An approach to the synthesis of 3-substituted piperidines bearing partially fluorinated alkyl groups

Article abstract of DOI:10.1016/j.jfluchem.2019.05.006

An approach to the synthesis of 3-substituted piperidines bearing partially fluorinated alkyl groups was proposed. The method was based on the DAST-mediated nucleophilic fluorination of easily available 2-bromopyridin-3-yl alcohols and ketones affording 2-bromo-3-(1-fluoroalkyl)pyridines and 2-bromo-3-(1,1-difluoroalkyl)pyridines, respectively, followed by catalytic hydrogenation. The hydrogenation step was studied with common heterogeneous Pd-, Pt-, and Rh-based catalyst. It was found that in the case of fluoroalkyl derivatives, the pyridine core reduction was accompanied by hydrodefluorination, which became a limitation of the strategy. Nevertheless, the method worked well with 1,1-difluoroalkyl derivatives

Full text of DOI:10.1016/j.jfluchem.2019.05.006

Accepted Manuscript
Title: An approach to the synthesis of 3-substituted
piperidines bearing partially fluorinated alkyl groups
Authors: Andrii I. Subota, Sergey V. Ryabukhin, Alina O.
Gorlova, Oleksandr O. Grygorenko, Dmitriy M. Volochnyuk
PII:
S0022-1139(19)30088-0
DOI:
Reference:
https://doi.org/10.1016/j.jfluchem.2019.05.006
FLUOR 9328
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Received date:
Revised date:
Accepted date:
13 March 2019
7 May 2019
7 May 2019
Please cite this article as: Subota AI, Ryabukhin SV, Gorlova AO, Grygorenko
OO, Volochnyuk DM, An approach to the synthesis of 3-substituted piperidines
bearing partially fluorinated alkyl groups, Journal of Fluorine Chemistry (2019),
https://doi.org/10.1016/j.jfluchem.2019.05.006
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Journal of Fluorine Chemistry
journal homepage: www.elsevier.com
An approach to the synthesis of 3-substituted piperidines bearing partially
fluorinated alkyl groups
Andrii I. Subota,a,b Sergey V. Ryabukhin,a,c Alina O. Gorlova,a,b Oleksandr O. Grygorenko,a,b*
Dmitriy M. Volochnyuka,c*
a Enamine Ltd. (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine
b Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine
c Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine
Corresponding authors. Tel.: +38-044-239-33-15; fax: +38-044-537-32-53; e-mail: gregor@univ.kiev.ua (O. O. G.); d.volochnyuk@gmail.com
(D. M. V.)
Graphical abstract
Highlights




An approach to 3-substituted piperidines bearing partially fluorinated alkyl groups is developed.
The strategy is based on deoxofluorination of 2-bromopyridin-3-yl derivatives with DAST followed by hydrogenation.
The major limitation of the approach is hydrodefluorination which occurred at the hydrogenation step.
Despite this limitation, the method is efficient for the preparation of 3-(1,1-difluoroalkyl)piperidines.
ARTICLE INFO
ABSTRACT

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Journal of Fluorine Chemistry
Article history:
Received
An approach to the synthesis of 3-substituted piperidines bearing partially fluorinated alkyl
groups was proposed. The method was based on the DAST-mediated nucleophilic fluorination
of easily available 2-bromopyridin-3-yl alcohols and ketones affording 2-bromo-3-(1-fluoro-
alkyl)pyridines and 2-bromo-3-(1,1-difluoroalkyl)pyridines, respectively, followed by catalytic
hydrogenation. The hydrogenation step was studied with common heterogeneous Pd-, Pt-, and
Rh-based catalyst. It was found that in the case of fluoroalkyl derivatives, the pyridine core
reduction was accompanied by hydrodefluorination, which became a limitation of the strategy.
Nevertheless, the method worked well with 1,1-difluoroalkyl derivatives.
Received in revised form
Accepted
Available online
Keywords:
Nitrogen heterocycles
Piperidine
Partially fluorinated alkyl groups
Hydrogenation
2019 Elsevier Ltd. All rights reserved.
Hydrodefluorination
1. Introduction
Recent applications of organofluorine compounds in medicinal chemistry demonstrate that while the "classical" CF3 or CHF2
substituents are explored extensively, their more “exotic” counterparts, in particular, partially fluorinated alkyl groups, have been left
behind previously and currently attract an increasing attention [1–4]. For example, introducing the 1,1-difluoroethyl group into a
piperidine ring of natural products resulted in development of anti-cancer drug vinifurine (1),[5] as well as highly efficient antiprotozoal
quinine derivative 2 (IC50 = 25 nM, against Plasmodium falciparum Thaie) [6]. Compounds of the type 3 were found to be promising
activators of gangliosidase and/or sialidase enzymes involved in ganglioside catabolism for Alzheimer's disease treatments [7].
Thiazolyl-substituted derivatives 4 were evaluated as promising agents for cancer prevention or progress monitoring [8].
Figure 1. Biologically active 3-substituted piperidines bearing partially fluorinated alkyl groups.

Taking into account an increasing interest to 3D-shaped building blocks with high fraction of sp3-hybridized carbon atoms [9], the
piperidine derivatives of general formula 5 can be considered as promising compounds for drug discovery (Scheme 1). To our surprise,
Reaxys® database search showed that synthesis of the compounds of the type 5 was not reported in the literature, although they appeared
in various commercial proposals. To date, only di- or trifluoromethyl-substituted piperidines 6 and 7 were described. 3-(Trifluoro-
methyl)piperidine (6) has been synthesized by catalytic hydrogenation of the corresponding pyridine derivatives 8 or 9, including an
asymmetric version [10,11]. For the corresponding difluoromethyl derivative 7, a single method was published in a patent in 2018,
which was based on DAST-mediated nucleophilic fluorination of the corresponding Boc-protected aldehyde 10 [12]. As a part of our
ongoing research on design and synthesis of fluorinated building blocks relevant to medicinal chemistry [13–18], we have aimed at
elaboration of a convenient approach to 3-substituted piperidines bearing partially fluorinated alkyl groups 5. The strategy implied in
this work is based on the catalytic hydrogenation of 3-substituted 2-bromopyridines 11, in turn prepared via directed ortho-metallation
of 2-bromopyridine (12); a similar method was used by us previously for the preparation of 3-(cyclo)alkylpyperidines [19].
Scheme 1. Approaches to 3-(fluoroalkyl)piperidines.
2. Results and discussion
First of all, the corresponding substrates 13 and 14 for further deoxofluorination were synthesized using the published procedures
[19,20]. DAST [21] and XtalFluor‐E [22] were evaluated as the deoxofluorinating reagents. In most cases studied, XtalFluor‐E did not
give any improvement as compared to less expensive DAST; therefore, DAST was used for further optimization of the reaction
conditions. The temperature of 25 °C and the use of CH2Cl2 as the solvent were found to be optimal. Higher temperatures allowed to
shorten the reaction time but also led to increased formation of side products. Optimal reagent ratios and reaction times, as well as
corresponding isolated yields of the products for the substrates 13b–d and 14a–c are given in Table 1. In the case of alcohol 13a, the
use of DAST was unfruitful. In the case of XtalFluor‐E as the deoxofluorinating reagent, ca. 15% of the corresponding product 15a was
formed according to 19F NMR of the reaction mixture; however, the product could not be isolated. Finally, neither reagent succeeded in
deoxofluorination of ketone 14d; in all cases, only the starting material was recovered, probably due to steric hindrance at the carbonyl
group. It should be noted that low reactivity of 14d as compared to e.g. 13d is not unusual since ketones are often less reactive towards
deoxofluorination as compared to the corresponding alcohols. For example, Ph2CHOH gives the corresponding fluoro derivative in 40%

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Journal of Fluorine Chemistry
yield upon treatment with DAST at –30 °C for 30 min [23]. Meanwhile, benzophenone leads to Ph2CF2 in 63% yield under more harsh
conditions (bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-fluor®), 90 °C, 24 h) [24]. We believe that this might be related to the
fact that in the case of similar alcohols (e.g. 13d), the SN1 mechanism is possible which is less affected by steric effects; in the case of
ketones (e.g. 14d), formation of the corresponding tetrahedral intermediate at the corresponding is necessary.
Optimization of catalytic hydrogenation conditions was performed with the compound 16b. First of all, typical conditions for the
pyridine hydrogenation (5% Pd/C, MeOH, 60 atm of H2, 60 °C) were used. At these conditions, the complete conversion of the starting
material 16b was achieved; however, the process was accompanied by hydrodefluorination leading to 3-ethylpyperidine (18b) as the
only product (Table 2, Entry 1). [25] Such hydrodefluorination was rather unusual since it was reported that activation of the C–F bonds
in such transformations had required special conditions. [26,27] To avoid this unwanted reaction, milder reaction conditions were
evaluated, i.e. room temperature and atmospheric pressure of hydrogen (Table 2, Entry 2); nevertheless, the hydrodefluorination was
still significant. Using a catalyst with increased content of Pd resulted in diminished yield of the target product 17b (Table 2, Entry 3).
Thorough optimization of the reaction conditions allowed minimizing the yield of the hydrodefluorination product 17b to 12%; it was
found that using 5% Rh/C in MeOH at atmospheric pressure of hydrogen and room temperature gave the best results (Table 2, Entry 6).
It should be noted that the solvent and the presence of acidic or basic additives had significant impact on the ratio of the products 17b
and 18b formed (Table 2, Entries 7–11).
Table 1. Deoxofluorination of 2-bromopyridin-3-yl alcohols 13 and ketones 14
#
1
2
3
4
5
6
Substrate
13b
R
Conditions
Product Yield, %
Me 1.2 eq of DAST, CH2Cl2, 25 °C, 16 h
15b
15c
15d
16a
16b
62
93
76
95
60
40
13c
iPr
Ph
H
––//––
13d
––//––
14a
3.8 eq of DAST, CH2Cl2, 25 °C, 4 h
14b
Me 3.0 eq of DAST, CH2Cl2, 25 °C, 48 h
iPr
14c
8.0 eq of DAST, CH2Cl2, 25 °C, 340 h 16c

Table 2. Hydrogenation of 2-bromo-3-(1,1-difluoroethyl)pyridine (16b)
#
1
2
3
4
5
6
7
8
9
Conditions
Yield of 17b, %a Yield of 18b, %a
5% Pd/C, MeOH, 60 atm, 60 °C
5% Pd/C, MeOH, 1 atm, 25 °C
10% Pd/C, MeOH, 1 atm, 25 °C
PtO2, AcOH, 1 atm, 25 °C
PtO2, MeOH, 1 atm, 25 °C
5% Rh/C, MeOH, 1 atm, 25 °C
0
>99
34
72
22
27
12
43
14
90
17
33
66
28
78
73
88
5% Rh/C, MeOH, NaHCO3 (2 eq), 1 atm, 25 °C 57
5% Rh/C, MeOH, aq HCl (5 eq), 1 atm, 25 °C
5% Rh/C, 1,4-dioxane, 1 atm, 25 °C
86
10
83
67
10 5% Rh/C, CF3CH2OH, 1 atm, 25 °C
11 5% Rh/C, (CF3)2CHOH, 1 atm, 25 °C
a Yields detected by 19F NMR and GC-MS of the reaction mixtures
Having in hand the optimized conditions mentioned above, we have studied hydrogenation of other substrates of general formula 15
and 16 (Table 3). In the case of mono-fluorinated compounds 15b (R = Me) and 15d (R = Ph), the reaction was accompanied by full
hydrodefluorination affording 3-methyl- (18b) and 3-benzylpiperidines (18d), respectively. Only the compound 15c bearing a sterically
hindered isopropyl substituent “shielding” the C–F bond gave the target fluorinated piperidine 19c as ca. 1:1 mixture with the
defluorination product 18c. The gem-difluorinated derivatives 16a,c gave the target gem-difluorinated piperidines 17a,c together with
by-products 18 in ca. 4:1 ratio.
Table 3. Hydrogenation of pyridine derivativess 15 and 16
#
Substrate
Target product
Yield of 17(19), %a
Yield of 18, %a
>99 (18b)
1
15b
19b
0

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Journal of Fluorine Chemistry
2
3
4
5
15c
15d
16a
16c
19c
19d
17a
17c
44
0
56 (18c)
>99 (18d)
21 (18a)
19 (18c)
79
81
a Yields detected by 19F NMR and GC-MS of the reaction mixtures
The mechanistic aspect of the formation of 18a–d is not clear. A previously reported precedent of catalytic hydrodefluorination (for
the case of 4,4-difluoro-4-(4-nitrophenyl)butanoic acid) was explained by hydrolysis of the gem-difluoro moiety to ketone with
subsequent hydrogenolysis [28]. We believe that alternative mechanism might be also involved including surface metal insertion into
the C–F benzylic bond, followed by reductive elimination (which is common for other benzylic substrates). Although to the best of our
knowledge, such activation of the C–F bond has not been proposed in the literature (for uncommon examples of the catalytic
hydrodefluorination, see [29]), this explanation correlates with the corresponding radical stability and steric hindrance.
Finally, the preparative applicability of the developed method was evaluated. It was found that separation of difluoromethyl- and
1,1-difluoroethyl-substituted piperidines 17a and 17b from the corresponding 3-methyl and 3-ethyl derivatives 18a and 18b could be
easily achieved on a gram scale by distillation at atmospheric pressure, which gave the target 17a and 17b in 61% and 72% isolated
yields, respectively. Separation of the less volatile derivatives 17c and 19c from the by-product 18c by distillation was not successful.
Therefore, column chromatography was applied in this case. In order to facilitate detection of the products, the mixtures of the
corresponding amines were transformed into their Cbz derivatives. The subsequent HPLC separation with UV detection gave the
corresponding Cbz-protected derivatives 20 and 21, respectively. Their deprotection was performed by treatment with HBr in AcOH
giving the target fluorinated piperidines 17c and 19c as hydrobromides. It should be noted that the product 19cHBr was obtained as ca.
1:1 mixture of diastereomers; their separation at the corresponding step (compound 21) was not successful.
Scheme 2. Synthesis of piperidines 17c and 19c.
3. Conclusions
DAST-mediated nucleophilic fluorination of easily available 2-bromopyridin-3-yl alcohols and ketones with subsequent catalytic
hydrogenation is a promising strategy for the synthesis of 3-substituted piperidines bearing partially fluorinated alkyl groups. The major
limitation of this approach is related to hydrodefluorination which accompanied the pyridine hydrogenation step. This unwanted side
reaction was observed only for the pyridine derivatives bearing partially fluorinated alkyl groups; it was not characteristic for
hydrogenation of trifluoromethyl-substituted pyridines reported previously. This difference in the reactivity might be addressed to

increase of the C–F bond dissociation energy, E(C–F), upon increasing the fluorination degree of a carbon atom (for PhCH2F, E(C–F) =
99 kcal/mol, whereas for PhCF3, E(C–F) = 115 kcal/mol [30]). Further results obtained in this work supported this hypothesis. In
particular, mono-(α-fluoroalkyl)pyridine derivatives were prone to hydrodefluorination to a greater extent as compared to the
corresponding gem-difluorinated counterparts.
Despite the aforementioned problems, the preparative applicability of the strategy was illustrated for 3-(1,1-
difluoroalkyl)piperidines, as well as for the 3-(1-fluoroalkyl)piperidine derivative bearing a hindered isopropyl substituent in a close
proximity to the C–F bond. Further optimization of the proposed synthetic strategy, as well as extension of its scope requires
development of catalysts tolerating the presence of C–F bonds, like those proposed recently by Glorious and co-workers. [31]
4. Experimental
4.1. General
The solvents were purified according to the standard procedures [32]. 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. 1H, 13C and 19F NMR spectra were recorded on a Bruker 170 Avance 500 spectrometer (at 500 MHz for 1H NMR,
1
126 MHz for 13C NMR and 470 MHz for 19F NMR) and Varian Unity Plus 400 spectrometer (at 400 MHz for H NMR, 101 MHz for
13C NMR and 376 MHz for 19F NMR). 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 preparation of 15b–d.
A solution of DAST (4.84 g, 30.0 mmol) in dry CH2Cl2 (25 mL) was added dropwise to a solution of 13 (24.7 mmol) in dry CH2Cl2
(100 mL) at 0 °C. The reaction mixture was warmed to rt and stirred overnight. The resulting mixture was poured into H2O (50 mL),
sat. aq NaHCO3 was added to pH = 8, and organic phase was separated. The aqueous layer was extracted with CH2Cl2 (3×50 mL), the
combined organic layers were dried over Na2SO4, and then evaporated under reduced pressure. The obtained crude product was purified
by flash column chromatography (SiO2, CH2Cl2 was used as eluent).
2-Bromo-3-(1-fluoroethyl)pyridine (15b).
1
Yield 3.09 g (62%) from 1-(2-bromopyridin-3-yl)ethan-1-ol (13b) (5.0 g, 24.7 mmol); light yellow oil. H NMR (400 MHz, CDCl3)
δ 8.33 (dd, J = 4.7, 2.0 Hz, 1H), 7.81 (dd, J = 7.7, 2.0 Hz, 1H), 7.34 (dd, J = 7.7, 4.7 Hz, 1H), 5.84 (dq, J = 47.4, 6.4 Hz, 1H), 1.64 (dd,
J = 24.2, 6.4 Hz, 3H) ppm. 13C NMR (126 MHz, CDCl3) δ 149.6 (d, J = 1.6 Hz), 139.9 (d, J = 6.1 Hz), 138.7 (d, J = 22.1 Hz), 135.0 (d,
J = 10.1 Hz), 123.4 (d, J = 1.3 Hz), 89.1 (d, J = 171.6 Hz), 22.0 (d, J = 25.1 Hz) ppm. 19F NMR (470 MHz, CDCl3) δ –175.8 (dq, J =

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Journal of Fluorine Chemistry
47.4, 24.2 Hz) ppm. EIMS, m/z = 203/205 [M]+. Anal. Calcd. for C7H7BrFN: C, 41.21; H, 3.46; N, 6.86; Br, 39.16. Found: C, 41.58; H,
3.51; N, 6.89; Br, 39.50
2-Bromo-3-(1-fluoro-2-methylpropyl)pyridine (15c).
1
Yield 5.64 g (93%) from 1-(2-bromopyridin-3-yl)-2-methylpropan-1-ol (13c) (6.00 g, 26.1 mmol); light yellow oil. H NMR (400
MHz, CDCl3) δ 8.33 (dd, J = 4.7, 2.0 Hz, 1H), 7.72 (dd, J = 7.7, 2.0 Hz, 1H), 7.32 (dd, J = 7.7, 4.7 Hz, 1H), 5.53 (dd, J = 46.4, 4.6 Hz,
1H), 2.29 – 2.12 (m, 1H), 1.08 (d, J = 7.0 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H) ppm. 13C NMR (126 MHz, CDCl3) δ 149.6 (d, J = 1.8 Hz),
140.9 (d, J = 6.4 Hz), 136.6 (d, J = 22.8 Hz), 136.4 (d, J = 9.7 Hz), 122.9, 96.1 (d, J = 177.0 Hz), 33.0 (d, J = 22.5 Hz), 19.0 (d, J = 4.3
Hz), 15.8 ppm. 19F NMR (470 MHz, CDCl3) δ –192.6 (dd, J = 46.4, 25.3 Hz) ppm. CIMS, m/z = 232/234 [M+H]+. Anal. Calcd. for
C9H11BrFN: C, 46.58; H, 4.78; N, 6.04; Br, 34.43. Found: C, 46.92; H, 5.04; N, 5.79; Br, 34.15.
2-Bromo-3-(fluoro(phenyl)methyl)pyridine (15d).
1
Yield 3.80 g (76%) from (2-bromopyridin-3-yl)(phenyl)methanol (13d) (5.00 g, 18.9 mmol); light yellow oil. H NMR (500 MHz,
CDCl3) δ 8.37 (dd, J = 4.7, 2.0 Hz, 1H), 7.88 (dd, J = 7.7, 2.0 Hz, 1H), 7.40 – 7.35 (m, 6H), 6.72 (d, J = 46.2 Hz, 1H) ppm. 13C NMR
(126 MHz, CDCl3) δ 150.0 (d, J = 1.9 Hz), 141.5 (d, J = 5.6 Hz), 137.2 (d, J = 21.4 Hz), 136.6 (d, J = 24.3 Hz), 136.4 (d, J = 8.8 Hz),
129.3 (d, J = 2.8 Hz), 128.8, 127.4 (d, J = 5.5 Hz), 123.2, 92.3 (d, J = 174.5 Hz) ppm. 19F NMR (470 MHz, CDCl3) δ –167.4 (d, J =
46.2 Hz) ppm. EIMS, m/z = 265/267 [M]+. Anal. Calcd. for C12H9BrFN: C, 54.16; H, 3.41; N, 5.26; Br, 30.03. Found: C, 54.41; H,
3.52; N, 5.6; Br, 30.42.
4.3. General procedure for preparation of 16a–c.
An solution of indicated quantity of DAST in dry CH2Cl2 was added dropwise to a solution of 14 (26.9 mmol) in dry CH2Cl2 (50
mL) at 0 °C. The reaction mixture was warmed to rt and stirred for indicated period of time. The resulting mixture was poured into H2O
(50 mL), sat. aq NaHCO3 was added to pH = 8, and organic phase was separated. The aqueous layer was extracted with CH2Cl2 (3×50
mL), the combined organic layers were dried over Na2SO4, and then evaporated under reduced pressure.
2-Bromo-3-(difluoromethyl)pyridine (16a).
The compound was obtained using using 16.8 g (104 mmol, 3.8 equiv) of DAST, and stirring for 4 h before work-up. The obtained
crude product was purified by flash column chromatography (SiO2, CH2Cl2 as eluent). Yield 5.34 g (95%) from 2-
1
bromonicotinaldehyde (14a) (5.00 g, 26.9 mmol); light yellow oil. H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 4.6 Hz, 1H), 7.95 (d, J =
7.7 Hz, 1H), 7.40 (dd, J = 7.7, 4.6 Hz, 1H), 6.87 (t, J = 54.4 Hz, 1H) ppm. 13C NMR (126 MHz, CDCl3) δ 152.2, 141.1 (t, J = 6.4 Hz),
135.9 (t, J = 5.6 Hz), 131.0 (t, J = 24.3 Hz), 123.2, 113.0 (t, J = 239.7 Hz) ppm. 19F NMR (470 MHz, CDCl3) δ –115.8 (d, J = 54.4 Hz)
ppm. EIMS, m/z = 207/209 [M]+. Anal. Calcd. for C6H4BrF2N: C, 34.65; H, 1.94; N, 6.73; Br, 38.41. Found: C, 34.50; H, 2.24; N, 6.66;
Br, 38.59.
2-Bromo-3-(1,1-difluoroethyl)pyridine (16b).

The compound was obtained using using 24.2 g (150 mmol, 3.0 equiv) of DAST, and stirring for 48 h before work-up. Crude
product was purified by flash column chromatography (SiO2, hexane–EtOAc = 10:1 as eluent). Yield 6.70 g (60%) from 1-(2-
bromopyridin-3-yl)ethan-1-one (14b) (10.0 g, 50.0 mmol); light yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.42 (t, J = 4.7, 1.9 Hz, 1H),
7.90 (dd, J = 7.8, 1.9 Hz, 1H), 7.34 (dd, J = 7.8, 4.7 Hz, 1H), 2.08 (t, J = 18.4 Hz, 3H) ppm. 13C NMR (126 MHz, CDCl3) δ 150.9,
139.5 (t, J = 3.5 Hz), 135.8 (t, J = 8.8 Hz), 134.6 (t, J = 27.5 Hz), 122.6, 120.4 (t, J = 241.9 Hz), 24.5 (t, J = 28.0 Hz) ppm. 19F NMR
(470 MHz, CDCl3) δ –88.7 (q, J = 18.4 Hz) ppm. EIMS, m/z = 221/223 [M]+. Anal. Calcd. for C7H6BrF2N: C, 37.87; H, 2.72; N, 6.31;
Br, 35.99. Found: C, 38.10; H, 2.34; N, 6.38; Br, 35.89.
2-Bromo-3-(1,1-difluoro-2-methylpropyl)pyridine (16c).
The compound was obtained using 38.7 g (240 mmol, 8.0 equiv) of DAST, and stirring for 340 h before work-up. Crude product was
purified by flash column chromatography (SiO2, hexane–EtOAc = 10:1 as eluent). Yield 3.10 g (40%) from 1-(2-bromopyridin-3-yl)-2-
methylpropan-1-one (14c) (7.0 g, 30.7 mmol); light yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.42 (t, J = 4.7, 1.8 Hz, 1H), 7.83 (dd, J =
7.8, 1.8 Hz, 1H), 7.34 (dd, J = 7.8, 4.7 Hz, 1H), 3.04 – 2.87 (m, 1H), 1.00 (d, J = 6.9 Hz, 6H) ppm. 13C NMR (126 MHz, CDCl3) δ
150.8, 139.3 (t, J = 3.6 Hz), 137.2 (t, J = 9.1 Hz), 133.5 (t, J = 27.9 Hz), 122.9 (t, J = 247.6 Hz), 122.3, 33.7 (t, J = 24.7 Hz), 15.5 ppm.
19F NMR (470 MHz, CDCl3) δ –106.3 ppm. EIMS, m/z = 249/251 [M]+. Anal. Calcd. for C9H10BrF2N: C, 43.22; H, 4.03; N, 5.60; Br,
31.95. Found: C, 43.58; H, 4.38; N, 5.49; Br, 31.60.
4.4. General procedure for preparation of 17a,b and 18b,d.
To a solution of 15 or 16 (10.0 mmol) in MeOH (35 mL) was added Rh/C (1.03 g, 5% on carbon, 5 mol%), and the reaction mixture
was stirred under H2 atmosphere (1 atm). The solid catalyst was filtered off, and filtrate was evaporated under reduced pressure. Et2O
(30 mL) and 3M aq KOH (5 mL) were added to the resiue, and the mixture was stirred ar rt for 15 min. The organic phase was
separated, and the aqueous phase was extracted with Et2O (2×15 mL). The combined organic layers were washed with brine (10 mL),
and concentrated under reduced pressure.
3-(Difluoromethyl)piperidin-1-ium chloride (17a).
The crude product was purified by fractional distillation (bp = 142–147 °C / 760 mmHg). The obtained fraction was dissolved in
Et2O (30 mL) and 4M HCl in dioxane (10 mL) was added. The reaction mixture was stirred for 3 h, and then concentrated under
1
vacuum. Yield 1.04 g (61%) from 2-bromo-3-(difluoromethyl)pyridine (16a) (2.08 g, 10.0 mmol); white solid, mp = 122–123 °C. H
NMR (400 MHz, DMSO-d6) δ 9.32 (s, 2H), 6.05 (td, J = 55.9, 4.1 Hz, 1H), 3.23 (t, J = 13.5 Hz, 2H), 2.76 (dt, J = 11.8, 10.7 Hz, 2H),
2.44 – 2.30 (m, 1H), 1.85 – 1.76 (m, 2H), 1.76 – 1.63 (m, 1H), 1.46 – 1.28 (m, 1H) ppm. 13C NMR (126 MHz, DMSO-d6) δ 117.0 (t, J
= 240.1 Hz), 42.9, 41.4 (t, J = 6.4 Hz), 36.7 (t, J = 20.4 Hz), 20.9 (t, J = 4.6 Hz), 20.4 ppm. 19F{1H} NMR (376 MHz, DMSO-d6) δ –
124.4 (d, J = 283.0 Hz), –125.3 (d, J = 283.0 Hz) ppm. CIMS, m/z = 136 [M–Cl]+. Anal. Calcd. for C6H12ClF2N: C, 41.99; H, 7.05; N,
8.16; Cl, 20.66. Found: C, 41.91; H, 6.92; N, 8.38; Cl, 20.43.
3-(1,1-Difluoroethyl)piperidine (17b).

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Journal of Fluorine Chemistry
The crude product was purified by fractional distillation. Yield 1.07 g (72%) from 2-bromo-3-(1,1-difluoroethyl)pyridine (16b) (2.22
1
g, 10.0 mmol); colourless liquid, bp = 160–165 °C / 760 mmHg. H NMR (400 MHz, CDCl3) δ 3.17 (d, J = 11.7 Hz, 1H), 3.00 (d, J =
12.2 Hz, 1H), 2.49 (t, J = 11.7 Hz, 2H), 1.96 – 1.81 (m, 2H), 1.76 – 1.66 (m, 1H), 1.52 (t, J = 18.9 Hz, 3H), 1.41 (tt, J = 12.0, 3.7 Hz,
1H), 1.32 (td, J = 12.4, 3.6 Hz, 1H) ppm. 13C NMR (126 MHz, CDCl3) δ 124.7 (t, J = 239.9 Hz), 46.7, 46.6 (t, J = 5.2 Hz), 44.8 (t, J =
23.4 Hz), 26.1, 24.9 (t, J = 4.3 Hz), 21.4 (t, J = 28.2 Hz) ppm. 19F{1H} NMR (376 MHz, CDCl3) δ –96.2 (d, J = 243.5 Hz), –97.2 (d, J
= 243.5 Hz) ppm. CIMS, m/z = 150 [M+H]+. Anal. Calcd. for C7H13F2N: C, 56.36; H, 8.78; N, 9.39. Found: C, 56.56; H, 8.99; N, 9.42.
3-Ethylpiperidin-1-ium chloride (18b).
The obtained residue was dissolved in Et2O (30 mL) and 4M HCl in dioxane (10 mL) was added. The reaction mixture was stirred
for 3 h, and then concentrated under vacuum. Yield 1.13 g (76%) from 2-bromo-3-(1-fluoroethyl)pyridine (15b) (2.04 g, 10.0 mmol);
white solid, mp = 148–149 °C. For spectral and physical data see ref.[33]
3-Benzylpiperidine (18d).
Yield 1.74 g (99%) from 2-bromo-3-(fluoro(phenyl)methyl)pyridine (15d) (2.66 g, 10.0 mmol); light yellow oil. For spectral and
physical data see refs.[19,34]
4.5. General procedure for preparation of 20 and 21.
To a solution of 15c or 16c (10.0 mmol) in MeOH (35 mL) was added Rh/C (1.03 g, 5% on carbon, 5 mol%), and the reaction
mixture was stirred under H2 atmosphere (1 atm). The solid catalyst was filtered off, and filtrate was evaporated under reduced pressure.
The crude product was dissolved in THF (30 mL), and benzyl chloroformate (2.00 g, 11.7 mmol) and NEt3 (2.96 g, 29.3 mmol) were
added. The reaction mixture was stirred at rt for 24 h and then concentrated under vacuum. The residue was dissolved in CH2Cl2 (50
mL) and H2O (25 mL), the organic phase was separated, washed with brine (15 mL) and evaporated under reduced pressure. The
obtained crude product was purificated by preparative HPLC.
Benzyl 3-(1,1-difluoro-2-methylpropyl)piperidine-1-carboxylate (20).
Yield 1.69 g (54%) from 2-bromo-3-(1,1-difluoro-2-methylpropyl)pyridine (16c) (2.50 g, 10.0 mmol); light yellow oil. The
1
compound existed as ca. 55:45 mixture of rotamers. H NMR (500 MHz, DMSO-d6) δ 7.45 – 7.23 (m, 5H), 5.08 (s, 2H), 4.15 (d, J =
13.2 Hz, 1H), 3.96 (d, J = 13.2 Hz, 1H), 2.82 – 2.70 (m, 2H), 2.20 – 2.08 (m, 1H), 2.08 – 1.96 (m, 1H), 1.91 – 1.80 (m, 1H), 1.72 – 1.62
(m, 1H), 1.46 – 1.32 (m, 2H), 0.98 – 0.91 (m, 6H) ppm. 13C NMR (126 MHz, DMSO-d6) δ 154.4, 136.9, 128.4, 127.8, 127.5, 126.2 (t, J
= 245.9 Hz), 66.3, 43.9, 43.1, 31.2 (t, J = 24.3 Hz), 23.9 (d, J = 38.2 Hz), 23.2, 15.3, 14.8 ppm. 19F{1H} NMR (470 MHz, DMSO-d6) δ
–114.3 (d, J = 243.4 Hz, 0.45F), –114.4 (d, J = 242.5 Hz, 0.55F), –115.3 (d, J = 241.3 Hz, 0.45F), –115.4 (d, J = 243.1 Hz, 0.55F) ppm.
CIMS, m/z = 312 [M+H]+. Anal. Calcd. for C17H23F2NO2: C, 65.58; H, 7.45; N, 4.50. Found: C, 65.77; H, 7.68; N, 4.43.
Benzyl 3-(1-fluoro-2-methylpropyl)piperidine-1-carboxylate (21).

Yield 0.98 g (34%) from 2-bromo-3-(1-fluoro-2-methylpropyl)pyridine (15c) (2.32 g, 10.0 mmol); light yellow oil. The compound
1
existed as ca. 70:30 mixture of diastereomers. H NMR (500 MHz, DMSO-d6) δ 7.43 – 7.25 (m, 5H), 5.08 (s, 2H), 4.06 (dt, J = 48.1,
5.9 Hz, 1H), 3.95 – 3.82 (m, 2H), 2.89 – 2.69 (m, 2H), 1.93 – 1.74 (m, 2H), 1.72 – 1.59 (m, 2H), 1.41 – 1.23 (m, 2H), 0.98 – 0.81 (m,
6H) ppm. 13C NMR (126 MHz, DMSO-d6) δ 154.4, 137.0, 128.4, 127.8, 127.5, 99.2 (d, J = 170.2 Hz) and 98.7 (d, J = 172.0 Hz), 66.1,
46.0 and 45.3, 44.1 and 44.0, 37.1, 28.6 (d, J = 20.4 Hz) and 28.3 (d, J = 20.7 Hz), 25.9 (d, J = 6.7 Hz), 24.3 and 23.8, 19.0 (d, J = 5.5
Hz) and 18.6 (d, J = 7.0 Hz), 16.5 and 15.6 ppm. 19F NMR (470 MHz, DMSO-d6) δ –198.2 – –198.9 (m) ppm. CIMS, m/z = 294
[M+H]+. Anal. Calcd. for C17H24FNO2: C, 69.60; H, 8.25; N, 4.77. Found: C, 69.33; H, 7.87; N, 4.56.
General procedure for preparation of 17c·HBr, and 19c·HBr.
Compound 20 or 21 was dissolved in solution of HBr in AcOH (5.0 mL, 33 wt%). The reaction mixture was stirred at rt for 48 h, and
then evaporated to under reduced pressure.
3-(1,1-Difluoro-2-methylpropyl)piperidin-1-ium bromide (17c·HBr).
Yield 0.41 g (99%) from benzyl 3-(1,1-difluoro-2-methylpropyl)piperidine-1-carboxylate (20) (0.50 g, 1.60 mmol); light brown
solid, mp = 130–132 °C. 1H NMR (400 MHz, D2O) δ 3.56 (d, J = 12.4 Hz, 1H), 3.40 (d, J = 12.4 Hz, 1H), 3.07 – 2.88 (m, 2H), 2.58 –
2.39 (m, 1H), 2.28 – 2.12 (m, 1H), 2.06 – 1.95 (m, 2H), 1.80 – 1.66 (m, 1H), 1.60 – 1.48 (m, 1H), 1.00 (t, J = 6.4 Hz, 6H) ppm. 13C
NMR (126 MHz, D2O) δ 126.2 (t, J = 245.4 Hz), 43.8, 42.7 (t, J = 6.5 Hz), 37.2 (t, J = 24.3 Hz), 31.2 (t, J = 23.7 Hz), 21.3, 20.9, 14.7
(dd, J = 6.9, 2.3 Hz), 14.0 (t, J = 5.1 Hz) ppm. 19F{1H} NMR (376 MHz, D2O) δ –114.8 (d, J = 242.1 Hz), –116.9 (d, J = 242.1 Hz)
ppm. CIMS, m/z = 178 [M–Br]+. Anal. Calcd. for C9H18BrF2N: C, 41.87; H, 7.03; N, 5.43; Br, 30.95. Found: C, 42.05; H, 7.23; N, 5.24;
Br, 30.65.
3-(1-Fluoro-2-methylpropyl)piperidin-1-ium bromide (19c·HBr).
Yield 0.40 g (99%) from benzyl 3-(1-fluoro-2-methylpropyl)piperidine-1-carboxylate (21) (0.50 g, 1.67 mmol); light brown vitreous
solid. The compound existed as ca. 72:28 mixture of diastereomers. 1H NMR (400 MHz, D2O) δ 4.26 (dt, J = 47.7, 5.9 Hz, 0.28H), 4.20
(ddd, J = 48.0, 7.8, 3.9 Hz, 0.72H), 3.59 – 3.50 (m, 0.28H), 3.44 – 3.34 (m, 1.72H), 3.03 – 2.85 (m, 2H), 2.24 – 2.08 (m, 1H), 2.06 –
1.82 (m, 3H), 1.81 – 1.65 (m, 1H), 1.57 – 1.38 (m, 1H), 1.03 – 0.87 (m, 6H) ppm. 13C NMR (101 MHz, D2O) δ 100.6 (d, J = 171.4 Hz)
and 100.1 (d, J = 169.3 Hz), 46.0 (d, J = 6.6 Hz) and 44.9 (d, J = 5.8 Hz), 44.3 and 44.1, 35.0 (d, J = 19.0 Hz) and 34.9 (d, J = 21.0 Hz),
28.6 (d, J = 19.6 Hz) and 28.4 (d, J = 16.2 Hz), 24.3 and 24.2, 21.45 and 21.37, 18.2 (d, J = 5.9 Hz) and 17.5 (d, J = 8.1 Hz), 17.1 (d, J
= 4.1 Hz) and 15.5 (d, J = 4.0 Hz) ppm. 19F{1H} NMR (376 MHz, D2O) δ –196.7 (0.72 F), –198.6 (0.28 F) ppm. CIMS, m/z = 160 [M–
Br]+. Anal. Calcd. for C9H19BrFN: C, 45.01; H, 7.97; N, 5.83; Br, 33.27. Found: C, 45.25; H, 7.93; N, 5.67; Br, 33.26.
Acknowledgements
The work was funded by Enamine Ldt. O.O.G. was also funded by Ministry of Education and Science of Ukraine (Grant No.
19БФ037-03). The authors thank Prof. Andrey Tolmachev for his encouragement and support, Ms. Yuliya Kuchkovska for her help

12
Journal of Fluorine Chemistry
with manuscript preparation, Ms. Olga Maksymenko and her department for HPLC separations, and UOSLab (www.en.uoslab.com) for
providing high pressure reactors.

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