N-Difluoromethylthiophthalimide: A Shelf-Stable, Electrophilic Reagent for Difluoromethylthiolation

Article abstract of DOI:10.1021/jacs.5b03170

A new, electrophilic difluoromethylthiolating reagent N-difluoromethylthiophthalimide 3 was developed. Reagent 3 can be readily synthesized in four steps from easily available starting materials phthalimide and TMSCF₂H. N-difluoromethylthiophthalimide 3 is a powerful electrophilic difluoromethylthiolating reagent that allows the difluoromethylthiolation of a wide range of nucleophiles including aryl/vinyl boronic acids, alkynes, amines, thiols, β-ketoesters, and oxindoles and electron-rich heteroarenes such as indole, pyrrole, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,2-a]pyridine, aminothiazole, isoxazole, and pyrazole under mild conditions.

Full text of DOI:10.1021/jacs.5b03170

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Journal of the American Chemical Society
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N-Difluoromethylthiophthalimide: A Shelf-Stable, Electrophilic Rea-
gent for Difluoromethylthiolation
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‡
‡
Dianhu Zhu, Yang Gu, Long Lu* and Qilong Shen*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
3
45 Lingling Road, Shanghai 200032
ABSTRACT: A new, electrophilic difluoromethylthiolating reagent N-difluoromethylthiophthalimide 3 was developed. Rea-
gent 3 can be readily synthesized in four steps from easily available starting materials phthalimide and TMSCF H. N-
2
difluoromethylthiophthalimide
3
is
a
powerful electrophilic difluoromethylthiolating reagent that allows the
difluoromethylthiolation of a wide range of nucleophiles including aryl/vinyl boronic acids, alkynes, amines, thiols, β-
ketoesters, oxindoles and electron-rich heteroarenes such as indole, pyrrole, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,2-
a]pyridine, aminothiazole, isoxazole and pyrazole under mild conditions.
INTRODUCTION
Due to their intrinsic beneficial properties, fluorine and
fluoroalkyl groups have been increasingly recognized and
practiced by medicinal chemists as an important tool to
1
improve drug’s efficacy over the past three decades. In
particular, one of the fluoroalkyl groups, difluoromethylthio
group (-SCF H) which is generally considered as a highly
2
lipophilic weak hydrogen-bonding donor, is of great cur-
2
rent interest. Examples of drugs and agrochemicals bear-
ing a difluoromethylthio unit include β-lactamase-resistant
3
oxcephalosporin antibiotic Flomoxef sodium, pesticide
4
Pyriprole
and broad-spectrum paddy herbicide
5
Pyrimisulfan (Fig. 1).
Figure
2.
Strategies
for
the
formation
of
difluoromethylthioether.
gas, thus its future usage for the difluoromethylthioether
formation is rather limitted. In this respect, a number of
different difluoromethyl carbene precursors such as
BrCF P(O)(OEt) , ClCF CO Na, TMSCF Br, HCF OTf,
Figure 1. Drugs and agrochemicals containing
difluoromethylthio group.
a
2
2
2
2
2
2
One general and routinely used approach for the
preparation of difluoromethylthiolated compounds
typically involves the nucleophilic attack of the an in situ
8
PhS(O)(NTs)CF H etc. have been developed. A less
2
common
approach
for
the
preparation
of
6
difluoromethylthiolated compounds is the reaction of
thiolate with either an electrophilic difluoromethylated
formed difluoromethyl carbene intermediate by an
appropriate thiolate. For example, formation of
9
reagent or a reagent that can easily generate a
difluoromethylthioether
using
chlorodifluoromethane
10
difluoromethyl radical, as reported by Prakash, Hu and
Baran, respectively. Nevertheless, both approaches were
conducted under strong basic conditions and many
HCF Cl (Freon 22) as a difluoromethyl carbene source has
2
7
been well-developed. Yet, HCF Cl is a ozone-depleting
2
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functional groups are not compatible. In addition, both However, the formation of reagent 3 was not observed
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t
t
approaches require the preformation of thiols, that might
be a problem for more complicated molecules. Very
recently, Goossen and coworkers reported that
difluoromethylthiolethers could be accessed via a copper-
mediated difluoromethylation of organothiocyanates,
when various activators such as KO Bu, NaO Bu, CsF, AgF
16
and TBAF were used. Instead, difluoromethane (CF H )
2
2
19
was observed as the main product as determined by
F
NMR spectroscopy. We then shifted our efforts for the
synthesis of reagent 3 to the difluoromethylation of
thoilated phthalimide substrates such as di(1-
11
which represents a major step-forward. Shortly after, we
reported copper-mediated Sandermeyer-type
difluoromethylthiolation of aryl and heteroaryl diazo
1
7
a
phthalimidy1)disulfane
1
and
N-(chlorosulfenyl)
18
phthalimide 2 that can be readily synthesized from
phthalimide in excellent yields. Interestingly, reactions of
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compounds under mild conditions. However, the scope
of both reactions was limited to the substrates that could
compound 1 or 2 with TMSCF H in the presence of
2
+
-
t
form RSCN or ArN BF . Many other substrates including
activators such as NaO Bu, CsF or AgF in solvents such as
2
4
amines, thiols, alkynes, β-ketoesters or oxindoles could not
THF, CH Cl , CH CN or DMF were messy. In contrast,
2
2
3
be difluoromethylthiolated via these methods.
reaction of compound 2 with [(SIPr)Ag(CF H)] (SIPr = 1,3-
2
19
bis(2,6-diisopropylphenyl)imidazolin-2-ylidene),
a
Thus, new approaches that could easily form the
difluoromethylthioethers are still urgently needed and
remain a significant challenge. Inspired by the recent
stable difluoromethylsilver complex discovered in our
laboratory recently, formed cleanly difluoromethylthio-
phthalimide 3 in 81-83% yields when the reaction were
development
trifluoromethylthiolating
electrophilic trifluoromethylthiolating
trifluoromethylthiophthalimide which
of
powerful
reagents,
electrophilic
13
conducted in solvents such as CH Cl , CH CN or toluene.
especially
reagent
was
the
N-
initially
2
2
3
The reaction could be easily scaled up to 175 mmol to give
reagent 3 in 66% yield (Fig. 3). Notably, the silver product
[
(SIPr)AgCl] was recycled in 83% yield, which was reused
developed by Munavalli and was further studied recently
14
for the preparation of [(SIPr)Ag(CF H)]. Even after three
by Rueping and us, we envisiged that if an analogous
electrophilic difluoromethylthiolating reagent could be
invented, a strategically new approach for the introduction
of the difluoromethylthio group into small molecules would
be created. This new approach could circumvent the harsh
conditions and the requirement of preformation of thiols of
the classical difluoromethyl carbene stratergy (Fig. 2).
Such a reagent would be valuable for the medicinal
chemists since the difluoromethylthio group could be
readily incorporated at the late-stage of the drug
development process. Herein, we report the design and
synthesis of N-difluoromethylthiophthalimide 3, which can
be efficiently synthesized from phthalimide in four-steps in
2
cycles, roughly half of [(SIPr)AgCl] still could be recovered.
high yields. The reactivity of compound
3
was
demonstrated by difluoromethylthiolation of a wide range
of nucleophiles including aryl/vinyl boronic acids, alkynes,
amines, thiols, β-ketoesters, oxindoles and electron-rich
heteroarenes such as indole, pyrrole, 1H-pyrrolo[2,3-
Figure 3. Preparation of N-difluoromethylthiophthalimide 3
and recovery of [(SIPr)AgCl].
b]pyridine,
imidazo[1,2-a]pyridine,
aminothiazole,
isoxazole and pyrazole under mild conditions. To the best
of our knowledge, reagent 3 represents the first shelf-
15
stable electrophilic difluoromethylthiolating reagent.
RESULTS AND DISCUSSION
Preparation of N-difluoromethylthiophthalimide 3. Our
efforts for the synthesis of difluoromethylthiophthalimide 3
began with the search for reaction condidions to assemble
Figure 4. ORTEP diagrams of N-difluoromethylthiophthalimide
3. Ellipsoids are shown at the 50% level.
N-chlorophthalimide, sulphur and TMSCF H in the
2
Difluoromethylthiophthalimide 3 was fully characterized
presence of different activators in different solvents. We
expect that the in situ formed difluoromethyl anion could
be trapped by sulfur to form difluoromethylthio anion,
1
13
19
by H, C, F NMR spectroscopies. The structure of com-
pound 3 was unambiguously confirmed by X-ray analysis
of its single crystals (Figure 4). Compound 3, a white crys-
talline solid with a melting point 115-116 °C, is not air and
subsequent
nucleophilic
substitution
with
N-
chlorophthalimide leading to the generation of reagent 3.
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light sensitive. No detectable decomposition was ob-
served after more than two-month storage on shelf at am-
bient temperature. Compound 3 is stable in solvents such
were observed in less than 5% yields as determined by
NMR spectroscopy (Scheme 1, 4w-z).
F
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Scheme 1. Me SiCl-Mediated Difluoromethylthiolation of
3
a,b
as ClCH CH Cl, toluene, THF, acetone and CH CN at
2
2
3
Electron-Rich Heteroarenes.
o
19
1
00 C for at least 12 h as determined by F NMR spec-
troscopy. Compound 3 is less stable in solvents such as
DMF or methanol. It was completely decomposed after 5
min in methanol at room temperature and 12 h in DMF at
o
19
8
0 C as determined by F NMR spectroscopy.
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Reaction of N-difluoromethylthiophthalimide 3 with elec-
tron-rich heteroarenes. With this new reagent in-hand, we
first explored its reactivity with electron-rich arenes since
Friedel-Crafts-type difluoromethylthiolation of electron-
rich arenes represents a straightforward method for the
introduction of difluoromethylthio group into arenes. It was
found that reaction of indole with reagent 3 in the pres-
2
0
ence of 1.5 equivalents of Me SiCl occurred smoothly
3
o
after 16 h at 80 C to give 3-difluoromethylthiolated indole
in quantitative yield. Reactions in the presence of other
Lewis acid such as LiCl, MgCl , MgBr , AlCl , ZnCl , TiCl
21
2
2
3
2
4
or BF OEt were much less effective while reaction using
3
2
LiBr as the activator occurred in high yield. Likewise,
BrØnsted acids such as triflic acid, p-toluenesulfonic acid
or camphorsulfonic acid were ineffective activators as well
(see Supporting Information Table S1 for details).
In general, reactions of a variety of other indoles with
electron-donating or withdrawing groups occurred in
good to excellent yields under slightly modified conditions
(Scheme 1). Reactions of indoles with electron-rich substi-
tuted groups were much faster than those of indoles with
electron-withdrawing groups. Reactions of indoles with
electron-withdrawing groups were conducted at 100-120
o
C for full conversion. Indoles with functional groups such
as chloride, bromide, fluoride, aldehyde, ester and cyano
group reacted to generate the corresponding
difluoromethylthiolated indoles in high yields (Scheme 1,
4
b-f, 4h-i). Reaction of 3-methyl-indole formed the corre-
sponding difluoromethylthiolated compounds in 96% yield
Scheme 1, 4k). N-Methyl indole also reacted under the
optimized conditions to give the corresponding product in
8% yield (Scheme 1, 4l). Similarly, reaction of pyrroles
a
Reaction conditions: heteroarene (0.5 mmol), reagent 3
(
(0.60 mmol), Me SiCl (0.75 mmol) in 3.0 mL of 1,2-
dichloroethane 80 C for 16 h; Isolated yields; Reaction was
conducted at 100 C for 16 h; Reaction was conducted at
3
o
b
c
o
d
9
o
e
1
20 C for 24 h; Reaction was conducted at room tempera-
with different substituted groups occurred to give the cor-
responding difluoromethylthiolated pyrroles in 75-94%
yield (Scheme 1, 4m-q). Not only indoles and pyrroles but
also other electron-rich heteroarenes such as 1H-
f
ture for 24 h; Reaction conditions: heteroarene (0.70 mmol),
reagent 3 (0.84 mmol), NaCl (0.07 mmol) in DMF (4.0 mL) at
8
o
0 C for 16 h.
pyrrolo[2,3-b]pyridine,
imidazo[1,2-a]pyridine,
Pleasingly, it was discovered that conditions for Friedel-
aminothiazole and isoxazole reacted with N-
difluoromethylthiophthalimide 3 in the presence of 1.5
Crafts-type difluoromethylthiolation of electron-rich
heteroarenes were also able to difluoromethylthiolate
Pyriprole precursor. Under the standard conditions,
Pyriprole 4aa was generated in 93% yield (Eq. 1). Fur-
thermore, the same reaction could be achieved when the
reaction was conducted in the presence of 10 mol% of
NaCl as the catalyst in DMF. Likewise, a furyl-substituted
analog of Pyriprole 4ab could also be synthesized in 94%
yield under the similar reaction conditions (Eq. 1).
22
equivalents of Me SiCl or catalytic amount of NaCl to
3
15b
give
the
corresponding
difluoromethylthiolated
heteroarenes in 62-95% yields (Scheme 1, 4r-v). However,
when other electron-rich heteroarenes or arenes such as
benzothiophene, benzofuran, 1-4-dimethoxybenzene or
22
3
-iodophenol were subjected to these conditions, for-
mation of the desired difluoromethylthiolated products
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olefins in reasonable yields (Scheme 3, 5r-s). Challenging
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functional groups were compatible with the reaction con-
ditions. Reactions of aryl boronic acids with functional
groups such as enolizable ketone, ester, aldehyde, amide,
olefin, cyano, bromo, iodo and nitro group occurred in
good yields (Scheme 3, 5d-l). Notably, two
difluoromethylthiolated analogs of natural products were
generated from their corresponding boryl derivatives in 58%
and 78% yields, respectively (Eqs. 2-3). Thus, the copper-
Copper-catalyzed difluoromethylthiolation of aryl/vinyl
boronic acids with N-difluoromethylthiophthalimide 3.
Although reagent 3 is highly reactive for Friedel-Crafts-
type difluoromethylthiolation of electron-rich heteroarenes,
reactions of electron-rich or poor arenes with reagent 3
under the same conditions were much less effective. To
overcome the limitation of the Lewis acid-mediated elec-
trophilic difluoromethylthiolation reaction, we seek to use
easily available, bench stable aryl boronic acids to couple
with reagent 3 in the presence of a copper catalyst for the
formation of difluoromethylthiolated arenes. A careful
screening of the reaction conditions for the copper-
catalyzed difluoromethylthiolation of biphenyl boronic
acid revealed that the base was crucial for the formation
of the difluoromethylthiolated biphenyl. High yields were
observed when KF, Li CO or Na CO was used as the
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catalyzed
method
for
the
formation
of
difluoromethylthiolated arenes and alkenes provides a
complimentary method for the introduction of the
difluoromethylthio group into the medicinally-important
arene subunit.
Scheme 3. Scope for Copper-Catalyzed Difluoromethyl-
a,b
thiolation of Aryl and Vinyl Boronic Acids.
2
3
2
3
base, whereas no product was formed when slightly
stronger base K CO or Cs CO was used (Scheme 2).
2
3
2
3
Scheme 2. Effects of Bases on Copper-Catalyzed
a,b
Difluoromethylthiolation of Biphenylboronic Acid.
a
Reaction conditions: aryl or vinyl boronic acid (0.7 mmol),
reagent 3 (0.84 mmol), Li CO (0.35 mmol), CuI (0.035
2
3
a
o
Reaction conditions: biphenyl boronic acid (0.1 mmol),
mmol), bpy (0.035 mmol) in diglyme (5.0 mL) at 60 C for
15 h; Isolated yields; The reactions were conducted at 80
b
c
reagent 3 (0.12 mmol), CuI (0.005 mmol), bpy (0.005
o
o
mmol), base (0.05 mmol) in diglyme (1.0 mL) at 60 C for
C for 20 h.
b
19
1
5 h; Yields were determined by F NMR spectroscopy
with PhCF as the internal standard.
3
Scheme 3 summarized the scope of the copper-
catalyzed difluoromethylthiolation of aryl and vinyl boronic
acids under the reaction conditions described above. In
general, in the presence of a combination of 5.0 mol% of
CuI and 5.0 mol% of bipyridine (bpy), a variety of aryl
boronic acids with ortho-, meta- or para-substituents were
able to couple with reagent
difluoromethylthiolated arenes in good to excellent yields
Scheme 3, 5a-q). Likewise, alkenyl boronic acids also
converted effectively into difluoromethylthio substituted
3
to give the
(
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Copper-catalyzed difluoromethylthiolation of alkynes with
smoothly at 80 C after 16-24 h to generate the corre-
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N-difluoromethylthiophthalimide 3. To further expand the
scope of reagent 3, we studied the copper-catalyzed
difluoromethylthiolation of alkynes. To our delight, after
initial optimization of the reaction conditions, we obtained
phenylacetynyldifluoromethylthioether (6a) in 85% yield
sponding difluoromethylthiolated amines in high yields, as
summarized in Scheme 5.
In general, primary alkyl amines reacted with reagent 3
to generate difluoromethylthiolated amines in excellent
yields (Scheme 5, 7a-k). Reaction of a secondary
alkylamine 1,2,3,4-tetrahydroisoquinoline also occurred in
high yield (Scheme 5, 7n). Notably, optically active
amines such as (R)-1-phenylethanamine or -amino ester
were readily converted into the corresponding
difluoromethylthiolated amines in 88% and 74% yields,
respectively, without erosion of the optical purity (Scheme
5, 7l-m). Reaction of electron-rich aniline derivatives such
as 4-tert-butylaniline and 4-methoxyaniline occurred
smoothly to give the difluoromethylthiolated anilines in 96%
and 95% yields, respectively (Scheme 5, 7o-p), when the
o
after 15 h at 60 C in diglyme when a combination of 5.0
mol% copper(I)-thiophen-2-carboxylate (CuTc) and 5.0
mol% 2,2’-bipyridine (bpy) was used as the catalyst. Var-
ious alkynes could be readily converted into the
difluoromethylthiolated alkynes in high yields, as summa-
rized in Scheme 4.
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In general, reactions of both electron-rich and electron-
poor aryl-substituted alkynes with reagent 3 occurred in
high yields. In addition, heteroaryl alkynes such as 2-
ethynylpyridine and 3-ethynylthiophene were also con-
verted to the corresponding difluoromethylthiolated al-
kynes in 62% and 80% yields, respectively (Scheme 4,
o
reactions were conducted at 120 C for 16 h. Under the
same reaction conditions, aniline derivatives with electron-
withdrawing group such as 4-nitroaniline occurred in less
than 5% yield.
entries 6h-i). Because a weak base Li CO was used as
2
3
the base, the reaction was compatible with a variety of
functional groups such as cyano, nitro, ester, bromo, fluo-
ro and amide (Scheme 4, entries 6d-g, 6j-l). These com-
pounds could not be accessed by the classic method via a
difluoromethyl carbene intermediate.
Scheme 5. Scope for Difluoromethylthiolation of Amines
a,b
with Reagent 3.
Scheme 4. Scope for Copper-Catalyzed Difluoromethyl-
a,b
thiolation of Alkynes.
a
Reaction conditions: amines (0.7 mmol), reagent 3 (1.05
o
b
mmol) in toluene (4.0 mL) at 80 C for 16-24 h; Isolated
yields; Reaction was conducted at 120 C for 16 h.
c
o
a
Reaction conditions: alkyne (0.7 mmol), reagent 3 (0.91
mmol), Li CO (0.35 mmol), CuTc (5.0 mol%), bpy (5.0 mol%)
2
3
Reaction of thiols with N-difluoromethylthiophthalimide 3.
Previously, we have established that thiols were able to be
trifluoromethylthiolated to form trifluoromethyl substituted
disulfides when thiols were treated with an electrophilic
trifluoromethylthiolating reagent in the presence of
o
b
in diglyme (4.0 mL) at 60 C for 15 h; Isolated yields.
Reaction of amines with N-difluoromethylthiophthalimide
3
. With the successful development of methods for the
formation of difluoromethylthiolated arenes, heteroarenes
and alkynes, we next sought to investigate the nucleophilic
1
3c
triethylamine.
To probe if difluoromethyl substituted
difluoromethylthiolation
of
amines
since
the
disulfides could similarly be generated, we studied the
reaction of thiols with reagent 3. It was found that heating
of a mixture of 4-methylbenzenethiol with 1.5 equivalents
fluoroalkylthiolated amino group is also considered as an
23
important structural moiety with increased lipophilicity.
Reactions of aliphatic amines with reagent 3 occurred
o
of reagent 3 occurred smoothly at 80 C after 16 h to give
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1
-(difluoromethyl)-2-(p-tolyl)disulfane 8a in 86% yield
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9
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3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(Scheme 6, 8a). Likewise, a variety of electron-rich and
electron-poor arylthiols were subjected to the reaction
conditions to give the corresponding difluoromethylated
disulfides in good yields (Scheme 6, 8a-k). Heteroaryl
thiols also reacted with reagent 3 in excellent yields
(Scheme 6, 8l-n). In addition, reactions of various
alkylthiols with reagent 3 occurred smoothly to afford the
difluoromethyl substituted disulfides in high yields (Scheme
6, 8o-r).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 6. Scope for Difluoromethylthiolation of Thiols
with Reagent 3.
a,b
a
Reaction conditions: β-ketoester or 2-oxindole (0.7 mmol),
reagent 3 (0.84 mmol), K CO (0.77 mmol) in dichloro-
2
3
b
methane (4.0 mL) at room temperature for 24 h; Isolated
yields.
CONCLUSION
In summary,
difluoromethylthiophthalimide
a
new electrophilic reagent N-
for direct
a
Reaction conditions: thiols (0.7 mmol), reagent 3 (1.05
difluoromethylthiolation has been developed. Reagent 3
can be efficiently synthesized in four steps from cheap
commodity chemical phthalimide. In the presence of Lewis
o
mmol) in 1,2-dichloroethane (4.0 mL) at 80 C for 16-24 h;
b
Isolated yields.
acid Me SiCl, reagent
3
was able to efficiently
3
Reaction of β-ketoesters and 2-oxindoles with N-
difluoromethylthiophthalimide 3. To futher expand the
scope and utility of reagent 3, we studied the reaction of
reagent 3 with soft nucleophiles such as β-ketoesters and
difluoromethylthiolate indoles, pyrroles and other electron-
rich heteroarenes such as 1H-pyrrolo[2,3-b]pyridine,
imidazo[1,2-a]pyridine, aminothiazole and isoxazole ef-
fectively. In addition, an efficient procedure for direct
difluoromethylthiolation of Pyriprole precursor was devel-
oped to afford pesticide Pyriprole in high yield. Likewise,
in the presence of a copper catalyst, functionalized ar-
yl/vinyl boronic acids and alkynes were able to couple
with reagent 3 to generate difluoromethylthiolated arenes
and alkynes in good to excellent yields. Furthermore, gen-
eral nucleophiles such as amines, thiols, β-ketoesters and
oxindoles reacted with reagent 3 smoothly in the absence
of any transition metal catalyst to afford the corresponding
difluoromethylthiolated compounds in high yields. The ex-
cellent functional group tolerance in these reactions under-
lines the great potential of reagent 3 as a general reagent
for the preparation of more complicated, densely func-
tional drug-like molecules. Expanding the scopes of this
reagent is underway and will be reported in the near fu-
ture.
2
-oxindoles. After a quick screening of the reaction condi-
tions, it was discovered that reaction of methyl 6-methyl-
-oxo-2,3-dihydro-1H-indene-2-carboxylate with reagent
in CH Cl occurred smoothly at room temperature to
1
3
2
2
afford the desired difluoromethylthiolated product in 96%
yield when K CO was used as the base. As summarized
in Scheme 7, under these reaction conditions, reactions of
various β-ketoesters derived from indanone or tetralone
with
difluoromethylthiolated products in good to excellent
yields (Scheme 7, 8a-j). Likewise, N-Boc-2-substituted-
oxindoles were also difluoromethylthiolated in excellent
yields (Scheme 7, 8k-l).
2
3
reagent
3
gave
the
corresponding
Scheme 7. Scope for Difluoromethylthiolation of β-
Ketoesters and 2-Oxindoles with Reagent 3.
a,b
EXPERIMENTAL SECTION
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General procedure for the synthesis of
chlorosulfenyl)phthalimide 2. Phthalimide (14.7 g, 100
mmol) was dissolved in THF (300 mL) and triethylamine
16.7 mL, 120 mmol). The mixture was cooled in a
NaCl/ice bath, and then sulfur monochloride (4.0 mL, 50
mmol) was added dropwise. The mixture was stirred for 2
N-
(difluoromethylthio)phthalimide 3 (193 mg, 0.84 mmol),
Li CO (25.9 mg, 0.35 mmol), CuI (6.7 mg, 0.035 mmol),
1
(
2
3
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2,2'-bipyridine (5.5 mg, 0.035 mmol) were placed into
an oven-dried Schlenk tube that was equipped with a stir-
ring bar under argon. Freshly distilled diglyme (4.0 mL)
(
o
was added and the reaction was stirred at 60 C for 15 h.
h, and then quenched with H O (300 mL). The resulting
Distilled water (25.0 mL) and Et O (50.0 mL) were added
2
2
precipitate was filtered and washed with diethyl ether.
and the organic phase was separated. The aqueous
Crystallization from CHCl :MeOH (2:1, v:v) yielded di(1-
phase was extracted with Et O (3 × 15 mL) and the com-
3
2
0
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2
3
4
5
6
7
8
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2
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2
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4
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7
8
9
0
phthalimidy1)disulfane as a white solid (15.1 g, 85%).
bined organic layer was washed with distilled water (50.0
mL) and dried over anhydrous Na SO . The solvent was
Di(1-phthalimidy1)disulfane (25 g,
70 mmol)
was
2
4
removed in vacuo. The residue was purified by flash chro-
matography on silica gel to give the
difluoromethylthiolated arene or alkene.
General procedure for
difluoromethylthiolation
(difluoromethylthio)phthalimide 3. Alkyne (0.6 mmol), N-
difluoromethylthio)phthalimide 3 (178.8 mg, 0.78 mmol),
Li CO (22.2 mg, 0.30 mmol), CuTc (5.8 mg, 0.030
suspended in CHCl (200 mL). The reaction was heated at
3
5
5 °C and Cl gas was bubbled for 12 h. Nitrogen was
2
bubbled through the solution to remove the residue Cl2
and the solvent was evaporated in vacuo. The residue was
copper-catalyzed
alkyne with N-
recrystallized
chlorosulfenyl)phthalimide as a yellow solid (24 g, 80%).
Alternatively, to a solution of di(1-phthalimidy1)disulfane
(25 g, 70 mmol) and 700 mL of HPLC-grade CH Cl were
from
CCl4
to
give
N-
of
(
(
2
3
2
2
mmol), 2,2'-bipyridine (4.7 mg, 0.030 mmol) were
placed into an oven-dried Schlenk tube that was
equipped with a stirring bar under argon. Freshly distilled
added dry pyridine (3.0 mL) and sulfuryl chloride (56.2 g,
3.8 mL, 420 mmol) via a dropping funnel at room
3
temperature. The yellow mixture was stirred at room
temperature for 2 days. The solvent and excess sulfuryl
chloride were removed under vacuum to give N-
diglyme (3.0 mL) was added and the reaction was stirred
o
at 60 C for 15 h. Distilled water (25.0 mL) and Et O (50.0
2
mL) were added and the organic phase was separated.
(
9
chlorosulfenyl)phthalimide as a yellow solid (27 g,
0%).
24
The aqueous phase was extracted with Et O (3 × 15 mL)
2
and the combined organic layer was washed with distilled
water (50.0 mL) and dried over anhydrous Na SO . The
General procedure for the Preparation of N-
(difluoromethylthio)phthalimide 3. To a mixture of N-
(chlorosulfenyl)phthalimide (5.0 g, 23.6 mmol), and
2
4
solvent was removed in vacuo. The residue was purified
by flash chromatography on silica gel to give the
difluoromethylthiolated alkynes.
[(SIPr)Ag(CF H)] (13.0 g, 23.6 mmol) in a flask was added
2
dried toluene (50.0 mL) under argon atmosphere. The mix-
ture was stirred at room temperature for 4 h and then fil-
tered through a funnel. Dichloromethane (50.0 mL) and
petroleum ether (100 mL) was added to the residue. The
undissolved [(SIPr)AgCl] (9.0 g, 85%) was filtered, which
was recycled to be used for the preparation of
General procedure for difluoromethylthiolation of amines
with N-(difluoromethylthio)phthalimide 3. A 25 mL Schlenk
tube charged with amines (0.7 mmol) and N-
(
difluoromethylthio) phthalimide 3 (1.05 mmol) was added
o
toluene (4.0 mL). The mixture was stirred at 80 C for 16-
2
4 h. The solvent was removed under vacuum and the
[
(SIPr)Ag(CF H)]. The solvent in the filtrate was evaporated
2
residue was purified by flask column chromatography to
give difluoromethylthiolated amines.
in vacuo and the residue was purified by flash chromatog-
raphy on silica gel to give N-
difluoromethylthio)phthalimide 3 as a white solid (3.6 g,
67%).
(
General procedure for difluoromethylthiolation of thiols
with N-(difluoromethylthio)phthalimide 3. A 25 mL Schlenk
tube charged with thiols (0.7 mmol) and N-
(difluoromethylthio) phthalimide 3 (1.05 mmol) was added
1,2-dichloroethane (4.0 mL). The mixture was stirred at 80
General procedure for difluoromethylthiolation of
heteroarenes with N-(difluoromethylthio)phthalimide 3. A
2
5 mL Schlenk tube charged with heteroarenes (0.5 mmol)
o
C for 16-24 h. The solvent was removed under vacuum
and N-(difluoromethylthio)phthalimide 3 (0.6 mmol) in
ClCH CH Cl (3.0 mL) was added Me SiCl (0.75 mmol).
and the residue was purified by flask column chromatog-
raphy to give difluoromethylthiolated thiols.
2
2
3
o
The mixture was stirred at 80-120 C for 16 h. The solvent
was removed under vacuum and the residue was purified
General procedure for difluoromethylthiolation of β-
by
difluoromethylthiolated heteroarenes.
General procedure for
difluoromethylthiolation of aryl/vinyl boronic acids with N-
difluoromethylthio)phthalimide 3. Aryl boronic acids or
vinyl boronic acids (0.7 mmol), N-
flask
column
chromatography
to
give
ketoesters
(difluoromethylthio)phthalimide 3. A 25 mL Schlenk tube
charged with β-ketoesters or oxindoles (0.7 mmol), K CO
or
oxindoles
with
N-
copper-catalyzed
2
3
(0.77 mmol) and N-(difluoromethylthio)phthalimide 3
(0.84 mmol) was added dichloromethane (4.0 mL). The
mixture was stirred at room temperature for 24 h. The sol-
(
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Journal of the American Chemical Society
Page 8 of 10
vent was removed under vacuum and the residue was pu-
rified by flask column chromatography to give
difluoromethylthiolated β-ketoesters or oxindoles.
Hartwig, J. F. Angew. Chem. Int. Ed. 2013, 52, 2092; h)
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Thomoson, C. S.; Jr. Dolbier, W. R. J. Org. Chem. 2013, 78,
8904; i) Mehta, V. P.; Greaney, M. F. Org. Lett. 2013, 15,
5036; j) Fuchibe, K.; Bando, M.; Takayama, R.; Ichikawa, J.
J. Fluorine Chem. 2015, 171, 133.
ASSOCIATED CONTENT
Supporting Information
9. a) Zhang, W.; Zhu, J.-M.; Hu, J.-B. Tetrahedron Lett. 2008,
49, 5006; b) Surya Prakash, G. K.; Zhang, Z.; Wang, F.; Ni,
C.-F.; Olah, G. A. J. Fluorine Chem. 2011, 132, 792.
0. Fujiwara, Y.; Dixon, J. A.; Rodriguez, R. A.; Baxter, R. D.;
Dixon, D. D.; Collin, M. R.; Blackmond, D. G.; Baran, P. S. J.
Am. Chem. Soc. 2012, 134, 1494.
1. Bayarmagnai, B.; Matheis, C.; Jouvin, K.; Goossen, L. J.
Angew. Chem. Int. Ed. 2015, 54, 5753.
2. Wu, J.; Gu, Y.; Shen, Q. Angew. Chem. Int. Ed. 2015, 54,
asap, doi: 10.1002/anie.201502113.
Synthesis, analytic data, NMR data and X-ray diffraction
data of compound 3. This material is available free of charge
via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
* Email: lulong@sioc.ac.cn; shenql@sioc.ac.cn
3. a) Shao, X.-X.; Wang, X.-Q.; Yang, T.; Lu, L.; Shen, Q.
Angew. Chem. Int. Ed. 2013, 52, 3457; b) Vinogradova, E.
V.; Müller, P.; Buchwald, S. L. Angew. Chem. Int. Ed. 2014,
Author Contributions
‡
These authors contributed equally.
5
3, 3125; c) Xu, C.-F.; Ma, B.-Q.; Shen, Q. Angew. Chem.
Notes
Int. Ed. 2013, 52, 9316; d) Ferry, A. l.; Billard, T.; Langlois, B.
R.; Bacque, E. J. Org. Chem. 2008, 73, 9362; e) Ferry, A.;
Billard, T.; Langlois, B. R.; Bacque, E. Angew. Chem. Int. Ed.
The authors declare no competing financial interests.
ACKNOWLEDGMENT
2
009, 48, 8551; f) Yang, Y.-D.; Azuma, A.; Tokunaga, E.;
Yamasaki, M.; Shiro, M.; Shitaba, N. J. Am. Chem. Soc.
013, 135, 8782; g) Alazet, S.; Zimmer, L.; Billard, T. J. Fluo-
The authors gratefully acknowledge the financial support
from National Basic Research Program of China
2
rine Chem. 2015, 171, 78; h) Alazet, S.; Billard, T. Synlett
2015, 26, 76.
(2012CB821600), National Natural Science Foundation of
China (21172245/21172244/21372247/21421002) and
SIOC for financial support.
14. a) Munavalli, S.; Rohrbaugh, D. K.; Rossman, D. I.; Berg, F. J.;
Wagner, G. W.; Durst, H. D. Synth. Commun. 2000, 30,
2847; b) Bootwicha, T.; Liu, X.; Pluta, R.; Atodiresei, I.;
Rueping, M. Angew. Chem. Int. Ed. 2013, 52, 12856; c)
Rueping, M.; Liu, X.; Bootwicha, T.; Pluta, R.; Merkens, C.
Chem. Commun. 2014, 50, 2508; d) Pluta, R.; Nikolaienko,
P.; Rueping, M. Angew. Chem. Int. Ed. 2014, 53, 1650; e)
Lefebvre, Q.; Fava, E.; Nikolaienko, P. Rueping, M. Chem.
Commun. 2014, 50, 6617; f) Pluta, R.; Rueping, M. Chem.
Eur. J. 2014, 20, 17315; g) Kang, K.; Xu, C.-F.; Shen, Q. Org.
Chem. Front. 2014, 1, 294; h) Yang, T.; Lu, L.; Shen, Q.
Chem. Commun. 2015, 51, 5479.
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5. Only one example of difluoromethylthiolation using
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7. Huang, N. Z.; Lakshmikantham, M. V.; Cava, M. P. J. Org.
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7
8
. Selected examples for the difluoromethylation of thiolates: a)
Chen, Q.-Y.; Wu, S.-W. J. Fluorine Chem. 1989, 44, 433; b)
Deprez, P. Vevert, J.-P. J. Fluorine Chem. 1996, 80, 159; c)
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0. Wiehn, M. S.; Vinogradova, E. V.; Togni, A. J. Fluorine Chem.
010, 131, 951.
2
6
5, 5278; d) Zhang, W.; Wang, F.; Hu, J. Org. Lett. 2009,
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9
2
1. A new species with a chemical shift at -97.2 ppm in F NMR
spectroscopy was formed in 15% yield after 6 h at 80 C for
1
1, 2109; e) Wang, F.; Huang, W.-Z.; Hu, J.-B. Chin. J.
o
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the reaction of N-difluoromethylthiophthalimide
3 with
Me SiCl in 1,2-dichloroethane. Addition of 1.0 equivalent of
3
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Journal of the American Chemical Society
indole into this mixture at room temperature for 0.5 h resulted
1
2
3
4
5
6
7
8
in the disappearance of the new species and the formation of
3-difluoromethylthioindole in 15% yield. This experiment indi-
cated that the new species is an active intermediate for the
difluoromethylthiolation of indole in the presence of Me
3
SiCl.
We suspected that the active intermediate is HCF SCl. How-
2
ever, GC/MS studies of the reaction mixture did not support
the formation of such a compound. More experiment is clear-
ly needed to support the formation of HCF SCl.
2
2
2. a) Recently, Glorius and coworkers discovered that NaCl
could activate N-trifluoromethylthiophthamilide, although the
mechanism of the process was not understood yet. Ernest, B.;
Glorius, F. Chem. Eur. J. 2015, 21, 8047; b) The reaction of
indole with N-difluoromethylthiophthalimide 3 in DMF in the
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
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presence or absence of NaCl was monitored by F NMR
spectroscopy. However, no active intermediate was ob-
served.
2
2
3. Alazet, S.; Ollivier, K.; Billard, T. Beilstein J. Org. Chem.
2
013, 9, 2354, doi: 10.3762/bjoc.9.270.
4. Win, W. W.; Franck. R. W. J. Org. Chem. 1997, 62, 4510.
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