Synthesis of 1-hetaryl-2,2-difluorocyclopropane-derived building blocks: The case of pyrazoles

Article abstract of DOI:10.1016/j.jfluchem.2018.11.006

An approach to 1-hetaryl-2,2-difluorocyclopropane building blocks compatible with the current criteria of lead-oriented synthesis was developed and implemented for the case of 3-, 4- and 5-subsituted pyrazole derivatives. The method implied 6–9 synthetic steps, including difluorocyclopropanation with the TMSCF₃–NaI system as the key transformation, and provided the title compounds on up to gram scale. The scope of the procedures towards substitution in the pyrazole ring and typical functional groups (i.e. COOH, NH₂, CH₂NH₂, CH₂OH) was established. The results obtained allowed formulation of preliminary guidelines for the synthetic feasibility of various functionalized 1-hetaryl-2,2-difluorocyclopropanes. 2018 Elsevier Ltd. All rights reserved.

Full text of DOI:10.1016/j.jfluchem.2018.11.006

Accepted Manuscript
Title: Synthesis of 1-hetaryl-2,2-difluorocyclopropane-derived
building blocks: the case of pyrazoles
Authors: Pavel S. Nosik, Sergey V. Ryabukhin, Mykola O.
Pashko, Galyna P. Grabchuk, Oleksandr O. Grygorenko,
Dmitriy M. Volochnyuk
PII:
S0022-1139(18)30423-8
DOI:
Reference:
https://doi.org/10.1016/j.jfluchem.2018.11.006
FLUOR 9249
To appear in:
FLUOR
Received date:
Accepted date:
15 October 2018
10 November 2018
Please cite this article as: Nosik PS, Ryabukhin SV, Pashko MO, Grabchuk GP,
Grygorenko OO, Volochnyuk DM, Synthesis of 1-hetaryl-2,2-difluorocyclopropane-
derived building blocks: the case of pyrazoles, Journal of Fluorine Chemistry (2018),
https://doi.org/10.1016/j.jfluchem.2018.11.006
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Journal of Fluorine Chemistry
journal homepage: www.elsevier.com
Synthesis of 1-hetaryl-2,2-difluorocyclopropane-derived building blocks: the
case of pyrazoles
a,b
a,b
a,b
b
Pavel S. Nosik, Sergey V. Ryabukhin, Mykola O. Pashko, Galyna P. Grabchuk, Oleksandr O.
a,b
a,c
Grygorenko, * Dmitriy M. Volochnyuk
a
Enamine Ltd. (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine
b
c
National Taras Shevchenko University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine

Corresponding author. Tel.: +38-044-239-33-15; fax: +38-044-537-32-53; e-mail: gregor@univ.kiev.ua
Graphical abstract
Highlights





An approach to functionalized 1-pyrazolyl-2,2-difluorocyclopropanes was developed
The method relied on difluorocyclopropanation with the TMSCF –NaI system as the key transformation
3
1,2-Disubstituted difluorocyclopropanes were prepared via the difluorocyclopropanation of 3-(pyrazolyl)allylacetates
1,1-Disubstituted difluorocyclopropanes could be obtained via the difluorocyclopropanation of 2-(pyrazolyl)acrylates
Synthetic feasibility of major building block classes (amines, carboxylic acids) within the series was established
ARTICLE INFO
Article history:Received
Received in revised form
Accepted

2
Journal of Fluorine Chemistry
Available online
ABSTRACT
An approach to 1-hetaryl-2,2-difluorocyclopropane building blocks compatible with the current criteria of lead-oriented synthesis was developed and
implemented for the case of 3-, 4- and 5-subsituted pyrazole derivatives. The method implied 6–9 synthetic steps, including difluorocyclopropanation
with the TMSCF
substitution in the pyrazole ring and typical functional groups (i.e. COOH, NH
formulation of preliminary guidelines for the synthetic feasibility of various functionalized 1-hetaryl-2,2-difluorocyclopropanes.
018 Elsevier Ltd. All rights reserved.
3
–NaI system as the key transformation, and provided the title compounds on up to gram scale. The scope of the procedures towards
2
, CH NH , CH OH) was established. The results obtained allowed
2
2
2
2
Keywords: Cycloalkanes, Organofluorine compounds, Nitrogen heterocycles, Lead-oriented synthesis, Ruppert–Prakash reagent
1
. Introduction
In recent years, fluorinated fluorocyclopropanes have been outlined as a promising structural motif for drug discovery, agricultural
chemistry and other areas [1–10]. In particular, gem-difluorocyclopropane moiety can be found in the structures of antineoplastic
agentzosuquidar, which has reached Phase III clinical studies [11], glutamic acid analogue 1 – a selective metabotropic glutamate
receptor mGluR2 agonist [12], -secretase inhibitor 2 (IC50 = 0.2 M) [13], or sodium channel modulator 3 [14].
Figure 1. Some biologically active gem-difluorocyclopropanes
Numerous methods for the construction of gem-difluorocyclopropanes were published to date; typically, they rely on the
difluorocyclopropanation of substrates bearing a double bond [2,15]. Nevertheless, the widespread use of these building blocks was
hampered until recently since most of the above-mentioned methods had moderated efficiency and limited substrate scope, or involved
3 3
the use of toxic and hardly available reagents. In 2011, Prakash, Olah and co-workers reported that the CF SiMe – NaI system is an
efficient reagent for the difluorocyclopropanation of sufficiently reactive alkenes e.g. styrenes [16] (Scheme 1). Later, several groups
extended this procedure to various functionalized substrates, i.e. N-Boc derivatives, ethers, esters, nitriles, and ketals [15,17–22]. In

particular, we have described the “slow addition” protocol, which includes gradual introduction of the Ruppert – Prakash reagent
CF SiMe ) into the reaction mixture. This modification allowed extending the scope of the method to less reactive substrates such as
,-unsaturated esters [15,18].
In this work, we have aimed at further extension of the CF
(
3
3

3
3
SiMe – NaI system applicability towards hetaryl-substituted alkenes
bearing an additional functional group. gem-Difluorocyclopropanes thus obtained are promising synthetic intermediates which can be
used to obtain low-molecular-weight, hydrophilic building blocks compatible with the concept of lead-oriented synthesis [23]. It should
be noted that to date, only a few examples of similar transformations has been reported in the literature, involving pyridyl-substituted
alkenes 4 [24] and a fused pyrazole derivative 5 [21]. It is also remarkable that other diflluorocyclopropanation reagents, e.g.
ClCF
hetaryl-substituted double bonds [25,26]. Herein, we describe our synthetic efforts towards pyrazole derivatives of general formula 6
and 7 involving the use of the CF SiMe – NaI system (Scheme 1). The choice of pyrazole as the model heterocycle relied on
2 2
CO Na or methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (MFDA), demonstrated low to moderate efficiency in reaction with
3
3
attractiveness of this moiety to medicinal and agricultural chemistry [27–29], as well as ability of isomeric pyrazolyl substituents to
mimic -acceptor, -amphoteric, and -donor heterocycles (in the case of 3-, 4-, and 5-isomers, respectively) [30,31]. Since the
3 3
CF SiMe – NaI system is not compatible with the free NH groups, the corresponding N-methyl-substituted pyrazole derivatives were
used as the model substrates; the smallest alkyl substituent would allow maintaining low molecular weight of the building blocks
obtained.

4
Journal of Fluorine Chemistry
3 3
Scheme 1. Difluorocyclopropanation of alkenes with the CF SiMe – NaI system
2
. Results and discussion
First of all, the most obvious retrosynthetic approach to the chemotypes 6 was evaluated, which was based on α,β-unsaturated esters
, in turn being easily accessible from the corresponding aldehydes 10 [30] (Scheme 2). Unfortunately, the difluorocyclopropanation of
using either “slow addition” protocol [15,18] or flow approach [19] was unfruitful. Therefore, electronic deficiency of the double
8
9
bond in the substrate was reduced by transforming the compounds of the type 9 into the corresponding protected alcohols 11. According
to the previous data [15], such modification should increase the alkene reactivity in the reaction with the CF TMS – NaI system.
3
Scheme 2. Retrosynthetic analysis of 1,2-disubstituted (2,2-difluorocyclopropyl)pyrazoles 6
Therefore, synthesis of the target building blocks of the type 6 was performed using the reaction sequence shown in Scheme 3. In
particular, aldehydes 10 were transformed into the corresponding carboxylic acids 12 (E-isomers) via the Knoevenagel condensation
[
30] and then – into esters 11 via the classical esterification. The reduction of esters 11 to the corresponding alcohols 13 was
accomplished with DIBAL (–78 °C, THF) on a multigram scale, with E stereochemistry of the double bond being retained (93–98%
yields). It should be noted that all our attempts to replace the DIBAL with cheaper LiAlH were unsuccessful, since in the latter case,
the reaction either proceeded unselectively, or the products of the C=C double bond reduction were formed.
4

Scheme 3. Retrosynthetic analysis of 1,2-disubstituted (2,2-difluorocyclopropyl)pyrazoles
3
Since the difluorocyclopropanation with the TMSCF – NaI system is not compatible with the free hydroxyl group, the protection
was required for the substrates 13. Among numerous protective groups for the hydroxyl function, acetylation was selected due to atom-
economy considerations and easiness of its introduction. The reaction was performed using AcCl in basic media, which gave
compounds 14 in 94–99% yields. The key step of the reaction sequence, i.e. difluorocyclopropanation, was accomplished using the
“
slow addition” TMSCF
3
batch protocol [15,18] on ca. 5 g scale. The 3- and 4-pyrazolyl derivatives 14a and 14b gave the target
was used. In the case of the 5-pyrazolyl
products 15a and 15b in 50% and 52% yields, respectively, when a six-fold excess of TMSCF
3
derivative 14c, the yield of the product 15c under the same conditions was lower (up to 35%). This effect might be explained by steric
hindrance provided by the neighbouring N-methyl group in the substrate 14c in contrast to the compounds 14a and 14b – an effect
observed by us for the similar objects earlier [30,31]. It should be noted that the yield of the target products 15 could be improved by
repeating the difluorocyclopropanation step with the unreacted alkenes 14 recovered after the first run. In particular, we could achieve
up to 63% conversion of 14a into 15a using this modification of the procedure.
It should be noted that the difluorocyclopropanation proceeded stereospecifically and led to the exclusive formation of trans isomers
1
5, which was proven by 19F NMR spectroscopic analysis of the reaction mixtures. The trans stereochemistry of the products was
1
19
established by H– F heteronuclear NOESY experiments with the compound 17a obtained from 16a (Scheme 4). In the case of other
1
regioisomeric series, the stereochemistry was confirmed by similarity of the spectral patterns in their H NMR spectra.
Scheme 4. Synthesis of carboxylic acids 17 and attempted preparation of amines 18
Subsequent deprotection of the masked hydroxyl group in 15 was performed by K
alcohols 16 in 94–98% yields. In the subsequent step (i.e. oxidation to the carboxylic acids 17), the nature of the pyrazole substitution
appeared to be crucial for the reaction outcome. The common oxidation procedures implying the use of KMnO , CrO , and RuCl
NaIO [32] were tested with the compound 16a. The best results were obtained using the Jones reagent (CrO –H SO in aqueous
2 3
CO -mediated hydrolysis in MeOH to give
4
3
3
–
4
3
2
4
acetone), which gave the corresponding acid 17a in 65% yield on a 3 g scale of the alcohol (Scheme 2). The other oxidation conditions
resulted in decomposition of a considerable part of the product; the over-oxidized products e.g. (difluoromethyl)pyrazolylketones were
detected in the crude product by LCMS.

6
Journal of Fluorine Chemistry
3 2 4
In the case of less electron-deficient 5-pyrazolyl derivative 16c, the CrO –H SO procedure resulted in moderate yield of the
corresponding acid 17c to 51%; substantial formation of unidentified by-products was observed. Unfortunately, all our attempts to
synthesize the acid 17b by analogous procedure failed. In all experiments, only the decomposition products were detected by 19F NMR
analysis of the reaction mixtures. We assume that in the case of π-donor 4-pyrazolyl derivative 17b, heterolytic cleavage of the three-
membered ring occurred (which is characteristic for the donor-acceptor (“push-pull”) cyclopropanes [33]), leading to the intermediate
2
2 and the products of its further decomposition (Scheme 4). It should be noted that analogous carboxylic acid lacking the fluorine
atoms is stable under the aforementioned conditions [30]; the effect of the two fluorine atoms in the case of 17b is unclear and needs
further investigation.
All our attempts to carry out the Curtius-type degradation (e.g. DPPA, toluene, t-BuOH) of the carboxylic acids 17a and 17c into the
corresponding amines 18 were not successful. Despite the commercial availability and wide use of the parent 2,2-difluorocyclo-
propylamine as a hydrochloride in medicinal chemistry literature [34,35], this result is in agreement with the previously reported
instability of such compounds [36]. The reason behind instability of the compounds 18 might be related to the push-pull-type cleavage
of the cyclopropane ring with elimination of the fluorine anion (see Scheme 4).
Finally, the synthesis of homologous amines 21 was performed from alcohols 16 using a standard three-step reaction sequence (i.e.
mesylation – phtalimide introduction – deprotection), which gave the target products in excellent preparative yields for all three
regioisomers (Scheme 5).
Scheme 5. Synthesis of amines 21
As in the case of 1,2-disubstituted difluorocyclopropanes 6, our initial retrosynthetic approach to the building blocks of the type 7
was also based on the difluorocyclopropanation of the corresponding ,-unsaturated esters 24 (Scheme 6). The compounds 24 might
be obtained from the corresponding nitriles 25, in turn prepared from the aldehydes 10 using a published method [31].
Scheme 6. Retrosynthetic analysis of 1,2-disubstituted (2,2-difluorocyclopropyl)pyrazoles 7
Unlike the 1,2-disubstituted alkenes of the type 9, the 1,1-disubstituted substrates 24 appeared to be amenable to the difluorocyclo-
3 3
propanation with the CF SiMe – NaI system. This fact might be explained by more favorable combination of the electronic and steric

factors in the case of 24. Therefore, the initial strategy for the preparation of the esters 23 was implemented as planned without
substantial modification.
The detailed synthetic scheme of the synthesis of the building blocks of type 6 is shown in Scheme 7. In particular, the nitriles 25
were obtained from the aldehydes 10 and then hydrolyzed into the corresponding carboxylic acids 26, which were isolated as
hydrochlorides in moderate to good preparative yields (64–71%). Then, esterification with SOCl
2
in MeOH was used to obtain esters 27
(78–83% yields). The alkene moiety was introduced by the reaction of 27 with paraformaldehyde according to the procedure described
in the literature for analogous arylacetic esters [37]. In the case of 4- and 5-pyrazolyl derivatives 27b and 27c, this method yielded the
corresponding alkenes 24b and 24c in moderate preparative yields (43% and 59%, respectively) after chromatographic purification. The
half-life time of alkenes 24b and 24c at rt was less than 12 h, but it was sufficient for their purification and further use in the next step.
Their longer storage (even at low temperatures and under inert atmosphere) resulted in polymerization. In the case of 3-pyrazolyl
derivative 27a, the reaction accomplished with the formation of the unknown by-product (m/z = 279, GCMS, EI = 70 eV). All attempts
to separate this by-product by either normal-phase chromatography or reverse-phase HPLC failed due to its very close retention time
value to that of the target compound 24a (see the SI). Other isolation techniques were also unfruitful since the half-life time of the
alkene 24a was less than 5 h. Nevertheless, the crude mixture containing 24a could be subjected to the difluorocyclopropanation with
3 3
the CF SiMe –NaI system affording the compound 23a as a mixture with the aforementioned by-product, which remained intact.
Separation of this mixture at this step also failed due to the close retention time values in the preparative HPLC method used (see the
SI). Nevertheless, the subsequent alkaline hydrolysis of the mixture led to decomposition of the unknown by-product affording the pure
carboxylic acid 28a in 13% total yield after the simple liquid-liquid extraction.
Scheme 7. Synthesis of the building blocks of the type 7
3
In the case of the pure alkenes 24b and 24c, the difluorocyclopropanation with the TMSCF –NaI system resulted in 27% and 21%
yields of the compounds 23b and 23c, respectively, and was complicated by polymerization of the starting alkene. The polymerization
process did not allow increasing the conversion by additional repeating of the procedure, as it was done in the case of compound 14.
Further hydrolysis of the ester 23b and 23c gave the corresponding target carboxylic acids 28b and 28c (72% and 75% yields,
respectively).

8
Journal of Fluorine Chemistry
As in a case of the carboxylic acids 17, all our attempts to synthesize the amines 29 by Curtius-type degradation of 28 were
unfruitful; only decomposition of the starting materials was observed.
3
. Conclusions
The building blocks of the trans-1,2-disubstituted 1-pyrazolyl-2,2-difluorocyclopropane series can be obtained on a multigram scale
3 3
starting from easily available N-alkylpyrazole-3-, -4-, and -5-carboxaldehydes and using difluorocyclopropanation with the CF SiMe –
NaI system as the key step. Analogous approach to the 1,1-disubstituted 1-pyrazolyl-2,2-difluorocyclopropane series appeared to be less
efficient; only the corresponding carboxylic acids were prepared on a 100 mg scale. In total, 18 building blocks of the pyrazolyl-
substituted difluorocyclopropane series were studied, and 11 of them appeared to be stable enough to be isolated and fully
characterized. The building blocks obtained are compatible with criteria for the lead-oriented synthesis [23]; moreover, since the
isomeric pyrazolyl substituents differ in their electronic properties, the electronic distribution can be varied significantly within the
compounds libraries obtained, whilst the structural changes being kept minimal. The preliminary guidelines for the preparation of the
building blocks of the type 6 and 7 are summarized in Table 1; we believe that these results can be extended to other 1-hetaryl-2,2-
difluorocyclopropane-derived building blocks.
Table 1. Preliminary guidelines for the synthesis of 1-hetaryl-2,2-difluorocyclopropane-derived building blocks: the case of pyrazoles (legend: “+” – accessible
on a multigram scale; “±” – can be prepared but problematic; “–” – cannot be obtained; “ND” – was not studied)
#
Het
FG
Building block type
1
2
3
4
5
6
7
8
9
COOH
+
+
–
–
+
–
+
+
–
±
CH
NH
COOH
CH OH, CH
NH
COOH
CH OH, CH
NH
2
OH, CH
2
2
2
NH
NH
NH
2
2
2
ND
–
2
±
2
ND
–
2
±
2
ND
–
2
4
. Experimental
4
.1. General

The solvents were purified according to the standard procedures [38]. All starting materials were purchased from commercial
sources. Analytical TLC was performed using Polychrom SI F254 plates. Column chromatography was performed using silica gel as
the stationary phase. H, 13C, and 19F NMR spectra were recorded on a Varian Unity Plus 400 spectrometer (at 400 MHz for Protons,
1
01 MHz for Carbon-13, and 376 MHz for Fluorine-19). Tetramethylsilane ( H, 13C) or C
1
F
6
(19F) were used as internal standards. The
1
2
6
D NMR experiments were made on Bruker 170 Avance 500 spectrometer. Elemental analyses were performed at the Laboratory of
Organic Analysis, Institute of Organic Chemistry, National Academy of Sciences of Ukraine, their results were found to be in good
agreement (±0.4%) with the calculated values. Mass spectra were recorded on an Agilent 1200 LCMSD SL instrument (chemical
ionization (APCI), electrospray ionization (ESI)) or Agilent 7820A gas chromatograph system (electron impact ionization (EI),
ionization energy – 70 eV)).
4
.2. General procedure for the preparation of 13
Diisobutylaluminum hydride (108.3 mL, 108.3 mmol, 1 M in hexane) was added dropwise to a solution of ester 11 (6.07 g,
3
6.1 mmol) in dry THF (200 mL) under argon atmosphere upon stirring at -78 °C during 1 h. The resulting mixture was further stirred
at -78°C for 3 h, then the reaction was quenched by careful addition of 10% aq NH
4
Cl (30 mL) at 0 °C. The solid by-product was
filtered off and washed with THF (3×50 mL). The filtrates were evaporated under reduced pressure to give the product 13.
4
.2.1. (E)-3-(1-Methyl-1H-pyrazol-3-yl)prop-2-en-1-ol (13a).
1
Yield 4.9 g (98%). Yellowish oil. H NMR (CDCl
3
, 400 MHz) δ 7.23 (d, J = 2.0 Hz, 1H), 6.56 (d, J = 16.1 Hz, 1H), 6.30 (dt, J =
, 101 MHz) δ 150.1,
O: C, 60.85; H,
1
1
7
6.1, 5.6 Hz, 1H), 6.26 (d, J = 2.1 Hz, 1H), 4.22 (d, J = 5.5 Hz, 2H), 3.81 (s, 3H), 3.32 (s, 1H). 13C NMR (CDCl
3
+
+
31.1, 130.4, 122.6, 102.8, 63.0, 38.7. MS (ESI): m/z = 139 ([M+H] ), 109 ([M–CH
2
OH] ). Anal. Calcd. for C
7
H
10
N
2
.30; N, 20.28. Found: C, 60.98; H, 7.18; N, 20.64.
4
.2.2. (E)-3-(1-Methyl-1H-pyrazol-4-yl)prop-2-en-1-ol (13b).
1
Yield 8.2 g (95%). Yellowish solid. H NMR (CDCl
3
, 400 MHz) δ 7.44 (s, 1H), 7.26 (s, 1H), 6.33 (d, J = 15.9 Hz, 1H), 6.00 (dt, J =
1
1
2
5.9, 5.8 Hz, 1H), 4.15 (d, J = 5.8 Hz, 2H), 3.78 (s, 3H), 3.32 (brs, 1H). 13C NMR (CDCl
, 101 MHz) δ 136.6, 127.3, 126.6, 120.2,
3
+
19.6, 62.7, 38.3. MS (ESI): m/z = 139 ([M+H] ). Anal. Calcd. for C
7 10 2
H N O: C, 60.85; H, 7.30; N, 20.28. Found: C, 60.80; H, 7.10; N,
0.26.
4
.2.3. (E)-3-(1-Methyl-1H-pyrazol-5-yl)prop-2-en-1-ol (13c).
1
Yield 6.5 g (93%). Yellowish oil. H NMR (CDCl
3
, 400 MHz) δ 7.32 (s, 1H), 6.45 (d, J = 15.8 Hz, 1H), 6.28 (s, 1H), 6.30–6.22 (m,
1
H), 4.27 (d, J = 3.6 Hz, 2H), 3.77 (s, 3H), 3.32 (brs, 1H). 13C NMR (CDCl
, 101 MHz) δ 140.4, 138.3, 133.2, 116.2, 102.9, 62.5, 36.4.
3
+
MS (ESI): m/z = 139 ([M+H] ). Anal. Calcd. for C
7
H
10
N
2
O: C, 60.85; H, 7.30; N, 20.28. Found: C, 61.11; H, 7.24; N, 20.62.
4
.3. General procedure for the preparation of 14
Acetyl chloride (3.1 g, 39.1 mmol) was added dropwise to a solution of alcohol 13 (4.94 g, 35.5 mmol) and NEt
mmol) in dry CH Cl (100 mL) at 0°C over 30 min. The reaction mixture was stirred overnight at rt. The resulting mixture was washed
with 10 % aq citric acid (100 mL). The organic layer was dried over Na SO and evaporated under reduced pressure to give 14.
3
(5.92 mL, 42.6
2
2
2
4

1
0
Journal of Fluorine Chemistry
4
.3.1. (E)-3-(1-Methyl-1H-pyrazol-3-yl)allyl acetate (14a).
1
Yield 6 g (94%). Yellowish oil. H NMR (CDCl
3
, 400 MHz) δ 7.21 (d, J = 2.2 Hz, 1H), 6.57 (d, J = 16.0 Hz, 1H), 6.25 (d, J = 2.2
, 101 MHz) δ 170.7,
9 12 2 2
COO] ). Anal. Calcd. for C H N O :
Hz, 1H), 6.19 (dt, J = 16.0, 6.3 Hz, 1H), 4.63 (d, J = 6.3 Hz, 2H), 3.79 (s, 3H), 2.01 (s, 3H). 13C NMR (CDCl
3
+
+
1
49.4, 131.1, 126.0, 124.0, 103.1, 64.7, 38.8, 20.9. MS (ESI): m/z = 181 ([M+H] ), 121 ([M–CH
3
C, 59.99; H, 6.71; N, 15.55. Found: C, 59.84; H, 6.69; N, 15.68.
4
.3.2. (E)-3-(1-Methyl-1H-pyrazol-4-yl)allyl acetate (14b).
1
Yield 10.5 g (98%). Yellowish oil. H NMR (CDCl
3
, 400 MHz) δ 7.46 (s, 1H), 7.29 (s, 1H), 6.39 (d, J = 15.9 Hz, 1H), 5.92 (dt, J =
, 101 MHz) δ 170.8, 137.3, 128.1, 124.7, 121.0,
COO] ). Anal. Calcd. for C : C, 59.99; H, 6.71; N, 15.55.
1
1
5.8, 6.7 Hz, 1H), 4.56 (d, J = 6.3 Hz, 2H), 3.78 (s, 3H), 1.99 (s, 3H). 13C NMR (CDCl
3
+
+
19.6, 65.3, 38.9, 20.9. MS (ESI): m/z = 181 ([M+H] ), 121 ([M–CH
3
9 12 2 2
H N O
Found: C, 60.37; H, 6.98; N, 15.74.
4
.3.3. (E)-3-(1-Methyl-1H-pyrazol-5-yl)allyl acetate (14c).
1
Yield 7.8 g (99%). Orange oil. H NMR (CDCl
3
, 400 MHz) δ 7.34 (d, J = 1.3 Hz, 1H), 6.50 (d, J = 15.8 Hz, 1H), 6.32 (d, J = 1.6 Hz,
1
1
1
H), 6.17 (dt, J = 15.8, 6.3 Hz, 1H), 4.67 (dd, J = 6.2, 1.1 Hz, 2H), 3.82 (s, 3H), 2.06 (s, 3H). 13C NMR (CDCl
3
, 101 MHz) δ 170.6,
+
39.5, 138.4, 126.8, 120.2, 103.5, 64.4, 36.6, 20.9. MS (ESI): m/z = 181 ([M+H] ). Anal. Calcd. for C
H N O : C, 59.99; H, 6.71; N,
9 12 2 2
5.55. Found: C, 60.20; H, 6.82; N, 15.60.
4
.4. General procedure for the preparation of 15
Sodium iodide (1.65 g, 11.0 mmol) was added to a solution of alkene 14 (5.56 g, 30.5 mmol) in anhydrous THF (100 mL) under
nitrogen atmosphere and heated to reflux. Trimethyl(trifluoromethyl)silane (15.2 g, 106.8 mmol, 3.5 eq) was added dropwise over 24 h.
1
The reaction mixture was heated overnight; the conversion was detected by H NMR. More trimethyl(trifluoromethyl)silane (15.2 g,
1
06.8 mmol, 3.5 eq) was added dropwise over 24 h and the reaction mixture was heated overnight. The solvent was evaporated, and the
crude material was purified by column chromatography (EtOAc –hexane (1:2) as eluent) to give 15.
4
.4.1. (2,2-Difluoro-3-(1-methyl-1H-pyrazol-3-yl)cyclopropyl)methyl acetate (15a).
1
Yield 3.5 g (50%). Orange oil. H NMR (CDCl
3
, 400 MHz) δ 7.25 (s, 1H), 6.02 (s, 1H), 4.35 (dd, J = 11.9, 7.0 Hz, 1H), 4.11 (dd, J =
1
1
1
5
1.6, 8.6 Hz, 1H), 3.82 (s, 3H), 2.62 (q, J = 7.2 Hz, 1H), 2.34 – 2.22 (m, 1H), 2.04 (s, 3H). 13C NMR (CDCl
31.0, 112.7 (t, J = 289.3 Hz), 104.1, 60.6, 38.8, 27.5 (t, J = 10.3 Hz), 26.0 (t, J = 11.6 Hz), 20.8. 19F NMR (CDCl
3
, 101 MHz) δ 170.8, 144.5,
, 376 MHz) δ –
3
+
+
38.4. MS (ESI): m/z = 231 ([M+H] ), 171 ([M–CH
3
CO–F] . Anal. Calcd. for C10
H
12
F
2
N
2
O
2
: C, 52.17; H, 5.25; N, 12.17. Found: C,
1.91; H, 4.95; N, 12.56.
4
.4.2. (2,2-Difluoro-3-(1-methyl-1H-pyrazol-4-yl)cyclopropyl)methyl acetate (15b).
1
Yield 7.0 g (52%). Orange oil. H NMR (CDCl
3
, 400 MHz) δ 7.34 (s, 1H), 7.23 (s, 1H), 4.29 (dddd, J = 12.0, 7.7, 2.4, 1.1 Hz, 1H),
1
3
4
.15 (ddd, J = 12.0, 7.7, 1.8 Hz, 1H), 3.84 (s, 3H), 2.44 (dd, J = 14.1, 7.1 Hz, 1H), 2.07 (s, 3H), 1.95 (dq, J = 13.4, 7.4 Hz, 1H). C
NMR (CDCl
3
, 101 MHz) δ 170.3, 138.0, 128.1, 113.1, 112.9 (dd, J = 298.7, 278.3 Hz), 60.4 (d, J = 5.8 Hz), 38.7, 29.3 (t, J = 10.2 Hz),

2
2.8 (t, J = 10.2 Hz), 20.6. 19F NMR (CDCl
3
, 376 MHz) δ –137.2 (dd, J = 158.0, 13.6 Hz), –139.0 (dd, J = 158.0, 14.2 Hz). MS (ESI):
+
+
m/z = 231 ([M+H] ), 181, 171 ([M–CH
3
CO–F] ), 151. Anal. Calcd. for C10
H
12
F
2
N
2
O
2
: C, 52.17; H, 5.25; N, 12.17. Found: C, 52.05; H,
4
.89; N, 12.51.
4
.4.3. (2,2-Difluoro-3-(1-methyl-1H-pyrazol-5-yl)cyclopropyl)methyl acetate (15c).
1
Yield 4.0 g (35%). Yellowish oil. H NMR (CDCl
3
, 400 MHz) δ 7.41 (d, J = 1.8 Hz, 1H), 6.11 (s, 1H), 4.32 (d, J = 7.8 Hz, 2H), 3.89
, 101 MHz) δ 170.7, 138.5,
(
s, 3H), 2.54 (dd, J = 13.3, 7.1 Hz, 1H), 2.20 (dq, J = 13.4, 7.4 Hz, 1H), 2.11 (s, 3H). 13C NMR (CDCl
3
1
1
34.5, 112.2 (t, J = 289 Hz), 105.4, 60.3 (d, J = 5.0 Hz), 36.7, 29.1, 23.2, 20.9. 19F NMR (CDCl
3
, 376 MHz) δ –135.9 (dd, J = 159.0,
+
+
3.2 Hz), –137.8 (dd, J = 159.2, 13.0 Hz). MS (ESI): m/z = 231 ([M+H] ), 181, 171 ([M–CH
3
CO–F] ). Anal. Calcd. for C10
H F
12 2
N
2
O
2
:
C, 52.17; H, 5.25; N, 12.17. Found: C, 51.84; H, 5.17; N, 12.04.
4
.5. General procedure for the preparation of 16
A solution of K
.05 M) and the mixture was heated at 60 °C overnight. The complete conversion was confirmed by TLC. The reaction mixture was
Cl (30 mL). The organic layer was filtered through a pad of Na SO and
evaporated. The resulted sample was purified by column chromatography (EtOAc –hexane (1:1) as eluent) to give 16.
2 3 2
CO (1.8 g, 13 mmol) in H O (8 mL) was added to solution of acetate 15 (3.0 g, 13 mmol) in MeOH (240 mL,
0
concentrated under reduced pressure and quenched with CH
2
2
2
4
4
.5.1. (2,2-Difluoro-3-(1-methyl-1H-pyrazol-3-yl)cyclopropyl)methanol (16a).
1
Yield 2.4 g (98%). Yellowish oil. H NMR (CDCl
3
, 400 MHz) δ 7.27 (d, J = 2.2 Hz, 1H), 6.07 (dd, J = 2.3, 1.3 Hz, 1H), 3.89 – 3.78
, 101 MHz) δ
44.7, 130.6, 113.0 (t, J = 288.3 Hz), 103.9, 58.6 (d, J = 5.3 Hz), 38.5, 31.1 (t, J = 9.5 Hz), 25.3 (t, J = 9.5 Hz). F NMR (CDCl , 376
(
m, 2H), 3.83 (s, 3H), 3.65 (brs, 1H), 2.60 (dd, J = 13.7, 7.4 Hz, 1H), 2.21 (dq, J = 13.9, 7.1 Hz, 1H). 13C NMR (CDCl
3
1
9
1
3
+
+
MHz) δ –137.5 (dd, J = 158.2, 14.1 Hz), –139.3 (dd, J = 158.2, 13.9 Hz). MS (ESI): m/z = 189 ([M+H] ), 171 ([M-HF] , 151. Anal.
Calcd. for C O: C, 51.06; H, 5.36; N, 14.89. Found: C, 51.31; H, 5.03; N, 14.52.
.5.2. (2,2-Difluoro-3-(1-methyl-1H-pyrazol-4-yl)cyclopropyl)methanol (16b).
8
10 2 2
H F N
4
1
Yield 5.6 g (98%). Orange oil. H NMR (CDCl
H), 2.36 (dd, J = 14.2, 7.2 Hz, 1H), 1.86 (dq, J = 14.3, 7.2 Hz, 1H). 13C NMR (CDCl
00.8, 276.0 Hz), 58.7 (d, J = 5.8 Hz), 38.6, 32.6, 22.1. 19F NMR (CDCl
3
, 400 MHz) δ 7.31 (s, 1H), 7.22 (s, 1H), 3.86 – 3.74 (m, 2H), 3.82 (s, 3H), 3.64 (brs,
1
3
1
3
, 101 MHz) δ 137.9, 128.3, 113.8, 113.5 (dd, J =
3
, 376 MHz) δ –136.7 (dd, J = 157.2, 13.9 Hz), –139.8 (dd, J =
+
+
2 8 10 2 2
57.2, 14.2 Hz). MS (ESI): m/z = 189 ([M+H] ), 139 ([M–HF–CH OH] ). Anal. Calcd. for C H F N O: C, 51.06; H, 5.36; N, 14.89.
Found: C, 51.24; H, 5.57; N, 15.29.
4
.5.3. (2,2-Difluoro-3-(1-methyl-1H-pyrazol-5-yl)cyclopropyl)methanol (16c).
1
Yield 1.9 g (97%). Orange oil. H NMR (CDCl
3
, 400 MHz) δ 7.34 (d, J = 1.9 Hz, 1H), 6.08 (s, 1H), 3.90 (ddd, J = 12.0, 7.1, 1.5 Hz,
, 101 MHz) δ
1
1
H), 3.82 (s, 3H), 3.83 – 3.76 (m, 1H), 2.43 (dd, J = 13.2, 7.2 Hz, 1H), 2.07 (dq, J = 14.2, 7.1 Hz, 1H). 13C NMR (CDCl
3
37.7, 135.1, 112.3 (t, J = 287.7 Hz), 104.8, 57.7 (d, J = 5.0 Hz), 36.0, 31.8, 21.9 (dd, J = 13.2, 10.6 Hz). 19F NMR (CDCl
, 376 MHz)
3
+
+
δ –135.2 (dd, J = 158.0, 13.9 Hz), –138.6 (dd, J = 158.0, 13.2 Hz). MS (ESI): m/z = 189 ([M+H] ), 139 ([M–HF–CH
2
OH] ). Anal.
8 10 2 2
Calcd. for C H F N O: C, 51.06; H, 5.36; N, 14.89. Found: C, 51.04; H, 5.08; N, 14.78.

1
2
Journal of Fluorine Chemistry
4
.6. General procedure for the preparation of 17
Sulfuric acid (3.12 g, 95–98%) was added to a solution of chromium trioxide (2.39 g, 23.9 mmol) in water (5.4 mL) at 0 °C, and the
mixture was stirred for 30 min. This mixture was added to a solution of alcohol 16 (2.98 g, 15.9 mmol) in acetone (30 mL) at 0 °C, and
the resulting mixture was stirred overnight at rt. The organic layer was decanted and evaporated. The crude product was purified by
column chromatography (EtOAc –hexane – HCOOH (40:40:1) as eluent) to give pure acid 17.
4
.6.1. 2,2-Difluoro-3-(1-methyl-1H-pyrazol-3-yl)cyclopropane-1-carboxylic acid (17a).
1
Yield 1.4 g (65%). Yellowish solid. H NMR (CDCl
3
, 400 MHz) δ 10.93 (brs, 1H), 7.32 (d, J = 2.2 Hz, 1H), 6.17 (s, 1H), 3.90 (s,
, 101 MHz) δ 169.1, 142.7, 131.1 (d, J =
3
3
H), 3.52 (ddd, J = 12.9, 7.6, 2.5 Hz, 1H), 2.74 (dd, J = 13.5, 7.6 Hz, 1H). 13C NMR (CDCl
3
0.2 Hz), 110.2 (dd, J = 293.3, 286.9 Hz), 104.6 (d, J = 1.7 Hz), 38.6, 32.2 (t, J = 11.2 Hz), 27.3 (dd, J = 12.7, 8.4 Hz). 19F NMR
+
(CDCl
3
, 376 MHz) δ –133.9 (dd, J = 152.4, 13.4 Hz), –135.7 (dd, J = 152.5, 12.9 Hz). MS (ESI): m/z = 203 ([M+H] ), 185 ([M–
+
+
H
2
O] ), 157 ([M–COOH] ). Anal. Calcd. for C
8
H
8
F
2
N
2
O
2
: C, 47.53; H, 3.99; N, 13.86. Found: C, 47.72; H, 4.07; N, 13.83.
4
.6.2. 2,2-Difluoro-3-(1-methyl-1H-pyrazol-5-yl)cyclopropane-1-carboxylic acid (17c).
1
Yield 1 g (51%). Yellowish solid. H NMR (DMSO-d
6
, 400 MHz) δ 7.35 (s, 1H), 6.23 (s, 1H), 3.81 (s, 3H), 3.54 (dd, J = 12.1, 7.9
, 101 MHz) δ 166.7, 138.1, 133.7, 111.0 (t, J = 299.9, 287.0 Hz), 105.7,
, 376 MHz) δ –132.7 (d, J = 147.9 Hz), –134.5 (d, J = 147.9 Hz). MS (ESI): m/z =
Hz, 1H), 3.09 (dd, J = 14.3, 7.7 Hz, 1H). 13C NMR (DMSO-d
6
3
2
6.9, 32.2 (t, J = 10.0 Hz), 23.9. 19F NMR (DMSO-d
6
+
03 ([M+H] ). Anal. Calcd. for C
8
H
8
F
2
N
2
O
2
: C, 47.53; H, 3.99; N, 13.86. Found: C, 47.22; H, 3.63; N, 13.71.
4
.7. General procedure for the preparation of 19
3
Methanesulfonyl chloride (0.34 g, 3.0 mmol) was added dropwise to a solution of alcohol 16 (0.51 g, 2.7 mmol) and NEt (0.55 g,
5
.4 mmol) in dry CH
2
Cl
2
(10 mL) at 0 °C over 30 min. The reaction mixture was stirred overnight at rt. The organic layer was washed
SO and evaporated under reduced pressure to give 19.
.7.1. (2,2-Difluoro-3-(1-methyl-1H-pyrazol-3-yl)cyclopropyl)methyl methanesulfonate (19a).
with 10 % aq citric acid (10 mL), dried over Na
2
4
4
1
Yield 1.4 g (99%). Yellowish oil. H NMR (CDCl
3
, 400 MHz) δ 7.30 (d, J = 2.2 Hz, 1H), 6.10 (d, J = 2.2 Hz, 1H), 4.55 – 4.46 (m,
1
H), 4.35 (ddd, J = 11.4, 8.4, 1.4 Hz, 1H), 3.85 (s, 3H), 3.06 (s, 3H), 2.74 (ddd, J = 12.5, 7.2, 2.0 Hz, 1H), 2.51 – 2.40 (m, 1H). 13
C
NMR (CDCl
10.6 Hz). 19F NMR (CDCl
, 376 MHz) δ –138.5 (dd, J = 159.4, 12.3 Hz), –139.1 (dd, J = 159.4, 11.2 Hz). MS (ESI): m/z = 267
3
3
, 101 MHz) δ 143.1, 130.7, 111.8 (t, J = 288.8 Hz), 104.1, 65.6 (d, J = 5.7 Hz), 38.7, 37.8, 27.1 (t, J = 10.6 Hz), 26.2 (t, J
=
+
+
(
[M+H] ), 171([M–CH
3 2 9 12 2 2 3
SO –F] , 151. Anal. Calcd. for C H F N O S: C, 40.60; H, 4.54; N, 10.52; S, 12.04. Found: C, 40.77; H, 4.48;
N, 10.36; S, 12.17.
4
.7.2. (2,2-Difluoro-3-(1-methyl-1H-pyrazol-4-yl)cyclopropyl)methyl methanesulfonate (19b).
1
Yield 1.4 g (99%). Red oil. H NMR (CDCl
3
, 400 MHz) δ 7.35 (s, 1H), 7.27 (s, 1H), 4.45 – 4.30 (m, 2H), 3.83 (s, 3H), 3.03 (s, 3H),
1
3
2
3
.56 (dd, J = 14.3, 7.0 Hz, 1H), 2.04 (dq, J = 12.7, 7.7 Hz, 1H). C NMR (CDCl , 101 MHz) δ 137.9, 128.4, 112.5 (t, J = 288.7 Hz),

1
1
12.3, 65.7 (d, J = 5.9 Hz), 38.8, 37.6, 29.3 (t, J = 10.5 Hz), 23.3 (dd, J = 12.7, 10.7 Hz). 19F NMR (CDCl
3
, 376 MHz) δ –136.8 (dd, J =
+
+
59.2, 12.5 Hz), –138.3 (dd, J = 159.3, 14.2 Hz). MS (ESI): m/z = 267 ([M+H] ), 171 ([M–CH
3 2
SO –F] ), 151. Anal. Calcd. for
9 12 2 2 3
C H F N O
S: C, 40.60; H, 4.54; N, 10.52; S, 12.04. Found: C, 40.95; H, 4.74; N, 10.77; S, 11.74.
4
.7.3. (2,2-Difluoro-3-(1-methyl-1H-pyrazol-5-yl)cyclopropyl)methyl methanesulfonate (19c).
1
Yield 1.4 g (99%). Reddish oil. H NMR (CDCl
3
, 400 MHz) δ 7.41 (s, 1H), 6.15 (s, 1H), 4.53 (dd, J = 11.0, 7.5 Hz, 1H), 4.43 – 4.36
(
m, 1H), 3.90 (s, 3H), 3.08 (s, 3H), 2.68 (dd, J = 13.4, 7.0 Hz, 1H), 2.30 (dq, J = 15.0, 7.6 Hz, 1H). 13C NMR (CDCl
3
, 101 MHz) δ
1
37.9, 133.2, 111.2 (t, J = 287.7 Hz), 104.9, 64.5 (d, J = 4.9 Hz), 37.4, 36.2, 28.5 (t, J = 10.3 Hz), 23.0 (dd, J = 13.2, 10.5 Hz). 19
F
+
NMR (CDCl
3
, 376 MHz) δ –135.0 (d, J = 160.3 Hz), –136.6 (d, J = 160.3 Hz). MS (ESI): m/z = 267 ([M+H] ). Anal. Calcd. for
S: C, 40.60; H, 4.54; N, 10.52; S, 12.04. Found: C, 40.92; H, 4.24; N, 10.53; S, 12.29.
.8. General procedure for the preparation of 20
9 12 2 2 3
C H F N O
4
Potassium phthalimide (0.65 g, 3.5 mmol) was added to a solution of mesylate 19 (0.61 g, 2.3 mmol) in DMF (10 mL) at rt. The
reaction mixture was stirred vigorously at 100 °C for 3 h. The completion of the reaction was controlled by the disappearance of the
mesylate in TLC. The resulting mixture was cooled to rt. The combined organic layers were washed with H O (350 mL), brine (230
mL), dried over anhydrous Na SO , filtered and concentrated under reduced pressure. A crude product was purified by column
chromatography (EtOAc –hexane (1:1) as eluent) afforded pure 20.
2
2
4
4
.8.1. 2-((2,2-Difluoro-3-(1-methyl-1H-pyrazol-3-yl)cyclopropyl)methyl)-isoindoline-1,3-dione (20a).
1
Yield 0.60 g (82%). White solid. H NMR (CDCl
3
, 400 MHz) δ 7.87 – 7.80 (m, 2H), 7.74 – 7.67 (m, 2H), 7.23 (d, J = 2.2 Hz, 1H),
6
.00 (d, J = 2.1 Hz, 1H), 4.01 (dd, J = 14.7, 7.0 Hz, 1H), 3.91 (ddt, J = 14.5, 8.1, 1.5 Hz, 1H), 3.80 (s, 3H), 2.78 (ddd, J = 11.8, 7.4, 2.6
Hz, 1H), 2.50 – 2.38 (m, 1H). 13C NMR (CDCl
, 101 MHz) δ 167.3, 144.1, 133.6, 131.5, 130.4, 123.0, 112.5 (t, J = 289.5 Hz), 103.7,
8.6, 34.7 (d, J = 4.9 Hz), 27.4 (t, J = 10.1 Hz), 26.7 (t, J = 11.4 Hz). 19F NMR (CDCl
, 376 MHz) δ –138.5 (dd, J = 157.6, 11.5 Hz), –
3
3
3
1
6
+
39.0 (dd, J = 157.6, 11.5 Hz). MS (ESI): m/z = 318 ([M+H] ). Anal. Calcd. for C16
H
13
F
2
N
3
O
2
: C, 60.57; H, 4.13; N, 13.24. Found: C,
0.78; H, 4.00; N, 13.18.
4
.8.2. 2-((2,2-Difluoro-3-(1-methyl-1H-pyrazol-4-yl)cyclopropyl)methyl)-isoindoline-1,3-dione (20b).
1
Yield 1.1 g (91%). White solid. H NMR (CDCl
3
, 400 MHz) δ 7.89 – 7.81 (m, 2H), 7.76 – 7.69 (m, 2H), 7.27 (s, 1H), 7.18 (s, 1H),
4
.04 (dd, J = 14.6, 6.1 Hz, 1H), 3.85 – 3.76 (m, 1H), 3.80 (s, 3H), 2.59 (dd, J = 14.1, 7.2 Hz, 1H), 2.09 – 1.97 (m, 1H). 13C NMR
, 101 MHz) δ 167.4, 137.9, 133.7, 131.4, 128.0, 123.0, 113.3, 113.1 (t, J = 289.5 Hz), 38.7, 34.9 (d, J = 5.5 Hz), 29.4 (t, J = 9.9
(CDCl
3
Hz), 23.7 (t, J = 11.6 Hz). 19F NMR (CDCl
, 376 MHz) δ –137.0 (dd, J = 157.9, 13.7 Hz), –138.6 (dd, J = 157.9, 14.1 Hz). MS (ESI):
: C, 60.57; H, 4.13; N, 13.24. Found: C, 60.37; H, 3.94; N, 12.95.
3
+
m/z = 318 ([M+H] ), 171. Anal. Calcd. for C16
H
13
F
2
N
3
O
2
4
.8.3. 2-((2,2-Difluoro-3-(1-methyl-1H-pyrazol-5-yl)cyclopropyl)methyl)-isoindoline-1,3-dione (20c).
1
Yield 1 g (85%). White solid. H NMR (CDCl
H), 5.96 (s, 1H), 4.09 (dd, J = 14.6, 5.6 Hz, 1H), 3.84 (dd, J = 14.5, 9.3 Hz, 1H), 3.76 (s, 3H), 2.66 (dd, J = 13.0, 7.2 Hz, 1H), 2.27 (td,
, 101 MHz) δ 168.0, 138.3, 134.8, 134.4, 131.8, 123.6, 112.2 (t, J = 291.6 Hz), 104.9, 36.5, 34.6
3
, 400 MHz) δ 7.84 (dd, J = 5.1, 3.1 Hz, 2H), 7.72 (dd, J = 5.2, 3.0 Hz, 2H), 7.30 (s,
1
J = 13.5, 6.9 Hz, 1H). 13C NMR (CDCl
3

1
4
Journal of Fluorine Chemistry
(
d, J = 5.2 Hz), 29.0 (t, J = 9.9 Hz), 23.8. 19F NMR (CDCl
, 376 MHz) δ –135.7 (d, J = 158.8 Hz), –137.2 (d, J = 158.8 Hz). MS (ESI):
3
+
m/z = 318 ([M+H] ). Anal. Calcd. for C16
H
13
F
2
N
3
O
2
: C, 60.57; H, 4.13; N, 13.24. Found: C, 60.79; H, 4.28; N, 13.29.
4
.9. General procedure for the preparation of 21
Phthalimide derivative 20 (0.412 g, 1.30 mmol) was heated in EtOH (10 mL) to reflux. Hydrazine monohydrate (0.651 g, 13.0
mmol) was added dropwise at reflux over 10 min. The resulting mixture was further stirred for 15 min at reflux leading to formation of
a colorless solid product. The colorless suspension was allowed to cool down to rt and poured into a mixture of CH Cl (10 mL) and
O (5 mL). The layers were separated and the aqueous layer was extracted with CH Cl (310 mL). The combined organic layers were
washed with brine (210 mL), dried over anhydrous Na SO , filtered, and concentrated under reduced pressure to give 21.
.9.1. (2,2-Difluoro-3-(1-methyl-1H-pyrazol-3-yl)cyclopropyl)methanamine (21a).
2
2
H
2
2
2
2
4
4
1
3
Yield 0.24 g (99%). Yellowish oil. H NMR (CDCl , 400 MHz) δ 7.24 (d, J = 2.2 Hz, 1H), 6.02 (dd, J = 2.1, 1.3 Hz, 1H), 3.81 (s,
3
2
2
H), 3.03 – 2.95 (m, 1H), 2.87 (ddd, J = 13.6, 8.0, 1.3 Hz, 1H), 2.48 (dd, J = 13.7, 7.4 Hz, 1H), 2.04 (qd, J = 7.9, 1.1 Hz, 1H), 1.68 (brs,
H). 13C NMR (CDCl
3
, 101 MHz) δ 144.9, 130.5, 113.5 (t, J = 288.9 Hz), 103.6, 39.4 (d, J = 5.5 Hz), 38.5, 31.9 (dd, J = 10.0, 8.7 Hz),
5.9 (dd, J = 12.0, 10.7 Hz). 19F NMR (CDCl
, 376 MHz) δ –137.7 (dt, J = 156.8, 16.3 Hz), –140.2 (dt, J = 156.8, 16.3 Hz). MS (ESI):
: C, 51.33; H, 5.92; N, 22.45. Found: C, 51.21; H, 5.64; N,
3
+
]+), 151. Anal. Calcd. for C
m/z = 188 ([M+H] ), 171([M–NH
3
8
H
11
F
2
N
3
2
2.73.
4
.9.2. (2,2-Difluoro-3-(1-methyl-1H-pyrazol-4-yl)cyclopropyl)methanamine (21b).
1
Yield 0.45 g (96%). Yellowish oil. H NMR (CDCl
3
, 400 MHz) δ 7.29 (s, 1H), 7.17 (s, 1H), 3.78 (s, 3H), 2.94 (ddd, J = 13.5, 6.7,
3
.0 Hz, 1H), 2.83 (dd, J = 13.5, 7.9 Hz, 1H), 2.23 (dd, J = 14.3, 7.2 Hz, 1H), 1.67 (dq, J = 14.5, 7.2 Hz, 1H), 1.48 (brs, 2H). 13C NMR
(CDCl
3
, 101 MHz) δ 137.9, 128.0, 114.0 (t, J = 288.3 Hz), 113.9, 39.5 (d, J = 5.6 Hz), 38.6, 33.6, 22.6. 19F NMR (CDCl
, 376 MHz) δ
3
+
]+), 151. Anal. Calcd. for
–
136.4 (dd, J = 156.3, 14.4 Hz), –140.6 (dd, J = 156.1, 14.3 Hz). MS (ESI): m/z = 188 ([M+H] ), 171([M–NH
3
8 11 2 3
C H F N : C, 51.33; H, 5.92; N, 22.45. Found: C, 51.61; H, 5.64; N, 22.80.
4
.9.3. (2,2-Difluoro-3-(1-methyl-1H-pyrazol-5-yl)cyclopropyl)methanamine (21c).
1
Yield 0.26 g (87%). Yellowish oil. H NMR (CDCl
3
, 400 MHz) δ 7.31 (d, J = 1.7 Hz, 1H), 6.01 (s, 1H), 3.80 (s, 3H), 2.99 (ddd, J =
1
3.5, 6.7, 2.8 Hz, 1H), 2.92 (dd, J = 13.5, 7.9 Hz, 1H), 2.31 (dd, J = 13.1, 7.2 Hz, 1H), 1.91 (dq, J = 14.7, 7.3 Hz, 1H), 1.41 (brs, 2H).
13C NMR (CDCl
, 101 MHz) δ 138.2, 135.4, 113.1 (t, J = 290.5 Hz), 105.0, 39.3 (d, J = 5.1 Hz), 36.5, 32.7 (dd, J = 10.5, 8.3 Hz), 22.6
3
(
(
dd, J = 12.8, 10.9 Hz). 19F NMR (CDCl
3
, 376 MHz) δ –134.7 (d, J = 156.9 Hz), –139.2 (d, J = 156.9 Hz). MS (ESI): m/z = 188
+
+
[M+H] ), 168([M–HF] ). Anal. Calcd. for C
8 11 2 3
H F N : C, 51.33; H, 5.92; N, 22.45. Found: C, 51.70; H, 5.53; N, 22.39.
4
.10. General procedure for the preparation of 23
Sodium iodide (1.27 g, 8.5 mmol) was added to a solution of alkene 24 (4.01 g) in anhydrous THF (60 mL) under nitrogen
atmosphere and heated to reflux. Trimethyl(trifluoromethyl)silane (12 g, 84.8 mmol) was added dropwise during 24 h. The reaction

1
mixture was heated overnight; the conversion was detected by H NMR. The solvent was evaporated, and the crude material was
purified by column chromatography (EtOAc –hexane (1:1) as eluent) to give 23.
4
.10.1. Methyl 2,2-difluoro-1-(1-methyl-1H-pyrazol-3-yl)cyclopropane-1-carboxylate (23a).
Used in the next step without purification. Yield 2.50 g. Yellowish oil. 19F NMR (CDCl
, 376 MHz) δ –131.4 (d, J = 146.8 Hz), –
3
+
+
1
3
35.7 (d, J = 146.8 Hz). MS (EI): m/z = 216 (M ), 185 (M –CH –F), 155.
4
.10.2. Methyl 2,2-difluoro-1-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxylate (23b).
1
Yield 1.5 g (27%). Yellowish oil. H NMR (CDCl
3
, 400 MHz) δ 7.44 (d, J = 2.5 Hz, 2H), 3.88 (s, 3H), 3.74 (s, 3H), 2.60 (ddd, J =
, 101 MHz) δ 167.0, 138.9, 130.2, 112.4, 110.8 (t, J =
1
2
3.2, 7.9, 6.0 Hz, 1H), 1.82 (ddd, J = 11.7, 7.9, 5.2 Hz, 1H). 13C NMR (CDCl
3
92.9 Hz), 52.6, 38.6, 30.9 (t, J = 11.5 Hz), 22.1 (dd, J = 9.9, 8.9 Hz). 19F NMR (CDCl
, 376 MHz) δ –130.8 (d, J = 147.2 Hz), –135.8
3
+
(
d, J = 147.2 Hz). MS (ESI): m/z = 217 ([M+H] ), 167. Anal. Calcd. for C
9
H
10
F
2
N
2
O
2
: C, 50.00; H, 4.66; N, 12.96. Found: C, 50.37; H,
4
.52; N, 13.09.
4
.10.3. Methyl 2,2-difluoro-1-(1-methyl-1H-pyrazol-5-yl)cyclopropane-1-carboxylate (23c).
1
Yield 1.1 g (21%). Yellowish oil. H NMR (CDCl
3
, 400 MHz) δ 7.36 (s, 1H), 6.16 (s, 1H), 3.80 (s, 3H), 3.68 (s, 3H), 2.71 (dt, J =
, 101 MHz) δ 165.9, 138.4, 134.3, 110.9 (dd, J = 292.0, 287.9
1
2.1, 7.4 Hz, 1H), 1.94 (ddd, J = 12.4, 7.7, 4.7 Hz, 1H). 13C NMR (CDCl
3
Hz), 107.5, 53.4, 36.9, 31.1 (dd, J = 12.4, 10.9 Hz), 23.3 (dd, J = 10.3, 8.7 Hz). 19F NMR (CDCl
, 376 MHz) δ –128.9 (d, J = 147.8 Hz),
3
+
–
135.7 (d, J = 147.8 Hz). MS (ESI): m/z = 217 ([M+H] ). Anal. Calcd. for C
9
H
10
F
2
N
2
O
2
: C, 50.00; H, 4.66; N, 12.96. Found: C, 50.37;
H, 4.9; N, 13.26.
4
.11. General procedure for the preparation of 24
2 3
Paraformaldehyde (6.6 g, 0.22 mol), TBAI (4.88 g, 0.013 mol) and K CO (12.2 g, 0.088 mol) were added to a solution of ester 27
(
7.50 g, 0.049 mol) in toluene (115 mL). The reaction mixture was stirred overnight at 80 C, then filtered, and the solvent was
evaporated. The residue was dissolved in CH Cl (150 mL) and washed with distilled water (100 mL) and brine (100 mL). The solution
was evaporated. The crude product was purified by column chromatography (EtOAc –hexane (1:1)
2
2
was dried over Na
as eluent).
2 4 2 2
SO , and CH Cl
4
.11.1. Methyl 2-(1-methyl-1H-pyrazol-3-yl)acrylate (24a).
Used in the next step immediately after preparation. Yield 4.0 g. Yellowish oil. MS (ESI): m/z = 168 ([M+H]+).
4
.11.2. Methyl 2-(1-methyl-1H-pyrazol-4-yl)acrylate (24b).
1
Yield 4.6 g (43%). Yellowish oil. H NMR (CDCl
3
, 400 MHz) δ 7.71 (s, 1H), 7.64 (s, 1H), 6.11 (s, 1H), 5.89 (s, 1H), 3.84 (s, 3H),
.78 (s, 3H). 13C NMR (CDCl
: C, 57.82; H, 6.07; N, 16.86. Found: C, 57.86; H, 6.44; N, 16.75.
.11.3. Methyl 2-(1-methyl-1H-pyrazol-5-yl)acrylate (24c).
, 101 MHz) δ 166.2, 137.2, 131.0, 129.1, 121.5, 117.0, 51.6, 38.4. MS (ESI): m/z = 167 ([M+H] ). Anal.
+
3
3
8 10 2 2
Calcd. for C H N O
4

1
6
Journal of Fluorine Chemistry
1
3
Yield 4.8 g (59%). Yellowish oil. H NMR (CDCl , 400 MHz) δ 7.45 (d, J = 1.9 Hz, 1H), 6.64 (d, J = 1.3 Hz, 1H), 6.25 (d, J = 1.9
Hz, 1H), 5.94 (d, J = 1.3 Hz, 1H), 3.82 (s, 3H), 3.76 (s, 3H). 13C NMR (CDCl
, 101 MHz) δ 164.9, 137.9, 137.7, 131.5, 130.7, 107.1,
3
+
5
1
2.3, 37.1. MS (ESI): m/z = 167 ([M+H] ), 107. Anal. Calcd. for C
8 10 2 2
H N O : C, 57.82; H, 6.07; N, 16.86. Found: C, 57.60; H, 5.97; N,
7.04.
4
.12. General procedure for the preparation of 26
Nitrile 25 (21,5 g, 0.1775 mol) was added to a solution of NaOH (71.0 g, 1.775 mol) in distilled water (640 mL). The reaction
mixture was stirred overnight at reflux. The mixture was allowed to cool to rt, washed with CH Cl (300 mL), and aq HCl was added to
2
2
acidify to pH = 1. The water from the solution was evaporated and triturated with i-PrOH (300 mL). The solid was filtered off, and the
filtrate was evaporated in vacuo to give acid 26.
4
.12.1. 2-(1-Methyl-1H-pyrazol-3-yl)acetic acid hydrochloride (26a).
1
Yield 20.0 g (64%). Yellowish solid. H NMR (DMSO-d
6
, 400 MHz) δ 11.15 (brs, 2H), 7.66 (s, 1H), 6.18 (s, 1H), 3.78 (s, 3H), 3.51
s, 2H). 13C NMR (DMSO-d
, 101 MHz) δ 171.8, 144.6, 131.8, 108.5, 38.1, 33.7. MS (ESI): m/z = 141 ([M+H] ). Anal. Calcd. for
+
(
6
C
6 9 2 2
H ClN O : C, 40.81; H, 5.14; N, 15.86; Cl, 20.08. Found: C, 41.04; H, 5.28; N, 16.13; Cl, 20.16.
4
.12.2. 2-(1-Methyl-1H-pyrazol-5-yl)acetic acid hydrochloride (26c).
1
Yield 8.1 g (71%). White solid. H NMR (DMSO-d
6
, 400 MHz) δ 8.78 (brs, 2H), 7.29 (s, 1H), 6.12 (s, 1H), 3.77 (s, 3H), 3.63 (s,
H). 13C NMR (DMSO-d
ClN : C, 40.81; H, 5.14; N, 15.86; Cl, 20.08. Found: C, 41.04; H, 5.32; N, 15.52; Cl, 20.30.
, 101 MHz) δ 170.8, 137.2, 135.9, 106.0, 36.1, 31.1. MS (ESI): m/z = 141 ([M+H] ), 95. Anal. Calcd. for
+
2
6
C
6
H
9
2 2
O
4
.13. General procedure for the preparation of 27
Thionyl chloride (20.2 g, 12.3 mL, 0.170 mol) was added dropwise to a solution of acid 26 (20.0 g, 0.113 mol) in dry methanol (200
mL) at 0 C over 1 h. The reaction mixture was stirred overnight at rt. The methanol was evaporated, the solid residue was dissolved in
water (300 mL) and washed with CH Cl (150 mL). The layers were separated, and NaOH was added to the aqueous layer to pH = 12–
4, with further extraction with CH Cl (3200 mL). The organic layers were mixed, dried over Na SO and CH Cl was evaporated to
give ester 27.
2
2
1
2
2
2
4
2
2
4
.13.1. Methyl 2-(1-methyl-1H-pyrazol-3-yl)acetate (27a).
1
Yield 13.5 g (78%). Yellowish oil. H NMR (CDCl
3
, 400 MHz) δ 7.20 (s, 1H), 6.09 (s, 1H), 3.75 (s, 3H), 3.60 (s, 3H), 3.58 (s, 2H).
13C NMR (CDCl
for C : C, 54.54; H, 6.54; N, 18.17. Found: C, 54.43; H, 6.65; N, 18.06.
.13.2. Methyl 2-(1-methyl-1H-pyrazol-4-yl)acetate (27b).
+
+
3
3
, 101 MHz) δ 170.8, 144.5, 130.5, 104.9, 51.4, 38.1, 33.5. MS (EI): m/z = 154 (M ), 95 (M –COOCH ). Anal. Calcd.
7
10 2 2
H N O
4

1
, 400 MHz) δ 7.30 (s, 1H), 7.27 (s, 1H), 3.77 (s, 3H), 3.61 (s, 3H), 3.41 (s, 2H). 13C NMR
3
Yield 18.2 g (83%). H NMR (CDCl
+
(CDCl
3
, 101 MHz) δ 171.4, 138.6, 128.9, 112.7, 51.6, 38.6, 29.7. MS (ESI): m/z = 155 ([M+H] ). Anal. Calcd. for C
7
H
10
N
2
O
2
: C,
5
4.54; H, 6.54; N, 18.17. Found: C, 54.63; H, 6.33; N, 18.56.
4
.13.3. Methyl 2-(1-methyl-1H-pyrazol-5-yl)acetate (27c).
1
Yield 5.6 g (79%). Yellowish oil. H NMR (CDCl
3
, 400 MHz) δ 7.33 (d, J = 1.7 Hz, 1H), 6.10 (d, J = 1.4 Hz, 1H), 3.75 (s, 3H), 3.65
s, 3H), 3.62 (s, 2H). 13C NMR (CDCl
, 101 MHz) δ 168.8, 137.7, 134.1, 106.1, 52.1, 36.2, 31.3. MS (ESI): m/z = 155 ([M+H] ). Anal.
+
(
3
7 10 2 2
Calcd. for C H N O : C, 54.54; H, 6.54; N, 18.17. Found: C, 54.61; H, 6.76; N, 18.03.
4
.14. General procedure for the preparation of 28
A solution of KOH (0.17 g, 4.2mmol) in water (1 mL) was added to solution of ester 23 (0.46 g) in methanol (5 mL). The reaction
mixture was stirred overnight at rt, evaporated and the solid residue was dissolved in water (7 mL). The solution was washed with
CH Cl (25 mL) and acidified with citric acid to pH = 3. The obtained solution was extracted with CH Cl (35 mL). The combined
organic layers were dried over Na SO and evaporated under reduced pressure to give 28.
2
2
2
2
2
4
4
.14.1. 2,2-Difluoro-1-(1-methyl-1H-pyrazol-3-yl)cyclopropane-1-carboxylic acid (28a).
1
Yield 0.55 g (43%). Yellowish solid. H NMR (DMSO-d
6
, 400 MHz) δ 13.26 (brs, 1H), 7.64 (d, J = 1.7 Hz, 1H), 6.35 (d, J = 1.8 Hz,
, 101 MHz) δ 167.4, 142.5, 131.6, 111.9 (t,
, 376 MHz) δ –131.1 (d, J = 144.5 Hz), –
34.2 (d, J = 144.4 Hz). MS (ESI): m/z = 203 ([M+H] ), 185 ([M–OH] ). Anal. Calcd. for C : C, 47.53; H, 3.99; N, 13.86.
Found: C, 47.21; H, 3.98; N, 13.64.
1
H), 3.79 (s, 3H), 2.47 – 2.38 (m, 1H), 2.31 (dt, J = 13.5, 6.8 Hz, 1H). 13C NMR (DMSO-d
6
J = 287.2 Hz), 106.6, 38.5, 34.1 (t, J = 11.0 Hz), 20.3 (t, J = 9.2 Hz). 19F NMR (DMSO-d
6
+
+
1
8 8 2 2 2
H F N O
4
.14.2. 2,2-Difluoro-1-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxylic acid (28b).
1
Yield 0.67 g (72%). Yellowish solid. H NMR (DMSO-d
6
, 400 MHz) δ 13.02 (brs, 1H), 7.74 (s, 1H), 7.42 (s, 1H), 3.80 (s, 3H), 2.42
1
3
(
dd, J = 13.5, 7.1 Hz, 1H), 2.13 (ddd, J = 12.9, 8.1, 5.0 Hz, 1H). C NMR (DMSO-d
6
, 101 MHz) δ 167.9, 138.8, 131.0, 112.3 (t, J =
, 376 MHz) δ –131.1 (d, J = 144.0 Hz), –134.8
8 8 2 2 2
d, J = 143.9 Hz). MS (ESI): m/z = 203 ([M+H] ), 153. Anal. Calcd. for C H F N O : C, 47.53; H, 3.99; N, 13.86. Found: C, 47.33; H,
2
89.4 Hz), 112.3, 38.5, 31.4 (t, J = 11.0 Hz), 21.2 (t, J = 8.8 Hz). 19F NMR (DMSO-d
6
+
(
3
.59; N, 14.10.
4
.14.3. 2,2-Difluoro-1-(1-methyl-1H-pyrazol-5-yl)cyclopropane-1-carboxylic acid (28c).
1
Yield 0.70 g (75%). Yellowish solid. H NMR (DMSO-d
6
, 400 MHz) δ 7.36 (s, 1H), 6.28 (s, 1H), 3.77 (s, 3H), 2.68 (dt, J = 12.5, 7.8
Hz, 1H), 2.31 (ddd, J = 13.1, 8.1, 5.5 Hz, 1H). 13C NMR (DMSO-d
07.2, 36.5, 30.9 (t, J = 11.4 Hz), 22.7 (t, J = 9.1 Hz). 19F NMR (DMSO-d
, 101 MHz) δ 166.6, 137.5, 134.6, 111.9 (dd, J = 290.9, 285.1 Hz),
6
1
6
, 376 MHz) δ –127.9 (d, J = 145.5 Hz), –134.9 (d, J = 145.4
+
Hz). MS (ESI): m/z = 203 ([M+H] ), 155. Anal. Calcd. for C
8 8 2 2 2
H F N O : C, 47.53; H, 3.99; N, 13.86. Found: C, 47.31; H, 3.59;
N, 13.60.

1
8
Journal of Fluorine Chemistry
Acknowledgements
The work was funded by Enamine Ldt. The authors thank Prof. Andrey Tolmachev for his encouragement and support, Dr. Halyna
Buvailo and Mr. Andrey Tarnovskiy for their help with manuscript preparation.
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