Synthesis and some transformations of all three isomers of α,α-difluoropyridinylacetonitrile

Article abstract of DOI:10.1016/j.jfluchem.2021.109792

An effective preparative approach to fluorinated pyridinylacetonitriles, based on electrophilic fluorination of pyridinylacetonitriles, was developed. Their synthetic potential for obtaining new fluorine-containing building blocks and heterocyclic systems was disclosed.

Full text of DOI:10.1016/j.jfluchem.2021.109792

Journal of Fluorine Chemistry 246 (2021) 109792
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis and some transformations of all three isomers of
α,α-difluoropyridinylacetonitrile
,b,*
Oksana M. Shavrinaa, Andrii V. Bezdudnya, Yuliya V. Rassukanaa
a Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmans’ka str., Kyiv 02660, Ukraine
b Department of Organic Chemistry, National Technical University of Ukraine "Igor Sikorsky Kyiv Polytechnic Institute", 37, Prospect Peremogy, Kyiv, 03056, Ukraine
A R T I C L E I N F O
A B S T R A C T
Keywords:
An effective preparative approach to fluorinated pyridinylacetonitriles, based on electrophilic fluorination of
pyridinylacetonitriles, was developed. Their synthetic potential for obtaining new fluorine-containing building
blocks and heterocyclic systems was disclosed.
Fluorination
Difluoromethyl
Pyridinyl
Nitrile
N-fluorobenzenesulfonimide
1. Introduction
2. Results and discussion
Heterocycles bearing difluoromethylene moiety attract considerable
interest for drug discovery due to its unique properties such as high
lipophilicity [1, 2], and significant resistance to oxidative metabolism
[3, 4]. The modification of pyridine derivatives with fluorine atoms is an
elegant example of improving pharmacokinetic properties. For instance,
3-aminopyrazinone acetamide thrombin inhibitors I, II were discovered
after metabolism-directed optimization by incorporation of difluor-
omethylpyridyl fragment [3, 4]. Moreover, recently it was shown that
the modification of the antifungal drug itraconazole with pyridinyldi-
fluoromethyl moiety gives the possibility to obtain the novel agent III
with significantly improved pharmacokinetic parameters and solubility
in water [5] (Figure 1).
In recent years, a series of studies on the synthesis of difluoropyr-
idinylacetic acid esters (convenient precursors of nitriles) have
appeared, among which there are three main approaches: 1) deoxo-
fluorination of pyridinylketoesters [4]; 2) cross-coupling of bromodi-
fluoroacetic ester with pyridyl halides [4, 7]; 3) electrophilic
gem-difluorination of pyridinylacetates with NF-reagents [3, 4, 8]. We
elected to synthesize target difluoroacetonitriles by electrophilic fluo-
rination of activated pyridinylacetonitriles with the commercially
accessible and non-toxic N-fluorobenzenesulfonimide (NFSI). The latter
was successfully used recently for the preparation of some difluor-
oalkylated pyridines [3, 8, 9].
It was found that the fluorination of nitriles 1a-c with NFSI proceeds
Fluorinated pyridinylacetonitriles seem attractive and promising
building blocks for the construction of many classes of organic com-
pounds containing difluoromethylpyridinyl fragment. However, to the
best of our knowledge, there are only few examples of such compounds
having bulky substituents in the heterocycle nucleus [6], whereas
unsubstituted fluorinated pyridinylacetonitriles are unknown so far.
This is obviously due to the lack of synthetic approaches to this
important type of compounds.
chemoselectively in the presence of tert-butyllithium (THF, –78◦C) with
complete conversion to give all isomers of
α,α-difluoropyrid
inylacetonitriles 2a-c (Scheme 1). The resulting nitriles 2a-c were pu-
rified by distillation allowing the preparation of these novel building
blocks in the analytically pure form with 52-76% yield.
Alternatively, difluoropyridinylacetonitriles 2a-c can be obtained
starting from fluorinated esters 4a-c, which were synthesized by us also
using electrophilic fluorination of esters 3a-c. Thus, the esters 4a-c were
converted quantitatively into respective amides 5a-c, the next dehy-
dration of them with phosphorus pentoxide allowed to obtain difluor-
opyridinylacetonitriles 2a-c, isolated with 55-69 % yields (Scheme 2).
The obtained difluorinated pyridinylacetonitriles 2a-c are quite
In the present work, we describe the synthesis of all possible isomers
of α,α-difluoropyridinylacetonitriles and disclose their synthetic poten-
tial for the preparation of new building blocks with difluor-
omethylpyridinyl fragment.
* Corresponding author.
E-mail address: juvivi@ukr.net (Y.V. Rassukana).
https://doi.org/10.1016/j.jfluchem.2021.109792
Received 25 February 2021; Received in revised form 2 April 2021; Accepted 7 April 2021
Available online 10 April 2021
0022-1139/© 2021 Elsevier B.V. All rights reserved.

O.M. Shavrina et al.
Journal of Fluorine Chemistry 246 (2021) 109792
blocks for the synthesis of functionalized nitrogen containing
compounds.
In the first stage of our effort to study
α,α-difluoropy
ridinylacetonitriles we focused on their reduction. The reaction of ni-
triles 2a-с with BH3⋅Me2S in THF leads to β,β-difluoropyridi
nylethylamines 6a-c with preparative yields (Scheme 3).
The possibility of the pyridine ring reduction was demonstrated on
the example of
α-isomer of difluoropyridinylethylamine 6а as an
example (Scheme 4). Thus, after protection of amino function with
Boc2O, compound 7 was subjected to reduction on a rhodium catalyst to
obtain fluorinated bifunctional aminopiperidine 8, isolated in a pure
form with a quantitative yield.
Fig. 1. xxx
Fluorinated pyridinylacetates 4a-c can be readily converted into
interesting objects for synthetic chemistry, for example, the corre-
sponding alcohols 9a-c and acids 10a-c (Scheme 5). It should be noted
that β- and γ-pyridinyldifluoroacetic acids 10b-c were unknown so far,
stable in inert atmosphere, although they rapidly hydrolyze in a humid
media, even in the presence of trace amounts of base impurities. Elec-
tron withdrawing pyridinyldifluoromethylene group increases electro-
philic character of nitriles and, as a result, markedly enhances their
reactivity toward nucleophilic reagents, making them valuable building
α
-isomer 10a was obtained previously in low yield [10].
On the other hand, fluorinated nitriles 2a-c can serve as a basis for
the synthesis of bifunctional nucleophilic systems, convenient pre-
Scheme 1. xxx
Scheme 2. xxx
Scheme 3. xxx
Scheme 4. xxx
Scheme 5. xxx
2

O.M. Shavrina et al.
Journal of Fluorine Chemistry 246 (2021) 109792
Scheme 6. xxx
Scheme 7. xxx
cursors of nitrogen-containing heterocycles modified with a difluor-
mL) was added dropwise. The mixture was stirred at –78◦C for 12 hours
and allowed to warm to room temperature. The reaction mixture was
neutralized with an aqueous solution of citric acid (5%, 30 mL), the
solvent was evaporated, and the residue was extracted with EtOAc (3 ×
30 mL). The organic phase was washed with brine (20 mL), dried over
Na2SO4, evaporated under reduced pressure, the residue was distilled.
–
–
–
omethylpyridinyl group. For example, the addition of ammonia to C
N
triple bond of the nitrile 2a, proceeding under mild conditions, leads to
pyridinylacetamidine 11, promising substrate for the synthesis of bio-
logically important pyrimidinones. Thus, cyclocondensations of pyr-
idinylacetamidine 11 with acetoacetate (12a) or trifluoroacetoacetate
(12b) in the presence of a base afford biorelevant 2-substituded
difluoropyridinylmethyl pyrimidones 13a-b with preparative yields
(Scheme 6).
4.2.2. Synthesis of fluorinated pyridinylacetonitriles 2a-c from
pyridinylacetamides 5a-c (method B)
Тhe reaction of
α
-difluoropyridinylacetonitrile 2a with hydroxyl-
To a solution of respective amide 5 (4.3 g, 25 mmol) in MeCN (80
mL) phosphorus pentoxide (7.1 g, 50 mmol) was slowly added. The
mixture was refluxed for 10 hrs, the solvent was evaporated under
reduced pressure, the residue was dissolved in water (50 mL), and
neutralized with NaHCO3. The product was extracted with EtOAc (3 ×
30 mL), the organic layers were combined and washed with brine (30
mL), dried over Na2SO4, and evaporated under reduced pressure, and
the residue was distilled in vacuo.
amine leads to the fluorinated pyridinyl-containing amidoxime 14, a
typical building block for the construction of the oxadiazole ring. For
instance, condensation of amidoxime 14 with triethyl orthoformate or
acetyl chloride allows preparing of oxadiazoles 15a,b with preparative
yields (Scheme 7).
3. Conclusions
4.2.3. 2,2-Difluoro-2-(pyridin-2-yl)acetonitrile 2a
In summary, we have developed a simple and efficient synthesis of
all isomers of previously unknown fluorinated pyridinylacetonitriles,
and demonstrated their considerable potential as novel convenient
building blocks in design and synthesis of biologically important amines,
diamines, nitrogen-containing heterocycles etc.
Yield 1.17 g (76%, method A); yield 2.12 g (55%, method B); colorless
liquid; bp 78◦C (10 Torr). 1H NMR (400 MHz, CDCl3) δ: 7.55 (dd, 3JHH
7.9 Hz, 3JHH = 4.8 Hz, 1H), 7.72 (d, 3JHH = 7.9 Hz, 1H), 7.93 (t, 3JHH
=
=
7.9 Hz, 1H), 8.77 (d, 3JHH = 4.8 Hz, 1H). 13C NMR (125.7 MHz, CDCl3) δ:
108.2 (t, 1JCF = 245 Hz, СF2), 112.0 (t, 2JCF = 45 Hz, СN), 119.9 (t, 3JCF
= 3 Hz, CPy), 127.1 (t, 4JCF = 2 Hz, CPy), 138.0 (s, CPy), 149.1 (t, 2JCF
=
4. Experimental
28 Hz, CCF2), 150.1 (s, CPy). 19F NMR (470.3 MHz, CDCl3) δ: –87.4 (s).
Anal. Calc. for C7H4F2N2: C, 54.55; H, 2.62; N, 18.18. Found: C, 54.61;
H, 2.60; N, 18.21.
4.1. General
1H, 19F, and 13C NMR spectra were recorded using Bruker Avance
NMR spectrometers operating at 301.5, 400 and 499.8 MHz 1H fre-
quencies (75.8, 100.6, 125.7 and 150.8 MHz for 13C, 188, 376.5 and
470.3 MHz for 19F). Chemical shifts are reported in ppm relative to in-
ternal TMS (1H) or CFCl3 (19F) standards. Melting points are uncorrec-
ted. Solvents were dried according to standard methods. Elemental
analysis was carried out in the analytical laboratory of Institute of
Organic Chemistry, NAS of Ukraine.
4.2.4. 2,2-Difluoro-2-(pyridin-3-yl)acetonitrile 2b
Yield 0.85 g (55%, method A); yield 2.39 g (62%, method B); colorless
1
liquid; bp 82-84◦C (12 Torr). H NMR (400 MHz, CDCl3) δ: 7.50 (dd,
3JHH = 8.0 Hz, 3JHH = 3.8 Hz, 1H), 7.97 (d, 3JHH = 8.0 Hz, 1H), 8.86 (d,
3JHH = 3.8 Hz, 1H), 8.94 (s, 1H). 13C NMR (125.7 MHz, CDCl3) δ: 107.8
2
(t, 1JCF = 244 Hz, СF2), 111.8 (t, JCF = 50.5 Hz, СN), 123.7 (s, CPy),
127.5 (t, 2JCF = 26.5 Hz, CCF2), 133.1(t, 3JCF = 4.5 Hz, CPy), 146.6 (t,
3JCF = 5.5 Hz, CPy), 153.7 (t, 5JCF = 1.5 Hz, CPy). 19F NMR (376.5 MHz,
CDCl3) δ: –84.9(s). Anal. Calc. for C7H4F2N2: C, 54.55; H, 2.62; N, 18.18.
Found: C, 54.43; H, 2.64; N, 18.16.
4.2. Synthesis of difluoropyridinylacetonitriles 2a-c
4.2.1. Synthesis of difluoropyridinylacetonitriles 2a-c from
4.2.5. 2,2-Difluoro-2-(pyridin-4-yl)acetonitrile 2с
pyridinylacetonitriles 1a-c (method A)
Yield 0.8 g (52%, method A); yield 2.66 g (69%, method B); colorless
To a solution of respective pyridinylacetonitrile 1 (1.18 g, 10 mmol)
in THF (30 mL) t-BuLi (1.7 M in pentane, 12.9 mL, 22 mmol) was slowly
added at –78◦C. The reaction mixture was kept at –78◦C for 0.5 h, and a
solution of N-fluorobenzenesulfonimide (6.94 g, 22 mmol) in THF (20
liquid; bp 55◦C (12 Torr). 1H NMR (400 MHz, CDCl3) δ: 7.58 (d, 3JHH
=
4.7 Hz, 2H), 8.88 (d, 3JHH = 4.7 Hz, 2H). 13C NMR (125.7 MHz, CDCl3) δ:
107.4 (t, 1JCF = 245 Hz, СF2), 111.5 (t, 2JCF = 50.5 Hz, СN), 119.0 (t,
3

O.M. Shavrina et al.
Journal of Fluorine Chemistry 246 (2021) 109792
3JCF = 5 Hz, CPy), 139.1 (t, 2JCF = 26.5 Hz, CCF2), 151.2 (s, CPy). 19F
NMR (470.3 MHz, CDCl3) δ: –87.1(s). Anal. Calc. for C7H4F2N2: C, 54.55;
H, 2.62; N, 18.18. Found: C, 54.50; H, 2.68; N, 18.24.
= 253 Hz, СF2), 120.2 (t, 3JCF = 6 Hz, CPy), 141.7 (t, 3JCF = 28 Hz, CCF2),
2
150.9 (s, CPy), 164.7 (t, JCF = 30 Hz, C(O)).19F NMR (376.5 MHz,
DMSO-d6) δ: –105.3 (s). Anal. Calc. for C7H6F2N2O: C, 48.84; H, 3.51; N,
16.27. Found: C, 48.92; H, 3.43; N, 16.38.
4.3. Synthesis of difluoropyridinylacetates 4a-c: general procedure
4.5. Synthesis of difluoropyridinylethanamines 6a-c: general procedure
To a solution of respective pyridinylacetic acid ester 3 (8.25 g, 50
mmol) in THF (80 mL) LiHMDS (1.1 M in THF/heptane/ethylbenzene,
100 mL, 110 mmol) was slowly added at -78◦C. The reaction mixture
was kept at –78◦C for 40 minutes, and then a solution of NFSI (34.65 g,
110 mmol) in THF (150 mL) was added. The mixture was stirred at -78◦C
for 8 hrs, and was allowed to warm to 0◦C. The mixture was neutralized
with an aqueous solution of citric acid (5%, 30 mL), the solvent was
evaporated, and the residue was extracted with ethyl acetate (3 × 50
mL). The organic phase was washed with water (50 mL), saturated
aqueous NH4Cl solution (50 mL), dried over Na2SO4 and evaporated
under reduced pressure, the residue was distilled.
To a solution of respective nitrile 2 (0.1 g, 0.65 mmol) in THF (2 mL)
a borane-dimethyl sulfide complex (0.053 g, 0.7 mmol) was added
dropwise at –40◦C. The reaction mixture was kept at this temperature
for 0.5 h and allowed to warm to r.t., and then the mixture was refluxed
for 2 hours. After cooling to r.t., the reaction mixture was diluted with
water and neutralized with 6N HCl (2mL). Stirred for 1 hour at room
temperature and added dry NaOH to pH~12. The organic layer was
separated, and the aqueous was extracted with EtOAc (2 × 20 mL). The
combined organic extracts were dried over Na2SO4 and the solvents
were evaporated under reduced pressure.
4.5.1. 2,2-Difluoro-2-(pyridin-2-yl)ethanamine 6a
4.3.1. Ethyl 2,2-difluoro-2-(pyridin-2-yl)acetate 4a
Yield 9.2 g (92%); yellow liquid; bp 85-87◦C (0.5 Torr). Other
physicochemical and spectral data were identical to literature data [4].
Yield 0.07 g (68%); yellow oil. Other physicochemical and spectral
data were identical to literature data [3]. Anal. Calc. for C7H8F2N2: C,
53.16; H, 5.10; N, 17.71. Found: C, 53.27; H, 5.01; N, 17.83.
4.3.2. Ethyl 2,2-difluoro-2-(pyridin-3-yl)acetate 4b
Yield 8.6 g (86%); yellow liquid; bp 72◦C (0.3 Torr). Other physi-
cochemical and spectral data were identical to literature data [11].
4.5.2. 2,2-Difluoro-2-(pyridin-3-yl)ethanamine 6b
Yield 0.06 g (58%); yellow oil. 1H NMR (499.8 MHz, CDCl3) δ: 1.74
(br s, 2H, NH2), 3.20 (t, 3JHF = 14.6 Hz, 2H, CH2), 7.37 (dd, 3JHH = 8 Hz,
3JHH = 3 Hz, 1H), 7.80 (d, 3JHH = 8.0 Hz, 1H), 8.69 (d, 3JHH = 3 Hz, 1H),
8.74 (s, 1H). 13C NMR (100.6 MHz, CDCl3) δ: 49.3 (t, 2JCF = 30 Hz, СH2),
4.3.3. Ethyl 2,2-difluoro-2-(pyridin-4-yl)acetate 4c
Yield 8.9 (89%); yellow liquid; bp 45◦C (0.3 Torr). 13C NMR (125.7
1
2
1
120.7 (t, JCF = 243 Hz, СF2), 123.3 (s, CPy), 131.4 (t, JCF = 28 Hz,
MHz, CDCl3) δ: 13.7 (s, CH3), 63.5 (s, CH2), 111.9 (t, JCF = 254 Hz,
CCF2), 133.2 (t, 3JCF = 6 Hz, CPy), 146.9 (t, 3JCF = 7 Hz, CPy), 151.3 (s,
СF2), 119.7 (m, 3JCF = 6 Hz, CPy), 140.8 (t, 2JCF = 26 Hz, CCF2), 151.4 (s,
Py). 19F NMR (470.3 МHz, CDCl3) δ: –106.0 (t, 3JFH = 14.6 Hz). Anal.
2
CPy), 162.9 (t, JCF = 34 Hz, C(O)). 19F NMR (376.5 МHz, CDCl3) δ:
C
Calc. for C7H8F2N2: C, 53.16; H, 5.10; N, 17.71. Found: C, 53.03; H, 5.26;
N, 17.59.
–106.5(s). Other spectral data were identical to literature data [12].
4.4. Synthesis of difluoropyridinacetamides 5a-c: general procedure
4.5.3. 2,2-Difluoro-2-(pyridin-4-yl)ethanamine 6c
Yield 0.064 g (62%); yellow crystals; mp 165-167◦C. 1H NMR (400
MHz, DMSO-d6) δ: 3.33 (br s, 2H, NH2), 3.66 (m, 3JHF = 15.8 Hz, 2H,
CH2), 7.61 (d, 3JHH = 4 Hz, 2H), 8.78 (d, 3JHH = 4 Hz, 2H). 13C NMR
To a solution of respective ester 4 (5.03 g, 25 mmol) in MeOH (20
mL) was added NH3/MeOH (20 mL). The reaction mixture was kept at r.
t. for 6 hrs, the solvent was evaporated under reduced pressure, and the
solid residue was washed with hexane (2 × 50mL) and dried.
(150.8 MHz, DMSO-d6) δ: 43.8 (t, 2JCF = 28.0 Hz, СH2), 119.2 (t, 1JCF
=
244 Hz, СF2), 120.3 (t, 3JCF = 5.5 Hz, CPy), 141.5 (t, 2JCF = 26 Hz, CCF2),
150.9 (s, CPy). 19F NMR (470.3 МHz, DMSO-d6) δ: –102.0 (t, 3JFH = 15.8
Hz). Anal. Calc. for C7H8F2N2: C, 53.16; H, 5.10; N, 17.71. Found: C,
53.07; H, 5.15; N, 17.9.
4.4.1. 2,2-Difluoro-2-(pyridin-2-yl)acetamide 5a
Yield 4.3 g (100%); white powder; mp 162-164◦C. 1H NMR (400
MHz, DMSO-d6) δ: 7.35 (br s, 2H, NH2), 7.41 (dd, 3JHH = 7.8 Hz, 3JHH
=
4.0 Hz, 1H), 7.57 (d, 3JHH = 7.8 Hz, 1 H), 7.86 (t, 3JHH = 7.8 Hz, 1H),
8.55 (d, 3JHH = 4 Hz, 1H). 13C NMR (125.7 MHz, DMSO-d6) δ: 114.1 (t,
1JCF = 254 Hz, СF2), 120.8 (t, 3JCF = 4 Hz, CPy), 124.8 (s, CPy), 137.3 (s,
4.6. tert-Butyl (2,2-difluoro-2-(pyridin-2-yl)ethyl)carbamate 7
C
Py), 149.2 (s, CPy), 155.4 (t, 2JCF = 28 Hz, CCF2), 165.4 (t, 2JCF = 27 Hz,
To a solution of amine 6a (0.21 g, 1.33 mmol) in DCM (3 mL) NEt3
(0.2 g, 2 mmol), and Boc2O (0.29 g, 1.33 mmol) in DCM (3 mL) were
added with ice cooling. The reaction mixture was stirred at r.t. for 16 h.
Then it was quenched with water (2 mL), layers were separated and
aqueous layer was extracted with DCM (3 × 10mL). The combined
organic layers were washed with brine (5 mL), dried over anhydrous
Na2SO4, and concentrated under reduced pressure to give 0.28 g (yield
82%) of 7 as white powder; mp 130-132◦C. 1H NMR (301.5 MHz, CDCl3)
δ: 1.41 (s, 9H, C(CH3)3), 3.98 (t, 3JHF = 14 Hz, 2H, CH2), 5.09 (br s, 1H,
NH), 7.38 (dd, 3JHH = 7.9 Hz, 3JHH = 4.6 Hz, 1H), 7.67 (d, 3JHH = 7.9 Hz,
1H), 7.82 (t, 3JHH = 7.9 Hz, 1H), 8.64 (d, 3JHH = 4.6 Hz, 1H). 13C NMR
C(O)). 19F NMR (376.5 MHz, DMSO-d6) δ: –102.5(s). Anal. Calc. for
C7H6F2N2O: C, 48.84; H, 3.51; N, 16.27. Found: C, 48.96; H, 3.42; N,
16.1.
4.4.2. 2,2-Difluoro-2-(pyridin-3-yl)acetamide 5b
Yield 4.3 g (100%); white powder; mp 160-162◦C. 1H NMR (400
MHz, DMSO-d6) δ: 7.58 (dd, 3JHH = 7.9 Hz, 3JHH = 4.1 Hz, 1H), 8.00 (d,
3JHH = 7.9 Hz, 1H), 8.2 (br s, 2H, NH2), 8.76 (d, 3JHH = 4.1 Hz, 1 H),
8.79 (s, 1H). 13C NMR (125.7 MHz, DMSO-d6) δ: 114.3 (t, 1JCF = 253 Hz,
СF2), 124.2 (s, CPy), 129.7 (t, 3JCF = 26 Hz, CCF2), 133.8 (t, 3JCF = 5.5
Hz, CPy), 146.6 (t, 3JCF = 6 Hz, CPy), 152.4 (s, CPy), 165.1 (t, 2JCF = 30
Hz, C(O)). 19F NMR (376.5 MHz, DMSO-d6) δ: –103.2(s). Anal. Calc. for
C7H6F2N2O: C, 48.84; H, 3.51; N, 16.27. Found: C, 48.71; H, 3.64; N,
16.11.
2
(125.7 MHz, CDCl3) δ: 28.2 (s, C(CH3)3), 44.7 (t, JCF = 30 Hz, СH2),
79.8 (s, C(CH3)3), 118.6 (t, 1JCF = 243 Hz, СF2), 120.6 (s, CPy), 125.0 (s,
C
Py), 137.2 (s, CPy), 149.2 (s, CPy), 153.3 (t, 2JCF = 31 Hz, CCF2), 155.6
(s, C(O)). 19F NMR (188 МHz, CDCl3) δ: –108.3 (t, 3JFH = 14 Hz). Anal.
Calc. for C12H16F2N2O2: C, 55.81; H, 6.24; N, 10.85. Found: C, 55.59; H,
6.13; N, 10.66.
4.4.3. 2,2-Difluoro-2-(pyridin-4-yl)acetamide 5c
Yield 4.3 g (100%); white powder; mp 182-184◦C. 1H NMR (400
MHz, DMSO-d6) δ: 7.58 (d, 3JHH = 5.1 Hz, 2H), 8.35 (br s, 2H, NH2), 8.77
(d, 3JHH = 5.1 Hz, 2H). 13C NMR (125.7 MHz, DMSO-d6) δ: 113.9 (t, 1JCF
4

O.M. Shavrina et al.
Journal of Fluorine Chemistry 246 (2021) 109792
4.7. tert-Butyl (2,2-difluoro-2-(piperidin-2-yl)ethyl)carbamate 8
MHz, DMSO-d6) δ: 7.4 (dd, 3JHH = 7.7 Hz, 3JHH = 4.8 Hz, 1H), 7.57 (d,
3JHH = 7.7 Hz, 1 H), 7.85 (t, 3JHH = 7.7 Hz 1H), 8.54 (d, 3JHH = 4.8 Hz,
1H). 13C NMR (150.8 MHz, DMSO-d6) δ: 114.1 (t, 1JCF = 253 Hz, СF2),
120.9 (t, 3JCF = 4.5 Hz, CPy), 124.7 (s, CPy), 137.2 (s, CPy), 149.0 (s, CPy),
The autoclave (50 mL) was filled with a solution of Boc-amine 7 (0.1
g, 0.39 mmol) in MeOH (5 mL), and 10% Rh/C (10 mg) was added. The
mixture was hydrogenated under 50 atm. of H2 for 16 h. After
completion of the reaction, the catalyst was filtered off, and the solvent
was evaporated to give 0.1 g of 8 (yield 98%) as white solid; mp 184-
186◦C. 1H NMR (301.5 MHz, CDCl3) δ: 1.36-1.41 (m, 1H, CH), 1.46 (s,
2
2
155.6 (t, JCF = 27.5 Hz, CCF2), 164.8 (t, JCF = 27 Hz, C(O)). Other
physicochemical and spectral data were identical to literature data [9].
Anal. Calc. for C7H5F2NO2: C, 48.57; H, 2.91; N, 8.09. Found: C, 48.48;
H, 2.97; N, 8.21.
2
9H, C(CH3)3), 1.47-1.69 (m, 2H), 1.91 (d, JHH = 12.1 Hz, 2H, CH2),
2.68 (td, 2JHH = 12.1 Hz, 1H, CH), 2.95-3.17 (m, 2H, CH, NH), 3.28 (d,
2JHH = 12.4 Hz, 2H, CH2), 3.63 (tt, 3JHF = 14 Hz, 2H, CF2CH2), 5.35 (t,
3JHH = 6.5 Hz, 1H, NHCO). 13C NMR (125.7 MHz, DMSO-d6) δ: 22.6 (s,
CH2), 23.6 (s, CH2), 23.9 (s, CH2), 28.1 (s, C(CH3)3), 41.6 (t, 2JCF = 28
4.9.2. 2,2-Difluoro-2-(pyridin-3-yl)acetic acid 10b
Yield 0.15 g (88%); white powder; mp 193-195◦C. 1H NMR (400
MHz, DMSO-d6) δ: 7.45 (dd, 3JHH = 7.9 Hz, 3JHH = 4.7 Hz, 1H), 7.89 (d,
3JHH = 7.9 Hz, 1 H), 8.62 (d, 3JHH = 4.7 Hz, 1 H), 8.69 (s, 1H). 13C NMR
(125.7 MHz, DMSO-d6) δ: 114.9 (t, 1JCF = 254 Hz, СF2), 123.7 (s, CPy),
133.1 (t, 3JCF = 27 Hz, CCF2), 133.7 (t, 3JCF = 4.5 Hz, CPy), 146.9 (t, 3JCF
= 4.5 Hz, CPy), 150.80 (s, CPy), 164.9 (t, 2JCF = 27.5 Hz, C(O)). 19F NMR
(376.5 Hz, DMSO-d6) δ: –103.3 (s). Anal. Calc. for C7H5F2NO2: C, 48.57;
H, 2.91; N, 8.09. Found: C, 48.63; H, 2.99; N, 7.99.
2
Hz, CF2СH2), 45.6 (s, СH2), 57.4 (t, JCF = 24 Hz, СHCF2), 78.4 (s, C
(CH3)3), 121.6 (t, 1JCF = 246 Hz, СF2), 155.8 (s, C(O)). 19F NMR (188
МHz, CDCl3) δ: –115.8 (dd, 2JFAFB = 254 Hz, 3JFH = 10.6 Hz, 1F), –117.7
(dd, 2JFBFA = 254 Hz, 3JFH = 12.8 Hz, 1F). Anal. Calc. for C12H22F2N2O2:
C, 54.53; H, 8.39; N, 10.60. Found: C, 54.39; H, 8.47; N, 10.65.
4.9.3. 2,2-Difluoro-2-(pyridin-4-yl)acetic acid 10c
4.8. Synthesis of difluoropyridinylethanoles 9a-c: general procedure
1
Yield 0.155 g (91%); white powder; mp 230-240◦C (decomp.). H
NMR (400 MHz, DMSO-d6) δ: 7.45 (d, 3JHH = 4.5 Hz, 2H), 8.61 (d, 3JHH
= 4.5 Hz, 2H). 13C NMR (125.7 MHz, DMSO-d6) δ: 114.6 (t, 1JCF = 254
Hz, СF2), 120.5 (t, 3JCF = 5.5 Hz, CPy), 145.7 (t, 3JCF = 27.5 Hz, CCF2),
To a solution of respective ester 4 (1 g, 5 mmol) in EtOH (10 mL) was
slowly added NaBH4 (0.29 g, 7.5 mmol) at –10◦C. The reaction mixture
was stirred at r. t. for 18 hrs, the solvent was evaporated under reduced
pressure, the residue was neutralized with saturated NH4Cl solution
(2mL), dissolved in 10 mL of EtOAc, washed by brine (5 mL), dried over
Na2SO4, and the solvent was evaporated under reduced pressure to give
9.
2
150.0 (s, CPy), 164.2 (t, JCF = 26.5 Hz, C(O)). 19F NMR (376.5 МHz,
DMSO-d6) δ: –102.0 (s). Anal. Calc. for C7H5F2NO2: C, 48.57; H, 2.91; N,
8.09. Found: C, 48.68; H, 2.79; N, 8.23.
4.10. 2,2-Difluoro-2-(pyridin-2-yl)acetimidamide 11
4.8.1. 2,2-Difluoro-2-(pyridin-2-yl)ethanol 9a
Yield 0.7 g (88%); white crystals; mp 69-72◦C (lit. mp 67-69◦C [4]).
Anal. Calc. for C7H7F2NO: C, 52.83; H, 4.43; N, 8.80. Found: C, 52.68; H,
4.51; N, 8.93.
Nitrile 2a (2 g, 13 mmol) was added dropwise to the ammonia (40
mL) condensed in a three-necked reactor, maintaining the temperature
at about –33◦C. The reaction mixture was kept at this temperature for 4
hrs, and then warmed to room temperature. The residue was dried in
vacuo to give 2.13 g of 11 (yield 96%) as white solid; mp 130-132◦C. 1H
NMR (400 MHz, CDCl3) δ: 5.53 (br s, 3H, NH2, NH), 7.44 (dd, 3JHH = 7.7
Hz, 3JHH = 4.8 Hz, 1H), 7.70 (d, 3JHH = 7.7 Hz, 1H), 7.85 (t, 3JHH = 7.7
Hz, 1H), 8.69 (d, 3JHH = 4.8 Hz, 1H). 13C NMR (125.7 MHz, CDCl3) δ:
112.9 (t, 1JCF = 248 Hz, СF2), 120.3 (s, CPy), 125.49 (s, CPy), 137.4 (s,
4.8.2. 2,2-Difluoro-2-(pyridin-3-yl)ethanol 9b
Yield 0.6 g (75%); yellow oil. 1H NMR (400 MHz, CDCl3) δ: 4.0 (t,
3JHF = 13.2 Hz, 2H), 4.72 (br s, 1H, OH), 7.40 (dd, 3JHH = 7.4 Hz, 3JHH
= 3.9 Hz, 1H), 7.88 (d, 3JHH = 7.4 Hz, 1H), 8.63 (d, 3JHH = 3.9 Hz, 1H),
8.7 (s, 1H). 13C NMR (125.7 MHz, CDCl3) δ: 65.1 (t, 2JCF = 34 Hz, СH2),
1
2
119.9 (t, JCF = 244 Hz, СF2), 123.6 (s, CPy), 131.4 (t, JCF = 27 Hz,
CCF2), 134.4 (t, 3JCF = 6 Hz, CPy), 146.7 (t, 3JCF = 6.5 Hz, CPy), 150.56
(s, CPy). 19F NMR (470.3 МHz, CDCl3) δ: –106.7 (t, 3JFH = 13.2 Hz). Anal.
Calc. for C7H7F2NO: C, 52.83; H, 4.43; N, 8.80. Found: C, 52.71; H, 4.38;
N, 8.91.
C
Py), 149.7 (s, CPy), 152.17 (t, 2JCF = 29 Hz), 160.3 (t, 2JCF = 28.5 Hz).
19F NMR (470.3 МHz, CDCl3) δ: –105.2 (s). Anal. Calc. for C7H7F2N3: C,
49.12; H, 4.12; N, 24.55. Found: C, 49.23; H, 4.01; N, 24.63.
4.11. Synthesis of difluoro(pyridin-2-yl)methyl)pyrimidin-4(1H)-ones
13a-b: general procedure
4.8.3. 2,2-Difluoro-2-(pyridin-4-yl)ethanol 9c
Yield 0.76 g (96%); yellow oil. 1H NMR (400 MHz, CDCl3) δ: 3.98 (t,
3JHF = 13.2 Hz, 2H), 4.27 (br s, 1H, OH), 7.45 (d, 3JHH = 5.5 Hz, 2H), 8.6
To a solution of amidine 11 (0.17 g, 1 mmol) in methanol (5 ml) were
added sodium methoxide (0.16 g, 3 mmol) and respective ketoester 12
(1 mmol). The reaction mixture was refluxed for 24 hrs. After comple-
tion of the reaction, the solvent was evaporated, the residue was dis-
solved in water, and 1N HCl was added until pH=7. The aqueous
solution was extracted with ethyl acetate (3 × 20 mL), and then the
organic extract was washed with brine. The solvent was dried over
Na2SO4 and evaporated under reduced pressure.
(d, 3JHH = 5.5 Hz, 2H). 13C NMR (125.7 MHz, CDCl3) δ: 64.8 (t, 2JCF
=
32.5 Hz, СH2), 119.5 (t, 1JCF = 245 Hz, СF2), 120.8 (t, 3JCF = 6 Hz, CPy),
2
144.1 (t, JCF = 27.5 Hz, CCF2), 149.4 (s, CPy). 19F NMR (376.5 Hz,
CDCl3) δ: –109.5 (t, 3JFH = 13.2 Hz). Anal. Calc. for C7H7F2NO: C, 52.83;
H, 4.43; N, 8.80. Found: C, 52.94; H, 4.39; N, 8.88.
4.9. Synthesis of difluoropyridinylacetic acids 10a-c: general procedure
4.11.1. 2-(Difluoro(pyridin-2-yl)methyl)-6-methylpyrimidin-4(1H)-one
13a
To a solution of respective ester 4 (0.2 g, 1 mmol) in EtOH (10 mL)
was added LiOH (0.024 g, 1 mmol). The mixture was stirred at r.t. for 12
h, neutralized with MeOH/HCl (5 mL), the solvents were evaporated
under reduced pressure. The residue was dissolved in THF (3 mL), and
treated with propylene oxide (0.17 g, 3 mmol). The solvent was evap-
orated under reduced pressure; the dry residue was washed with THF (1
mL), dried under vacuum.
Yield 0.13 (54%); gray solid; mp 170-174◦C. 1H NMR (400 MHz,
CDCl3) δ: 2.30 (s, CH3), 6.32 (s, Cpyrim), 7.46 (dd, 3JHH = 7.1 Hz, 3JHH
=
4.2 Hz 1H), 7.85-7.92 (m, 2H), 8.66 (d, 3JHH = 4.2 Hz, 1H). 13C NMR
1
(150.8 MHz, CDCl3) δ: 21.6 (s, Me), 110.5 (t, JCF = 248.5 Hz, СF2),
111.8 (s, CHpyrim), 118.5 (t, 3JCF = 4 Hz, CPy), 123.5 (s, CPy), 126.1 (s,
C
pyrim-Me), 135.3 (s, CPy), 147.4 (s, CPy), 149.5 (t, 2JCF = 28.5 Hz, CCF2),
150.4 (t, 2JCF = 29 Hz, CF2C=N), 162.63 (s, C(O)). 19F NMR (376.5 МHz,
CDCl3) δ: –103.8 (s). Anal. Calc. for C11H9F2N3O: C, 55.70; H, 3.82; N,
17.71. Found: C, 55.59; H, 3.89; N, 17.58.
4.9.1. 2,2-Difluoro-2-(pyridin-2-yl)acetic acid 10a
Yield 0.16 g (94%); white powder; mp 134-138◦C. 1H NMR (499.8
5

O.M. Shavrina et al.
Journal of Fluorine Chemistry 246 (2021) 109792
4.11.2. 2-(Difluoro(pyridin-2-yl)methyl)-6-(trifluoromethyl)pyrimidin-4
(1H)-one 13b
NMR (470.3 МHz, CDCl3) δ: –99.6 (s). Anal. Calc. for C9H7F2N3O: C,
51.19; H, 3.34; N, 19.90. Found: C, 49.98; H, 3.12; N, 19.76.
Yield 0.15 (53%); yellow solid; mp 150-154◦C. 1H NMR (499.8 MHz,
CDCl3) δ: 6.86 (s, Hpyrim), 7.51 (dd, 3JHH = 8.0 Hz, 3JHH = 5.0 Hz, 1H),
7.88 (d, 3JHH = 8.0 Hz, 1 H), 7.94 (t, 3JHH = 8 Hz, 1H), 8.67 (d, 3JHH = 5
Hz, 1H). 13C NMR (150.8 MHz, CDCl3) δ): 112.3 (t, 1JCF = 249 Hz, СF2),
114.9 (s, CHpyrim), 120.0 (q, 1JCF = 275 Hz, CF3), 120.9 (t, 3JCF = 4 Hz,
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
C
Py), 126.1 (s, CPy), 137.8 (s, CPy), 149.6 (s, CPy), 151.1 (t, 2JCF = 28.5
2
2
Hz, CPyCF2), 152.7 (q, JCF = 36.5 Hz, CCF3), 155.5 (t, JCF = 32 Hz,
CF2C=N), 160.9 (s, CO). 19F NMR (470.3 МHz, CDCl3) δ: –71.4 (s, CF3),
–103.1 (s, CF2). Anal. Calc. for C11H9F2N3O: C, 45.37; H, 2.08; N, 14.43.
Found: C, 45.21; H, 2.15; N, 14.34.
Supplementary materials
Supplementary material associated with this article can be found, in
the online version, at doi:10.1016/j.jfluchem.2021.109792.
4.11.3. 2,2-Difluoro-N’-hydroxy-2-(pyridin-2-yl)acetimidamide 14
To a solution of hydroxylamine hydrochloride (0.23 g, 3.3 mmol) in
methanol (1 mL) was added sodium hydroxide (0.13 g, 3.3 mmol) with
ice cooling. The reaction mixture was stirred for 0.5 h, then the pre-
cipitate was filtered off, and the solution of nitrile 2a (0.462 g, 3 mmol)
in MeOH (1 mL) was added to the filtrate with ice cooling. The reaction
mixture was kept at r. t. for 6 hrs, then the solvent was evaporated, the
residue was washed with hexane to give 0.45 g of 14 (yield 80%) as
white solid; mp 95-97◦C. 1H NMR (400 MHz, DMSO-d6) δ: 7.51 (dd,
3JHH = 7.8 Hz, 3JHH = 4.7 Hz, 1H), 7.64 (d, 3JHH = 7.8 Hz, 1 H), 7.93 (t,
3JHH = 7.8 Hz, 1H), 8.64 (d, 3JHH = 4.7 Hz, 1H).13C NMR (125.7 MHz,
DMSO-d6) δ: 115.5 (t, 1JCF = 242 Hz, СF2), 121.1 (t, 3JCF = 4 Hz, CPy),
125.1 (s, CPy), 137.0 (s, CPy), 148.4 (m, 2JCF = 29 Hz, (CN)CF2), 148.9 (s,
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white solid; mp 55-57◦C. 1H NMR (400 MHz, CDCl3) δ: 7.45 (dd, 3JHH
=
7 Hz, 3JHH = 4.2 Hz, 1H), 7.88-7.90 (m, 2H), 8.67 (d, 3JHH = 4.2 Hz, 1H),
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¨
166.0 (s, Coxadiaz.). 19F NMR (376.5 МHz, CDCl3) δ: –99.5 (s). Anal. Calc.
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was added NEt3 (0.036 g, 0.35 mmol), and acetyl chloride (0.028 g, 0.35
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= 28 Hz, CCF2), 166.3 (t, 2JCF = 32 Hz, C=N), 178.1 (s, Coxadiaz.). 19
F
6