N-Difluorocyclopropyl-Substituted Pyrazoles: Synthesis and Reactivity

Article abstract of DOI:10.1002/ejoc.201900123

Difluorocyclopropanation of N-vinylazoles with the CF₃SiMe₃–NaI system was studied. It was found that N-vinylpyrazoles could be transformed into the corresponding N-difluorocyclopropyl-substituted derivatives. The method was efficient on a 100 g scale and could be applied for the preparation of various functionalized regioisomeric pyrazole derivatives bearing a gem-difluorocyclopropane moiety, such as amines, carboxylic acids, aldehydes, bromides, and boronic esters. It was found that N-difluorocyclopropylpyrazole moiety tolerated many common reagents including nitrating mixture, bromine, aqueous acids and alkali, KMnO₄, LiBH₄, and Pd⁰ complexes; it was unstable towards AlCl₃, catalytic hydrogenation and lithiation conditions. The products obtained are advanced building blocks which of potential importance to medicinal and agrochemistry.

Full text of DOI:10.1002/ejoc.201900123

A Journal of
Accepted Article
Title: N-Difluorocyclopropyl-substituted pyrazoles: synthesis and
reactivity
Authors: Pavel S. Nosik, Andrii S. Poturai, Mykola O. Pashko,
Kostiantyn P. Melnykov, Sergey V. Ryabukhin, Dmitriy M.
Volochnyuk, and Oleksandr O Grygorenko
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900123
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900123
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201900123
N-Difluorocyclopropyl-substituted pyrazoles: synthesis and
reactivity
a,b
a,b
a,b
a,b
Pavel S. Nosik, Andrii S.Poturai, Mykola O. Pashko, Kostiantyn P. Melnykov, Dr. Sergey V.
b
c,
a, b
Ryabukhin, Dr. Dmitriy M. Volochnyuk * and Dr. Oleksandr O. Grygorenko
*
[
26,30–
Abstract: Difluorocyclopropanation of N-vinylazoles with the
CF3SiMe – NaI system was studied. It was found that N-vinyl-
difluorocyclopropylamine (5) or its derivatives (Scheme 1);
33]
3
it should be noted that similar aliphatic amines (e.g. 6) were
[
34]
pyrazoles could be transformed into the corresponding N-difluoro-
reported to have limited stability.
In a recent paper by Xiao
cyclopropyl-substituted derivatives. The method was efficient on a
and co-workers, a few N-difluorocyclopropyl-substituted indole,
1
00 g scale and could be applied for the preparation of various
benzimidazole and benzotriazole derivatives of general formula
functionalized regioisomeric pyrazole derivatives bearing a gem-
difluorocyclopropane moiety, e.g. amines, carboxylic acids,
aldehydes, bromides, and boronic ester. It was found that N-
difluorocyclopropylpyrazole moiety tolerated many common reagents
including nitrating mixture, bromine, aqueous acids and alkali,
7
were synthesized by N-alkylation of the corresponding hetero-
[35]
cyclic anions with tosylate 8. In the current work we describe
an alternative approach to N-difluorocyclopropyl-substituted azo-
F
(
0)
F
O
S
4 4 3
KMnO , LiBH , and Pd complexes; it was unstable towards AlCl ,
F
F
catalytic hydrogenation and lithiation conditions. The products
obtained are advanced building blocks which of potential importance
to medicinal and agrochemistry.
F
O
O
F
O
N
F
O
N
O N
N
N
O
N
F
F
F
F
Introduction
1
, mGluR2 agonist
EC50 = 6.9 nM
F
2, GlyT1 inhibitor
IC50 = 4 nM
Fluorinated cyclopropanes have become extraordinary structural
motifs which attracted much attention in organic synthesis, drug
Cl
F
O
[
1–10]
F
N
HN
discovery and agrochemistry over the last years.
In
particular, highly potent compounds bearing a gem-difluoro-
cyclopropyl substituent were disclosed in recent patents, e.g. as
highly potent metabotropic glutamate receptor 2 (mGluR2)
N
O
N
O N
Cl
N
N
F
N
N
N
H
N
N
N
H
H
O
[
11]
[12]
agonists 1,
glycine transporter 1 (GlyT1) inhibitor 2,
3
, ERK2 inhibitor
IC50 = 3.6 nM
4, FXIa inhibitor
K = 0.36 nM
i
F
[
13]
extracellular signal-regulated kinase 2 (ERK2) inhibitors 3, or
[
14]
macrocyclic factor XIa (FXIa) inhibitor 4 (Figure 1).
While a number of papers describe synthetic approaches to the
compounds having a gem-difluorocyclopropyl group attached to
Figure 1. Biologically active heterocyclic compounds bearing a gem-difluoro-
cyclopropyl substituent
[
15–24]
the carbon atom,
as well as their chemical transfor-
the corresponding N-substituted analogues are
much less studied. Most of them referred to the parent gem-
[
6,25–29]
mations,
F
NH2
n
Gassen,
Baasner
F
F
F
Kubyshkin et al.
F
F
N
2015
1
990
H
5
6, n = 13
[
[
a]
b]
P.S. Nosik, A. S.Poturai, M. O. Pashko, K. P. Melnykov,
Dr. O. O. Grygorenko
Enamine Ltd. (www.enamine.net)
R1
A
N
R1
A
Chervonotkatska Street 78, Kyiv 02094, Ukraine
P.S. Nosik, A. S.Poturai, M. O. Pashko, K. P. Melnykov,
A
OTs
NaH
Xiao et al.
+
A
2
014
a
5469%
6 examples
N
H
2
Dr. S. V. Ryabukhin, Dr. O. O. Grygorenko
F
Taras Shevchenko National University of Kyiv
Volodymyrska Street 60, Kyiv 01601, Ukraine
E-mail: gregor@univ.kiev.ua (O.O.G.)
URL: https://orcid.org/0000-0002-6036-5859
Dr. D. M. Volochnyuk
F
8
A = CH, CR
, N
7
A
A
A
A
FG
A
CF
3
SiMe
3
 NaI
This work
[
c]
A
N
Institute of Organic Chemistry, National Academy of Sciences of
Ukraine
Murmanska Street 5, Kyiv 02094, Ukraine
E-mail: d.volochnyuk@gmail.com (D.M.V.)
A
N
FG = CO H, Br,
2
(
works only for
pyrazoles)
NH , CHO etc.
2
F
F
9
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. Synthesis of compounds bearing
substituent at the nitrogen atom
a
gem-difluorocyclopropyl
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201900123
les, which is based on the difluorocyclopropanation of the
substitution reactions (i.e. nitration, bromination, and the
Vilsmeier – Haack formylation) proceeded smoothly and gave
the corresponding 1,4-disubstituted pyrazole derivatives 11a–
13a in 57–94% yields (Scheme 3). Further transformations of
these products allowed for the preparation of some other
important building blocks. In particular, amine 14a was obtained
in 79% yield by reduction of the nitro derivative 11a with Fe –
corresponding N-vinylazoles 9 with the CF
3 3
SiMe – NaI system,
which was initially developed by Hu, Prakash, Olah and co-
[
15]
workers in 2011,
and has been used by many other groups
[
16–19,36–38]
since then.
Although this method appeared to be
suitable only for the pyrazole derivatives, a wide range of
functionalized compounds could be obtained, which are valuable
low-molecular-weight building blocks for drug discovery and
agrochemistry. In addition to that, tolerance of the N-difluoro-
cyclopropyl-substituted azole moiety towards the conditions of
common organic reactions is studied herein.
NH
KMnO
acid 15a (82% yield). It should be noted that catalytic
hydrogenation of 11a (H (1 atm), Pd-C, rt) was unfruitful; a
4
Cl in aq EtOH, whereas oxidation of aldehyde 13a with
4
in 1,4-dioxane – H O gave the corresponding carboxylic
2
2
complex mixture of products was obtained, apparently due to
instability of the difluorocyclopropane moiety at these conditions.
Boronic ester 16 was prepared from the bromide 12a by reaction
Results and Discussion
with
bis(pinacolato)diboron
in
the
presence
of
Pd(dppf)Cl
2
CH Cl and KOAc in DMSO at 80 C (71% yield).
2 2
[
35]
First of all, the conditions of Xiao and co-workers (i.e. reaction
of tosylate 8 with azole anion) were tested for the case of
pyrazole. It was found that the method was unfruitful in this case.
Therefore, we have prepared the parent N-vinylazoles 9a–g
O
O
O N
2
HO
KMnO4
82%
N
N
HNO3
SO
92%
N
DMF
POCl
[39,40]
N
N
N
using the known procedures
reaction with the CF SiMe – NaI system. It was found that
pyrazole derivative 9a reacted smoothly when “slow addition”
protocol was used (CF SiMe (3.5 mol, added over 12–16 h),
and the corresponding product 10
and evaluated them in the
N
N
H
2
4
3
3
3
F
5
7%
F
F
F
F
F
F
F
3
3
1
1a
1
0
13a
15a
[
15,19]
NaI (0.35 mol, reflux),
Fe,
NH Cl
7
9%
94% Br2
Br
was obtained in 83% yield (Scheme 2). It should be noted that
this transformation was performed at up to 128 g scale without
considerable changes in the yield. In some cases, however, the
reaction proceeded vigorously after addition of ca. 0.8–1.2
4
O
O
O
B
O
O
B
H N
2
B
O
N
N
3
equivalents of CF SiMe
3
; an induction period was observed.
N
N
.
N
PdCl
2
(dppf) 2CH
2
Cl
2
N
This is yet another fact showing that the reaction cannot be
KOAc, 71%
[
18,20]
F
F
described simply as difluorocarbene cycloaddition;
particular, some type of radical mechanism might be involved.
in
F
F
F
12a
F
1
4a
16
Unfortunately, other azole derivatives 9b–g were unreactive
towards the Ruppert–Prakash reagent with the use of either
Scheme 3. Functionalization of N-(gem-difluorocyclopropyl)pyrazole (10)
[
18,19]
“one-batch” or “slow addition” protocol;
no conversion of
9
b–g was observed. Although the reason behind this result is
unclear, it might be addressed either to the presence of a
nucleophilic nitrogen atom (especially in the case of 9b) or to
electronic effects (for other representatives). Therefore, further
study was focused on the preparation of various N-(difluoro-
cyclopropyl)pyrazoles.
Unfortunately, the compound 10 appeared to be unstable under
the Friedel – Crafts acylation conditions (AcCl, AlCl , CH Cl
C); a complex mixture of products was obtained in this case.
In addition to that, stability of 10 towards aqueous acids and al-
kali was studied. It was found that the compound remained
intact upon heating with either 2 M or conc aq. HCl, as well as
with 2 M aq NaOH at 100 C for 1 h.
3
2
2
,
0
N
CF SiMe (3.5 mol)
N
3
3
N
N
On the contrary, functionalization of the compound 10 at the
position 5 of the pyrazole ring via lithiation was not fruitful; a
complex mixture of unidentified products was formed instead,
which clearly indicated instability of the N-gem-difluorocyclopro-
pyl group towards the reaction conditions tested (n-BuLi,
LiHMDS, LDA or i-PrMgClLiCl, THF, –78 C; LiTMP, THF,
–100C). Therefore, we decided to introduce the corresponding
functional groups into the starting material 9a prior the difluoro-
cyclopropanation step. In particular, bromide 17, aldehyde 18,
and carboxylic acid 19 were obtained by lithiation of 9a and
subsequent trapping of the organolithium species with the
corresponding electrophile (65–83% yield) (Scheme 4). Since
the free aldehyde and carboxylic functions are not compatible
with the difluorocyclopropanation conditions, the products 18
and 19 were transformed into the corresponding protected
derivatives 20 (86% yield) and 21 (99% yield), respectively.
Difluorocyclopropanation of 17, 20 and 21 gave the correspon-
"
slow addition"
NaI (0.35 mol)
F
9
a
THF, 65
N
o
C
10
F
N
N
N N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
9
b
9c
9d
9e
9f
9g
no reaction
Scheme 2. Difluorocyclopropanation of parent N-vinylazoles
Initially, the product 10 was envisaged as the key intermediate
for the preparation of the corresponding functionalized
derivatives. Indeed, it was found that common electrophilic
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European Journal of Organic Chemistry
10.1002/ejoc.201900123
O
O
N
N
N
N
N
N
N
1
2
. LDA
1. LDA
2. DMF
HC(OMe)3
CF SiMe
3
3
N
N
N
N
N
O
Br
O
O
. C Br F
2 4
TsOH
86%
NaI
93%
F
93%
2
O
F
7
1%
8
3%
F
F
1
7
9a
18
20
22
13b
CF
3
SiMe
3
1. LDA
2. CO
2
9
2%
65%
NaI
O 1. DPPA,
O
N
N
N
Br
O
O
N
NH2
N
N
MeI
CF SiMe
NaOH
80%
N
Et N,
N
N
3
3
N
3
.HCl
N
N
OH
O
OH Cs
CO
9%
O
NaI
t-BuOH
2. HCl
71%
2
3
F
F
F
F
9
79%
F
F
F
F
.
1
2b
19
21
23
15b
14b HCl
Scheme 4. Synthesis of 1,5-disubstituted N-(gem-difluorocyclopropyl)pyrazole derivatives
ding products 12b, 22 and 23 (92%, 93% and 79% yield,
respectively). The compounds 22 and 23 were transformed into
the target building blocks 13b and 15b in 93% and 80% yield,
respectively, upon deprotection. Finally, amine 14b was
obtained in 71% yield though a modified Curtius rearrangement
via the corresponding N-Boc derivative 24.
to alcohol 28 with LiBH
to aldehyde 13c with MnO
4
(74% yield), which in turn was oxidized
2
(76% yield).
EtO
EtO
EtO
EtO
O
O
O
O
Br(CH
NaH
8%
2
)
2
OH
MsCl
Et
2%
DBU
63%
N
N
N
N
3
N
N
H
N
N
N
6
9
NO2
NO2
NO2
CF SiMe
OMs NaI
3
3
(
CH Cl)
CF SiMe
2
2
3
3
2
6
N
N
OH
31
+

NaI
93%
N
N
Bu
KOH
3%
4
N Br
N
32
75%
N
H
F
F
O
HO
EtO
HO
6
O
O
2
5
11c
MnO2
76%
LiBH4
NaOH
85%
Fe
NH Cl
N
N
N
N
6
7%
4
N
N
74%
F
N
N
F
F
F
F
F
Br
N
NH
2
F
F
1
3c
28
27
15c
1. NaNO
2
, HBr
N
N
N
2
. CuBr
82%
Scheme 6. Synthesis of 1,3-disubstituted N-(gem-difluorocyclopropyl)pyrazole
derivatives 13c and 15c
F
F
F
F
12c
14c
Scheme 5. Synthesis of 1,3-disubstituted N-(gem-difluorocyclopropyl)pyrazole
derivatives 11c, 12c and 14c
PhB(OH) , Pd(PPh ) , K CO Ph
N
2
3 4
2
o
3
N
H
2
O  (CH
2
OMe)
2
, 85 C
F
F
2
2
2
9a, 75%
9b, 65%
9c, 67%
Br
N
An approach to the remaining N-(gem-difluorocyclopropyl)pyra-
zole derivatives, i.e. 1,3-disubstituted isomers, relied on a
synthesis of the corresponding N-vinylpyrazoles 25 and 26. It
should be noted that only compound 26 was described in the
a
: 4-isomer
b: 5-isomer
c: 3-isomer
N
F
F
1
2ac
Ph
N
[
41]
literature to date;
methods for the preparation of both derivatives (Schemes 5 and
). Difluorocyclopropanation of 25 and 26 occurred under
nevertheless, we have used our own
N
PhC CH, Pd(OAc)
2
, CuI
F
F
o
6
PPh , Et N, DMF, 85 C
3
3
30a, 78%
30b, 72%
standard conditions described above and gave the
corresponding products 11c and 27 in 93% and 75% yield,
respectively. Transformations of the nitro derivative 11c included
3
0c, 44%
Scheme 7. Palladium-catalyzed couplings in the N-(gem-difluorocyclo-
4
reduction with Fe – NH Cl giving amine 14c (67% yield), as well
propyl)pyrazole series
as subsequent diazotation of 14c and Sandmeyer reaction
leading to the formation of bromide 12c (82% yield). Ester 27
was transformed into the corresponding carboxylic acid 15c
Since it is known from the literature that gem-difluorocyclopro-
panes are susceptible to palladium-catalyzed ring opening, we
(
85% yield) by alkaline hydrolysis; alternatively, it was reduced
[
26]
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201900123
have studied common C–C and C–N coupling reactions with
bromides 12a–c (Scheme 7). It was found that the Suzuki –
Miyaura and Sonogashira reactions were effective with 12a–c,
so that the corresponding products of C–C coupling 29a–c and
General. The solvents were purified according to the standard
[44]
procedures.
All starting materials were purchased from commercial
sources. Melting points were measured on MPA100 OptiMelt automated
melting point system. Analytical TLC was performed using Polychrom SI
F254 plates. Column chromatography was performed using Kieselgel
3
0a–c were obtained in 44–78% yield. Notably, the difluoro-
1
13
Merck 60 (230–400 mesh) as the stationary phase. H and C NMR
spectra were recorded on a Bruker 170 Avance 500 spectrometer (at
cyclopropane ring tolerated the presence of palladium- and
copper-containing species at 85 C.
4
99.9 MHz for Protons and 124.9 MHz for Carbon-13) and Varian Unity
Plus 400 spectrometer (at 400.4 MHz for protons and 100.7 MHz for
Carbon-13). Chemical shifts are reported in ppm downfield from TMS as
an internal standard. Elemental analyses were performed at the
Laboratory of Organic Analysis, Department of Chemistry, National Taras
Shevchenko University of Kyiv. Mass spectra were recorded on an
Agilent 1100 LCMSD SL instrument (chemical ionization (APCI),
electrospray ionization (ESI)) and Agilent 5890 Series II 5972 GCMS
instrument (electron impact ionization (EI)).
Conclusions
Difluorocyclopropanation of N-vinylpyrazoles with subsequent
modification of the products obtained is a convenient method for
the regioselective synthesis of various functionalized N-(gem-di-
fluorocyclopropyl)pyrazoles, including amines, carboxylic acids,
aldehydes, bromides, and boronic derivative (Figure 2). The
method is not fruitful for the preparation of other azole
derivatives studied (i.e. imidazole and 1,2,4-triazole). The N-
gem-difluorocyclopropyl moiety attached to the pyrazole ring
tolerates a number of typical organic transformations including
nitration, bromination, treatment with acids and alkali, mild
oxidation and reduction, as well as Pd-catalyzed couplings; it is
unstable towards action of metallation agents like n-BuLi or
General procedure for the preparation of 10, 11c, 12b, 22, 23,
and 27.
NaI (26.2 g, 0.175 mol) was added to a solution of the corresponding N-
vinylpyrazole (0.500 mol) in THF (500 mL) under nitrogen atmosphere,
3 3
and the mixture was heated to reflux. CF SiMe (249 g, 1.75 mol) was
added dropwise over 12–16 h at this temperature (CAUTION! In some
cases, the reaction proceeded vigorously after addition of ca. 0.4–0.6 mol
of CF
conversion was monitored by
completion of the reaction, the solvent was evaporated in vacuo, the
residue was diluted with CH Cl (500 mL), the precipitate was filtered off,
3 3
SiMe ). The reaction mixture was heated overnight, and the
1
H
NMR and/or GCMS. After the
3
lithium amides, strong Lewis acids like AlCl , or catalytic
hydrogenolysis (Table 1). The building blocks described in this
work were obtained on up to 50 g scale. Therefore, they can be
considered as readily available to scientific community and are
promising reagents for drug discovery and agrochemistry, which
are fully compatible with even the strictest compound selection
2
2
and the combined filtrates were evaporated or subjected to distillation in
vacuo.
1
-(2,2-Difluorocyclopropyl)-1H-pyrazole (10). The compound was
[
42,43]
purified by distillation in vacuo. Yield 59.1 g (82%); yellowish liquid; bp
criteria.
1
4
1
5
3
6–48 °C / 13 mmHg. H NMR (400 MHz, CDCl ) δ 7.53 (d, J = 1.9 Hz,
H), 7.48 (d, J = 2.4 Hz, 1H), 6.28 (t, J = 2.1 Hz, 1H), 4.06 (tdd, J = 9.6,
.8, 2.3 Hz, 1H), 2.18 (ddt, J = 14.7, 9.6, 5.8 Hz, 1H), 2.11–1.99 (m, 1H).
Br
H
2
N
N
N
N
13
N
O
N
N
C NMR (126 MHz, CDCl
8.7 (dd, J = 16.2, 9.8 Hz), 18.0 (t, J = 11.0 Hz). F{ H} NMR (376 MHz,
CDCl ) δ –130.7 (d, J = 163 Hz), –143.3 (d, J = 163 Hz). GC/MS (EI): m/z
144 [M] . Anal. Calcd. for C
Found: C, 49.78; H, 4.37; N, 19.26.
3
) δ 140.4, 130.5, 109.3 (t, J = 286 Hz), 106.5,
19
1
3
F
F
F
3
+
F
2ac
F
F
=
6 6 2 2
H F N : C, 50.00; H, 4.20; N, 19.44.
1
13ac
14ac
HO
O
O
B
a: 4-isomer
b: 5-isomer
c: 3-isomer
5
-Bromo-1-(2,2-difluorocyclopropyl)-1H-pyrazole
(12b).
The
N
O
N
N
compound was purified by distillation in vacuo. Yield 103 g (92%);
yellowish oil; bp 71–73 °C / 13 mmHg. H NMR (400 MHz, CDCl
N
1
3
) δ 7.50
(
d, J = 1.9 Hz, 1H), 6.35 (d, J = 1.9 Hz, 1H), 3.94 (dddd, J = 10.3, 7.8, 5.8,
F
F
F
1
.9 Hz, 1H), 2.51 – 2.39 (m, 1H), 2.12 (dtd, J = 12.4, 10.3, 7.8 Hz, 1H).
F
5ac
13
C NMR (126 MHz, CDCl
3
) δ 140.9 (d, J = 0.7 Hz), 115.4, 109.6, 108.9
1
16
(
dd, J = 287, 286 Hz), 37.9 (dd, J = 16.3, 9.9 Hz), 17.2 (t, J = 11.3 Hz).
1
9
1
F{ H} NMR (376 MHz, CDCl
62 Hz). GC/MS (EI): m/z = 222/224 [M] . Anal. Calcd. for C
2.31; H, 2.26; N, 12.56; Br, 35.83. Found: C, 32.69; H, 1.95; N, 12.89;
3
) δ –132.0 (d, J = 162 Hz), –144.0 (d, J =
Figure 2. The key building blocks obtained in this work
+
1
3
6 5 2 2
H BrF N : C,
Br, 35.59.
Table 1. Tolerance of N-(gem-difluorocyclopropyl)pyrazoles to common
organic reactions
1-(2,2-Difluorocyclopropyl)-5-(dimethoxymethyl)-1H-pyrazole
(22).
1
Yield 101 g (93%); yellowish oil. H NMR (400 MHz, CDCl
3
) δ 7.41 (d, J =
Tolerate
Unstable towards
1
8
5
.8 Hz, 1H), 6.34 (d, J = 1.8 Hz, 1H), 5.52 (s, 1H), 4.01–4.07 (m, J = 10.0,
.2, 5.9, 1.8 Hz, 1H), 3.37 (s, 3H), 3.28 (s, 3H), 2.48 (ddt, J = 14.4, 10.0,
HNO
Br
DMF – POCl
LiBH
KMnO
3
– H
2
SO
4
2/12 M aq. HCl, 100 C
2 M aq. NaOH, 100 C
n-BuLi, LiHMDS, LDA or
i-PrMgClLiCl, THF, –78 C
LiTMP, THF, –100C
13
.9 Hz, 1H), 2.01 (ddd, J = 12.8, 10.0, 7.1 Hz, 1H). C NMR (126 MHz,
2
a
CDCl
8.2 (dd, J = 15.7, 9.7 Hz), 16.6 (t, J = 11.1 Hz). F NMR (470 MHz,
δ –131.3 (dddd, J = 161, 12.8, 5.9, 1.8 Hz), –144.3 (ddd, J = 161,
3
) δ 141.3, 138.7, 109.4 (dd, J = 288, 285 Hz), 107.3, 53.5, 52.3,
3
Pd(dppf)Cl
Pd(PPh , 85 C
Pd(OAc) , PPh , CuI, 85 C
2 2 2
, B Pin , 80 C
19
3
4
3
)
4
H
2
(1 atm), Pd-C, rt
or MnO
2
CDCl3)
4.4, 8.2 Hz). Anal. Calcd. for C
Found: C, 49.42; H, 5.16; N, 12.86.
4
2
3
CH C(O)Cl, AlCl
3
3
1
9 12 2 2 2
H F N O : C, 49.54; H, 5.54; N, 12.84.
2 2
a) B Pin – bis(pinacolato)diboron
Methyl 1-(2,2-difluorocyclopropyl)-1H-pyrazole-5-carboxylate (23).
1
Yield 79.9 g (79%); yellowish oil. H NMR (400 MHz, CDCl
3
) δ 7.50 (d, J
Experimental Section
= 2.0 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 4.40 (dddd, J = 10.4, 8.4, 5.9, 2.1
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201900123
Hz, 1H), 3.91 (s, 3H), 2.46 (ddt, J = 13.9, 8.4, 5.9 Hz, 1H), 2.12 – 2.06 (m,
residue was poured into ice. Then aq NaHCO
and the mixture was extracted CHCl (4250 mL). The combined organic
layers were dried over Na SO and evaporated in vacuo. The compound
was purified by distillation in vacuo. Yield 34.0 g (57%); colorless liquid;
3
was added to pH = 7–8,
13
1
3
H). C NMR (126 MHz, CDCl ) δ 159.6, 138.9, 134.3, 112.2, 108.8 (dd,
3
J = 288, 284 Hz), 52.1, 39.8 (dd, J = 15.8, 9.7 Hz), 16.9 (t, J = 11.2 Hz).
2
4
1
9
1
F{ H} NMR (470 MHz, CDCl
63 Hz). LC/MS (CI): m/z = 203 [M+H] . Anal. Calcd. for C
9.54; H, 5.54; N, 12.84. Found: C, 49.50; H, 5.32; N, 12.64.
3
) δ –132.0 (d, J = 163 Hz), –144.6 (d, J =
+
1
1
4
9 12
H F
N
2 2
2
O : C,
bp 64–66 °C / 0.26 mmHg H NMR (400 MHz, CDCl
8.05 (s, 1H), 8.01 (s, 1H), 4.22 – 4.11 (m, 1H), 2.28 – 2.14 (m, 2H).
NMR (126 MHz, CDCl ) δ 183.7, 141.1, 134.3, 124.9, 108.6 (dd, J = 288,
86 Hz), 39.0 (dd, J = 16.3, 9.9 Hz), 18.1 (t, J = 11.1 Hz). F{ H} NMR
376 MHz, CDCl ) δ –130.6 (d, J = 164 Hz), –142.7 (d, J = 164 Hz).
3
) δ 9.88 (s, 1H),
13
C
3
19
1
2
1
-(2,2-Difluorocyclopropyl)-3-nitro-1H-pyrazole (11c). The compound
(
3
was purified by flash chromatography on silica gel using hexanes –
+
1
GC/MS (EI): m/z = 172 [M] . Anal. Calcd. for C H F N O: C, 48.84; H,
EtOAc (4:1) as eluent. Yield 67.1 g (71%); yellowish oil. H NMR (500
7
6
2
2
3
.51; N, 16.27. Found: C, 49.00; H, 3.53; N, 15.97.
MHz, CDCl
3
) δ 7.62 (d, J = 2.7 Hz, 1H), 6.94 (d, J = 2.7 Hz, 1H), 4.22
(
1
1
dddd, J = 10.9, 8.8, 5.5, 2.4 Hz, 1H), 2.40 – 2.31 (ddt, 14.4, 10.9, 5.5 Hz,
13
H), 2.21 (dtd, J = 12.6, 8.8, 7.1 Hz, 1H). C NMR (126 MHz, CDCl
3
) δ
General procedure for the preparation of 14a and 14c.
To a solution of nitropyrazole 11a or 11c (68.5 g, 0.362 mol) in EtOH
(700 mL), aqueous solution of NH Cl (193 g, 3.62 mol) and Fe powder
4
56.2, 133.7, 108.3 (dd, J = 289, 286 Hz), 103.6, 39.7 (dd, J = 16.4, 9.7
19
Hz), 17.9 (t, J = 11.2 Hz). F NMR (470 MHz, CDCl
3
) δ –130.4 (dddd, J
=
165, 12.6, 8.8, 5.5 Hz), –142.3 (dddd, J = 165, 14.4, 7.1, 2.4 Hz).
(80.4 g, 1.44 mol) were added. The reaction mixture was refluxed
overnight, then cooled to rt, filtered through silica gel (500 g) and washed
with EtOH (100 mL). The solvent was evaporated in vacuo, the residue
+
LC/MS (CI): m/z = 190 [M+H] . Anal. Calcd. for C
6 5 2 3 2
H F N O : C, 38.11; H,
2
.66; N, 22.22. Found: C, 38.09; H, 2.95; N, 22.52.
was diluted with H
2
O (500 mL) and extracted with CH
2
Cl
2
(3200 mL).
The combined organic layers were dried over Na SO and evaporated in
vacuo.
2 4
Ethyl 1-(2,2-difluorocyclopropyl)-1H-pyrazole-3-carboxylate (27).
1
Yield 81.1 g (75%); yellowish oil. H NMR (400 MHz, CDCl
3
) δ 7.49 (d,
J = 2.4 Hz, 1H), 6.78 (d, J = 2.4 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 4.13
(
2
dddd, J = 9.7, 6.9, 6.1, 2.3 Hz, 1H), 2.24 (ddt, J = 14.7, 9.7, 5.7 Hz, 1H),
1-(2,2-Difluorocyclopropyl)-1H-pyrazol-4-amine (14a). The compound
was purified by column chromatography on silica gel using CHCl
MeOH (30:1) as eluent. Yield 45.5 g (79%); violet powder; mp 54–56 °C.
13
.09 (dtd, J = 12.2, 9.8, 6.1 Hz, 1H), 1.34 (t, J = 7.1 Hz, 3H). C NMR
) δ 161.8, 144.8, 132.0, 109.4, 108.8 (dd, J = 288, 286
3
–
(
101 MHz, CDCl
Hz), 61.1, 39.3 (dd, J = 16.3, 9.7 Hz), 18.2 (t, J = 11.0 Hz), 14.3.
NMR (470 MHz, CDCl ) δ –130.3 (dddd, J = 164, 12.2, 9.8, 5.7 Hz),
142.3 (ddd, J = 164, 14.7, 6.9 Hz). LC/MS (CI): m/z = 217 [M+H] . Anal.
Calcd. for C : C, 50.00; H, 4.66; N, 12.96. Found: C, 50.39; H,
3
19
1
F
H NMR (400 MHz, CDCl
3
) δ 7.21 (s, 1H), 7.09 (s, 1H), 3.97 (tdd, J =
3
10.1, 5.8, 2.3 Hz, 1H), 2.82 (br s, 2H), 2.17 (ddt, J = 14.6, 9.4, 5.8 Hz,
+
13
–
1H), 2.01 (dtd, J = 12.8, 10.1, 6.2 Hz, 1H). C NMR (126 MHz, CDCl
3
) δ
9 10 2 2 2
H F N O
132.6, 129.7, 118.9, 109.4 (t, J = 287 Hz), 38.9 (dd, J = 16.1, 9.7 Hz),
19
1
4
.43; N, 12.65.
17.6 (t, J = 10.9 Hz). F{ H} NMR (376 MHz, CDCl
Hz), –143.9 (d, J = 162 Hz). LC/MS (CI): m/z = 160 [M+H] . Anal. Calcd.
for C : C, 45.28; H, 4.43; N, 26.41. Found: C, 45.27; H, 4.56; N,
6.73.
3
) δ –130.9 (d, J = 162
+
6 7 2 3
H F N
1
-(2,2-Difluorocyclopropyl)-4-nitro-1H-pyrazole (11a). HNO
SO (96%, 150
mL) at 0 °C. The reaction mixture was stirred at 70 C for 3 h, then
cooled to rt and poured into ice, and extracted with CH Cl (3100 mL).
The combined organic layers were dried over Na SO and evaporated in
vacuo. Yield 12.1 g (92%); yellowish oil. H NMR (500 MHz, CDCl ) δ
.27 (s, 1H), 8.11 (s, 1H), 4.18 (dddd, J = 12.5, 9.8, 5.8, 2.4 Hz, 1H), 2.33
3
(20 mL)
2
was added to a solution of 10 (10.0 g, 69.4 mmol) in H
2
4
2
2
1-(2,2-Difluorocyclopropyl)-1H-pyrazol-3-amine (14c). The compound
was purified by flash chromatography on silica gel using CHCl – MeOH
(24:1) as eluent. Yield 38.6 g (67%); brown liquid. H NMR (400 MHz,
CDCl ) δ 7.23 (d, J = 2.4 Hz, 1H), 5.64 (d, J = 2.4 Hz, 1H), 3.97 – 3.83 (m,
1H), 3.54 (s, 2H), 2.08 – 1.92 (m, 2H). C NMR (126 MHz, CDCl
155.1, 132.0, 109.7 (t, J = 286 Hz), 94.4, 38.2 (dd, J = 16.1, 9.6 Hz), 18.1
2
4
3
1
1
3
8
–
3
13
13
2.27 (m, 1H), 2.21 (dtd, J = 12.5, 9.8, 6.9 Hz, 1H). C NMR (101 MHz,
) δ 136.4, 136.3, 129.9, 108.2 (dd, J = 287, 286 Hz), 39.5 (dd, J =
3
) δ
CDCl
1
1
3
19
1
19
1
6.7, 9.6, Hz) 18.0 (t, J = 11.1 Hz). F{ H} NMR (376 MHz, CDCl
3
) δ –
(t, J = 10.8 Hz). F{ H} NMR (376 MHz, CDCl
–143.1 (d, J = 162 Hz). LC/MS (CI): m/z = 160 [M+H] . Anal. Calcd. for
: C, 45.28; H, 4.43; N, 26.41. Found: C, 45.19; H, 4.78; N,
3
) δ –130.5 (d, J = 162 Hz),
+
30.8 (d, J = 165 Hz), –142.7 (d, J = 165 Hz). LC/MS (CI): m/z = 190
+
[
M+H] . Anal. Calcd. for C
6 5 2
H F N
3
O
2
: C, 38.11; H, 2.66; N, 22.22. Found:
6 7 2 3
C H F N
C, 38.27; H, 2.72; N, 22.15.
26.19.
4
-Bromo-1-(2,2-difluorocyclopropyl)-1H-pyrazole (12a).
solution of 10 (10.0 g, 69.4 mmol) in CH Cl (100 mL) was cooled to
(16.6 g, 0.104 mol) was added over
0 min (NOTE: the temperature should not exceed 28 °C) and the
A
stirred
1-(2,2-Difluorocyclopropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)-1H-pyrazole (16). Bromide 12a (1.20 g, 5.38 mmol),
bis(pinacolato)diboron (1.65 g, 6.49 mmol) and KOAc (1.81 g, 18.4
mmol) were dissolved in DMSO (20 mL) under nitrogen atmosphere, and
2
2
1
1
0 °C under argon atmosphere. Br
2
resulting mixture was stirred at 25 °C for 1.5 h. Then, the solution was
quenched with small portions of 10% aq Na SO (50 mL) over 10 min,
NOTE: the temperature should not exceed 25 °C). The organic layer
was separated, washed with brine (50 mL), dried over Na SO and
evaporated in vacuo. Yield 14.5 g (94%); brown oil. H NMR (500 MHz,
CDCl ) δ 7.52 (s, 1H), 7.49 (s, 1H), 4.06 (dtd, J = 9.5, 6.6, 2.2 Hz, 1H),
.19 (ddt, J = 14.2, 9.5, 5.6 Hz, 1H), 2.06 (dtd, J = 12.3, 9.9, 6.5 Hz, 1H).
2 2 2
PdCl (dppf)2CH Cl (220 mg, 0.269 mmol) was added. The resulting
mixture was stirred under argon atmosphere at 80 °C overnight. Then the
reaction mixture was cooled to rt, filtered through a Celite pad and
2
3
(
2
4
washed with EtOAc (325 mL). The filtrate was washed with H
mL) and brine (50 mL), the organic layer was dried over Na
2
O (250
SO and
1
2
4
3
evaporated in vacuo. The crude compound was purified by flash
2
chromatography on silica gel using hexanes – EtOAc (3:2) as eluent.
1
3
1
C NMR (126 MHz, CDCl
3.6, 38.5 (dd, J = 16.2, 9.7 Hz), 17.3 (t, J = 11.1 Hz). F NMR (470
) δ –130.3 (dddd, J = 163, 12.3, 9.2, 5.6 Hz), –142.7 (dddd, J
3
) δ 140.5, 130.2, 108.4 (dd, J = 288, 286 Hz),
Yield 1.03 g (71%); yellowish oil. H NMR (500 MHz, CDCl
3
) δ 7.80 (s,
19
9
1H), 7.79 (s, 1H), 4.09 (tdd, J = 10.0, 9.8, 2.2 Hz, 1H), 2.17 (ddt, J = 14.3,
13
MHz, CDCl
163, 14.2, 6.6, 2.2 Hz). GC/MS (EI): m/z = 222/224 [M] . Anal. Calcd.
for C BrF : C, 32.31; H, 2.26; N, 12.56; Br, 35.83. Found: C, 32.44;
H, 1.87; N, 12.26; Br, 35.44.
3
9.6, 5.4 Hz, 1H), 2.07 (dtd, J = 13.7, 9.8, 6.3 Hz, 1H), 1.30 (s, 12H).
NMR (126 MHz, CDCl ) δ 146.2, 137.4, 109.1 (t, J = 287 Hz), 83.4, 38.6
(dd, J = 16.2, 9.7 Hz), 24.8, 24.7, 17.9 (t, J = 11.0 Hz). F NMR (470
MHz, CDCl ) δ –130.3 (dddd, J = 163, 13.7, 10.0, 5.4 Hz), –142.6 (ddd, J
163, 14.3, 6.3 Hz). LC/MS (CI): m/z = 189 [M–(HO(CH
C
+
=
3
19
H
6 5
2 2
N
3
+
=
3
)
2
C)
2
+H] , 271
+
[
M+H] . Anal. Calcd. for C12
H17BF N O : C, 53.36; H, 6.34; N, 10.37.
2 2 2
1
-(2,2-Difluorocyclopropyl)-1H-pyrazole-4-carbaldehyde (13a). POCl
3
Found: C, 53.52; H, 6.29; N, 10.74.
(
162 mL, 266 g, 1,74 mol) was added dropwise to DMF (750 mL) at rt,
the resulting mixture was stirred for 0.5 h, and pyrazole 10 (50.0 g, 0.347
mol) in DMF (500 mL) was added. The reaction mixture was stirred at
1-(2,2-Difluorocyclopropyl)-1H-pyrazole-4-carboxylic acid (15a).
Aldehyde 13a (19.8 g. 0.115 mol) was dissolved in 1,4-dioxane (75 mL)
1
10 °C overnight, and most of DMF were evaporated in vacuo and the
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201900123
and a solution KMnO
added. The resulting mixture was stirred ar rt for 5 h, then filtered and
evaporated in vacuo. The residue was diluted with H O (100 mL) and
acidified with 10% aq citric acid to pH 3–4. The precipitate was filtered,
washed with H O (230 mL) and dried in vacuo. Yield 17.7 g (82%);
white solid; mp 150–152 °C. H NMR (400 MHz, CDCl
4
(20 g. 0.126 mol, 1.1 eq.) in H
2
O (15 mL) was
Ester 23 or 27 (80.0 g. 0.396 mol) was dissolved in EtOH (800 mL), and
a solution of NaOH (23.8 g. 0.594 mol) in H
mixture was stirred at rt overnight, and most of EtOH was evaporated in
vacuo. The residue was diluted with H O (500 mL) and the mixture was
washed with CH Cl (3100 mL). The aqueous phase was acidified with
10% aq citric acid to pH 2–3, extracted with with EtOAc (3250 mL). The
2
O (50 mL) was added. The
2
2
2
2
2
1
3
) δ 11.12 (s, 1H),
.05 (s, 1H), 7.99 (s, 1H), 4.17 – 4.10 (m, 1H), 2.27 – 2.18 (m, 1H), 2.16
8
–
1
1
2 4
combined organic layers were dried over Na SO and evaporated in
vacuo.
1
3
2.06 (m, 1H). C NMR (126 MHz, CDCl
3
+ DMSO-d
6
) δ 164.1, 141.7,
34.1, 116.4, 108.9 (dd, J = 288, 286 Hz), 39.0 (dd, J = 16.2, 9.7 Hz),
7.5 (t, J = 11.1 Hz). F{ H} NMR (376 MHz, CDCl ) δ –130.7 (d, J = 165
3
19
1
1
-(2,2-Difluorocyclopropyl)-1H-pyrazole-5-carboxylic acid (15b).
+
Hz), –142.9 (d, J = 165 Hz). LC/MS (CI): m/z = 189 [M+H] . Anal. Calcd.
for C : C, 44.69; H, 3.21; N, 14.89. Found: C, 44.49; H, 2.83; N,
1
Yield 59.2 g (80%); yellowish crystals; mp 127–129 °C. H NMR (400
MHz, CDCl ) δ 8.71 (br s, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.04 (d, J = 2.1
Hz, 1H), 4.50 – 4.38 (m, 1H), 2.55 – 2.45 (m, 1H), 2.18 – 2.08 (m, 1H).
7 6 2 2 2
H F N O
3
1
4.75.
1
3
C NMR (126 MHz, CDCl
288, 284 Hz), 39.9 (dd, J = 16.1, 9.7 Hz), 17.1 (t, J = 11.0 Hz). F{ H}
NMR (376 MHz, CDCl ) δ –132.5 (d, J = 164 Hz), –144.8 (d, J = 164 Hz).
LC/MS (CI): m/z = 189 [M+H] . Anal. Calcd. for C
3.21; N, 14.89. Found: C, 44.71; H, 3.45; N, 15.25.
3
) δ 163.5, 139.2, 133.8, 113.7, 108.7 (dd, J =
19
1
5
-Bromo-1-vinyl-1H-pyrazole (17). Diisopropylamine (8.10 g, 80.0
mmol) was dissolved in THF (70 mL) and 2.5 M solution of n-BuLi in
hexanes (29.2 mL, 73.0 mmol) was added dropwise. The resulting
solution was stirred for 20 min at –15 °C, then cooled to –40 °C, and a
solution of N-vinylpyrazole 9a (5.00 g, 53.1 mmol) in THF (10 mL) was
added dropwise. The resulting mixture was stirred at –30 °C for 30 min,
then cooled to –78 °C, and 1,2-dibromo-1,1,2,2-tetrafluoroethane (23.4 g,
3
+
7 6 2 2 2
H F N O : C, 44.69; H,
1
-(2,2-Difluorocyclopropyl)-1H-pyrazole-3-carboxylic acid (15c).
1
Yield 62.9 g (85%); beige powder; mp 113–115 °C. H NMR (400 MHz,
CDCl ) δ 11.19 (s, 1H), 7.56 (d, J = 2.4 Hz, 1H), 6.89 (d, J = 2.5 Hz, 1H),
.24 – 4.08 (m, 1H), 2.41 – 2.25 (m, 1H), 2.20 – 2.09 (m, 1H). C NMR
126 MHz, CDCl ) δ 166.3, 143.7, 132.5, 110.1, 108.7 (dd, J = 288, 287
Hz), 39.4 (dd, J = 16.3, 9.8 Hz), 18.2 (t, J = 11.1 Hz). F{ H} NMR (376
MHz, CDCl ) δ –130.8 (d, J = 164 Hz), –142.7 (d, J = 164 Hz). LC/MS
9
3
.01 mmol) was added dropwise. The mixture was stirred at –78 °C for
0 min, then warmed up to 0 °C. H O (100 mL) was added dropwise, and
3
13
2
4
the mixture was stirred at rt for 5 min, and then diluted with EtOAc (100
mL). The organic phase was separated, and the aqueous phase was
extracted with EtOAc (270 mL). The combined organic layers were
(
3
19
1
3
washed with 10% aq citric acid (100 mL), dried over Na
2
SO
4
and
+
(
7 6 2 2 2
CI): m/z = 189 [M+H] . Anal. Calcd. for C H F N O : C, 44.69; H, 3.21; N,
evaporated in vacuo. The crude compound was purified by flash
1
4.89. Found: C, 44.52; H, 3.53; N, 14.87.
chromatography on silica gel using hexanes – EtOAc (14:1) as eluent.
1
Yield 7.63 g (83%); yellowish oil. H NMR (500 MHz, CDCl
3
) δ 7.60 (d, J
tert-Butyl
24). The compound existed as ca. 5:1 mixture of rotamers. Et
.173 mol) was added to a solution of carboxylic acid 15b (19.2 g, 0.102
mol) in toluene (200 mL) at rt. DPPA (42.1 g, 0.153 mol) and t-BuOH
60.5 g, 0.816 mol) were added and the mixture was refluxed overnight.
(1-(2,2-difluorocyclopropyl)-1H-pyrazol-5-yl)carbamate
=
5
1.8 Hz, 1H), 7.15 (dd, J = 15.3, 8.8 Hz, 1H), 6.36 (d, J = 1.8 Hz, 1H),
(
0
3
N (17.5 g,
13
.81 (d, J = 15.3 Hz, 1H), 4.95 (d, J = 8.8 Hz, 1H). C NMR (126 MHz,
) δ 141.7, 129.1, 112.9, 109.6, 102.9. GC/MS (EI): m/z = 172/174
M] . Anal. Calcd. for C BrN : C, 34.71; H, 2.91; N, 16.19; Br, 46.18.
Found: C, 35.09; H, 2.82; N, 15.96; Br, 46.50.
CDCl
[
3
+
H
5 5
2
(
The solvent was evaporated in vacuo, and the residue was dissolved in
EtOAc (500 mL). The organic phase was washed with 10% aq citric acid
1
1
-Vinyl-1H-pyrazole-5-carboxylic acid (19). N-vinylpyrazole (100 g
.06 mol) was dissolved in THF (1800 mL). 2.5 M n-BuLi in hexanes (468
(
150 mL), saturated aq. NaHCO
over Na SO , and evaporated in vacuo. The crude compound was
purified by column chromatography on silica gel using hexanes – EtOAc
3
(150 mL), and brine, (150 mL), dried
2
4
mL, 1.17 mol) was added dropwise, and the solution was stirred at 0 °C
for 30 min. Then, dry CO (440 g. 10.0 mol) was added in portions at –
8 °C, the mixture was stirred for 30 min and warmed up to 0 °C. Then,
1
2
(
4:1) as eluent. Yield 19.6 g (74%) H NMR (500 MHz, CDCl
3
) δ 7.44 (d,
7
J = 2.0 Hz, 1H), 6.45 (s, 1H), 6.20 (s, 1H), 3.95 – 3.83 (m, 1H), 2.41 –
13
H
2
O (600 mL) was added dropwise, most of THF was evaporated in
Cl (300 mL) and acidified
with 10% aq citric acid to pH 3–4. The precipitate was filtered and
washed with H O (2100 mL). Yield 95.2 g (65%); yellowish powder; mp
2
.32 (m, 1H), 2.15 – 2.06 (m, 1H), 1.52 (s, 7.5H) and 1.43 (s, 1.5H).
C
vacuo, and the residue was extracted with CH
2
2
3
NMR (126 MHz, CDCl ) δ 152.3, 139.7, 137.9, 109.6 (dd, J = 286, 284
Hz), 99.8, 82.0, 36.1 (dd, J = 16.1, 9.8 Hz), 28.1 and 26.9, 17.3 (t, J =
1
9
1
2
1
1
0.9 Hz). F{ H} NMR (470 MHz, CDCl
42.8 (d, J = 160 Hz). LC/MS (CI): m/z = 260 [M+H] . Anal. Calcd. for
: C, 50.96; H, 5.83; N, 16.21. Found: C, 50.78; H, 5.70; N,
3
) δ –130.6 (d, J = 160 Hz), –
1
1
1
35–137 °C. H NMR (400 MHz, DMSO-d
6
) δ 13.71 (s, 1H), 7.99 (dd, J =
+
5.4, 8.8 Hz, 1H), 7.73 (d, J = 1.9 Hz, 1H), 6.95 (d, J = 1.9 Hz, 1H), 5.75
11 15 2 3 2
C H F N O
13
(
d, J = 15.4 Hz, 1H), 5.01 (d, J = 8.8 Hz, 1H). C NMR (126 MHz,
DMSO-d ) δ 160.9, 140.4, 133.1, 131.8, 113.1, 103.3. LC/MS (CI): m/z =
39 [M+H] . Anal. Calcd. for C
Found: C, 51.93; H, 4.66; N, 20.36.
1
6.49.
6
+
1
6 6 2 2
H N O : C, 52.17; H, 4.38; N, 20.28.
1
3
-(2,2-Difluorocyclopropyl)-1H-pyrazol-5-amine hydrochloride (14b).
.5 M HCl in 1,4-dioxane (100 mL) was added to a solution of N-Boc-
amine 24 (45.0 mmol) in Et
stirred overnight at rt. The precipitate was filtered, washed with Et
2
O (100 mL), and the reaction mixture was
Methyl 1-vinyl-1H-pyrazole-5-carboxylate (21). Cs
mol) was added to a solution of the acid 19 (83.2 g, 0.602 mol) in MeCN
850 mL) at rt. The solution was stirred for 30 min at rt and MeI (37.5 mL,
5.4 g, 0.602 mol, 1 eq.) was added dropwise andthe resulting mixture
was stirred at rt overnight. Then, most of MeCN was evaporated in
vacuo, the residue was crystallized from CH Cl (500 mL) and the
precipitate was filtered off. The mother liquor was dried over Na SO and
evaporated in vacuo. Yield 90.1 g (99%); yellowish oil. H NMR (500 MHz,
CDCl ) δ 8.02 (dd, J = 9.5, 8.6 Hz, 1H), 7.60 (d, J = 0.8 Hz, 1H), 6.91 (d,
J = 2.0 Hz, 1H), 5.90 (d, J = 15.4 Hz, 1H), 5.00 (d, J = 8.8 Hz, 1H), 3.90
2 3
CO (196 g, 0.602
2
O
(
350 mL) and dried in vacuo. Yield 8.71 g (99%); beige solid; mp 140–
1
(
8
1
3
2
42 °C. H NMR (400 MHz, DMSO-d
6
) δ 7.78 (d, J = 2.8 Hz, 1H), 6.29 (s,
H), 5.67 (d, J = 2.8 Hz, 1H), 4.27 (dddd, J = 10.4, 8.5, 6.1, 2.8 Hz, 1H),
13
6
.49 – 2.32 (m, 2H). C NMR (126 MHz, DMSO-d ) δ 151.6 (d, J = 34.4
2
2
Hz), 137.4, 110.4 (dd, J = 288, 283 Hz), 91.22, 34.45 (dd, J = 16.6, 9.2
19
1
2
4
Hz), 17.76 (t, J = 10.6 Hz). F{ H} NMR (376 MHz, DMSO-d
d, J = 159 Hz), –142.1 (d, J = 159 Hz). LC/MS (CI): m/z = 160
6
) δ –130.5
1
(
+
3
[
M-HCl+H] . Anal. Calcd. for C
6 8 2 3
H ClF N : C, 36.84; H, 4.12; N, 21.48; Cl,
1
8.12. Found: C, 37.13; H, 4.27; N, 21.63; Cl, 17.89.
13
(
1
5
3
s, 3H). C NMR (126 MHz, CDCl ) δ 159.9, 139.6, 131.5, 131.3, 112.6,
+
03.6, 52.1. LC/MS (CI): m/z = 153 [M+H] . Anal. Calcd. for C
7 8 2 2
H N O : C,
1
1
-Vinyl-1H-pyrazole-5-carbaldehyde (18). Diisopropylamine (116 g,
.14 mol) was dissolved in THF (1000 mL), and 2.5 M n-BuLi in hexanes
5.26; H, 5.30; N, 18.41. Found: C, 55.49; H, 4.96; N, 18.50.
(
414 mL, 1.04 mol) was added dropwise. The resulting solution was
General procedure for the preparation of 15b and 15c.
stirred for 20 min at –15 °C, then cooled to –30 °C, and a solution of N-
vinylpyrazole 9a (71.4 g, 0.757 mol) in THF (150 mL) was added
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201900123
dropwise. The resulting mixture was stirred at –30 °C for 30 min, and
then cooled to –78 °C. DMF (111 g, 1.52 mol) was added dropwise, and
the mixture was stirred at –78 °C for 30 min. Then, the mixture was
the reaction mixture was warmed up to 30 °C and stirred for 1 h. Then
CuBr (4.50 g; 31.4 mmol) was added in portions at 0 °C. After the
completion of intensive gas evolution, the reaction mixture was warmed
warmed up to 0 °C, H
stirred for 15 min at rt, and diluted with EtOAc (500 mL). The organic
phase was separated, and the aqueous phase was extracted with EtOAc
2
O (700 mL) was added dropwise. The mixture
up to 35 °C and stirred for 40 min. H
2
O (120 mL) was added, and the
Cl (350 mL), combined organic
(50 mL), dried over Na SO
filtered through silica gel and evaporated in vacuo. Yield 11.5 g (82%);
resulting mixture was washed with CH
2
2
layers were washed with 10% aq Na
2
CO
3
2
4
,
(
2500 mL). The combined organic layers were washed with aq citric
acid (10%, 750 mL), dried over Na SO and evaporated in vacuo. The
crude compound was purified by distillation in vacuo. Yield 66.6 g (72%);
1
2
4
yellowish oil. H NMR (500 MHz, CDCl
3
) δ 7.40 (d, J = 2.6 Hz, 1H), 6.30
(d, J = 2.4 Hz, 1H), 4.04 (tdd, J = 9.7, 5.8, 2.5 Hz, 1H), 2.19 (ddt, J = 14.4,
9.7, 5.8 Hz, 1H), 2.12 – 2.04 (m, 1H). C NMR (101 MHz, CDCl
1
13
yellowish oil; bp 77–79 °C / 13 mmHg. H NMR (400 MHz, CDCl
3
) δ 9.86
3
) δ
(
s, 1H), 7.89 (dd, J = 15.4, 8.7 Hz, 1H), 7.63 (d, J = 2.2 Hz, 1H), 6.94 (d,
132.8, 126.8, 109.6, 109.0 (t, J = 287 Hz), 38.9 (dd, J = 16.4, 9.7 Hz),
13
19
J = 1.9 Hz, 1H), 5.89 (d, J = 15.4 Hz, 1H), 5.01 (d, J = 8.8 Hz, 1H).
NMR (126 MHz, CDCl ) δ 179.6, 140.3, 137.9, 131.4, 116.6, 104.4.
GC/MS (EI): m/z = 122 [M] . Anal. Calcd. for C
C
18.1 (t, J = 11.0 Hz). F NMR (376 MHz, CDCl
Hz), –142.8 (d, J = 164 Hz). LC/MS (CI): m/z = 223/225 [M+H] . Anal.
Calcd. for C BrF : C, 32.31; H, 2.26; N, 12.56; Br, 35.83. Found: C,
3
) δ –130.7 (d, J = 164
+
3
+
H N
6 6 2
O: C, 59.01; H, 4.95;
H
6 5
2 2
N
N, 22.94. Found: C, 59.36; H, 5.20; N, 23.14.
31.92; H, 2.15; N, 12.22; Br, 35.66.
5
0
-(Dimethoxymethyl)-1-vinyl-1H-pyrazole (20). Aldehyde 18 (64.9 g,
.513 mol) was dissolved in MeOH (900 mL), and trimethyl orthoformate
Ethyl 1-(2-hydroxyethyl)-1H-pyrazole-3-carboxylate (31). NaH (60%,
18.8 g, 0.470 mol) was suspended in THF (900 mL) at 0 °C and ethyl-1H-
pyrazole-3-carboxylate (60.0 g; 0.428 mol) was added in portions at 0 °C.
After addition, the reaction mixture was warmed up to 35 °C and stirred
for 1.5 h, then cooled to 5 °C, and 2-bromoethanol (62.2 g; 0.514 mol)
was added at 5 - 10 °C. The mixture was stirred overnight at 38 °C, then
(
65.3 g, 0.616 mol) and p-toluenesulfonic acid monohydrate (5.44 g, 2.86
mmol) were added to the solution. The reaction mixture was stirred at rt
for 20 h. Then, H O (500 mL) and 10% aq NaHCO were added to pH 9–
0, and most of MeOH was evaporated in vacuo. The resulting mixture
was extracted with CH Cl (3300 mL), dried over Na SO and
evaporated in vacuo. The crude compound was purified by distillation in
2
3
1
2
2
2
4
,
cooled to 5 °C, and H
evaporated in vacuo, and the residue was washed with CH
mL). The combined organic layers were washed with H O (300 mL),
dried over Na SO and evaporated in vacuo. The residue was purified by
flash chromatography on silica gel using CHCl – MeOH (40:1) as eluent.
) δ 7.50 (d, J = 2.2 Hz, 1H),
6.78 (d, J = 2.2 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 4.31 (t, J = 5.1 Hz, 2H),
2
O (450 mL) was added dropwise. Most of THF was
2
Cl (3450
2
1
vacuo. Yield 74.2 g (86%); yellowish oil; bp 70–72 °C / 0.27 mmHg.
NMR (400 MHz, CDCl ) δ 7.48 (d, J = 2.2 Hz, 1H), 7.17 (dd, J = 9.6, 8.9
Hz, 1H), 6.35 (d, J = 1.7 Hz, 1H), 5.71 (d, J = 15.3 Hz, 1H), 5.47 (s, 1H),
4
1
H
2
3
2
4
3
1
3
1
.81 (d, J = 8.8 Hz, 1H), 3.26 (s, 6H). C NMR (101 MHz, CDCl
3
) δ
Yield 53.6 g (68%). H NMR (500 MHz, CDCl
3
+
39.8, 138.7, 130.4, 107.8, 101.4, 97.1, 52.8. GC/MS (EI): m/z = 168 [M] .
13
Anal. Calcd. for C
H, 7.59; N, 17.03.
H
8 12
2 2
N O : C, 57.13; H, 7.19; N, 16.66. Found: C, 57.44;
4.02 (t, J = 5.1 Hz, 2H), 2.71 (s, 1H), 1.38 (t, J = 7.2 Hz, 3H). C NMR
(126 MHz, CDCl ) δ 162.3, 143.9, 131.7, 108.8, 61.3, 60.9, 54.9, 14.3.
LC/MS (CI): m/z = 185 [M+H] . Anal. Calcd. for C
.57; N, 15.21. Found: C, 52.40; H, 6.85; N, 14.86.
3
+
8 12 2 3
H N O : C, 52.17; H,
6
1
2
-(2,2-Difluorocyclopropyl)-1H-pyrazole-5-carbaldehyde (13b). Acetal
2 (57.0 g. 0.261 mol) was dissolved in THF (285 mL), and 1 M aq HCl
(
285 mL) was added. The reaction mixture was stirred at rt overnight.
Then most of THF was evaporated in vacuo, the residue was diluted with
O (200 mL) and neutralized with 10% NaHCO to pH = 7. The mixture
was extracted with CH Cl (3200 mL), dried over Na SO and
Ethyl 1-(2-((methylsulfonyl)oxy)ethyl)-1H-pyrazole-3-carboxylate (32).
MsCl (24.6 g, 0.215 mol) was added to a solution of alcohol 31 (36.0 g,
H
2
3
0.195 mol) in CH
5 °C and Et N (32.8 mL, 0.235 mol) was added at 5 °C. After addition,
the mixture was stirred at rt overnight, then washed with 10% aq citric
acid (150 mL), dried over Na SO and evaporated in vacuo. The residue
2 2
Cl (250 mL) at rt. The reaction mixture was cooled to
2
2
2
4
3
evaporated in vacuo. The crude compound was purified by distillation in
vacuo. Yield 41.8 g (93%); yellowish liquid; bp 77–79 °C / 0.27 mmHg. H
1
2
4
NMR (400 MHz, CDCl
J = 2.0 Hz, 1H), 4.47 (tdd, J = 10.1, 6.8, 2.0 Hz, 1H), 2.53 – 2.44 (m, 1H),
3
) δ 9.93 (s, 1H), 7.60 (d, J = 2.0 Hz, 1H), 6.96 (d,
was diluted with hexanes - EtOAc (10:1, v/v, 200 mL) and the precipitate
was filtered. Yield 47.1 g (92%); yellowish solid. H NMR (500 MHz,
1
13
2
1
1
1
.12 (dtd, J = 12.3, 10.1, 6.8 Hz, 1H). C NMR (126 MHz, CDCl
79.2, 140.7, 139.5, 115.2, 108.7 (dd, J = 289, 285 Hz), 39.6 (dd, J =
5.9, 9.7 Hz), 16.7 (t, J = 11.1 Hz). F{ H} NMR (376 MHz, CDCl
3
) δ
CDCl
3
) δ 7.52 (d, J = 2.3 Hz, 1H), 6.81 (d, J = 2.3 Hz, 1H), 4.61 (t, J = 4.5
Hz, 2H), 4.52 (t, J = 4.9 Hz, 2H), 4.39 (q, J = 7.1 Hz, 2H), 2.88 (s, 3H),
19
1
13
3
) δ –
1.38 (t, J = 7.2 Hz, 3H). C NMR (126 MHz, CDCl
132.1, 109.2, 67.5, 61.1, 51.8, 37.4, 14.4. LC/MS (CI): m/z = 263 [M+H] .
Anal. Calcd. for C S: C, 41.22; H, 5.38; N, 10.68; S, 12.22.
3
) δ 162.0, 144.8,
+
32.0 (d, J = 163 Hz), –145.1 (d, J = 163 Hz). GC/MS (EI): m/z = 172
+
[
M] . Anal. Calcd. for C
7 6 2
H F N
2
O: C, 48.84; H, 3.51; N, 16.27. Found: C,
9 14 2 5
H N O
4
9.19; H, 3.55; N, 15.87.
Found: C, 41.26; H, 5.72; N, 10.98; S, 12.44.
3
-Nitro-1-vinyl-1H-pyrazole (25). To a solution of 3-nitropyrazole (88.5 g,
Ethyl 1-vinyl-1H-pyrazole-3-carboxylate (26). DBU (178 g, 1.29 mol)
was added to a solution of mesylate 32 (169 g, 0.644 mol) in THF (1500
mL), and the mixture was heated 48 h. Then, the reaction mixture was
cooled to rt and most of THF was evaporated in vacuo. The residue was
+
-
0
.783 mol) in (CH
2
Cl)
2
(1200 mL), Bu
4
N Br (12.6 g, 39.1 mmol) was
O (600 mL).
The reaction mixture was refluxed overnight, then cooled to rt, and the
layers were separated. The aqueous layer was extracted with CH Cl
2300 mL), the combined organic layers were washed with 10% aq citric
acid (300 mL), dried over Na SO and evaporated in vacuo. The crude
added, followed by a solution of KOH (350 g, 6.24 mol) in H
2
2
2
dissolved in CH
citric acid (2600 mL), dried over Na
2
Cl
2
(1000 mL), the solution was washed with 10% aq
SO and evaporated in vacuo. The
(
2
4
2
4
crude compound was purified by column chromatography on silica gel
using hexanes – EtOAc (8:1 to 4:1) as eluent. Yield 67.4 g (63%). For
compound was purified by column chromatography on silica gel using
hexanes – EtOAc (gradient 8:1 to 4:1) as eluent. Yield 68.6 g (63%);
yellowish oil. H NMR (500 MHz, CDCl
[41]
phisical and spectral data, see ref.
1
3
) δ 7.71 (d, J = 2.6 Hz, 1H), 7.08
(
dd, J = 15.6, 8.8 Hz, 1H), 7.00 (d, J = 2.7 Hz, 1H), 5.80 (dd, J = 15.7, 2.1
(
1-(2,2-Difluorocyclopropyl)-1H-pyrazol-3-yl)methanol (28). The crude
13
Hz, 1H), 5.18 (dd, J = 8.8, 2.2 Hz, 1H). C NMR (126 MHz, CDCl
3
) δ
56.6, 132.5, 129.7, 105.3, , 103.9. LC/MS (CI): m/z = 140 [M+H] . Anal.
Calcd. for C : C, 43.17; H, 3.62; N, 30.21. Found: C, 43.31; H,
compound was purified by flash chromatography on silica gel using
hexanes – EtOAc (4:1) as eluent. A suspension of ester 28 (43.0 g; 0.199
mol) and LiBH (6.53 g; 0.300 mol) in THF (1300 mL) was refluxed
4
+
1
5 5 3 2
H N O
3
.85; N, 29.90.
overnight. Then, the reaction mixture was cooled to 0 °C and quenched
with 1N aq HCl to pH = 6. The resulting mixture was diluted with EtOAc
3
-Bromo-1-(2,2-difluorocyclopropyl)-1H-pyrazole (12c). A solution of
(8.67 g, 126 mmol) in H O (10 mL) was added dropwise to a
solution of amine 14c (10.0 g; 62.8 mmol) in 40% aq HBr (40 mL) at 0 °C,
(3500 mL) and washed with saturated aq NaHCO
combined organic layers were dried over Na SO and evaporated in
vacuo. Yield 25.8 g (74%); yellowish oil. H NMR (400 MHz, CDCl ) δ
3
(2400 mL), the
NaNO
2
2
2
4
1
3
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201900123
7
.42 (d, J = 2.4 Hz, 1H), 6.26 (d, J = 2.4 Hz, 1H), 4.64 (s, 2H), 4.01 (tdd,
6.3, 2.4 Hz, 1H), 2.25 (ddt, J = 14.5, 10.1, 5.6 Hz, 1H), 2.11 (dtd, J = 12.9,
13
J = 9.7, 5.8, 2.3 Hz, 1H), 2.62 (s, 1H), 2.17 – 2.08 (m, 1H), 2.03 (ddt, J =
1
9.8, 6.3 Hz, 1H). C NMR (126 MHz, CDCl
3
) δ 152.5, 133.0, 131.9,
13
2.6, 9.7, 5.8 Hz, 1H). C NMR (126 MHz, CDCl
3
) δ 150.8, 129.2, 106.7
128.64, 128.0, 125.8, 109.4 (t, J = 289 Hz), 103.8, 38.9 (dd, J = 16.1, 9.7
19
(
dd, J = 287, 286 Hz), 102.5, 56.2, 35.9 (dd, J = 16.0, 9.6 Hz), 15.5 (t, J =
Hz), 18.20 (t, J = 10.9 Hz). F NMR (470 MHz, CDCl
3
) δ –130.0 (dddd,
19
1
1
–
C
1.0 Hz). F{ H} NMR (376 MHz, CDCl
143.0 (d, J = 163 Hz). LC/MS (CI): m/z = 157 [M-F+H] . Anal. Calcd. for
O: C, 48.28; H, 4.63; N, 16.09. Found: C, 48.21; H, 4.62; N,
3
) δ –130.7 (d, J = 163 Hz),
J = 163, 12.9, 9.8, 5.6 Hz), –142.4 (ddd, J = 163, 14.5, 6.3 Hz). LC/MS
+
+
10 2 2
(CI): m/z = 221 [M+H] . Anal. Calcd. for C12H F N : C, 65.45; H, 4.58; N,
H
7 8
2
F N
2
12.72. Found: C, 65.73; H, 4.89; N, 12.73.
1
5.93.
General procedure for the preparation of 30a–c.
1
-(2,2-Difluorocyclopropyl)-1H-pyrazole-3-carbaldehyde (13c). MnO
2
The corresponding bromide 12 (250 mg, 1.12 mmol) was dissolved in
(
50.0 g, 0.575 mol) was added to a solution of alcohol 28 (10.0 g, 57.4
DMF (2 mL), Et
(172 mg, 0.185 mL, 1.68 mmol) were added under argon atmoshere.
Then, Pd(OAc) (7.63 mg, 34.0 µmol), PPh (17.6 mg, 67.0 µmol) and
CuI (21.3 mg, 112 µmol) were added in argon flow. The resulting mixture
was stirred at 85 °C overnight, then cooled to rt and diluted with EtOAc
3
N (339 mg, 0.468 mL, 3.36 mmol) and phenylacetylene
mmol) in EtOAc (200 mL) and reaction mixture was refluxed overnight.
Then, the mixture was cooled to rt, filtered through silica gel (50 mL) and
evaporated in vacuo. The crude compound was purified by column
chromatography on silica gel using hexanes – EtOAc (6:1) as eluent.
2
3
1
Yield 7.51 g (76%); yellowish crystals; mp 127–129 °C. H NMR (500
(25 mL) and H
2
O (10 mL). Organic layer was separated, dried over
MHz, CDCl
3
) δ 9.97 (s, 1H), 7.58 (d, J = 2.3 Hz, 1H), 6.85 (d, J = 1.6 Hz,
Na SO and evaporated in vacuo.
2
4
1
5
1
H), 4.20 (dddd, J = 10.5, 8.2, 5.9, 2.1 Hz, 1H), 2.35 (ddt, J = 15.1, 8.2,
13
.9 Hz, 1H), 2.22 – 2.16 (m, 1H). C NMR (101 MHz, CDCl
3
) δ 186.1,
1
-(2,2-Difluorocyclopropyl)-4-(phenylethynyl)-1H-pyrazole (30a). The
52.0, 132.7, 108.6 (dd, J = 288, 286 Hz), 106.5, 39.3 (dd, J = 16.1, 9.9
compound was purified by column chromatography on silica gel using
hexanes – EtOAc (9:1) as eluent. Yield 210 mg (78%); yellowish solid;
mp 61–63 °C. H NMR (400 MHz, CDCl
7
2
1
38.8 (dd, J = 16.2, 9.7 Hz), 17.9 (t, J = 11.1 Hz). F{ H} NMR (376 MHz,
CDCl ) δ –130.7 (d, J = 163 Hz), –143.1 (d, J = 163 Hz). LC/MS (CI): m/z
= 245 [M+H] . Anal. Calcd. for C14
19
1
Hz), 17.8 (t, J = 11.2 Hz). F{ H} NMR (376 MHz, CDCl
164 Hz), –143.3 (d, J = 164 Hz). LC/MS (CI): m/z = 173 [M+H] . Anal.
Calcd. for C O: C, 48.84; H, 3.51; N, 16.27. Found: C, 48.69; H,
.58; N, 16.01.
3
) δ –130.8 (d, J
+
=
1
3
) δ 7.68 (s, 1H), 7.68 (s, 1H),
7 6 2 2
H F N
.49 – 7.45 (m, 2H), 7.34 – 7.29 (m, 3H), 4.12 – 4.04 (m, 1H), 2.26 –
3
13
.16 (m, 1H), 2.14 – 2.03 (m, 1H). C NMR (126 MHz, CDCl
3
) δ 142.8,
33.1, 131.4, 128.4, 128.2, 123.2, 108.9 (t, J = 287 Hz), 104.5, 90.5, 79.8,
19
1
General procedure for the preparation of 29a–c.
The corresponding bromide 12 (250 mg, 1.12 mmol), phenylboronic acid
3
+
(
(
164 mg, 1.35 mmol) and K
CH OMe) - H O (3:1, v/v, 12 mL) under argon atmosphere at rt. The
(64.7
2
CO
3
(387 mg, 2.80 mmol) were dissolved in
10 2 2
H F N : C, 68.85; H, 4.13; N, 11.47.
2
2
2
Found: C, 68.77; H, 3.98; N, 11.26.
3 4
resulting solution was heated at 40 °C for 20 min, and Pd(PPh )
mg, 56.0 mol) was added under argon flow. The reaction mixture was
1
-(2,2-Difluorocyclopropyl)-5-(phenylethynyl)-1H-pyrazole (30b). The
stirred at 85 °C overnight, then cooled to rt and diluted with EtOAc (25
compound was purified by column chromatography on silica gel using
mL) and H
silica gel and washed with EtOAc (25 mL). The mother liquor was dried
over Na SO and evaporated in vacuo. The compound was purified by
column chromatography on silica gel using hexanes – EtOAc (6:1) as
eluent.
2
O (10 mL). The organic layer was separated, filtered through
hexanes – EtOAc (9:1) as eluent. Yield 195 mg (72%); yellowish oil.
H NMR (400 MHz, CDCl ) δ 7.54 (dd, J = 6.7, 3.0 Hz, 2H), 7.51 (d, J =
3
1
2
4
1
1
.8 Hz, 1H), 7.38 – 7.34 (m, 3H), 6.52 (d, J = 1.9 Hz, 1H), 4.17 – 4.06 (m,
H), 2.49 – 2.40 (m, 1H), 2.18 – 2.07 (m, 1H). C NMR (126 MHz,
13
CDCl
87 Hz), 97.5, 38.0 (dd, J = 16.2, 9.7 Hz), 17.2 (t, J = 11.2 Hz). F{ H}
NMR (376 MHz, CDCl ) δ –131.6 (d, J = 162 Hz), –143.5 (d, J = 162 Hz).
Anal. Calcd. for C14 : C, 68.85; H, 4.13; N, 11.47. Found: C,
68.86; H, 3.75; N, 11.52.
3
) δ 139.6, 131.53, 129.2, 128.5, 127.5, 121.9, 110.8, 109.2 (t, J =
19
1
2
1
-(2,2-Difluorocyclopropyl)-4-phenyl-1H-pyrazole (29a). The com-
3
pound was purified by column chromatography on silica gel using
hexanes – EtOAc (6:1) as eluent. Yield 185 mg (75%); white solid; mp
10 2 2
H F N
1
6
7
1
8–70 °C. H NMR (400 MHz, CDCl
3
) δ 7.81 (s, 1H), 7.73 (s, 1H), 7.48 –
.44 (m, 2H), 7.38 – 7.33 (m, 2H), 7.28 – 7.20 (m, 1H), 4.11 – 4.03 (m,
1
-(2,2-Difluorocyclopropyl)-3-(phenylethynyl)-1H-pyrazole (30c). The
13
H), 2.27 – 2.21 (m, 1H), 2.13 – 2.06 (m, 1H). C NMR (126 MHz,
) δ 138.0, 131.9, 128.9, 127.3, 126.8, 125.7, 124.0, 109.2 (t, J =
compound was purified by column chromatography on silica gel using
hexanes – EtOAc (9:1) as eluent. Yield 120 mg (44%); white solid; mp
CDCl
87 Hz), 38.9 (dd, J = 16.2, 9.7 Hz), 18.0 (t, J = 11.0 Hz). F NMR (470
MHz, CDCl ) δ –124.5 – –132.9 (m), –142.6 (ddd, J = 163, 14.5, 6.2 Hz).
LC/MS (CI): m/z = 221 [M+H] . Anal. Calcd. for C12
3
19
1
2
7
7
–
1
9
5–77 °C H NMR (400 MHz, CDCl
3
) δ 7.53 (s, 2H), 7.48 (s, 1H), 7.35 –
3
.28 (m, 3H), 6.48 (s, 1H), 4.15 – 3.98 (m, 1H), 2.31 – 2.21 (m, 1H), 2.13
2.04 (m, 1H). C NMR (126 MHz, CDCl
28.3, 122.6, 110.5, 109.0 (t, J = 287 Hz), 90.1, 81.6, 38.96 (dd, J = 16.3,
3
.7 Hz), 18.0 (t, J = 10.9 Hz). F NMR (470 MHz, CDCl ) δ –130.2 (ddd,
+
10 2
H F N
2
: C, 65.45; H,
13
3
) δ 136.0, 131.7, 131.3, 128.6,
4
.58; N, 12.72. Found: C, 65.58; H, 4.80; N, 12.86.
19
1
-(2,2-Difluorocyclopropyl)-5-phenyl-1H-pyrazole
(29b).
The
J = 163, 14.4, 7.0 Hz), –142.5 (ddd, J = 163, 14.2, 6.4 Hz). LC/MS (CI):
m/z = 245 [M+H] . Anal. Calcd. for C14H F N : C, 68.85; H, 4.13; N,
10 2 2
11.47. Found: C, 68.65; H, 4.31; N, 11.25.
+
compound was purified by column chromatography on silica gel using
1
hexanes – EtOAc (6:1) as eluent. Yield 160 mg (65%); yellowish oil.
NMR (500 MHz, CDCl ) δ 7.57 (d, J = 1.8 Hz, 1H), 7.53 – 7.50 (m, 2H),
.50 – 7.47 (m, 2H), 7.46 – 7.42 (m, 1H), 6.41 (d, J = 1.8 Hz, 1H), 4.03
tdd, J = 9.6, 6.9, 2.1 Hz, 1H), 2.47 (ddt, J = 14.4, 9.6, 5.8 Hz, 1H), 2.02
H
3
7
(
(
13
Acknowledgements
dtd, J = 13.1, 9.6, 6.9 Hz, 1H). C NMR (126 MHz, CDCl
3
) δ 145.2,
1
3
39.4, 129.8, 128.8, 128.8, 128.4, 110.0 (dd, J = 288, 286 Hz), 107.0,
19
8.5 (dd, J = 15.7, 9.8 Hz), 17.0 (t, J = 11.1 Hz). F NMR (470 MHz,
) δ –131.5 (ddt, J = 161, 13.1, 6.9 Hz), –143.8 (ddd, J = 161, 14.4,
The work was funded by Enamine Ltd. The authors thank Mr.
Bohdan V. Vashchenko for his invaluable help with manuscript
preparation, and Prof. Andrey A. Tolmachev for his
encouragement and support.
CDCl
6
6
3
+
.9 Hz). LC/MS (CI): m/z = 221 [M+H] . Anal. Calcd. for C12
10 2 2
H F N : C,
5.45; H, 4.58; N, 12.72. Found: C, 65.53; H, 4.28; N, 12.64.
1
-(2,2-Difluorocyclopropyl)-3-phenyl-1H-pyrazole
(29c).
The
Keywords: organofluorine compounds • cycloalkanes • Ruppert
compound was purified by column chromatography on silica gel using
hexanes – EtOAc (6:1) as eluent. H NMR (400 MHz, CDCl
7
2
1
) δ 7.82 –
.79 (m, 1H), 7.78 (s, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.39 (t, J = 7.5 Hz,
H), 7.30 (t, J = 7.3 Hz, 1H), 6.58 (d, J = 2.5 Hz, 1H), 4.12 (tdd, J = 10.1,
– Prakash reagent • azoles • building blocks
3
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European Journal of Organic Chemistry
10.1002/ejoc.201900123
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European Journal of Organic Chemistry
10.1002/ejoc.201900123
Entry for the Table of Contents
FULL PAPER
Fluorinated Cyclopropanes
Pavel S. Nosik, Andrii S. Poturai, Mykola
O. Pashko, Kostiantyn P. Melnykov,
Sergey V. Ryabukhin, Dmitriy M.
Volochnyuk and Oleksandr O.
*
Grygorenko
N-Difluorocyclopropyl-substituted pyrazoles were prepared on a multigram scale by
reaction of N-vinylpyrazoles and CF SiMe – NaI system. Tolerance of the N-difluo-
3 3
Page No. – Page No.
rocyclopropylpyrazole moiety towards many typical organic transformations (i.e.
N-Difluorocyclopropyl-substituted
electrophilic substitution, oxidation, reduction was demonstrated.
pyrazoles: synthesis and reactivity
This article is protected by copyright. All rights reserved.