.7, 28.5, 15.0.
1H NMR (CDCl3): δ = 9.19 (s, 1 H), 7.28–7.22 (m, 2 H), 7.22–7.14 (m, 2
H), 7.07 (s, 1 H), 4.27 (q, J = 7.1 Hz, 2 H), 3.69 (s, 2 H), 1.39 (t, J = 7.1 Hz,
3 H).
HRMS: m/z [M + H] calcd for C12H15N2O: 203.1184; found: 203.1122.
3-Chlorobenzylzinc Chloride (2c); Typical Procedure for 2b–f
13C NMR (CDCl3): δ = 161.7, 139.5, 131.7, 129.8, 128.4, 105.0, 64.5,
LiCl (1.00 g, 23.6 mmol, 2 equiv) was added to a microwave reaction
vial, and dried with a flame for a few min in the open air. This vial was
left to cool in a desiccator under high vacuum. Air was used to back
pressurize the desiccator and Zn powder (size <10 μm) (1.54 g, 23.6
mmol, 2 equiv) was added. The vial was heated again with a flame for
a few min in the open air, and left to cool in a desiccator under high
vacuum; argon was used to back-pressurize the desiccator. A stirring
bar was added and the vial was sealed, anhyd THF (10 mL) was inject-
ed via the septum, followed by 0.81 M 1,2-dibromoethane in dry THF
(0.73 mL, 0.6 mmol, 0.05 equiv). This was heated in a microwave oven
at 85 °C for 5 min. A solution of 0.2 M TMSCl in anhyd THF (0.59 mL,
0.12 mmol, 0.01 equiv) was then added and the suspension was heat-
ed once again at 85 °C for 5 min. 3-Chlorobenzyl chloride (1c, 2.05
mL, 16.1 mmol, 1 equiv) was added by syringe and the vial was heat-
ed with a microwave oven for 1 h at 70 °C. Iodometric titration33 indi-
27.8, 14.9.
HRMS: m/z [M
237.0772.
+ H] calcd for C12H14ClN2O: 237.0795; found:
4-(2,4-Dichlorobenzyl)-3-ethoxy-1H-pyrazole (4e)
In this case, prior to a chromatography, the crude reaction product
was stirred in 12 M HCl for 1 h. The mixture was extracted with EtOAc
(2 × 50 mL). The combined organic layers were washed with sat.
NaHCO3 (40 mL) and brine (30 mL), dried (MgSO4), and concentrated
to dryness. The residue was further purified as described in the typi-
cal procedure to give 4e (0.56 g, 50%) as a white solid; mp 107 °C.
1H NMR (CDCl3): δ = 8.81 (br s, 1 H), 7.38 (d, J = 1.9 Hz, 1 H), 7.24–7.12
(m, 3 H), 4.27 (q, J = 7.1 Hz, 2 H), 3.79 (s, 2 H), 1.39 (t, J = 7.1 Hz, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 511–516

515
E. P. Coutant, Y. L. Janin
Paper
Synthesis
13C NMR (CDCl3): δ = 161.7, 137.1, 134.4, 132.4, 131.3, 129.1, 128.8,
HRMS: m/z [M
+
H] calcd for
C
12H13ClIN2O: 362.9761; found:
127.0, 103.0, 64.6, 25.7, 14.9.
362.9756.
HRMS: m/z [M
271.0347.
+ H] calcd for C12H13Cl2N2O: 271.0405; found:
4-Benzyl-3-ethoxy-5-iodo-1H-pyrazole (5a)
Chromatography (silica gel, cyclohexane–EtOAc, 5:1) gave the prod-
uct (0.25 g, 61%) as a white solid; mp 113 °C.
3-Ethoxy-1-(1-ethoxyethyl)-4-iodo-1H-pyrazole (10)
Under a CaCl2-protected atmosphere, 3-ethoxy-4-iodo-1H-pyrazole
(3, 1.50 g, 6.3 mmol, 1 equiv), ethyl vinyl ether (0.73 mL, 7.6 mmol,
1.2 equiv), and TsOH (32 mg, 0.13 mmol, 0.02 equiv) were dissolved
in CH2Cl2 (stabilized with 2-methylbut-2-ene, 50 mL), After 3 h, the
mixture was concentrated in vacuo and the resulting oil was used
without further purification.
1H NMR (CDCl3): δ = 7.34–7.20 (m, 5 H), 6.10 (s, 1 H), 4.25 (q, J = 7.0
Hz, 2 H), 3.68 (s, 2 H), 1.38 (t, J = 7.0 Hz, 3 H).
13C NMR (CDCl3): δ = 161.1, 140.3, 128.6, 128.3, 127.2, 126.0, 110.1,
83.2, 64.9, 29.4, 14.9.
HRMS: m/z [M + H] calcd for C12H14IN2O: 329.0151; found: 329.0152.
1H NMR (DMSO-d6): δ = 7.90 (s, 1 H), 5.32 (q, J = 6.0 Hz, 1 H), 4.17 (q,
J = 7.0 Hz, 2 H), 3.39 (dq, J = 9.6, 7.0 Hz, 1 H), 3.22 (dq, J = 9.6, 7.0 Hz, 1
H), 1.52 (d, J = 6.0 Hz, 3 H), 1.30 (t, J = 7.0 Hz, 3 H), 1.03 (t, J = 7.0 Hz, 3
H).
13C NMR (DMSO-d6): δ = 162.1, 134.6, 86.8, 65.1, 63.4, 45.0, 21.1, 15.2,
15.1.
4-(2-Chlorobenzyl)-3-ethoxy-5-iodo-1H-pyrazole (5b)
Yellowish oil; yield: 0.49 g (68%).
1H NMR (CDCl3): δ = 11.14 (s, 1 H), 7.42–7.35 (m, 1 H), 7.21–7.12 (m, 2
H), 7.12–7.00 (m, 1 H), 4.26 (q, J = 7.0 Hz, 2 H), 3.83 (s, 2 H), 1.34 (t, J =
7.0 Hz, 3 H).
13C NMR (CDCl3): δ = 161.4, 137.0, 134.0, 130.1, 129.2, 127.4, 126.5,
108.0, 83.8, 65.0, 27.0, 14.9.
4-(3,4-Dichlorobenzyl)-3-ethoxy-1H-pyrazole (4f)
HRMS: m/z [M
362.9783.
+ H] calcd for C12H13ClIN2O: 362.9761; found:
Under an argon atmosphere, in a microwave reaction vial, compound
10 (0.80 g, 2.6 mmol, 1 equiv) and premixed Pd(OAc)2 and XPhos (1:2,
61 mg, 51 μmol, 0.02 equiv) were dissolved in anhyd THF (5 mL). A
solution of 0.32 M 3,4-dichlorobenzylzinc chloride (2f) in THF (8.0
mL, 2.6 mmol, 1 equiv) was added and the mixture was heated at
50 °C for 1 h. Concd HCl (2 mL, 37%) was added and the solution was
stirred for a further 5 min, and then diluted with EtOAc (100 mL). The
organic layer was separated and washed with brine (30 mL), dried
(MgSO4), and concentrated in vacuo. The crude product was purified
by chromatography (silica gel, CH2Cl2–EtOH, 99:1) to give 4f (0.44 g,
63%) as a yellowish solid; mp 87 °C.
4-(4-Chlorobenzyl)-3-ethoxy-5-iodo-1H-pyrazole (5d)
White solid; yield: 0.66 g (71%); mp 116 °C.
1H NMR (CDCl3): δ = 7.22 (m, 4 H), 4.24 (q, J = 7.0 Hz, 2 H), 3.64 (s, 2
H), 1.37 (t, J = 7.0 Hz, 3 H).
13C NMR (CDCl3): δ = 161.1, 138.6, 131.8, 129.8 (2 C), 128.4 (2 C),
109.9, 82.7, 64.7, 28.8, 14.8.
HRMS: m/z [M
362.9820.
+ H] calcd for C12H13ClIN2O: 362.9761; found:
1H NMR (CDCl3): δ = 7.38–7.31 (m, 2 H), 7.12 (s, 1 H), 7.08 (dd, J = 8.1,
2.1 Hz, 1 H), 4.28 (q, J = 7.0 Hz, 2 H), 3.68 (s, 2 H), 1.39 (t, J = 7.0 Hz, 3
H).
4-(2,4-Dichlorobenzyl)-3-ethoxy-5-iodo-1H-pyrazole (5e)
13C NMR (CDCl3): δ = 161.5, 141.3, 132.2, 130.4, 130.2, 129.9, 128.5,
Yellowish solid; yield: 0.23 g (56%); mp 146 °C.
127.9, 104.2, 64.6, 27.6, 14.9.
1H NMR (DMSO-d6): δ = 12.37 (s, 1 H), 7.55 (d, J = 2.2 Hz, 1 H), 7.33
(dd, J = 8.4, 2.2 Hz, 1 H), 7.02 (d, J = 8.4 Hz, 1 H), 4.10 (q, J = 7.0 Hz, 2
H), 3.61 (s, 2 H), 1.20 (t, J = 7.0 Hz, 3 H).
HRMS: m/z [M
+ H] calcd for C12H13Cl2N2O: 271.0405; found:
271.0350.
13C NMR (DMSO-d6): δ = 161.2, 136.6, 134.1, 131.9, 131.8, 128.9,
127.6, 105.8, 85.4, 64.3, 26.5, 15.1.
4-(3-Chlorobenzyl)-3-ethoxy-5-iodo-1H-pyrazole (5c); Typical
Procedure for 5a–f
HRMS: m/z [M + H] calcd for C12H12Cl2IN2O: 396.9371; found:
4-(3-Chlorobenzyl)-3-ethoxy-1H-pyrazole (4c, 0.41 g, 1.73 mmol, 1
equiv) and NIS (0.41 g, 1.82 mmol, 1.05 equiv) were heated to reflux
in 1,2-dichloroethane (25 mL) for 10 h. The solution was diluted with
EtOAc (100 mL), the organic layer was separated and discolored with
Na2SO3 solution (0.5 g in 50 mL of H2O), washed with H2O (30 mL) and
brine (30 mL), and dried (MgSO4), and then concentrated in vacuo.
The crude product was purified by chromatography (silica gel,
CH2Cl2–EtOH, 99:1) to give 5c (0.45 g, 1.24 mmol, 71%) as a yellowish
oil.
396.9361.
4-(3,4-Dichlorobenzyl)-3-ethoxy-5-iodo-1H-pyrazole (5f)
Yellowish wax; yield: 0.26 g (57%).
1H NMR (CDCl3): δ = 7.36 (d, J = 2.1 Hz, 1 H), 7.34 (d, J = 8.2 Hz, 1 H),
7.09 (dd, J = 8.2, 2.1 Hz, 1 H), 4.25 (q, J = 7.0 Hz, 2 H), 3.63 (s, 2 H), 1.38
(t, J = 7.0 Hz, 3 H).
13C NMR (CDCl3): δ = 161.1, 140.3, 132.1, 130.5, 130.1, 130.0, 127.9,
1H NMR (CDCl3): δ = 7.27 (s, 1 H), 7.24–7.11 (m, 3 H), 4.25 (q, J = 7.0
Hz, 2 H), 3.64 (s, 2 H), 1.38 (t, J = 7.0 Hz, 3 H).
13C NMR (CDCl3): δ = 161.2, 142.1, 134.0, 129.5, 128.7, 126.7, 126.2,
109.2, 82.8, 64.8, 28.6, 14.8.
HRMS: m/z [M + H] calcd for C12H12Cl2IN2O: 396.9371; found:
396.9404.
109.6, 82.8, 64.8, 29.1, 14.8.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 511–516

516
E. P. Coutant, Y. L. Janin
Paper
Synthesis
Acknowledgment
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This work was supported by the Agence Nationale de la Recherche
(ANR), grant ANR-11-CRNT-0004, in the context of the investment
program ‘GLOBAL CARE’, an association of the Instituts Carnot ‘Pasteur-
Maladies Infectieuses’, ‘Curie-Cancer’, ‘Voir et Entendre’, ‘Institut du
Cerveau et de la moelle Épinière’ and the ‘Consortium pour l’Accéléra-
tion de l’Innovation et de son Transfert dans le domaine du Lym-
phome’ (CALYM).
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Supporting Information
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Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379458.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 511–516