Sodium difluoromethanesulfinate—A difluoromethylating agent toward protonated heterocyclic bases

Article abstract of DOI:10.1134/S1070428017040066

Free radical difluoromethylation of protonated heteroaromatic bases was accomplished using sodium difluoromethanesulfinate in combination with tert-butyl hydroperoxide in a two-phase system (methylene chloride–water) at room temperature. The difluoromethylation products of methyl pyridine-4-carboxylate, pyridine-4-carbonitrile, and 2-amino-1,3,4-thiadiazole were isolated on a preparative scale.

Full text of DOI:10.1134/S1070428017040066

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2017, Vol. 53, No. 4, pp. 539–546. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © M.A. Lytkina, E.V. Eliseenkov, V.P. Boyarskii, A.A. Petrov, 2017, published in Zhurnal Organicheskoi Khimii, 2017, Vol. 53, No. 4,
pp. 533–540.
Sodium Difluoromethanesulfinate—A Difluoromethylating Agent
toward Protonated Heterocyclic Bases
M. A. Lytkinaa, b, E. V. Eliseenkovb, V. P. Boyarskiib, and A. A. Petrovb*
a St. Petersburg State Institute of Technology, Moskovskii pr. 26, St. Petersburg, 190013 Russia
b St. Petersburg State University, Universitetskaya nab. 7/9, St. Petersburg, 199034 Russia
*e-mail: aap1947@yandex.ru
Received January 11, 2017
Abstract—Free radical difluoromethylation of protonated heteroaromatic bases was accomplished using
sodium difluoromethanesulfinate in combination with tert-butyl hydroperoxide in a two-phase system
(methylene chloride–water) at room temperature. The difluoromethylation products of methyl pyridine-
4-carboxylate, pyridine-4-carbonitrile, and 2-amino-1,3,4-thiadiazole were isolated on a preparative scale.
DOI: 10.1134/S1070428017040066
Introduction of a difluoromethyl group into mole-
cules of biologically active organic compounds attracts
considerable interest from the viewpoint of obtaining
new pharmaceuticals. Difluoromethyl group (CHF2)
can act as lipophilic hydrogen bond donor which
favors increased membrane permeability as compared
to such typical donors as OH and NH groups, so that it
becomes promising for the design of bioactive mole-
cules [1]. Similarity of the size of fluorine atom to
hydrogen (the van der Waals radius of the fluorine
atom is larger than that of hydrogen by only 23%)
makes fluorine an obvious candidate for replacement
of hydrogen without significant change of the molec-
ular geometry. Due to high electronegativity of fluo-
rine, this replacement strongly affects the properties of
the resulting compound, specifically changes the lipo-
philicity profile and inhibits some metabolic pathways
at the molecular level. At the physiological level,
replacement of hydrogen by fluorine improves bio-
availability, enhances the selectivity for tissues and
organs, and, in the general case, reduces the effective
therapeutic dose to a much lower value than could be
achieved for non-fluorinated analogs [2].
The main method for the introduction of a difluoro-
methyl group into organic molecules is based on the
reaction of aldehydes with sulfur tetrafluoride and its
derivatives. For example, diethylaminosulfur trifluo-
ride (Et2NSF3, DAST) [3] has found quite limited
application due to insufficient tolerance of many func-
tional groups to such fluorinating agents. Therefore, al-
ternative methods for selective introduction of difluoro-
methyl groups into molecules of organic compounds
have been extensively studied in recent years [4].
Free radical functionalization of C–H bonds via
Minisci reaction with zinc(II) difluoromethanesulfinate
Zn(SO2CHF2)2 as source of difluoromethyl radical is
among the most promising methods of direct introduc-
tion of a CHF2 group into heteroaromatic compounds
(Scheme 1) [1, 5, 6]. A drawback of this method is
difficult laboratory synthesis of zinc(II) difluoro-
methanesulfinate.
On the basis of the Minisci reaction mechanism
[5, 6] it may be expected that a more accessible and
less expensive reagent, sodium difluoromethanesul-
finate NaSO2CHF2 [7], would also be capable of di-
fluoromethylating nitrogen heterocycles according to
Scheme 1.
O
O
Me
Me
Me
O
Me
N
N
(F2CHSO2)2Zn
85%
N
N
CHF2
N
N
N
O
N
Me
Me
539

LYTKINA et al.
540
Scheme 2.
CHClF2
KOH
H2O2
(NH4)2Mo7O24
NaBH4
EtOH
CHF2
CHF2
O
N
S
N
S
N
S
CF2HSO2Na
SH
S
S
O
Scheme 3.
CF2HSO2Na (2.0–4.0 equiv), TFA (1 equiv), t-BuOOH (3.0–6.0 equiv)
CH2Cl2–H2O (2.5:1), 20°C, 24 h
Ht–H
Ht–CHF2
1–6
7–12
COOMe
N
CN
COOMe
N
N
N
Ht–H =
(1, 7),
(2, 8),
(3, 9),
(4, 10),
(5, 11),
(6, 12).
NH2
S
N
N
N
N
the free radical mechanism. Therefore, in the present
work we studied the possibility of introducing a di-
fluoromethyl group into molecules of various aromatic
nitrogen heterocycles with the aid of sodium difluoro-
methanesulfinate.
methylene chloride–water (see table). The reaction rate
was controlled by varying the reactant ratio. tert-Butyl
hydroperoxide as oxidant was always added in slight
excess with respect to sodium difluoromethanesul-
finate. Our results, as well as published data [6],
showed that excess difluoromethanesulfinic acid salt
should always be taken. Presumably, the yield of di-
fluoromethyl radical generated by reaction of sodium
difluoromethanesulfinate with tert-butyl hydroperox-
ide is not quantitative. Furthermore, this very reactive
radical can be involved in many side reactions (e.g.,
recombination to form 1,1,2,2-tetrafluoroethane or
abstraction of hydrogen). As follows from the data
in table, the optimal reagent/substrate ratio is 4:1. If
that ratio was lower, the reaction was too slow (run
no. 1), whereas in the presence of 5 equiv of
NaSO2CHF2 poor regioselectivity was observed (molar
ratio 7a/7b ≈ 8; run nos. 2, 3). In run no. 4, 4 equiv of
NaSO2CHF2 was used, and tert-butyl hydroperoxide
was gradually (over a period of 15 min) added with
stirring to the reaction mixture. In this case, the
substrate conversion was complete after 1 h, and the
regioselectivity (molar ratio 7a/7b exceeded 30) and
substrate selectivity [molar ratio 7a/(7c +7d)] in-
creased (Scheme 4).
Sodium difluoromethanesulfinate was synthesized
according to [7, 8] via a three-step procedure starting
from benzothiazole-2-thiol and chlorodifluoromethane
(Freon R-22) (Scheme 2). The difluoromethylation of
hetarenes 1–6 was carried out under the conditions
similar to those described for trifluoromethylation with
sodium trifluoromethanesulfinate [5] and difluoro-
methylation with zinc(II) difluoromethanesulfinate [6]
(Scheme 3). Sodium difluoromethanesulfinate was
synthesized for the first time in 2015 [7], and it was
not used previously in Minisci difluoromethylation of
hetarenes.
The reaction of sodium difluoromethanesulfinate
with methyl pyridine-4-carboxylate (1) was selected as
model for optimization of the conditions with a view to
achieving maximum selectivity in a reasonable time
necessary for the complete substrate conversion under
relatively mild conditions. Sodium difluoromethane-
sulfinate readily reacted with methyl pyridine-4-car-
boxylate at room temperature in the two-phase system
Radical difluoromethylation of methyl pyridine-4-carboxylate (1) with sodium difluoromethanesulfinate
Yield,a %
Reaction
time, min
Run no. Molar ratio 1–F2CHSO2Na–t-BuOOH
Conversion of 1,a %
7a
7b
7c+7d
1
2
3
4
1:2:4
1:5:6
1:5:6
1:4:6
60
10
60
60
044
078
090
100
100
079
079
093
–
–
9
12
10
03
11
04
a
Calculated on the reacted substrate according to the GC and GC/MS data.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 4 2017

SODIUM DIFLUOROMETHANESULFINATE—A DIFLUOROMETHYLATING AGENT
541
Scheme 4.
COOMe
COOMe
COOMe
CHF2
COOMe
t-BuOOH, TFA
+
CF2HSO2Na
+
+
F2CH
CHF2
N
N
CHF2
N
N
1
7a
7b
7c, 7d
Scheme 5.
CHF2
COOMe
COOMe
COOMe
COOMe
t-BuOOH, TFA
+
CF2HSO2Na
+
+
N
N
CHF2
8a, 42%
F2CH
N
N
2
8b, 29%
8c, 29%
Difluoromethylation of ester 1 was carried out
under the optimal conditions on a preparative scale,
and the target product, methyl 2-(difluoromethyl)pyri-
dine-4-carboxylate (7a), was isolated in 39% yield by
silica gel column chromatography.
tert-butyl hydroperoxide (3 h) three isomeric mono-
difluoromethyl derivatives were formed (Scheme 5).
The ratio of these products in the reaction of 2 with
zinc(II) difluoromethanesulfinate was 40:30:30, the
substrate conversion being 60% [6].
The scope of the proposed difluoromethylation
procedure was assessed using hetarenes 2–6 that are
characterized by considerably different reactivities. Di-
fluoromethyl radical shows a weak nucleophilicity in
reactions with protonated hetarenes [6]; therefore,
introduction of electron-withdrawing substituents, such
as cyano or methoxycarbonyl group, into heteroaro-
matic substrate molecule should enhance its reactivity.
On the other hand, donor substituents should inhibit
difluoromethylation under Minisci reaction conditions.
For instance, 4-methylpyridine failed to react with
sodium difluoromethanesulfinate: GC/MS analysis of
the reaction mixture did not revealed even traces
(~0.1%) of difluoromethylation products.
The difluoromethylation of pyridine-4-carbonitrile
(3) was carried out under the conditions optimized for
substrate 1, namely 4 equiv of sodium difluoro-
methanesulfinate and 6 equiv of tert-butyl hydroper-
oxide were used, and the reaction time was 20 h. The
results indicated similar behaviors of compounds 1 and
3. The major product was 2-(difluoromethyl)pyridine-
4-carbonitrile (9a) which was isolated by silica gel
column chromatography. The yield of 9a was 29% at
a conversion of 90%. The yields of 9a–9d given in
Scheme 6 were calculated on the reacted substrate
from the chromatographic data.
Quinoline (4) reacted with 2.5 equiv of sodium
difluoromethanesulfinate and 3 equiv of tert-butyl hy-
droperoxide for 8 h (Scheme 7). At a substrate con-
version of 60%, the reaction mixture contained two
isomeric mono-difluoromethylation products 10a and
The reaction with methyl pyridine-3-carboxylate
(2) was fairly fast but poorly selective. In the reaction
of 2 with 3 equiv of NaSO2CHF2 and 4 equiv of
Scheme 6.
CN
CN
CN
CN
CHF2
t-BuOOH, TFA
+
CF2HSO2Na
+
+
F2CH
CHF2
N
N
CHF2
N
N
3
9a, 79%
9b, 9%
9c, 9d, 12%
Scheme 7.
CHF2
CHF2
t-BuOOH, TFA
+
CF2HSO2Na
+
+
N
N
CHF2
N
10b, 72%
N
CHF2
4
10a, 25%
10c, 3%
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 4 2017

LYTKINA et al.
542
Scheme 8.
N
N
N
F2CH
N
N
t-BuOOH, TFA
+
CF2HSO2Na
+
N
CHF2
5
11a, 95%
11b, 5%
Scheme 9.
N
N
N
N
t-BuOOH, TFA
+
CF2HSO2Na
NH2
H2N
CHF2
S
S
6
12, 46%
10b and one bis(difluoromethyl) derivative 10c. The
products were identified on the basis of the GC/MS
data in combination with published data on the regio-
selectivity of reactions of protonated quinoline with
various free radical species [9]. Most of the examined
radicals, including nucleophilic alkyl radicals, less
nucleophilic carbonyl, and much less nucleophilic
alkoxycarbonyl, reacted with quinoline only at posi-
tions 2 and 4; in all cases, mixtures of 2-mono-,
4-mono-, and 2,4-disubstituted quinolines were ob-
tained. Strongly nucleophilic tert-butyl radical gave
rise exclusively to 2-tert-butylquinoline, whereas equal
amounts of 2- and 4-methylquinoline were formed in
the reaction with methyl radical. The lesser the nucleo-
philicity of the radical species, the less active is posi-
tion 2 in the quinoline molecule relative to position 4.
For example, the reaction with ethoxycarbonyl radical
gave 4.5% of ethyl quinoline-2-carboxylate, 17.5% of
ethyl quinoline-4-carboxylate, and 76% of diethyl
quinoline-2,4-dicarboxylate [9]. Difluoromethyl
radical is a weak nucleophile [6]; therefore, it should
react preferentially at the 4-position to produce isomer
10b rather than at the 2-position with formation of 10a.
The same conclusion follows from analysis of the
retention times of difluoromethyl derivatives on
a weakly polar chromatographic column, which
roughly correlate with their boiling points.
Quinoxaline (5) turned out to be weakly reactive
toward sodium difluoromethanesulfinate. In the reac-
tion of 5 with 4 equiv of CHF2SO2Na and 5 equiv of
tert-butyl hydroperoxide, the substrate conversion did
not exceed 40% in 24 h. Increase of the amounts of
CHF2SO2Na and t-BuOOH to 6 and 7 equiv, respec-
tively, insignificantly increased the conversion (45%).
The major product was 2-(difluoromethyl)quinoxaline
(11a), and 6-difluoromethyl isomer 11b was the minor
one (Scheme 8). The structure of 11a and 11b was
confirmed by the data on the relative reactivity of
different positions in quinoxaline molecule toward
alkyl radicals in the Minisci reactions [10].
The conversion of 1,3,4-thiadiazol-2-amine (6) in
the reaction with 5 equiv of sodium difluoromethane-
sulfinate and 6 equiv of tert-butyl hydroperoxide at-
tained 100% in 20 h. The product, 5-(difluoromethyl)-
1,3,4-thiadiazol-2-amine (12), was isolated in 46.2%
yield (Scheme 9). According to published data [6], the
isolated yield of 12 in the reaction of 6 with zinc(II)
difluoromethanesulfinate was 40%.
Our results showed the possibility of using sodium
difluoromethanesulfinate for free radical difluoro-
methylation of a fairly wide series of protonated het-
eroaromatic bases under the Minisci reaction condi-
tions. Sodium difluoromethanesulfinate turned out to
be very similar to the known analog, zinc(II) difluoro-
methane-sulfinate [6], in reactivity, selectivity, and
reaction conditions. No essential differences between
these reagents were revealed. These findings are quite
understandable in terms of the reaction mechanism
proposed for the trifluoromethylation with trifluoro-
methanesulfinic acid salts [5] and extended to difluoro-
methylation with difluoromethansulfinic acid salts [6].
In the first stage, metal salt-induced homolytic dis-
sociation of tert-butyl hydroperoxide generates tert-
butoxyl and hydroxyl radicals. The oxidation of
difluoromethanesulfinate ion with tert-butoxyl radical
gives tert-butoxide ion and difluoromethanesulfonyl
radical. The latter readily loses sulfur dioxide molecule
with formation of difluoromethyl radical. The sodium
counterion is not directly involved in the process,
though it is capable of affecting the rate of generation
of tert-butoxyl radicals by decomposition of tert-butyl
hydroperoxide. Thus, both sodium and zinc difluoro-
methanesulfinates behave similarly in the free radical
difluoromethylation of hetarenes.
Among the seven examined heterocyclic substrates,
only 4-methylpyridine failed to react with sodium
difluoromethanesulfinate to give the expected difluoro-
methylation products (no analogous reactions of
4-methylpyridine were studied previously). Quinoline
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SODIUM DIFLUOROMETHANESULFINATE—A DIFLUOROMETHYLATING AGENT
543
and quinoxaline reacted with sodium difluoromethane-
sulfinate at a relatively low rate even in the presence of
excess reagent, and the reactions were characterized
by relatively low regioselectivity. Introduction of
electron-withdrawing substituents (CN, COOR) into
molecules of heteroaromatic substrates accelerates the
reaction (the substrate conversion increases under
comparable conditions). This effect is observed espe-
cially clearly for methyl pyridine-4-carboxylate: the
reaction with as small amount of the substrate as
1 mmol was accompanied by appreciable heat evolu-
tion (the reaction mixture warmed up by 4–6°C) and
was complete in ~10 min. On the other hand, no
appreciable exothermic effect was observed in the
reaction with pyridine-4-carbonitrile, and it required
~20 h for completion.
1H) at room temperature. The chemical shifts were
measured relative to the residual proton and carbon
signals of the solvent (CHCl3, δ 7.27 ppm; CDCl3,
δC 77.0 ppm; DMSO-d5, δ 2.50 ppm; DMSO-d6,
δC 39.52 ppm) or PhCF3 (internal, δF –63.73 ppm
relative to CFCl3). Gas chromatographic analysis was
performed on a Khromatek Kristall 5000.2 instrument
equipped with a flame ionization detector and BPX-1
capillary column (10 m×0.53 mm, film thickness
2.65 μm). Gas chromatographic–mass spectrometric
data were obtained using a Shimadzu GCMS QP-2010
SE instrument (electron impact, 70 eV; a.m.u. range
50–500; detector temperature 220°C; Rtx-5MS col-
umn, 30 m×0.32 mm, film thickness 0.25 μm; carrier
gas argon, flow rate 0.8 mL/min). The mass spectra
(electrospray ionization) were recorded with a Bruker
micrOTOF mass spectrometer (a.m.u. range 50–3000;
ion source voltage 4500 V, capillary voltage 70–
150 V); samples were dissolved in methanol. Alumi-
num plates coated with a layer of silica gel (Merck)
were used for thin-layer chromatography. Commercial
chemicals (except for tert-butyl hydroperoxide and
1,3,4-thiadiazol-2-amine) and solvents of chemically
pure or analytical grade were used without preliminary
purification. The purity of all compounds was moni-
tored by NMR. Individual compounds were isolated
from the reaction mixtures by column chromatography
on silica gel (Merck, 230–400 mesh, pore size 60 Å;
column 2 cm in diameter and 16 cm in height).
Analysis of our GC/MS data and published data for
the reaction with zinc(II) difluoromethanesulfinate [6]
allowed us to select some substrates potentially
suitable for difluoromethylation on a preparative scale
and isolation of individual pure products. Obviously,
low reactive (quinoline, quinoxaline) and selective
substrates (methyl pyridine-3-carboxylate) are hardly
suitable for this purpose, whereas methyl pyridine-4-
carboxylate, pyridine-4-carbonitrile, and 1,3,4-thiadi-
azol-2-amine, judging by our preliminarily results, are
promising candidates for preparative difluoro-
methylation.
In summary, cheap and readily accessible (under
laboratory conditions) sodium difluoromethanesul-
finate is a promising alternative to zinc(II) difluoro-
methanesulfinate for the difluoromethylation of hetero-
aromatic bases according to Minisci. The developed
procedure is well reproducible, and it showed high
reactivity of sodium difluoromethanesulfinate. The
yield of NaSO2CHF2 was 98–101%, which indicated
the presence of some impurities of sodium salts such
as borates and carbonate. We believe that the true yield
is ~95%. An aqueous solution of NaSO2CHF2 is
slightly alkaline (pH 8–8.5). Since pH of the medium
is an important factor in difluoromethylation reactions
(required pH value is maintained by adding trifluoro-
acetic acid), the presence of alkaline impurities in the
obtained sodium difluoromethanesulfinate should be
taken into account.
2-[(Difluoromethyl)sulfanyl]-1,3-benzothiazole.
Chloro(difluoro)methane was bubbled over a period of
1 h at a rate of 15–18 mL/min through a mixture of
3.34 g (20 mmol) of 1,3-benzothiazole-2-thiol, 20 mL
of dioxane, 13.17 g (200 mmol) of 85% KOH, and
40 mL of water under stirring. The mixture was diluted
with 40 mL of water and extracted with methylene
chloride (3×25 mL), the organic phase was dried over
MgSO4, and the solvent was removed under reduced
1
pressure. Yield 2.55 g (59%), yellow liquid. H NMR
spectrum (CDCl3), δ, ppm: 7.42 t.d (1H, J = 7.7,
1.2 Hz), 7.50 t.d (1H, J = 7.7, 1.2 Hz), 7.65 t (1H,
CHF2, J = 56.0 Hz), 7.84 d (1H, J = 8.1 Hz), 8.01 d
(1H, J = 8.1 Hz). 13C NMR spectrum (CDCl3), δC,
ppm: 120.24 t (CH, JCF = 276.6 Hz), 121.16 (CH),
122.84 (CH), 125.64 (CH), 126.60 (CH), 135.96,
152.90, 157.00 t (JCF = 4.2 Hz). 19F NMR spectrum
(CDCl3): δF –93.18 ppm [8].
EXPERIMENTAL
2-(Difluoromethanesulfonyl)-1,3-benzothiazole.
A mixture of 7.18 g (33.05 mmol) of 2-[(difluoro-
methyl)sulfanyl]-1,3-benzothiazole, 2.04 g (1.65 mmol)
of ammonium molybdate (NH4)6Mo7O24 · 4 H2O,
The NMR spectra were recorded on Bruker Avance
II+ [400.13 (1H), 100.61 (13C), and 376.50 MHz (19F)]
and Bruker DPX-300 spectrometers (300.13 MHz for
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 4 2017

LYTKINA et al.
544
1
33.0 mL of ethanol, and 12.8 mL (132 mmol) of 30%
H2O2 was stirred for 24 h at room temperature. An ad-
ditional 3.5 mL of 30% H2O2 was added, the mixture
was stirred for 18 h and diluted with 300 mL of water,
and the precipitate was filtered off, washed with
500 mL of water, and dried at 120–130°C. Yield 6.80 g
(83%), white needles, mp 155–158°C (from EtOAc);
published data: mp 133–135°C [11], 149°C [12].
199°C; published data [13]: mp 192–194°C. H NMR
spectrum (DMSO-d6), δ, ppm: 7.02 s (2H), 8.36 s (1H).
tert-Butyl hydroperoxide. tert-Butyl alcohol,
48 mL (0.5 mol), was added dropwise with stirring to
35 g (0.25 mol) of 70% sulfuric acid cooled to 5°C on
an ice bath. The mixture was cooled to 0°C, and 76 mL
(0.75 mol) of 30% hydrogen peroxide was added from
a dropping funnel under continuous stirring, maintain-
ing the temperature not higher than 5°C. The mixture
was then stirred for 12 h at room temperature, and it
divided into two layers. The upper layer consisting of
tert-butyl hydroperoxide and di-tert-butyl peroxide
was separated and washed with water (20 mL). tret-
Butyl hydroperoxide was extracted with 200 mL of
15% aqueous KOH. The extract was washed with
hexane (3×25 mL) to remove di-tert-butyl peroxide
impurity and treated with 33 g of powdered ammo-
nium chloride under stirring. tert-Butyl hydroperoxide
was extracted with methylene chloride (5×20 mL), the
combined extracts were dried over anhydrous sodium
sulfate, the solvent was distilled off under reduced
pressure (water-jet pump), and the residue was distilled
to collect a fraction boiling at bp 31–33°C (16 mm).
Yield 21.72 g (59%), purity 98% (according to the
1H NMR spectrum (CDCl3), δ, ppm: 6.60 t (1H, JHF
=
53.1 Hz), 7.66 m (1H), 7.72 m (1H), 8.08 m (1H),
8.33 m (1H). 13C NMR spectrum (CDCl3), δC, ppm:
114.50 t (JCF = 288.1 Hz), 122.38, 126.25, 128.26,
129.07, 137.85, 153.01, 158.90. 19F NMR spectrum
(CDCl3): δF –121.41 ppm.
Sodium difluoromethanesulfinate. Sodium tetra-
hydridoborate was added in 12–18-mg portions every
5–7 min to a suspension of 997 mg (4 mmol) of 2-(di-
fluoromethanesulfonyl)-1,3-benzothiazole in 8–9 mL
of anhydrous ethanol. After addition of 302 mg
(8 mmol) of NaBH4, the mixture was stirred for 2–3 h,
and the solvent was distilled off under reduced pres-
sure (water-jet pump). The viscous residue was treated
with 5–7 mL of hexane, and the mixture was stirred
with grinding using a spatula. The white crystals were
filtered off through a Schott filter and washed with
hexane (2×4 mL) to remove benzothiazole. The prod-
uct was then treated with 4 mL of hexane–ethanol
(4:1) with stirring, and the precipitate was filtered off,
washed on a filter with methylene chloride (2×3 mL),
and dried at 40–50°C (25–30 mm) until constant
1
iodometric titration data). H NMR spectrum (CDCl3),
δ, ppm: 1.19 s (9H), 7.73 s (1H).
Difluoromethylation of heterocyclic substrates
1–6 with sodium difluoromethanesulfinate. GC/MS
study. The first reaction series was carried out using
0.2 mmol of 1–6, 0.6 mmol of sodium difluoro-
methanesulfinate, 0.3 mL of distilled water, 0.2 mmol
of trifluoroacetic acid (after adjustment of the aqueous
solution to pH 7), 0.75 mL of methylene chloride, and
0.8 mmol of tert-butyl hydroperoxide. The components
were placed in succession into a 10-mL flask which
was capped with a septum, and the mixture was stirred
for 0.1–24 h at 20–22°C on a magnetic stirrer at 100–
200 rpm. The mixture was then treated with 2 mL of
a saturated aqueous solution of NaHCO3, 2 mL of
methylene chloride was added, and the mixture was
stirred for 10 min on a magnetic stirrer. A 0.1-mL
sample of the organic phase was withdrawn, trans-
ferred to a clean vial, diluted with 3 mL of methylene
chloride, dried for 0.5 h with anhydrous sodium
sulfate, and analyzed by GC/MS [oven temperature
programming from 60°C (3 min) to 250°C at a rate of
10 deg/min and 10 min at 250°C].
1
weight (551 mg). H NMR spectrum (DMSO-d6):
δ 4.86 ppm, t (1H, J = 55.3 Hz). 19F NMR spectrum
(DMSO-d6): δF –125.80 ppm [7]. It is advisable to
store sodium difluoromethanesulfinate at 2–4°C in
a hermetically closed vessel made of dark glass. Evap-
oration of the filtrates combined with the washings
afforded 524 mg (97%) of benzothiazole.
1,3,4-Thiadiazol-2-amine. A mixture of 5.00 g
(54.86 mmol) of thiosemicarbazide and 10 mL
(0.262 mmol) of 99% formic acid was stirred for 1 h at
room temperature. The mixture was cooled to 0°C on
an ice bath, 10 mL of concentrated aqueous HCl was
added, and the mixture was stirred for 3–4 h at 0°C
and for 12 h at 20–22°C. The mixture was then cooled
again to 0°C and carefully neutralized with cold
aqueous ammonia to pH 7–8. The white crystals were
filtered off through a Schott filter, washed with cold
water (3×6 mL), and dried at 150°C. Yield of the
crude product 4.09 g (74%), mp 197–198°C. Recrys-
tallization from methanol gave a sample with mp 198–
Preparative difluoromethylation of methyl pyri-
dine-4-carboxylate (1). A mixture of 104 mg
(0.77 mmol) of methyl pyridine-4-carboxylate, 522 mg
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SODIUM DIFLUOROMETHANESULFINATE—A DIFLUOROMETHYLATING AGENT
545
(3.78 mmol) of sodium difluoromethanesulfinate, and
1.3 mL of water was stirred on a magnetic stirrer,
trifluoroacetic acid was added to pH 7, and an addi-
tional 120 mg (1.08 mmol) of trifluoroacetic acid was
then added. Methylene chloride, 3 mL, was added, and
360 mg (4 mmol) of tert-butyl hydroperoxide was
added in 20–25-mg portions over a period of 15 min.
The flask was capped with a septum, and the mixture
was stirred for 1 h at room temperature on a magnetic
stirrer. The mixture was treated with 6 mL of a satu-
rated aqueous solution of NaHCO3, 6 mL of methylene
chloride was added, and the mixture was stirred for
10 min on a magnetic stirrer. The organic phase was
separated, the aqueous phase was extracted with
methylene chloride (3×6 mL), the extracts were com-
bined with the organic phase and dried over Na2SO4,
and the solvent was distilled off. Yield of crude prod-
uct mixture 74 mg (60%). Compound 7a was isolated
by column chromatography using methylene chloride
as eluent; yield 39%, Rf 0.56. Compounds 7b–7d were
identified by GC/MS.
Methyl 2-(difluoromethyl)pyridine-3-carbox-
ylate (8a). Mass spectrum, m/z (Irel, %): 187 (36) [M]+,
186 (31) [M – 1]+, 156 (100) [M – CH3O]+, 128 (66)
[M – COOCH3]+, 101 (10), 78 (18), 51 (24), 50 (10).
Methyl 6-(difluoromethyl)pyridine-3-carbox-
ylate (8b). Mass spectrum, m/z (Irel, %): 187 (53) [M]+,
186 (14) [M – 1]+, 156 (100) [M – CH3O]+, 128 (72)
[M – COOCH3]+, 108 (9), 75 (10), 51 (20), 50 (10).
Methyl 4-(difluoromethyl)pyridine-3-carbox-
ylate (8c). Mass spectrum, m/z (Irel, %): 187(41) [M]+,
186 (31) [M – 1]+, 157 (8), 156 (100) [M – CH3O]+,
128 (59) [M – COOCH3]+, 124 (8), 101 (16), 78 (12),
51 (20), 50 (8).
Compounds 9a–9d were obtained by difluoro-
methylation of 83 mg (0.8 mmol) of pyridine-4-carbo-
nitrile 3 at room temperature (reaction time 20 h).
Yield of crude product mixture 120 mg (98%). The
major product was isolated by column chromatog-
raphy. Yield 30 mg (29%), Rf 0.54 (CH2Cl2).
2-(Difluoromethyl)pyridine-4-carbonitrile (9a).
1
Methyl 2-(difluoromethyl)pyridine-4-carbox-
Oily material. H NMR spectrum (CDCl3), δ, ppm:
1
ylate (7a). Oily material. H NMR spectrum (CDCl3),
6.68 t (1H, JHF = 54.9 Hz), 7.67 d (1H, JHF = 4.9 Hz),
7.88 s (1H), 8.87 d (1H, JHF = 4.9 Hz). 13C NMR spec-
δ, ppm: 4.00 s (3H, OMe), 6.71 t (1H, JHF = 55.0 Hz),
7.96 d (1H, J = 5.0 Hz), 8.20 s (1H), 8.82 d (1H, J =
5.0 Hz). 13C NMR spectrum (CDCl3), δC, ppm: 52.96
(Me), 113.46 t (CHF2, JCF = 241.0 Hz), 119.60, 124.66,
138.87, 150.39, 153.94 t (JCF = 26.4 Hz), 164.72
(C=O). 19F NMR spectrum (CDCl3): δF –116.12 ppm.
Mass spectrum (EI), m/z (Irel, %): 188 (6), 187 (61)
[M]+, 186 (4), 168 (6), 157 (8), 156 (100) [M – H3O]+,
136 (14), 129 (6), 128 (78) [M – CH3COO]+, 108 (9),
101 (12), 82 (5), 81 (4), 78 (15), 77 (5), 76 (4), 51 (43),
50 (16). Mass spectrum (ESI): m/z 188.0513 [M + H]+.
C8H8F2NO2. Calculated: [M + H]+ 188.0518.
trum (CDCl3), δC, ppm: 112.77 t (CHF2, JCF
=
241.5 Hz), 115.68 (CN), 122.06 t (JCF = 3.0 Hz),
126.96, 150.58, 154.34 t (JCF = 26.7 Hz). 19F NMR
spectrum (CDCl3): δF –116.75 ppm. Mass spectrum
(EI), m/z (Irel, %): 155 (9), 154 (100) [M]+, 153 (4), 135
(9), 134 (9), 127 (4), 105 (6), 104 (80), 103 (60), 77
(13), 76 (39), 75 (10), 51 (19). Mass spectrum (ESI):
m/z 155.0419 [M + H]+. C7H5F2N2. Calculated:
155.0415 [M + H]+ [6].
3-(Difluoromethyl)pyridine-4-carbonitrile (9b).
Mass spectrum, m/z (Irel, %): 155 (9), 154 (100) [M]+,
153 (17), 135 (11), 134 (11), 127 (44), 104 (53), 103
(9), 100 (19), 77 (13), 76 (25), 75 (15), 51 (19).
Methyl 3-(difluoromethyl)pyridine-4-carbox-
ylate (7b). Mass spectrum, m/z (Irel, %): 188 (7), 187
(80) [M]+, 156 (100) [M – CH3O]+, 155 (21), 152 (47),
128 (87) [M –CH3COO]+, 127 (13), 124 (13), 108 (16),
96 (13), 75 (19), 51 (38), 50 (14).
2,6-Bis(difluoromethyl)pyridine-4-carbonitrile
(9c). Mass spectrum, m/z (Irel, %): 205 (9), 204 (100)
[M]+, 203 (7), 185 (15), 184 (14), 154 (48), 153 (29),
135 (6), 134 (5), 127 (8), 126 (10), 103 (24), 104 (7),
76 (11), 75 (12), 51 (43).
Methyl bis(difluoromethyl)pyridine-4-carbox-
ylates 7c and 7d (isomer mixture). Mass spectrum,
m/z (Irel, %): 237 (84) [M]+, 206 (100) [M – CH3O]+,
202 (60), 178 (30) [M –CH3COO]+, 128 (63), 101
(16), 81 (20), 51 (31), 50 (10); 237 (62) [M]+, 217
(17), 206 (100) [M – CH3O]+, 202 (70), 178 (28)
[M – CH3COO]+, 151 (18), 128 (39), 101 (15), 81 (27),
75 (15), 59 (12), 51 (31), 50 (9).
2,3-Bis(difluoromethyl)pyridine-4-carbonitrile
(9d). Mass spectrum, m/z (Irel, %): 204 (100) [M]+, 185
(25), 184 (90), 154 (22), 153 (38), 135 (11), 134 (20),
126 (30), 103 (12), 107 (10), 104 (18), 82 (12), 76
(23), 75 (18), 51 (44).
Difluoromethylation of 2–6 was carried out in
a similar way. The products were identified by GC/MS.
2-(Difluoromethyl)quinoline (10a). Mass spec-
trum, m/z (Irel, %): 180 (12), 179 (100) [M]+, 129 (39),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 4 2017

LYTKINA et al.
546
128 (71), 102 (8), 101 (23), 77 (11), 76 (5), 75 (13), 51
(9), 50 (5).
spectrum: m/z 152.0085 [M + H]+. C3H4F2N2S. Cal-
culated: [M + H]+ 152.0089.
4-(Difluoromethyl)quinoline (10b). Mass spec-
trum, m/z (Irel, %): 189 (10), 179 (100) [M]+, 178 (12),
158 (6), 151 (11), 129 (39), 128 (71), 101 (13), 75
(11), 51 (6).
This study was performed under financial support
by the St. Petersburg State University (project
no. 12.37.214.2016) using the equipment of the Mag-
netic Resonance Research Center, Chemical Analysis
and Materials Research Center, and Chemistry Educa-
tional Center of the St. Petersburg State University.
2,4-Bis(difluoromethyl)quinoline (10c). Mass
spectrum, m/z (Irel, %): 230 (11), 229 (100) [M]+, 210
(6), 179 (9), 178 (17), 158 (30), 101 (5), 75 (6).
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The difluoromethylation of compounds 5 and 6 was
carried out as described above for pyridine-4-carbo-
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129 (74), 103 (16), 102 (30), 77 (4), 76 (37), 51 (12),
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161 (14), 160 (73), 153 (6), 152 (6), 133 (23), 130
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1,3,4-thiadiazol-2-amine (6) gave 118 mg (97%) of the
crude product. By column chromatography using
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of 12, Rf 0.58.
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solvent from the dried combined extracts, the crystal-
line product was washed on a filter with a cold 2:1
hexane–methylene chloride mixture (3×1.5 mL). Yield
105 mg (46%), colorless crystals, mp 182–183°C
(from EtOAc); published data [6]: mp 122–124°C.
1H NMR spectrum (DMSO-d6), δ, ppm: 7.20 t (1H,
CHF2, JHF = 53.5 Hz), 7.74 s (2H, NH2). 13C NMR
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=
235.1 Hz), 150.66 t (C5, JCF = 28.3 Hz), 171.08 (C3).
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 4 2017