Organocatalytic, difluorocarbene-based S-difluoromethylation of thiocarbonyl compounds

Article abstract of DOI:10.1016/j.jfluchem.2014.08.013

Upon treatment with trimethylsilyl 2,2-difluoro-2-fluorosulfonylacetate (TFDA) and a catalytic amount of N,N,N′,N′-tetramethyl-1,8-diaminonaphthalene, secondary thioamides and thiocarbamates undergo selective difluoromethylation on the sulfur atom to give S-difluoromethyl thioimidates and thioiminocarbonates in good yields, respectively. This is the first report on the synthesis of acyclic difluoromethyl thioimidates and thioiminocarbonates. The key for S-difluoromethylation is the organocatalytic generation of difluorocarbene (:CF₂) under mild conditions, which prevents decomposition of the substrates. This process provides an efficient approach to pharmaceuticals and agrochemicals bearing a difluoromethylsulfanyl group, starting from widely available thiocarbonyl compounds.

Full text of DOI:10.1016/j.jfluchem.2014.08.013

Journal of Fluorine Chemistry 171 (2015) 133–138
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Organocatalytic, difluorocarbene-based S-difluoromethylation of
thiocarbonyl compounds
*
Kohei Fuchibe, Masaki Bando, Ryo Takayama, Junji Ichikawa
Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba 305-8571, Japan
A R T I C L E I N F O
A B S T R A C T
Article history:
Upon treatment with trimethylsilyl 2,2-difluoro-2-fluorosulfonylacetate (TFDA) and a catalytic amount
of N,N,N0,N0-tetramethyl-1,8-diaminonaphthalene, secondary thioamides and thiocarbamates undergo
selective difluoromethylation on the sulfur atom to give S-difluoromethyl thioimidates and
thioiminocarbonates in good yields, respectively. This is the first report on the synthesis of acyclic
difluoromethyl thioimidates and thioiminocarbonates. The key for S-difluoromethylation is the
organocatalytic generation of difluorocarbene (:CF2) under mild conditions, which prevents
decomposition of the substrates. This process provides an efficient approach to pharmaceuticals and
agrochemicals bearing a difluoromethylsulfanyl group, starting from widely available thiocarbonyl
compounds.
Received 1 July 2014
Received in revised form 18 August 2014
Accepted 20 August 2014
Available online 28 August 2014
Keywords:
Difluorocarbene
Difluoromethylation
Organocatalyst
Sulfur
ß 2014 Elsevier B.V. All rights reserved.
Thioamide
Thiocarbamate
1. Introduction
hydroxide. The phenoxides are difluoromethylated with difluor-
ocarbene, which is generated in situ via
difluoromethyl aryl ethers in moderate to good yields. Although
difluorocarbene generation via -elimination has been improved
a-elimination, to give
In recent years, the difluoromethyl group (CHF2 group) has been
of considerable interest especially for developing pharmaceuticals
and agrochemicals [1]. The difluoromethyl group has a hydrogen
a
with modified protocols including nucleophilic attack on carbonyl
groups [17], phosphoryl groups [18], or sulfonyl groups [17c,19],
there remain limitations such as harsh reaction conditions [20].
Recently, we reported on the organocatalyzed generation of
difluorocarbene under mild conditions (Scheme 1) [21]. When
trimethylsilyl 2,2-difluoro-2-fluorosulfonylacetate (TFDA) [22] was
treatedwitha catalytic amount ofN-heterocycliccarbene (NHC) [23]
at 80–100 8C, decomposition of TFDA smoothly proceeded under
nearly neutral conditions to generate difluorocarbene. Ketones and
secondary amides underwent selective difluoromethylation on the
carbonyl oxygens with the electrophilic carbene thus generated,
whichaffordeddifluoromethylvinylethers[21a]anddifluoromethyl
imidates [21b] in high yields, respectively. By combining this
organocatalytic O-difluoromethylation and DDQ dehydrogenation,
the syntheses of difluoromethyl aryl ethers and difluoromethox-
yquinolines were accomplished in a one-pot operation.
In this report, we describe a difluorocarbene-based synthesis of
difluoromethylsulfanylated compounds (difluoromethyl sulfides)
starting from thiocarbonyl compounds. The difluoromethylsulfanyl
group is encountered in a variety of bioactive compounds. For
example, flomoxef, which is an oxacephem antibiotic, is successfully
used for therapeutic purposes (Fig. 2) [24]. 2-Difluoromethylsulfa-
nyl-4,6-bis(isopropylamino)-1,3,5-triazine (SSH-108) exhibits her-
bicidal activity [25]. In spite of their utility, the methods for
difluoromethylation of sulfur functional groups have been mostly
atom that behaves as
a non-nucleophilic proton donor for
hydrogen bonding [2], which leads to unique properties as a
bioisostere of the hydroxy group (Fig. 1) [3]. In addition,
introduction of fluoroalkyl groups, including the difluoromethyl
group, often lowers Hildebrand’s
d values and improves the
lipophilicity of the original molecule [4,5]. Due to these
advantages, the difluoromethyl group is now widely employed
as a highly versatile substituent [6].
Accordingly, synthetic methods for difluoromethylated com-
pounds have been developed in the past few years [7]. Concerning
the synthesis of difluoromethylated arenes, for example, the
conversion of a formyl group to a difluoromethyl group has often
been conducted using diethylaminosulfur trifluoride (DAST) [8]
and related reagents [9,10]. Direct [11] and several-step [12]
installations of the difluoromethyl unit onto an aromatic skeleton
have been also recently reported.
Difluorocarbene (:CF2) [13] is most commonly used to
introduce difluoromethyl groups onto
a heteroatom center
[7a,14–16]. Typically, phenols are treated with chlorodifluoro-
methane in the presence of strong bases such as potassium
*
Corresponding author. Tel.: +81 298534237; fax: +81 298534237.
E-mail address: junji@chem.tsukuba.ac.jp (J. Ichikawa).
http://dx.doi.org/10.1016/j.jfluchem.2014.08.013
0022-1139/ß 2014 Elsevier B.V. All rights reserved.

134
K. Fuchibe et al. / Journal of Fluorine Chemistry 171 (2015) 133–138
Fig. 1. Difluoromethyl group as bioisotere of hydroxy group.
Fig. 2. Useful difluoromethylsulfanylated compounds.
with a 79:21 diastereomeric ratio (Entry 1). Not only cyclohex-
anethiocarboxamide but also thioacetamides bearing a phenyl (1c)
or a p-chlorophenyl (1d) group on the nitrogen atom afforded the
corresponding products 2c,d in 70% and 75% yields, respectively
(Entries 2 and 3, 80 8C). Thioamides derived from aromatic
carboxamides also underwent S-difluoromethylation. Thioamides
1e–g afforded the expected thioimidates 2e–g in 51–85% yields
(Entries 4–6, 80 8C).
Scheme 1. Organocatalytic generation of difluorocarbene.
limited to those of aromatic thiols [15c–e,16,18,19b]. To broaden the
scope of difluoromethylsulfanylated compounds, the methods for
introduction of the difluoromethyl group to sulfur functionalities
other than thiols are highly desirable.
We thus focused our attention on the use of thiocarbonyl
compounds as substrates for difluoromethylation because they are
readily accessible from appropriate starting materials. However,
thiocarbonyl compounds are generally unstable toward hydroly-
sis; thus, in particular, there have been no reports on difluor-
omethylation of acyclic thiocarbonyl compounds [26]. We
expected that our organocatalyzed generation of difluorocarbene,
conducted under mild conditions, would allow an efficient S-
difluoromethylation of thiocarbonyl compounds without decom-
position of these substrates.
It was revealed that aliphatic thioamides were more reactive
than aromatic thioamides when the reactions were conducted at
50 8C. Namely, electron-donating alkyl thioamides 1b–d afforded
Table 1
Optimization of the catalyst.
.
2. Results and discussion
2.1. Optimization of the catalyst and synthesis of 2-
Yield [%]a,b
difluoromethylsulfanylpyridine 2a
Entry
Catalyst (mol%)
Temp. [8C]
1
2
3
4
5
6
7
4 (5), Na2CO3 (20)
5 (5), Na2CO3 (20)
PPh3 (10)
80
80
80
80
80
80
80
61
61
28
49
65
62
58
To make the best use of difluorocarbene for difluoromethyla-
tion, the rate of the difluorocarbene generation needs to be
controlled to prevent undesired dimerization, which leads to loss
of difluorocarbene. Therefore, optimization of the catalyst was
performed by using 2-thiopyridone 1a as the model substrate
(Table 1). Dimesitylimidazolidene 4 and diphenyltriazolidene 5,
which were effective in our previous O-difluoromethylation, were
first examined [21]. In each case, 2a was obtained in 61% yield
(Entries 1 and 2), which was confirmed using the reported
spectroscopic data of 2a [27]. It must be emphasized that the N-
difluoromethylated product 3 was not observed. Whereas triphe-
nylphosphine afforded 2a only in 28% yield (Entry 3), trialk-
ylamines and pyridine derivatives gave 2a in 49–69% yields
(Entries 4–10). Finally, aniline derivatives were more effective, and
N,N,N0,N0-tetramethyl-1,8-diaminonaphthalene 6 gave the highest
yield of 2a (78%) at 50 8C in 10 min (Entries 11 and 12).
NEt3 (20)
DABCO (20)
Pyridine (20)
(10)
(10)
8
9
80
80
63
69
(20)
(10)
(10)
10
11
80
80
65
68
2.2. Synthesis of S-difluoromethyl thioimidates
12
6 (10)
50
78
As described above, difluoromethylation of acyclic thiocarbonyl
compounds with difluorocarbene has not been reported yet. The
optimized catalytic system was successfully applied to the
synthesis of difluoromethylsulfanylated compounds with a linear
structure (Table 2) [28]. The required thioamides 1b–g were
prepared through the reported thionation reaction of carboxa-
mides with 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphe-
tane-2,4-disulfide (Lawesson’s reagent) [29].
DABCO = 1,4-Diazabicyclo[2.2.2]octane. Mes = 2,4,6-trimethylphenyl.
Thioamide 1b, which was derived from cyclohexanecarbox-
amide, underwent the expected difluoromethylation at 80 8C in
10 mintogiveS-difluoromethylthioimidate2binquantitativeyield
a
Determined by 19F NMR spectroscopy using (CF3)2C(C6H4p-Me)2 as the internal
standard.
b
TFDA was consumed in all entries.

K. Fuchibe et al. / Journal of Fluorine Chemistry 171 (2015) 133–138
135
Table 2
Catalytic synthesis of S-difluoromethyl thioimidates.
.
Entry
1
Thioamide
R
Thioimidate
Yield [%] (dr)a
80 8C
Ar
Ph
50 8C
c-C6H11
1b
2b
Quant (79/21)
71 (81/19)
2
3
Me
Me
Ph
1c
2c
70 (77/23)
75 (77/23)
47 (74/26)
47b (100/0)
C6H4p-Cl
1d
2d
4
5
Ph
Ph
Ph
1e
1f
2e
2f
85 (48/52)
51 (60/40)
27 (50/50)
12 (64/36)
C6H4p-Me
6
Ph
C6H4p-Cl
1g
2g
76 (63/37)
40b (65/35)
a
The geometries of 2 were not determined.
Determined by 19F NMR spectroscopy using (CF3)2C(C6H4p-Me)2 as the internal standard.
b
2b–d in 47–71% yields at 50 8C (Entries 1–3), whereas the less
electron-donating aryl thioamides 1e–g afforded 2e–g only in 12–
40% yields (Entries 4–6, 50 8C). This is probably due to the fact that
the electron-deficient difluorocarbene favors the electron-rich
aliphatic thioamides.
even at 50 8C in 10 min, and the expected S-difluoromethyl
thioiminocarbonate 10a was obtained in 93% yield [33]. Thiocar-
bamate 9b also afforded the corresponding thioiminocarbonate
10b in 97% yield [33]. S-Difluoromethylation of the cyclic
thiocarbamate 9c proceeded in
a similar manner to give
As mentioned above, the products were obtained as diastereo-
meric mixtures. Comparisons between the spectral data of the
products and those in the literature revealed that they were S-
difluoromethylated products. Namely, all the products exhibited
13C NMR signals at 158–172 ppm and IR absorption signals at
1618–1645 cmꢀ1 (Fig. 3). The reported thioimidate 7 exhibits its
13C NMR signal at 170 ppm (C55N) and an IR absorption signal at
1630 cmꢀ1 (C55N stretching) [30]. Thioamide 8 exhibits its 13C
NMR signal at 203 ppm (C55S) and an IR absorption signal at
1247 cmꢀ1 (C55S stretching) [31]. These data suggested that the
difluoromethylsulfanylated benzoxazole 10c in 83% yield (Eq.
(2)). Interestingly, Greaney and coworkers reported that the N-
difluoromethylation of 9c proceeded with difluorocarbene, which
was generated from sodium chlorodifluoroacetate in the presence
of potassium carbonate, in DMF at 95 8C for 14 h to afford
benzoxazol-2-thione 11 in 46% yield (Eq. (3), vide infra) [15c].
products had
a C55N double bond and therefore were S-
difluoromethylated compounds.
2.3. Synthesis of S-difluoromethyl thioiminocarbonates
Thiocarbamates were more reactive than thioamides in the S-
difluoromethylation. The required thiocarbamates 9a,b were
readily prepared from isothiocyanates and alkoxides [32].
Methyl thiocarbamate 9a was subjected to the organocatalyzed
difluoromethylation (Eq. (1)). The reaction proceeded smoothly
Fig. 3. Selected spectral data of products and reported compounds.

136
K. Fuchibe et al. / Journal of Fluorine Chemistry 171 (2015) 133–138
2.4. Reaction mechanism
generated from chlorodifluoromethane in the presence of potassi-
um hydroxide, proceeded kinetically on the sulfur atom and
thermodynamically on the nitrogen atom [35]. Mild reaction
temperature (50 8C in Eq. (2) vs. 95 8C in Eq. (3)) and short reaction
time (10 min vs. 14 h) provide a rationale for the high sulfur
selectivity observed in our organocatalyzed system [36].
Thus, the generation of difluorocarbene under organocatalysis
is particularly suitable for S-difluoromethylation of thioamides
because of its mild reaction conditions.
The abovementioned S-difluoromethylation of thiocarbonyl com-
pounds can be rationalized by the mechanism shown below. TFDA
undergoes decomposition caused by diaminonaphthalene 6 to
generate difluorocarbene (Eq. (4)) [22]. The formed silylated
diaminonaphthalene [6–SiMe3]+ undergoes desilylation in the pres-
ence of the released fluoride ion to regenerate free diamine 6 (not
shown) [34]. The difluorocarbene thus generated was attacked by the
electron-rich sulfur atom of the substrates 1/9 (Eq. (5)). Subsequently,
intra- and/or intermolecular proton shift gave the products 2/10.
3. Conclusion
Organocatalytic generation of difluorocarbene has allowed
efficient S-difluoromethylation of thiocarbonyl compounds. Treat-
ment of secondary thioamides with TFDA in the presence of
tetramethyldiaminonaphthalene 6 at 80 8C afforded S-difluoro-
methyl thioimidates in good to excellent yields. Difluoromethyla-
tion of secondary thiocarbamates proceeded in a similar manner at
50 8C to afford S-difluoromethyl thioiminocarbonates in excellent
yields. The starting thiocarbonyl compounds were readily pre-
pared from carboxamides or isothiocyanates. Decomposition of
these substrates was not substantially observed under the mild
reaction conditions represented by the organocatalysis. The mild
conditions also allowed high sulfur selectivity, leading to the
formation of the difluoromethylsulfanylated products in high
yields.
4. Experimental
4.1. General information
2.5. Comparison with the reported methods for the generation of
difluorocarbene
IR spectra were recorded on Horiba FT-300S spectrometer. NMR
spectra were recorded on a Bruker Avance 500 spectrometer in
CDCl3 at 500 MHz (1H NMR), at 126 MHz (13C NMR), and at
470 MHz (19F NMR). Chemical shift values were given in ppm
To demonstrate the advantage of the organocatalyzed genera-
tion of difluorocarbene, in addition to its sulfur-selectivity, S-
difluoromethylation of thioamides using previously reported
methods for the generation of difluorocarbene was also performed.
As mentioned above, thioamide 1b undergoes S-difluoromethyla-
tion with TFDA in the presence of diaminonaphthalene 6 to give
thioimidate 2b in quantitative yield at 80 8C (Table 2, Entry 1). On
the other hand, treatment of 1b with sodium chlorodifluoroacetate
at 80 8C did not give 2b (Eq. (6)), which was due to the fact that its
pyrolysis required harsh conditions (higher temperatures). Thioi-
midate 2b was actually formed from 1b on treatment with sodium
chlorodifluoroacetate in 98% yield, only when the reaction was
performed at 160 8C. Difluorocarbene generated under alkaline
conditions also did not afford 2b (Eq. (7)). Treatment of 1b with
bromodifluoroacetophenone, which is analogous to the reported
chlorodifluoroacetophenone [17a], in the presence of a large excess
amount of potassium hydroxide resulted in the partial decompo-
sition of 1b without formation of 2b.
relative to internal Me4Si (for 1H NMR:
d
= 0.00), CDCl3 (for 13C
d = 0.0). Mass spectra were
NMR:
d
= 77.0), and C6F6 (for 19F NMR:
taken with JMS-T100GCV spectrometer (EI, 70 eV). Elemental
analyses were performed with a YANAKO MT-3 CHN Corder
apparatus. TFDA was prepared from the corresponding acid, which
was purchased from Sigma–Aldrich Co. LLC, by the reported
procedure [22]. 19F NMR analysis suggested that the prepared
TFDA contained a small amount of the starting acid and that its
purity was higher than 98% (mol/mol). N,N,N0,N0-Tetramethyl-1,8-
diaminonaphthalene 6 was purchased from Sigma–Aldrich Co. LLC
and used as received.
4.2. Preparation of thioamides and thiocarbamates
2-Thiopyridone 1a and benzoxazole 9c were purchased from
Sigma–Aldrich Co. LLC. Thioamides 1b–g and thiocarbamates 9a,b
were prepared by the reported procedures, using commercially
available 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-
2,4-disulfide (Lawesson’s reagent) for 1b–g [29] and commercially
available isothiocyanates for 9a,b [32].
4.2.1. N-(p-Methylphenyl)benzenecarbothioamide (1f)
Preparation of thioamide 1f is described as a typical procedure.
To a THF solution (50 mL) of Lawesson’s reagent (432 mg,
1.07 mmol) was added a solution of N-(p-methylphenyl)benzene-
carboxamide (461 mg, 2.18 mmol) at room temperature. The
reaction mixture was stirred and heated to 50 8C for 2.5 h. After
cooling the resulting mixture to room temperature, the solvent
was removed under reduced pressure. The residue was purified by
column chromatography on silica gel (hexane:ethyl acetate = 2:1)
to give thioamide 1f (481 mg, 97% yield).
Based on their study, Yagupol’skii and coworkers reported that
difluoromethylation of sulfanyltetrazoles with difluorocarbene,

K. Fuchibe et al. / Journal of Fluorine Chemistry 171 (2015) 133–138
137
4.2.2. O-Methyl N-phenylthiocarbamate (9a)
Preparation of thiocarbamate 9a is described as a typical
procedure.
To methanol solution (3 mL) of phenyl isothiocyanate
19F NMR signal of the minor isomer: 19F NMR (470 MHz, CDCl3):
d
69.9 (d, J = 56 Hz).
a
4.4.3. S-Difluoromethyl N-(p-chlorophenyl)ethanethioimidate (2d)
(0.60 mL, 5.0 mmol) was added a methanol solution (1 mol/L,
10 mL) of sodium methoxide (10 mmol). The reaction mixture was
stirred for 30 min at room temperature. Concentrated hydrochloric
acid was then added to adjust the pH of the crude mixture to 4–5.
The resulting white precipitate was filtered with suction and
washed with methanol. The filtrate was concentrated under
reduced pressure to give thiocarbamate 9a (556 mg, 67% yield).
The product 2d was obtained as an inseparable diastereomeric
mixture. Spectral data of the major isomer: 1H NMR (500 MHz,
CDCl3):
7.64 (t, J = 55.4 Hz, 1H); 13C NMR (126 MHz, CDCl3):
J = 270 Hz), 121.2, 129.2, 129.3, 147.2, 163.2; 19F NMR (470 MHz,
d
2.06 (s, 3H), 6.70 (d, J = 8.6 Hz, 2H), 7.29 (d, J = 8.6 Hz, 2H),
d
21.7, 120.0 (t,
CDCl3):
d 60.9 (d, J = 55 Hz); IR (neat): n
˜ 2951, 1645, 1161, 1049,
694 cmꢀ1; HRMS: m/z calcd. for C9H8ClF2NOS ([M]+): 235.0034;
found: 235.0033. Characteristic 1H and 19F NMR signals of the
d F
minor isomer: 1H NMR (500 MHz, CDCl3): 7.14 (t, J = 55.6 Hz); 19
4.3. Synthesis of difluoromethylsulfanylated compounds
NMR (470 MHz, CDCl3):
d 70.0 (d, J = 56 Hz).
4.3.1. Synthesis of S-difluoromethyl thioimidates
Synthesis of S-difluoromethyl imidate 2b is described as a
typical procedure.
To a toluene solution (1.0 mL) of tetramethyldiaminonaphtha-
lene 6 (4.1 mg, 0.019 mmol) was added thioamide 1b (42 mg,
0.19 mmol) at room temperature. The reaction mixture was stirred
4.4.4. S-Difluoromethyl N-phenylbenzenecarbothioimidate (2e)
The product 2e was obtained as an inseparable diastereomeric
mixture. Spectral data of the mixture (50:50): 1H NMR (500 MHz,
CDCl3):
d
6.72 (t, J = 56.3 Hz, 1H ꢁ 0.50), 6.73 (d, J = 7.6 Hz,
2H ꢁ 0.50), 6.97 (d, J = 7.8 Hz, 2H ꢁ 0.50), 7.04 (t, J = 7.4 Hz,
1H ꢁ 0.50), 7.21 (t, J = 7.4 Hz, 2H ꢁ 0.50), 7.25–7.32 (m,
5H ꢁ 0.50), 7.38 (d, J = 7.2 Hz, 1H ꢁ 0.50), 7.47 (t, J = 7.4 Hz,
2H ꢁ 0.50), 7.57–7.72 (m, 3H ꢁ 0.50), 7.75 (t, J = 55.0 Hz,
1H ꢁ 0.50), 7.87 (d, J = 7.4 Hz, 2H ꢁ 0.50); 13C NMR (126 MHz,
and heated to 80 8C, and TFDA (80
mL, 0.40 mmol) was added. After
the resulting mixture was stirred for 10 min and cooled to room
temperature, the solvent was removed under reduced pressure.
The residue was purified by column chromatography on silica gel
(hexane:ethyl acetate = 10:1) to give thioimidate 2b (53 mg,
quant).
CDCl3):
d 119.5, 120.3 (t, J = 265 Hz), 120.4 (t, J = 270 Hz), 120.9,
121.1, 124.0, 125.3, 128.0, 128.5, 128.8, 129.0, 129.1, 130.5, 131.5,
133.5, 136.6, 148.2, 148.9, 157.9, 162.6; 19F NMR (470 MHz,
4.3.2. Synthesis of S-difluoromethyl thioiminocarbonates
Synthesis of S-difluoromethyl thioiminocarbonate 10b is
described as a typical procedure.
To a toluene solution (1.0 mL) of tetramethyldiaminonaphtha-
lene 6 (4.3 mg, 0.020 mmol) was added thiocarbamate 9b (46 mg,
0.21 mmol) at room temperature. The reaction mixture was stirred
CDCl3): d 60.5 (d, J = 55 Hz), 69.6 (d, J = 56 Hz); IR (neat): n
˜ 3062,
1618, 1593, 1049, 762, 690 cmꢀ1; HRMS: m/z calcd. for C14H11F2NS
([M]+): 263.0580; found: 263.0578. The GC peaks of the isomers
were not isolated from each other on GC-HRMS analysis.
4.4.5. S-Difluoromethyl N-(p-
and TFDA (80
m
L, 0.40 mmol) was added. The reaction mixture was
methylphenyl)benzenecarbothioimidate (2f)
heated to 50 8C, and stirred for 10 min. After cooling the resulting
mixture to room temperature, the solvent was removed under
reduced pressure. The residue was purified by column chroma-
tography on silica gel (hexane:ethyl acetate = 10:1) to give
thioiminocarbonate 10b (56 mg, 97% yield).
The product 2f was obtained as an inseparable diastereomeric
mixture. Spectral data of the mixture (63:37): 1H NMR (500 MHz,
CDCl3):
d
2.23 (s, 3H ꢁ 0.37), 2.37 (s, 3H ꢁ 0.63), 6.59 (d, J = 8.0 Hz,
2H ꢁ 0.37), 6.68 (t, J = 56.3 Hz, 1H ꢁ 0.63), 6.85 (d, J = 8.2 Hz,
2H ꢁ 0.63), 6.96 (d, J = 8.2 Hz, 2H ꢁ 0.37), 7.21–7.26 (m, 2H), 7.29
(t, J = 7.4 Hz, 1H ꢁ 0.63), 7.35 (d, J = 7.4 Hz, 1H ꢁ 0.37), 7.53–7.56
(m, 2H), 7.71 (t, J = 55.4 Hz, 1H ꢁ 0.37), 7.82 (d, J = 7.4 Hz,
4.4. Spectral data of products
2H ꢁ 0.63); 13C NMR (126 MHz, CDCl3):
d 20.9, 21.1, 119.5,
4.4.1. S-Difluoromethyl N-phenylcyclohexanecarbothioimidate (2b)
The product 2b was obtained as an inseparable diastereomeric
mixture. Spectral data of the major isomer: 1H NMR (500 MHz,
120.4 (t, J = 274 Hz), 120.4 (t, J = 270 Hz), 121.1, 128.2, 128.5,
129.0, 129.3, 129.5, 129.7, 130.4, 131.4, 133.6, 135.2, 136.6, 138.6,
145.5, 146.2, 157.5, 161.9; 19F NMR (470 MHz, CDCl3):
d
60.5 (d,
CDCl3):
d
0.99–1.09 (m, 3H), 1.35 (td, J = 12.0, 12.0 Hz, 2H), 1.53 (d,
J = 55 Hz), 69.5 (d, J = 56 Hz); IR (neat): n
˜ 2924, 1618, 1506, 1072,
J = 12.0 Hz, 1H), 1.65 (t, J = 12.0 Hz, 4H), 2.59 (t, J = 12.0 Hz, 1H),
6.66 (d, J = 7.4 Hz, 2H), 7.06 (t, J = 7.4 Hz, 1H), 7.28 (t, J = 7.4 Hz, 2H),
7.49 (t, J = 55.7 Hz, 1H); 13C NMR (126 MHz, CDCl3):
769 cmꢀ1; HRMS: m/z calcd. for C15H13F2NS ([M]+): 277.0737;
found: 277.0732. The GC peaks of the isomers were not isolated
from each other on GC-HRMS analysis.
d
24.9, 29.4,
30.4, 43.0, 119.2, 120.7 (t, J = 269 Hz), 123.6, 129.1, 148.6, 171.6;
19F NMR (470 MHz, CDCl3):
d
61.3 (d, J = 56 Hz); IR (neat):
n
˜ 2931,
4.4.6. S-Difluoromethyl N-(p-chlorophenyl)benzenecarbothioimidate
(2g)
The product 2g was obtained as an inseparable diastereomeric
mixture. Spectral data of the mixture (55:45): 1H NMR (500 MHz,
1628, 1596, 1448, 970 cmꢀ1; HRMS: m/z calcd. for C14H17F2NS
([M]+): 269.1050; found: 269.1050. Characteristic 1H and 19F NMR
signals of the minor isomer: 1H NMR (500 MHz, CDCl3):
J = 55.2 Hz); 19F NMR (470 MHz, CDCl3):
d
6.93 (t,
69.1 (d, J = 55 Hz).
d
CDCl3):
d
6.56–6.61 (m, 2H ꢁ 0.5), 6.65 (t, J = 56.3 Hz, 1H ꢁ 0.5),
6.81–6.88 (m, 2H ꢁ 0.5), 7.05–7.10 (m, 2H ꢁ 0.5), 7.13–7.19 (m,
2H ꢁ 0.5), 7.22–7.28 (m, 2H ꢁ 0.5), 7.30–7.37 (m, 3H ꢁ 0.5), 7.47–
7.56 (m, 4H ꢁ 0.5), 7.73–7.81 (m, 2H ꢁ 0.5); 13C NMR (126 MHz,
4.4.2. S-Difluoromethyl N-phenylethanethioimidate (2c)
The product 2c was obtained as an inseparable diastereomeric
mixture. Spectral data of the major isomer: 1H NMR (500 MHz,
CDCl3):
d 120.1 (t, J = 271 Hz), 120.3 (t, J = 275 Hz), 121.0, 122.5,
CDCl3):
7.33 (t, J = 8.1 Hz, 2H), 7.68 (t, J = 55.4 Hz, 1H); 13C NMR (126 MHz,
CDCl3): 21.7, 119.8, 120.2 (t, J = 270 Hz), 124.2, 129.1, 148.8,
162.1; 19F NMR (470 MHz, CDCl3):
60.9 (d, J = 55 Hz); IR (neat):
2870, 1645, 1487, 1138, 1068 cmꢀ1
HRMS: m/z calcd. for
C9H9F2NS ([M]+): 201.0424; found: 201.0421. A characteristic
d
2.06 (s, 3H), 6.76 (d, J = 8.1 Hz, 2H), 7.11 (t, J = 8.1 Hz, 1H),
128.0, 128.5, 128.7, 128.8, 129.0, 129.2, 130.5, 130.7, 131.7, 133.1,
136.4, 138.6, 146.7, 147.2, 158.8, 163.7; 19F NMR (470 MHz,
d
CDCl3): d 60.5 (d, J = 55 Hz), 69.5 (d, J = 56 Hz); IR (neat): n˜ 2927,
d
n
˜
1620, 1483, 1076, 698 cmꢀ1; HRMS: m/z calcd. for C14H10ClF2NS
([M]+): 297.0191; found: 297.0188. The GC peaks of the isomers
were not isolated from each other on GC-HRMS analysis.
;

138
K. Fuchibe et al. / Journal of Fluorine Chemistry 171 (2015) 133–138
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5563;
4.4.7. S-Difluoromethyl O-methyl N-phenylthioiminocarbonate (10a)
1H NMR (500 MHz, CDCl3):
4.04 (s, 3H), 6.85 (dd, J = 7.0,
1.0 Hz, 2H), 7.13 (tt, J = 7.0, 1.0 Hz, 1H), 7.32 (t, J = 7.0 Hz, 2H), 7.37
(t, J = 56.5 Hz, 1H); 13C NMR (126 MHz, CDCl3):
56.9, 119.0 (t,
J = 274 Hz), 121.2, 124.6, 129.2, 145.7, 152.6; 19F NMR (470 MHz,
d
(b) K. Fujikawa, A. Kobayashi, H. Amii, Synthesis 44 (2012) 3015–3018;
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d
CDCl3):
d 68.7 (d, J = 57 Hz); IR (neat): n
˜ 2951, 1645, 1161, 1049,
694 cmꢀ1; HRMS: m/z calcd. for C9H9F2NOS ([M]+): 217.0373;
[15] For the recent reports on the introduction of the difluoromethyl group onto
heteroatoms with difluorocarbene, see:
found: 217.0371.
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4.4.8. S-Difluoromethyl O-isopropyl N-p-
(methoxyphenyl)thioiminocarbonate (10b)
1H NMR (500 MHz, CDCl3):
d
1.40 (d, J = 6.2 Hz, 6H), 3.78 (s, 3H),
5.36 (sept, J = 6.2 Hz, 1H), 6.78 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz,
2H), 7.32 (t, J = 57.0 Hz, 1H); 13C NMR (126 MHz, CDCl3):
21.6,
55.4, 73.7, 114.4, 119.4 (t, J = 277 Hz), 122.2, 139.2, 151.4, 156.7;
d
(a) G.K.S. Prakash, Z. Zhang, F. Wang, C. Ni, G.A. Olah, J. Fluorine Chem. 132 (2011)
792–798 (CF2H cation equivalent);
Ref. [11a] (CF2H radical).
(b) W. Zhang, J. Zhu, J. Hu, J. Fluorine Chem. 49 (2008) 5006–5008 (two-step
synthesis).
19F NMR (470 MHz, CDCl3):
d
66.6 (d, J = 57 Hz); IR (neat):
n
˜ 2983,
1639, 1504, 1033, 769 cmꢀ1; HRMS: m/z calcd. for C12H15F2NO2S
([M]+): 275.0792; found: 275.0790.
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4.4.9. 2-(Difluoromethylsulfanyl)benzoxazole (10c)
Spectroscopic data of 1H and 19F NMR were in agreement with
those in the literature [11a].
Acknowledgments
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[20] A high reaction temperature as well as strongly basic conditions is a potential
drawback. Generation of difluorocarbene from sodium chlorodifluoroacetate or
This research is supported by JSPS KAKENHI (grant no.
25288016) and by MEXT KAKENHI (grant no. 26105705). This
work is partially supported by Asahi Glass Foundation.
˚
˚
hexafluoropropyrene oxide (HFPO) typically requires 120 C and 150 C, respec-
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