Synthesis of gem-difluorocyclopentane/hexane building blocks

Article abstract of DOI:10.1016/j.jfluchem.2017.04.012

An approach to the preparation of gem-difluorocyclopentane/hexane-derived carboxylic acids and amines is described. Whereas for 3,3-difluoro-substituted cycloalkanones, straightforward deoxofluorination of the corresponding ketoesters led to the target compounds, in the case of 2,2-difluoro isomers, the bypass or alternative routes were necessary.

Full text of DOI:10.1016/j.jfluchem.2017.04.012

Accepted Manuscript
Title: Synthesis of gem-difluorocyclopentane/hexane building
blocks
Authors: Kostiantyn P. Melnykov, Pavel S. Nosik, Bohdan B.
Kurpil, Dmitriy A. Sibgatulin, Dmitriy M. Volochnyuk,
Sergey V. Ryabukhin, Oleksandr O. Grygorenko
PII:
S0022-1139(17)30154-9
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2017.04.012
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30-4-2017
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Please cite this article as: Kostiantyn P.Melnykov , Pavel S.Nosik, Bohdan B.Kurpil,
Dmitriy A.Sibgatulin, Dmitriy M.Volochnyuk, Sergey V.Ryabukhin, Oleksandr
O.Grygorenko, Synthesis of gem-difluorocyclopentane/hexane building blocks, Journal
of Fluorine Chemistryhttp://dx.doi.org/10.1016/j.jfluchem.2017.04.012
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Graphical Abstract
Synthesis of gem-difluorocycloalkane building blocks is described.

2
Highlights




An approach to gem-difluorocyclopentane/hexane carboxylic acids and amines is developed.
Straightforward fluorination of 3-ketocycloalkanecarboxylates leads to the target 3,3-difluoro-substitited cycloalkanes.
For the 2,2-difluorocycloalkanecarboxylic acids, the bypass route via (2-oxocycloalkyl)methyl acetates is necessary.
2,2-Difluorocycloalkylamines can be obtained via deoxofluorination of 2-(trifluoroacetylamino)cycloalkanones.

Journal of Fluorine Chemistry
journal homepage: www.elsevier.com
Synthesis of gem-difluorocyclopentane/hexane building blocks
Kostiantyn P. Melnykov,a,b Pavel S. Nosik,a,b Bohdan B. Kurpil’,a Dmitriy A. Sibgatulin,a Dmitriy M.
Volochnyuk,a Sergey V. Ryabukhin,b Oleksandr O. Grygorenkob
aInstitute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine
bTaras Shevchenko National University of Kyiv, Volodymyrska Street 64, Kyiv 01601, Ukraine
ARTICLE INFO
ABSTRACT
Article history:
Received
An approach to the preparation of gem-difluorocyclopentane/hexane-derived carboxylic acids
and amines is described. Whereas for 3,3-difluoro-substituted cycloalkanones, straightforward
deoxofluorination of the corresponding ketoesters led to the target compounds, in the case of
2,2-difluoro isomers, the bypass or alternative routes were necessary.
Received in revised form
Accepted
Available online
2017 Elsevier Ltd. All rights reserved.
Keywords:
Cycloalkanes
Organofluorine compounds
Fluorination
Conformational restriction
Xtal-Fluor
DAST
1. Introduction
Fluorinated cycloalkane building blocks are important structural motifs which become increasingly important in various areas, and
most of all in drug discovery and agrochemistry [1]. One of the most prominent examples of this concept is related to development of
Maraviroc (1), an antiretroviral drug approved by FDA in 2007 [2]. In this case, using 4,4-diflurocyclohexanecarboxylic acid (2) as a
b—ui—ldin—g block for the modification of optimized substance resulted in the compound with unique antiviral profile and lack of affinity
Corresponding author. Tel.: +38-044-239-33-15; fax: +38-044-502-48-32; e-mail: gregor@univ.kiev.ua

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Journal of Fluorine Chemistry
for the hERG channel [3]. It is not surprising therefore that compound 2 and other building blocks bearing 4,4-difluorocyclohexyl
moiety were widely used in medicinal chemistry since then [4]. On the contrary, isomeric and homologous gem-difluorocycloalkanes
3–6 were much less explored to date. Derivatives of these building blocks were evaluated as potent and selective cathepsin inhibitors
[5], cholesteryl ester transfer protein (CETP) inhibitors [6], antibacterial agents [7], muscarinic M3 receptor antagonists [8], bradykinin
B1 receptor antagonists [9], and opioid receptor-like 1 (ORL1) antagonists [10].
Figure 1. gem-Difluorocycloalkane building blocks
Most of the methods for the preparation of building blocks of the type 3–6 relied on deoxofluorination of appropriate ketones with
(bis-(2-methoxyethyl)amino)sulfur trifluoride (Deoxo-Fluor®) (e. g., for the substrates 7 [11], 8 [12], 9 [13], 10 [9], 11–13 [14])
(Scheme 1). In some cases, this procedure gave complex mixtures of the products, with less than 25% yield of the target compounds
(e. g., for 11–13). Other known methods included deoxofluorination of -haloketones with SF4 [15], reaction of -diazoketones with F2
[16], ring-opening of 1-fluoro-2-cyanoepoxides [17], electrochemical ring expansion of cyclic ,-unsaturated esters [18] or reaction of
the corresponding dithiane derivatives with BrF3 [19]. Notably, synthetic approaches to amines and carboxylic acids of the type 3–6 (i.
e. FG = COOH, NH2), which might be especially useful as building blocks for early drug discovery, were not documented in the
literature.
Scheme 1. Synthesis of gem-difluorocycloalkane building blocks via deoxofluorination with Deoxo-Fluor®
2. Results and discussion
Herein, we describe a practical approach to gem-difluorocyclopentane/hexane building blocks 14–21 (Figure 2). For the synthesis of
building blocks 14–17, we relied on deoxofluorination of esters 22 and 23, which were prepared using slightly modified literature
methods (Scheme 2) [20, 21]. For the key step, we have chosen conditions described by Couturier and co-workers [22], which involved

using XtalFluor-E (24) – Et3N3HF as the deoxofluorination reagent; this system showed high efficiency the preparation for various
gem-difluorocycloalkanes, including ethyl ester of the compound 2. In the case of 22, the reaction gave no by-products but was very
slow: after a week at 80 C, only 60% conversion to 25 was achieved. Ester 23 was more reactive, and the corresponding gem-difluoro
derivative 26 was obtained in 68% yield. We have also checked if more reactive (and less expensive) diethylaminosulfur trifluoride
(DAST) can be used in this transformation instead of XtalFluor-E – Et3N3HF. In the case of 25, this was true, and ester 25 was
obtained in 61% yield. In the case of 26, however, formation of the elimination by-products was observed to a great extent. Hydrolysis
of 25 and 26 gave the target carboxylic acids 14 and 15 (92–99%), which were transformed to amines 16 and 17 (isolated as
hydrochlorides) in 52–62% yields via Schmidt rearrangement.
Figure 2. Building blocks 14–21 reported in this paper
Scheme 2. Synthesis of building blocks 14–17
This method did not work with ketoesters 27 and 28 – complex mixtures of products were obtained under the conditions described
above. For the preparation of building blocks 18–21, a bypass route was used (Scheme 3). First, compounds 27 and 28 were
transformed to acetates 29 and 30 in four steps, including protection of the carbonyl group, reduction of the ester moiety, acetylation
and deprotection (74–77% overall yield). It was found that XtalFluor-E did not give any advantage over less expensive DAST for
deoxofluorination of the esters 29 and 30. The corresponding gem-difluorocycloalkanes 31 and 32 were obtained using DAST in 48%
and 45% yields, respectively. Hydrolysis of 31 and 32 gave alcohols 33 and 34 (82–90%), which are themselves promising key
intermediates for synthesis. Oxidation of 33 and 34 with Jones reagent led to the target carboxylic acids 18 and 19 (48–54%).

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Journal of Fluorine Chemistry
Scheme 3. Synthesis of building blocks 18–21
Unfortunately, Schmidt reaction of 18 and 19 under conditions analogous to those used for 14 and 15 gave amine hydrochlorides
20HCl and 21HCl in low yields (7–9%). Therefore, we considered deoxofluorination of 2-aminocycloalkanone derivatives as an
alternative key step for the preparation of 20 and 21. Although deoxofluorination of the substrates 11–13 bearing phtalimide or benzoyl
protective groups was described in the literature (with 7–23% yields),14 deprotection of the corresponding products was not fruitful in
our hands. In our approach, we have used trifluoroacetyl derivatives 39 and 40, prepared in two steps from the corresponding amino
alcohols 41 and 42 (Scheme 4). Deoxofluorination of 39 and 40 led to isolation of the products 43 and 44 in 46% and 48% yields,
respectively. Deprotection of 43 and 44 occurred upon mild acidic hydrolysis and gave 20HCl and 21HCl in good yields (72–80%).
Scheme 4. Alternative approach to the synthesis of building blocks 20 and 21 (relative configurations are shown)
3. Conclusions
Deoxofluorination of appropriate substrates proved to be an efficient method for the preparation of gem-difluorocyclopentane/hexane
building blocks (i. e., carboxylic acids and primary amines) (Table 1). It was shown that less expensive DAST can be used for the
deoxofluorination step instead of Deoxo-Fluor® reported in the previous works for most of the building blocks discussed. In the case of
3,3-difluoro-substitited cycloalkane derivatives, straightforward fluorination of the corresponding 3-ketocycloalkanecarboxylates led to
the target compounds. For the 2,2-difluoro isomers, the bypass route via (2-oxocycloalkyl)methyl acetates was necessary, which
allowed for the preparation of the corresponding carboxylic acids. 2,2-Difluorocycloalkylamines were obtained by alternative route,

including deoxofluorination of the corresponding 2-(trifluoroacetylamino)cycloalkanones. The use of trifluoroacetyl protective group
allowed improving the yield of the deoxofluorination step as compared to the literature precedents. The procedures developed were
used at up to 10 g scale, and in our opinion, have potential for further scale-up.
Table 1. An overview of the synthetic methods developed in this work for the synthesis of building blocks 14–21.
Compound
No. of steps Overall yield (%) Deoxofluorination reagent
3
3
4
4
58
40
30
29
DAST
XTal-Fluor-E – Et3N3HF
DAST
XTal-Fluor-E – Et3N3HF
6
6
14
16
DAST
DAST
4
4
19
18
DAST
DAST
4. Experimental
4.1. General
The solvents were purified according to the standard procedures [23]. 3-Oxocyclopentane-3-carboxylic acid [20a] and 3-
oxocyclohexanecarboxylic acid [21a] were prepared using reported methods. All other starting materials were purchased from
commercial sources. Analytical TLC was performed using Polychrom SI F254 plates. Column chromatography was performed using
1
Kieselgel Merck 60 (230–400 mesh) as the stationary phase. H, 13C, and 19F NMR spectra were recorded on a Varian Gemini 2000

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Journal of Fluorine Chemistry
spectrometer (at 400 MHz for Protons, 101 MHz for Carbon-13, and 376 MHz for Fluorine-19). Chemical shifts are reported in ppm
downfield from TMS (1H, 13C) as an internal standard. 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 1100 LCMSD SL instrument (chemical ionization (APCI).
4.2. Ethyl 3-oxocyclopentane carboxylate (22)
Ester 22 was prepared from 3-oxocyclopentane-3-carboxylic acid using the procedure described below for the compound 23. The
crude product was purified by column chromatography (hexanes – EtOAc (4:1) as eluent). All the spectral and physical data are in
1
accordance with the literature data [24]. Yield 15.3 g, 96%. Colorless oil. Rf = 0.27 (hexanes – EtOAc (4:1)). H NMR (CDCl3, 400
MHz):  = 4.19 (q, J = 7.1 Hz, 2H), 3.17 – 3.07 (m, 1H), 2.57 – 2.08 (m, 6H), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3, 101 MHz): 
= 215.4, 173.5, 60.5, 40.8, 40.6, 37.0, 26.2, 13.9. MS (EI): m/z = 156 (M+), 128 (M+–C2H4), 111 (M+–COOH). Anal. Calcd for C8H12O3:
C, 61.52; H, 7.74. Found: C, 61.12; H, 7.99.
4.3. Ethyl 3-oxocyclohexane carboxylate (23)
To a solution of 3-oxocyclohexane carboxylic acid (63.0 g, 0.443 mol) in ethanol (950 mL), SOCl2 (38.8 mL, 0.532 mol) was added
at 15 C. The reaction mixture was stirred at rt overnight, and then evaporated under reduced pressure. The residue was dissolved in
CHCl3 (500 mL) and stirred with saturated aq NaHCO3 (200 mL) for 30 min. The layers were separated, and the aqueous layer was
extracted with CHCl3 (250 mL). The combined organic phases were dried over Na2SO4 and evaporated in vacuo. The residue was
distilled under reduced pressure to give 23. Yield 56.3 g, 75%. Colorless oil. Bp 90 C / 1.8 mbar (lit. [21c] Bp 80–83 C / 0.6 Torr). 1H
NMR (CDCl3, 400 MHz): δ = 4.14 (q, J = 7.1 Hz, 2H), 2.83 – 2.72 (m, 1H), 2.53 (d, J = 8.2 Hz, 2H), 2.41 – 2.26 (m, 2H), 2.16 – 2.01
(m, 2H), 1.89 – 1.66 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3, 101 MHz):  = 208.6, 173.1, 60.6, 43.0, 42.9, 40.7, 27.5, 24.3,
14.0. MS (EI): m/z = 170 (M+), 97(M+–CO2Et). Anal. Calcd for C9H14O3: C, 63.51; H, 8.29. Found: C, 63.14; H, 8.12.
4.4. Ethyl 3,3-difluorocyclopentane carboxylate (25)
To a solution of DAST (45.1 g, 37.0 mL, 282 mmol) in CH2Cl2 (450 mL) a solution of 22 (11.0 g, 70.4 mmol) in CH2Cl2 (150 mL)
was added at rt. The reaction mixture was refluxed until the starting material had disappeared (ca. 72 h, monitored by 1H NMR probe),
then cooled, and saturated aq NaHCO3 was added to pH = 7. The aqueous phase was extracted with CH2Cl2 (2100 mL), the combined
organic extracts were dried over Na2SO4 and evaporated in vacuo. The residue was distilled under reduced pressure. Yield 7.71 g, 61%.
1
Colorless oil. Bp 31–32C / 1.8 mbar. H NMR (CDCl3, 400 MHz):  = 4.17 (q, J = 7.1 Hz, 2H), 3.05 – 2.93 (m, 1H), 2.47 – 2.31 (m,
2H), 2.28 – 1.97 (m, 4H), 1.27 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3, 101 MHz):  = 173.3, 131.2 (dd, J = 250, 246 Hz), 60.6, 40.6 (dd,
J = 5.4, 2.9 Hz), 38.1 (t, J = 26.6 Hz), 34.7 (t, J = 25.2 Hz), 26.2 (dd, J = 4.4, 3.5 Hz), 13.9. 19F NMR (CDCl3, 376 MHz): δ = –92.0
(dquint, J = 229, 16.4 Hz), –93.2 (dquint, J = 229, 16.4 Hz). MS (EI): m/z = 178 (M+), 158 (M+–HF). Anal. Calcd for C8H12F2O2: C,
53.93; H, 6.79. Found: C, 53.89; H, 6.39.
4.5. Ethyl 3,3-difluorocyclohexane carboxylate (26)

To a suspension of XtalFluor-E (24) (33.8 g, 0.147 mol) in 1,2-dichloroethane (200 mL), Et3N3HF (14.2 g, 88.4 mmol) was added.
To the resulting mixture, a solution of ketoester 23 (10.0 g, 58.8 mmol) in 1,2-dichloroethane (20 mL) was added at 15 C. The reaction
1
mixture was stirred at rt for 30 min and then refluxed until the starting material disappeared (ca. 8 h, monitored by H NMR), then
cooled to rt, quenched with saturated aq NaHCO3 solution and extracted with 1,2-dichloroethane (3100 mL). The combined organic
extracts were washed with 10% aq citric acid (2100 mL), brine (100 mL), dried over Na2SO4 and evaporated. The residue was distilled
under reduced pressure to give 26. Yield 7.74 g, 68%. Colorless oil. Bp 39–41 C / 1.8 mbar. 1H NMR (CDCl3, 400 MHz):  = 4.15 (q,
J = 7.1 Hz, 2H), 2.61 (tdd, J = 12.2, 3.8, 2.2 Hz, 1H), 2.38 – 2.26 (m, 1H), 2.14 – 1.97 (m, 2H), 1.96 – 1.77 (m, 2H), 1.75 – 1.52 (m,
2H), 1.47 – 1.34 (m, 1H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3, 101 MHz):  = 173.3 (d, J = 1.6 Hz), 122.6 (dd, J = 242, 239 Hz),
60.4, 40.0 (d, J = 9.6 Hz), 35.7 (t, J = 25.0 Hz), 33.1 (dd, J = 25.1, 22.0 Hz), 27.1 (d, J = 1.6 Hz), 21.4 (d, J = 9.6 Hz), 14.0. 19F NMR
(CDCl3, 376 MHz): δ = –91.1 (d, J = 239 Hz), –101.5 (dt, J = 239, 32.1 Hz). MS (EI): m/z = 192 (M+), 172 (M+–HF). Anal. Calcd for
C9H14F2O2: C, 56.24; H, 7.34. Found: C, 56.60; H, 7.19.
4.6. 3,3-Difluorocyclopentanecarboxylic acid (14)
Carboxylic acid 14 was prepared from the compound 25 using the procedure described below for the compound 15. Yield 5.57 g,
99%. Yellowish oil. 1H NMR (CDCl3, 400 MHz):  = 12.01 (br s, 1H), 3.14 – 2.98 (m, 1H), 2.48 – 2.33 (m, 2H), 2.29 – 2.01 (m, 4H).
13C NMR (CDCl3, 101 MHz):  = 180.2, 131.0 (dd, J = 250, 247 Hz), 40.4 (dd, J = 5.2, 3.2 Hz), 37.9 (t, J = 26.9 Hz), 34.8 (t, J = 25.2
Hz), 26.1 (dd, J = 4.2, 3.6 Hz). 19F NMR (CDCl3, 376 MHz): δ = –92.4 (d, J = 225 Hz), –95.2 (d, J = 225 Hz). MS (EI): m/z = 130 (M+–
HF), 85 (M+ – HF – COOH). Anal. Calcd for C6H8F2O2: C, 48.00; H, 5.37. Found: C, 47.71; H, 5.14.
4.7. 3,3-Difluorocyclohexanecarboxylic acid (15)
To a solution of ester 26 (2.00 g, 10.4 mmol) in ethanol (20 mL), a cold solution of NaOH (0.50 g, 12.5 mmol) in H2O (1 mL) was
added. The reaction mixture was stirred at rt overnight. Ethanol was evaporated in vacuo, the residue was dissolved in H2O (10 mL) and
washed with Et2O (10 mL). The aqueous layer was acidified with 10% aq HCl to pH=3 and extracted with CHCl3 (310 mL). The
combined organic extracts were dried over Na2SO4 and evaporated in vacuo to give 15. The analytical sample was obtained by
1
recrystallization from cyclohexane. Yield 1.57 g, 92%. White solid. Mp = 71–73 C. H NMR (CDCl3, 400 MHz):  = 2.69 (ttd, J =
12.2, 3.7, 1.5 Hz, 1H), 2.43 – 2.30 (m, 1H), 2.16 – 2.01 (m, 2H), 1.99 – 1.79 (m, 2H), 1.77 – 1.54 (m, 2H), 1.51 – 1.37 (m, 1H); COOH
is exchanged with HDO. 13C NMR (CDCl3, 101 MHz):  = 179.8, 122.4 (t, J = 240 Hz), 39.8 (d, J = 9.3 Hz), 35.4 (t, J = 25.4 Hz), 33.1
(t, J = 23.5 Hz), 26.9, 21.4 (d, J = 9.4 Hz). 19F NMR (376 MHz, CDCl3) δ –91.3 (d, J = 238 Hz), –101.5 (dt, J = 238 31.5 Hz). MS (EI):
m/z = 164 (M+), 144 (M+–HF), 126 (M+–HF–H2O), 99 (M+ - HF – COOH). Anal. Calcd for C7H10F2O2: C, 51.22; H, 6.14. Found: C,
51.03; H, 6.25.
4.8. 3,3-Difluorocyclopentanamine hydrochloride (16HCl)
Hydrochloride 16HCl was prepared from the compound 14 using the procedure described below for the compound 17HCl. Yield
0.215 g, 52%. White solid. Mp 194–197 С (dec). 1H NMR (D2O), 400 MHz):  = 3.94 – 3.82 (m, 1H), 2.73 – 2.58 (m, 1H), 2.43 – 2.09

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Journal of Fluorine Chemistry
(m, 4H), 1.97 – 1.82 (m, 1H). 13C NMR (D2O, 101 MHz):  = 127.9 (t, J = 247 Hz), 45.3, 36.5 (t, J = 26.7 Hz), 30.6 (t, J = 24.7 Hz),
24.6. 19F NMR (DMSO-d6, 376 MHz): δ = –88.9 (dquint, J = 228, 15.0 Hz), –90.5 (br d, J = 228 Hz). MS (EI): m/z = 121 (M+), 92
+
(NH2 =CH–CH=CF2). Anal. Calcd for C5H10ClF2N: C, 38.11; H, 6.40; Cl, 22.50; N 8.89. Found: C, 38.00; H, 6.77; Cl, 22.37; N 9.07.
4.9. 3,3-Difluorocyclohexanamine hydrochloride (17HCl)
Carboxylic acid 15 (1.00 g, 6.10 mmol) was dissolved in CHCI3 (30 mL), and 98% H2SO4 (2 mL) was added. The mixture was
heated to 50 °C, and NaN3 (0.80 g, 12.2 mmol) was added in portions at this temperature over 3 h. Then the reaction mixture was stirred
at 45–50 °C for additional 3 h, cooled to rt and stirred for 48 h. Then the mixture was poured into ice (10 g), and the organic layer was
separated. The aqueous phase was adjusted to pH = 12–13 with 15% aq NaOH and extracted with CH2Cl2 (410 mL). The organic
phase was acidified with HCl in Et2O (20 mL) until the precipitate started to form, and then evaporated to dryness to give the target
1
product 17HCl. Yield 0.653 g, 62%. White solid. Mp 285–288 С (dec). H NMR (DMSO-d6, 400 MHz):  = 8.46 (br s, 3H), 3.20 –
3.06 (m, 1H), 2.48 – 2.36 (m, 1H), 2.08 – 1.86 (m, 3H), 1.86 – 1.60 (m, 2H), 1.51 – 1.31 (m, 2H). 13C NMR (DMSO-d6, 101 MHz):  =
123.2 (dd, J = 242, 239 Hz), 46.7 (d, J = 11.4 Hz), 37.2 (t, J = 24.8 Hz), 32.2 (dd, J = 24.2, 21.6 Hz), 27.8, 19.2 (d, J = 10.0 Hz). 19F
+
NMR (DMSO-d6, 376 MHz): δ = –87.5 (d, J = 240 Hz), –97.8 (dtt, J = 240, 34.4, 9.3 Hz). MS (EI): m/z = 135 (M+), 92 (NH2 =CH–
CH=CF2). Anal. Calcd for C6H12ClF2N: C, 41.99; H, 7.05; Cl, 20.66; N, 8.16. Found: C, 42.21; H, 7.26; Cl, 20.46; N, 8.48.
4.10. Ethyl 2,2-dimethoxycyclopentanecarboxylate (35)
Ethyl 2-oxocyclopentane-1-carboxylate (50.0 g, 0.320 mol), trimethyl orthoformate (84.9 g, 0.800 mol) and p-toluenesulfonic acid
monohydrate (550 mg, 2.89 mmol) in dry MeOH (300 mL) were heated under reflux under argon atmosphere overnight. The crude
mixture was cooled to room temperature, quenched with solid Na2CO3 (1 g), filtered and concentrated in vacuo. The residue was
1
distilled in vacuo. Yield 62.0 g, 96%. Colorless liquid. Bp 53–55 C / 1 mbar. H NMR (CDCl3, 400 MHz):  = 4.22 – 4.08 (m, 2H),
3.26 (s, 3H), 3.22 (s, 3H), 2.97 (dd, J = 8.4, 5.6 Hz, 1H), 2.09 – 1.98 (m, 1H), 1.94 – 1.78 (m, 4H), 1.68 – 1.55 (m, 1H), 1.25 (t, J = 7.1
Hz, 3H). 13C NMR (CDCl3, 101 MHz):  = 172.6, 111.9, 60.0, 50.2, 50.0, 48.5, 34.1, 27.3, 21.8, 14.0. MS (EI): m/z = 202 (M+), 171
(M+–OMe), 101 (MeO+=C(OMe)–CH=CH2). Anal. Calcd. for C10H18O4: C, 59.39; H, 8.97. Found: C, 59.52; H, 8.80.
4.11. Ethyl 2,2-dimethoxycyclohexanecarboxylate (36)
Compound 36 was prepared from ethyl 2-oxocyclohexane-1-carboxylate using the procedure described above for the compound 35.
Yield 50.2 g, 98%. Colorless liquid. Bp 75–76 C / 1 mbar. 1H NMR (CDCl3, 400 MHz):  = 4.19 – 4.10 (m, 2H), 3.21 (s, 3H), 3.17 (s,
3H), 2.95 (app. dt, J = 4.8, 2.5 Hz, 1H), 2.02 (app. td, J = 13.4, 4.1 Hz, 1H), 1.88 – 1.76 (m, 2H), 1.76 – 1.60 (m, 3H), 1.49 – 1.33 (m,
2H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3, 101 MHz):  =13C NMR (101 MHz, CDCl3) δ 172.0, 99.6, 59.8, 47.5, 47.0, 45.5, 28.2,
25.9, 22.0, 20.5, 14.0. MS (EI): m/z = 216 (M+), 185 (M+–OMe), 101 (MeO+=C(OMe)–CH=CH2). Anal. Calcd. for C11H20O4: C, 61.09;
H, 9.32. Found: C, 61.15; H, 9.27.
4.12. (2,2-Dimethoxycyclopentyl)methanol (37)

To a suspension of LiAlH4 (24.3 g, 0.640 mol) in dry THF (900 mL), ketal 35 (62.0 g, 0.306 mmol) in dry THF (200 mL) was added
dropwise at 0 C. The reaction mixture was warmed to rt, stirred for 1 h, then quenched by dropwise addition of H2O (25 mL), 10 % aq
NaOH (50 mL) and H2O (75 mL). The reaction mixture was filtered, and evaporated in vacuo. The residue was dissolved in CH2Cl2
1
(500 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the target product. Yield 46.7 g, 95%. Amber oil. H NMR
(CDCl3, 400 MHz):  = 3.64 – 3.49 (m, 2H), 3.28 (s, 3H), 3.23 (s, 3H), 2.67 (br s, 1H), 2.36 – 2.27 (m, 1H), 1.96 – 1.80 (m, 2H), 1.79 –
1.68 (m, 1H), 1.68 – 1.52 (m, 2H), 1.44 – 1.33 (m, 1H). 13C NMR (CDCl3, 101 MHz):  = 112.8, 64.0, 49.8, 48.0, 44.4, 35.1, 26.8, 21.6.
MS (EI): m/z = 160 (M+), 143 (M+–OH), 129 (M+–OMe), 101 (MeO+=C(OMe)–CH=CH2). Anal. Calcd. for C8H16O3: C, 59.97; H,
10.07. Found: C, 59.72; H, 10.27.
4.13. (2,2-Dimethoxycyclohexyl)methanol (38)
Compound 38 was prepared from compound 36 using the procedure described above for the compound 37. Yield 35.4 g, 88%.
Yellowish oil. 1H NMR (CDCl3, 400 MHz):  = 3.90 (dd, J = 11.2, 8.6 Hz, 1H), 3.60 – 3.49 (m, 1H), 3.23 (s, 3H), 3.20 (s, 3H), 2.99 (d,
J = 8.7 Hz, 1H), 2.20 – 2.11 (m, 1H), 1.90 – 1.77 (m, 1H), 1.64 – 1.55 (m, 4H), 1.55 – 1.36 (m, 2H), 1.32 – 1.18 (m, 1H). 13C NMR
(CDCl3, 101 MHz):  = 102.5, 63.4, 47.3, 47.2, 40.5, 28.7, 25.7, 22.5, 20.9. MS (EI): m/z = 174 (M+), 157 (M+–OH), 143 (M+–OMe),
101 (MeO+=C(OMe)–CH=CH2). Anal. Calcd. for C9H18O3: C, 62.04; H, 10.41. Found: C, 61.85; H, 10.59.
4.14. (2-Oxocyclopentyl)methyl acetate (29)
Alcohol 37 (46.7 g, 0.292 mol) and DMAP (370 mg, 3.03 mmol) were dissolved in dry pyridine (105 mL) under argon atmosphere.
Ac2O (40.0 mL, 0.419 mol) was added dropwise (CAUTION! Exothermic reaction), and the resulting mixture was stirred overnight.
The reaction mixture was quenched with 2 M HCl (600 mL) and Et2O (500 mL) upon vigorous stirring over 5 min. The organic phase
was separated, and the aqueous phase extracted with Et2O (3400 mL). The combined organic extracts were neutralized with saturated
aq NaHCO3, dried over MgSO4 and concentrated in vacuo. Yield 38.1 g, 84%. Yellowish oil 1H NMR (CDCl3, 400 MHz):  = 4.25 (dd,
J = 11.2, 4.1 Hz, 1H), 4.13 (dd, J = 11.2, 5.8 Hz, 1H), 2.41 – 2.22 (m, 2H), 2.17 (ddt, J = 11.4, 4.0, 2.6 Hz, 1H), 2.12 – 2.04 (m, 1H),
2.04 – 1.93 (m, 1H), 1.98 (s, 3H), 1.84 – 1.65 (m, 2H). 13C NMR (CDCl3, 101 MHz):  = 217.1, 170.3, 62.5, 47.8, 38.0, 26.6, 20.6,
20.4. MS (EI): m/z = 156 (M+), 114 (M+–CH2=C=O), 96 (M+–AcOH), 43(CH3CO+). Anal. Calcd. for C8H12O3: C, 61.52; H, 7.74.
Found: C, 61.24; H, 7.79.
4.15. (2-Oxocyclohexyl)methyl acetate (30)
Compound 30 was prepared from compound 38 using the procedure described above for the compound 29. Yield 29.6 g, 86%.
1
Yellowish oil. H NMR (CDCl3, 400 MHz):  = 1H NMR (400 MHz, CDCl3) δ 4.35 (dd, J = 11.3, 5.9 Hz, 1H), 4.02 (dd, J = 11.3, 6.3
Hz, 1H), 2.70 – 2.60 (m, 1H), 2.44 – 2.36 (m, 1H), 2.36 – 2.25 (m, 1H), 2.20 – 2.11 (m, 1H), 2.11 – 2.04 (m, 1H), 2.01 (s, 3H), 1.94 –
1.83 (m, 1H), 1.74 – 1.57 (m, 2H), 1.51 – 1.35 (m, 1H). 13C NMR (CDCl3, 101 MHz):  = 209.7, 170.4, 63.0, 49.2, 41.8, 30.7, 27.4,
24.5, 20.7. MS (EI): m/z = 170 (M+), 127 (M+–Ac), 110 (M+–AcOH), 43(CH3CO+). Anal. Calcd. for C9H14O3: C, 63.51; H, 8.29. Found:
C, 63.74; H, 7.98.

12
Journal of Fluorine Chemistry
4.16. (2,2-Difluorocyclopentyl)methyl acetate (31)
To a solution of DAST (156 g, 128 mL, 0.968 mol) in CH2Cl2 (650 mL), a solution of 29 (37.8 g, 0.242 mol) in CH2Cl2 (400 mL)
1
was added at rt. The reaction mixture was refluxed for 72 h (monitored by H NMR), then cooled. Saturated aq NaHCO3 was added to
pH = 7. Aqueous layer was extracted with CH2Cl2 (2100 mL). The combined organic extracts were dried over Na2SO4 and evaporated
in vacuo. The residue was purified by column chromathography (hexanes –EtOAc (14 : 1) as eluent). Yield 20.5 g, 48%. Colourless oil.
Rf = 0.42 (hexanes –EtOAc (14 : 1)). 1H NMR (CDCl3, 400 MHz):  = 4.21 (dd, J = 11.3, 7.1 Hz, 1H), 4.12 (dd, J = 11.3, 6.7 Hz, 1H),
2.56 – 2.39 (m, 1H), 2.24 – 1.93 (m, 3H), 2.06 (s, 3H), 1.88 – 1.66 (m, 2H), 1.59 – 1.48 (m, 1H). 13C NMR (CDCl3, 101 MHz):  =
170.3, 131.1 (t, J = 251 Hz), 61.8 (d, J = 7.4 Hz), 44.7 (dd, J = 23.8, 21.4 Hz), 35.2 (t, J = 24.7 Hz), 26.5 (d, J = 5.8 Hz), 20.6, 20.1 (t, J
= 4.5 Hz). 19F NMR (CDCl3, 376 MHz): δ = –96.0 (ddd, J = 231, 25.7, 13.4 Hz), –107.0 (ddd, J = 231, 32.9, 16.0 Hz). MS (EI): m/z =
178 (M+), 98 (M+ – AcOH – HF), 86, 43 (CH3CO+). Anal. Calcd. for C8H12F2O2: C, 53.93; H, 6.79. Found: C, 53.72; H, 6.66.
4.17. (2,2-Difluorocyclohexyl)methyl acetate (32)
Compound 32 was prepared from compound 30 using the procedure described above for the compound 29. Yield 15.0 g, 45%.
Colorless oil. Rf = 0.38 (hexanes –EtOAc (14 : 1)). 1H NMR (400 MHz, CDCl3): δ = 4.38 (dd, J = 11.2, 5.1 Hz, 1H), 4.03 (dd, J = 11.2,
7.9 Hz, 1H), 2.17 – 2.02 (m, 2H), 2.06 (s, 3H), 1.94 – 1.82 (m, 1H), 1.82 – 1.44 (m, 4H), 1.42 – 1.20 (m, 2H). 13C NMR (101 MHz,
CDCl3): δ = 170.4, 123.0 (t, J = 244 Hz), 62.2 (t, J = 4.0 Hz), 42.7 (dd, J = 22.0, 19.7 Hz), 34.0 (dd, J = 24.7, 22.0 Hz), 26.3 (d, J = 6.5
Hz), 23.5, 22.4 (d, J = 9.1 Hz), 20.7. 19F NMR (CDCl3, 376 MHz): δ = –96.9 (d, J = 237 Hz), -114.1 (br d, J = 237 Hz). MS (EI): m/z =
172 (M+–HF), 112 (M+–AcOH–HF), 43 (CH3CO+). Anal. Calcd. for C9H14F2O2: C, 56.24; H, 7.34. Found: C, 56.25; H, 7.10.
4.18. (2,2-Difluorocyclopentyl)methanol (33)
Ester 31 (19.4 g, 0.109 mol) was dissolved in MeOH (200 mL), and NaOH (8.70 g, 0.218 mol) in H2O (20 mL) was added. The
reaction mixture was stirred at room temperature overnight. The solvent was evaporated, water (100 mL) was added, and the mixture
was extracted with CH2Cl2 (3100 mL). The organic layer was dried over Na2SO4 and evaporated in vacuo. Yield 12.1 g, 82%.
1
Yellowish oil. H NMR (CDCl3, 400 MHz):  = 3.80 (dd, J = 11.5, 7.1 Hz, 1H), 3.69 (dd, J = 11.5, 5.5 Hz, 1H), 2.45 – 2.27 (m, 1H),
2.22 – 1.91 (m, 3H), 1.83 (br s, 1H), 1.82 – 1.64 (m, 2H), 1.63 – 1.50 (m, 1H). 13C NMR (CDCl3, 101 MHz):  = 132.5 (t, J = 251 Hz),
60.8 (d, J = 7.9 Hz), 47.7 (t, J = 21.7 Hz), 35.5 (t, J = 24.5 Hz), 25.9 (d, J = 5.0 Hz), 20.4. 19F NMR (CDCl3, 376 MHz): δ –93.4 (dq, J =
230, 14.0 Hz), –107.2 (dq, J = 230, 15.2 Hz). MS (EI): m/z = 136 (M+), 86 (M+–HF–CH2O). Anal. Calcd. for C6H10F2O: C, 52.93; H,
7.40. Found: C, 52.98; H, 7.12.
4.19. (2,2-Difluorocyclohexyl)methanol (34)
Compound 34 was prepared from compound 32 using the procedure described above for the compound 33. Used in the next step
without further purification. Yield 10.5 g, 90%. Yellowish oil. 1H NMR (400 MHz, CDCl3) δ 3.96 (dd, J = 11.4, 5.7 Hz, 1H), 3.62 (dd,
J = 11.4, 5.6 Hz, 1H), 2.16 – 2.02 (m, 1H), 2.02 – 1.82 (m, 2H), 1.82 – 1.45 (m, 5H), 1.34 (tt, J = 24.1, 12.2 Hz, 2H). 13C NMR (CDCl3,
101 MHz):  = 124.5 (t, J = 243 Hz), 61.2 (t, J = 3.7 Hz), 45.7 (dd, J = 21.6, 18.7 Hz), 34.1 (dd, J = 24.9, 22.0 Hz), 25.9 (d, J = 7.0 Hz),

23.7 (d, J = 1.4 Hz), 22.6 (d, J = 9.3 Hz). 19F NMR (CDCl3, 376 MHz): δ = –95.93 (d, J = 235 Hz), –113.71 (br d, J = 235 Hz). MS
(EI): m/z = 150 (M+), 130 (M+–HF), 100 (M+–HF–CH2O). Anal. Calcd. for C7H12F2O: C, 55.99; H, 8.05. Found: C, 55.69; H, 7.99.
4.20. 2,2-Difluorocyclopentanecarboxylic acid (18)
Sulfuric acid (17.4 g, 9.5 mL, 0.178 mol) was added carefully to CrO3 (13.3 g, 0.133 mol) and H2O (40 mL). The mixture was
cooled to 0 C, and a solution of the substrate (12.1 g, 88.9 mmol) in acetone (200 mL) was added at this temperature. The reaction
mixture was stirred overnight at rt, 10% aq NaOH to pH = 10 was added, and the mixture was washed with EtOAc (2100 mL).
Aqueous layer was acidified with 10% aq HCl to pH = 2–3 and extracted with EtOAc (4100 mL). The organic layer was dried over
Na2SO4 and evaporated in vacuo. The residue was purified by flash chromatography (hexanes – EtOAc (1:1) as eluent), followed by
recrystallization from heptane. Yield 6.45 g, 48%. White solid. Mp 68–69 C. Rf = 0.78 (hexanes – EtOAc (1:1)). 1H NMR (CDCl3, 400
MHz):  = 3.26 – 3.08 (m, 1H), 2.30 – 2.04 (m, 4H), 2.01 – 1.88 (m, 1H), 1.87 – 1.72 (m, 1H); COOH is exchanged with HDO. 13C
NMR (CDCl3, 101 MHz):  = δ 175.5, 130.1 (t, J = 254 Hz), 51.2 (t, J = 24.3 Hz), 35.1 (t, J = 24.0 Hz), 26.0 (d, J = 2.4 Hz), 20.4. 19
F
NMR (CDCl3, 376 MHz): δ = –93.2 (dq, J = 231.3, 14.3 Hz), –101.3 (dq, J = 231.4, 13.7 Hz). MS (EI): m/z = 150 (M+), 130 (M+–HF),
85 (M+–HF–COOH). Anal. Calcd. for C6H8F2O2: C, 48.00; H, 5.37. Found: C, 48.29; H, 5.22.
4.21. 2,2-Difluorocyclohexanecarboxylic acid (19)
Compound 19 was prepared from compound 34 using the procedure described above for the compound 18. Yield 6.18 g, 54%. White
solid. Mp 74–75 C. 1H NMR (CDCl3, 400 MHz):  = 3.00 – 2.83 (m, 1H), 2.33 – 2.17 (m, 1H), 2.05 – 1.89 (m, 2H), 1.89 – 1.61 (m,
4H), 1.48 – 1.34 (m, 1H); COOH is exchanged with HDO. 13C NMR (CDCl3, 101 MHz):  = 176.0 (d, J = 5.2 Hz), 121.0 (t, J = 245
Hz), 48.5 (t, J = 22.9 Hz), 33.0 (t, J = 22.7 Hz), 26.2 (dd, J = 3.2, 2.5 Hz), 22.1, 22.0. 19F NMR (CDCl3, 376 MHz): δ = -95.0 (d, J =
238 Hz), -105.7 (br s). MS (EI): m/z = 144 (M+–HF), 99 (M+–HF–COOH). Anal. Calcd. for C7H10F2O2: C, 51.22; H, 6.14. Found: C,
51.61; H, 6.12.
4.22. 2,2,2-Trifluoro-N-(trans-2-hydroxycyclopentyl)acetamide (45)
Amino alcohol 41 (11.4 g, 0.113 mol) and triethylamine (14.8 g, 0.146 mol) were dissolved in dry CH2Cl2 (900 mL). The resulting
solution was cooled to –30 C, and trifluoracetic anhydride (23.7 g; 0.113 mol) was added dropwise. The reaction mixture was stirred at
rt overnight, and then evaporated. The residue was purified by column chromatography (CHCl3 – MeOH (25:1) as eluent). Yield 17.3 g,
1
78%. Mp 116–117 C. Rf = 0.23 (CHCl3 – MeOH (25:1)). H NMR (DMSO-d6, 400 MHz):  = 9.27 (br s, 1H), 4.91 (br s, 1H), 3.93
(dd, J = 11.2, 6.3 Hz, 1H), 3.83 (dd, J = 13.4, 7.5 Hz, 1H), 2.00 – 1.89 (m, 1H), 1.87 – 1.76 (m, 1H), 1.69 – 1.56 (m, 2H), 1.51 – 1.39
(m, 2H). 13C NMR (DMSO-d6, 101 MHz):  = 155.8 (q, J = 35.8 Hz), 115.8 (q, J = 288 Hz), 75.2, 58.1, 32.1, 28.6, 20.1. 19F NMR
(DMSO-d6, 376 MHz): δ = –74.4. MS (EI): m/z = 197 (M+), 179 (M+–H2O), 84 (M+–CF3C(O)NH2). Anal. Calcd. for C7H10F3NO2: C,
42.64; H, 5.11; N, 7.10. Found: C, 42.78; H, 5.25; N, 7.11.
4.23. 2,2,2-Trifluoro-N-(trans-2-hydroxycyclohexyl)acetamide (46)

14
Journal of Fluorine Chemistry
Compound 46 was prepared from compound 42 using the procedure described above for the compound 45. Yield 27.1 g, 74%. White
solid. Mp 129–130 C. Rf = 0.26 (CHCl3 – MeOH (25:1)). 1H NMR (DMSO-d6, 400 MHz):  = 9.12 (br s, 1H), 4.76 (br s, 1H), 3.49 –
3.41 (m, 1H), 3.37 – 3.30 (m, 1H), 1.92 – 1.81 (m, 1H), 1.76 – 1.67 (m, 1H), 1.67 – 1.55 (m, 2H), 1.35 – 1.11 (m, 4H). 13C NMR
(DMSO-d6, 101 MHz):  = 155.7 (q, J = 35.6 Hz), 116.0 (q, J = 288 Hz), 70.3, 55.5, 34.4, 30.4, 24.3, 24.0. 19F NMR (DMSO-d6, 376
MHz): δ = –74.5. MS (EI): m/z = 206 (M+), 193 (M+–H2O), 98 (M+–CF3C(O)NH2). Anal. Calcd. for C8H12F3NO2: C, 45.50; H, 5.73; N,
6.63. Found: C, 45.33; H, 5.84; N, 6.52
4.24. 2,2,2-Trifluoro-N-(2-oxocyclopentyl)acetamide (39)
Freshly prepared pyridinium chlorochromate (34.9 g, 0.162 mol) was suspended in CH2Cl2 (1000 mL), and alcohol 45 (21.0 g, 0.106
mol) was added. The reaction mixture was stirred at rt overnight, decanted from the solid, filtered through SiO2 pad (100 g), washed
with CH2Cl2 (350 mL) and evaporated in vacuo. Yield 13.9 g, 67%. White solid. Mp 63–64 C. Rf = 0.21 (Hexanes – EtOAc (4:1)). 1H
NMR (CDCl3, 400 MHz):  = 7.04 (br s, 1H), 4.24 – 4.10 (m, 1H), 2.73 – 2.59 (m, 1H), 2.46 (dd, J = 19.2, 8.8 Hz, 1H), 2.24 (dd, J =
19.5, 9.5 Hz, 1H), 2.19 – 2.07 (m, 1H), 2.00 – 1.83 (m, 1H), 1.70 (app qd, J = 12.3, 6.7 Hz, 1H). 13C NMR (CDCl3, 101 MHz):  =
212.4, 157.0 (q, J = 37.4 Hz), 115.2 (q, J = 287 Hz), 57.6, 34.4, 28.8, 17.9. 19F NMR (CDCl3, 376 MHz): δ = –77.5. MS (EI): m/z = 195
(M+). Anal. Calcd. for C7H8F3NO2: C, 43.08; H, 4.13; N, 7.18. Found: C, 43.39; H, 4.39; N, 7.10.
4.25. 2,2,2-Trifluoro-N-(2-oxocyclohexyl)acetamide (40)
Compound 40 was prepared from compound 46 using the procedure described above for the compound 39. Yield 20.3 g, 72%. White
1
solid. Mp 69–70 C. Rf = 0.37 (hexanes – EtOAc (4:1)). H NMR (CDCl3, 400 MHz):  = 7.42 (br s, 1H), 4.44 (dt, J = 12.3, 6.0 Hz,
1H), 2.71 (dtd, J = 12.3, 6.0, 3.0 Hz, 1H), 2.58 (ddt, J = 13.5, 4.2, 2.1 Hz, 1H), 2.42 (app. td, J = 13.6, 6.3 Hz, 1H), 2.24 – 2.12 (m, 1H),
1.97 – 1.88 (m, 1H), 1.88 – 1.73 (m, 1H), 1.73 – 1.59 (m, 1H), 1.43 (app. qd, J = 12.7, 3.9 Hz, 1H). 13C NMR (CDCl3, 101 MHz):  =
13C NMR (101 MHz, CDCl3) δ 205.0, 156.0 (q, J = 37.3 Hz), 115.2 (q, J = 287 Hz). 57.8, 40.5, 34.0, 27.5, 23.5. 19F NMR (DMSO-d6,
376 MHz): δ –78.8. MS (EI): m/z = 209 (M+). Anal. Calcd. for C8H10F3NO2: C, 45.94; H, 4.82; N, 6.70. Found: C, 46.18; H, 4.50; N,
6.52.
4.26. N-(2,2-Difluorocyclopentyl)-2,2,2-trifluoroacetamide (43)
Ketone 39 (5.00 g, 25.6 mmol) was dissolved in CH2Cl2 (150 mL) under argon atmosphere, and the solution was cooled to –70 C.
DAST (10.3 g, 64.0 mmol) was added dropwise at this temperature. The reaction mixture was slowly warmed to rt and stirred for 24 h.
DAST (4.12 g, 25.6 mmol) was added, and the resulting mixture was stirred overnight (monitored by NMR). Saturated aq NaHCO3 was
added dropwise to pH = 8, and the phases were separated. The organic layer was dried over Na2SO4 and evaporated in vacuo. The
residue was purified by column chromatography (hexanes – EtOAc (4:1) as eluent); 19F NMR was used for the product detection). Yield
1
2.59 g, 46%. White solid. Mp 72–74 C. H NMR (CDCl3, 400 MHz):  =6.51 (br s, 1H), 4.55 – 4.34 (m, 1H), 2.39 – 2.11 (m, 3H),
1.99 – 1.76 (m, 2H), 1.74 – 1.57 (m, 1H). 13C NMR (CDCl3, 101 MHz):  = 156.6 (q, J = 37.4 Hz), 127.8 (dd, J = 258, 248 Hz), 115.2
(q, J = 287 Hz), 54.4 (dd, J = 26.1, 19.8 Hz), 32.5 (t, J = 23.5 Hz), 28.8 (d, J = 6.1 Hz), 17.8 (dd, J = 5.6, 3.1 Hz). 19F NMR (CDCl3,

376 MHz): δ = –79.0, –107.4 (d, J = 230 Hz), –108.9 (ddd, J = 229, 36.3, 20.0 Hz). MS (EI): m/z = 217 (M+), 197 (M+–HF), 152
+
(CF3C(O)NHCH=CHCH2 ). Anal. Calcd. for C7H8F5NO: C, 38.72; H, 3.71; N, 6.45. Found: C, 38.45; H, 3.79; N, 6.08.
4.27. N-(2,2-Difluorocyclohexyl)-2,2,2-trifluoroacetamide (44)
Compound 44 was prepared from compound 40 using the procedure described above for the compound 43. Yield 2.63 g, 48%. White
solid. Mp 106–107 C. 1H NMR (CDCl3, 400 MHz):  = 6.52 (br s, 1H), 4.35 – 4.10 (m, 1H), 2.31 – 2.16 (m, 1H), 2.10 – 1.99 (m, 1H),
1.89 – .77 (m, 2H), 1.80 – 1.65 (m, 1H), 1.61 – 1.34 (m, 3H). 13C NMR (CDCl3, 101 MHz):  = 156.7 (q, J = 37.5 Hz), 120.8 (dd, J =
249, 241 Hz), 115.2 (q, J = 287 Hz), 52.0 (t, J = 20.7 Hz), 33.2 (dd, J = 24.1, 20.4 Hz), 29.4 (d, J = 5.4 Hz), 23.1, 21.8 (d, J = 9.3 Hz).
19F NMR (CDCl3, 376 MHz): δ = –79.0, –103.6 (d, J = 244 Hz), –120.5 (br d, J = 244 Hz). MS (EI): m/z = 231 (M+), 211 (M+–HF),
+
152 (CF3C(O)NHCH=CHCH2 ). Anal. Calcd. for C8H10F5NO: C, 41.57; H, 4.36; N, 6.06. Found: C, 41.82; H, 4.41; N, 6.24.
4.28. 2,2-Difluorocyclopentanamine hydrochloride (20HCl)
Amide 43 (1.28 g, 5.90 mmol) was dissolved in MeOH (5 mL), and aq HCl (30%, 5 mL) was added. The reaction mixture was
stirred at 35 C overnight, and then evaporated to dryness. The residue was triturated with Et2O (5 mL), filtered and dried in vacuo.
Yield 0.746 g, 80%. Brownish solid. Mp 178–181 C (dec.). 1H NMR (D2O, 400 MHz):  = 3.98 – 3.82 (m, 1H), 2.44 – 2.17 (m, 3H),
2.04 – 1.79 (m, 3H). 13C NMR (DMSO-d6, 101 MHz):  = 129.0 (dd, J = 254, 253 Hz), 53.7 (dd, J = 30.5, 20.1 Hz), 32.9 (t, J = 23.1
Hz), 27.3 (d, J = 4.7 Hz), 18.4 (t, J = 4.4 Hz). 19F NMR (DMSO-d6, 376 MHz): –98.1 (dq, J = 231, 13.3 Hz), –105.2 (dq, J = 231, 14.3
+
Hz). MS (EI): m/z = 121 (M+), 56 (CH2=CH–CH=NH2 ). Anal. Calcd. for C5H10ClF2N: C, 38.11; H, 6.4; N, 8.89; Cl, 22.50. Found: C,
38.06; H, 6.62; N, 9.26; Cl, 22.67
4.29. 2,2-Difluorocyclohexanamine hydrochloride (21HCl)
Compound 21HCl was prepared from compound 44 using the procedure described above for the compound 20HCl. Yield 0.627 g,
1
72%. Brownish solid. Mp 239–242 C (dec.). H NMR (D2O, 400 MHz):  = 3.69 – 3.53 (m, 1H), 2.33 – 2.17 (m, 1H), 2.08 (dd, J =
8.4, 3.9 Hz, 1H), 1.92 – 1.71 (m, 3H), 1.68 – 1.55 (m, 1H), 1.55 – 1.32 (m, 2H). 13C NMR (D2O, 101 MHz):  = 118.6 (t, J = 244 Hz),
50.4 (t, J = 21.5 Hz), 29.5 (t, J = 21.3 Hz), 24.6 (d, J = 3.9 Hz), 19.5, 18.7 (dd, J = 9.4, 3.2 Hz). 19F NMR (DMSO-d6, 376 MHz): δ = –
+
98.8 (d, J = 239 Hz), –114.7 (br d, J = 239 Hz). MS (EI): m/z = 135 (M+), 56 (CH2=CH–CH=NH2 ). Anal. Calcd. for C6H12ClF2N: C,
41.99; H, 7.05; N, 8.16; Cl, 20.66. Found: C, 41.94; H, 7.27; N, 7.79; Cl, 20.57.
Acknowledgements
The work was supported by Ukrainian Government Funding (state registry No. 0114U003956) and Life Chemicals Group.
References and notes
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