N,N-Dimethyl-S-difluoromethyl-S-phenylsulfoximinium tetrafluoroborate: A versatile electrophilic difluoromethylating reagent

Article abstract of DOI:10.1016/j.jfluchem.2011.04.023

Over the past decade, sulfur-based fluoromethyl containing compounds have been exhaustively investigated as versatile fluoroalkylating reagents by our research laboratory as well as many others. Lately, we have designed a novel electrophilic difluoromethylating protocol employing in situ prepared N,N-dimethyl-S-difluoromethyl-S-phenylsulfoximinium salt. The present reagent provides excellent reactivity toward a broad spectrum of nucleophilic species (N-, P-, S-, and O-nucleophiles) to yield the corresponding difluoromethylated products with high efficacy under mild conditions. Additional studies have been performed to elucidate the mechanistic fundamentals of the reactions.

Full text of DOI:10.1016/j.jfluchem.2011.04.023

Journal of Fluorine Chemistry 132 (2011) 792–798
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Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
N,N-Dimethyl-S-difluoromethyl-S-phenylsulfoximinium tetrafluoroborate:
A versatile electrophilic difluoromethylating reagent
1
1
1
1
*
G.K. Surya Prakash , Zhe Zhang , Fang Wang , Chuanfa Ni , George A. Olah
Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, CA, 90089-1661, USA
A R T I C L E I N F O
A B S T R A C T
Article history:
Over the past decade, sulfur-based fluoromethyl containing compounds have been exhaustively
investigated as versatile fluoroalkylating reagents by our research laboratory as well as many others.
Lately, we have designed a novel electrophilic difluoromethylating protocol employing in situ prepared
N,N-dimethyl-S-difluoromethyl-S-phenylsulfoximinium salt. The present reagent provides excellent
reactivity toward a broad spectrum of nucleophilic species (N-, P-, S-, and O-nucleophiles) to yield the
corresponding difluoromethylated products with high efficacy under mild conditions. Additional studies
have been performed to elucidate the mechanistic fundamentals of the reactions.
Received 4 March 2011
Received in revised form 5 April 2011
Accepted 6 April 2011
Available online 24 May 2011
Keywords:
Electrophilic difluoromethylation
Sulfoximine
ß 2011 Elsevier B.V. All rights reserved.
Sulfoximinium
Oxidation
1. Introduction
fluorinated sulfoximines has been pioneered by Shreeve and co-
workers, who have investigated the properties of a series of
Fluoroorganics have been found to possess unique physico-
chemical and biological properties [1]. Among fluoromethyl
functionalities, the difluoromethyl moiety is of particular interest
due to its isostericity and isopolarity to an ethereal oxygen, and has
been utilized to replace specific oxygen atoms in various bioactive
species to increase their metabolic stability and bioavailability [2].
Over the past decade, sulfur-based fluoromethyl containing
compounds have been extensively investigated as versatile
fluoroalkylating reagents by Prakash and Hu, as well as many
others [3]. Particularly, S-(difluoromethyl)diarylsulfonium tetra-
fluoroborate was first synthesized and exploited in our laboratory
as an efficient electrophilic difluoromethylating reagent toward a
series of nucleophilic species to provide the corresponding
difluoromethylated products [4a,b]. Despite its feasible synthetic
bis(perfluoromethyl)sulfoximines [7]. In 1988, Finch reported a-
fluoromethyl-N-methyl-phenylsulfoximine as a fluoromethylena-
tion reagent for ketones and aldehydes [8]. Lately, Shibata and co-
workers demonstrated the synthetic utility of the trifluoromethy-
lated and the monofluoromethylated Johnson reagents in the
electrophilic fluoromethylation of various nucleophilic species
[4d,e]. It is worth mentioning that Hu et al. have exploited N-tosyl-
S-difluoromethyl-S-phenylsulfoximine as a difluorocarbene pre-
cursor, which readily reacts with a variety of S-, N-, and C-
nucleophiles [4c]. However, to the best of our knowledge, the
difluoromethylated Johnson reagent remains unexplored. Herein,
we would like to disclose the development of N,N-dimethyl-S-
difluoromethyl-S-phenylsulfoximinium tetrafluoroborate salt (1)
as a robust electrophilic difluoromethylating reagent. Generated in
situ from shelf-stable N-methyl-S-difluoromethyl-S-phenylsulfox-
imine (3), the present reagent has exhibited good reactivity toward
a broad scope of nucleophiles (N-, P-, S-, and O-nucleophiles).
´
applications under many chemical regimes, the drawback of this
reagent was found to be its slow decomposition over time even
under low temperatures.
Sulfoximines have been widely employed in synthetic chemis-
try as versatile reagents and valuable ligands [5]. Johnson et al.
treated N,N-dimethyl-S-methyl-S-phenylsulfoximinium tetra-
fluoroborate (the Johnson reagent) with bases to afford the
corresponding sulfur ylide, which is capable of transferring the
methylene group to various substrates [6]. The preparation of
2. Results and discussion
The preparation of 2 was initially conducted by treating
difluoromethyl phenyl sulfoxide (PhSOCF2H) with sodium azide
(NaN3) in 25% fuming H2SO4 as the reaction medium [4d,9], which
unfortunately led to a minor explosion (Scheme 1). In contrast,
PhSOCF2H was intact when subjected to NaN3 and 98% H2SO4 in
chloroform [8]. After several attempts, we were able to obtain the
desired product 2 in quantitative yield by using a combination of
NaN3/oleum/CH2Cl2 as the oxidative imination system [10]. The
* Corresponding author. Tel.: +1 213 7405984; fax: +1 213 7405087.
E-mail address: gprakash@usc.edu (G.K. Surya Prakash).
1
Tel.: +1 213 7405984; fax: +1 213 7405087.
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.04.023

G.K.S. Prakash et al. / Journal of Fluorine Chemistry 132 (2011) 792–798
793
(1) Me3O+BF4
-
oleum (20% SO3)
(2) K2CO3 then Me3OBF4
NaN3,neat
O
S
Me3O+BF4
CH2Cl2
- Me2N
Ph
(1) Me3O+BF4-/CH2Cl2
HN
O
BF4
O
MeN
Ph
O
oleum (20% SO3)
NaN3,CH2Cl2
99%
H2SO4 (98%)
S
Ph
CF2H
S
3
S
1
Ph
CF2H
(2) NaHCO3
68%
CF2H
CF2H
2
quantitative
CH3I, K2CO3
THF
CF3SO3Me
neat
NaN3,CHCl3
Scheme 1. Preparation of N,N-dimethyl-S-difluoromethyl-S-phenylsulfoximinium tetrafluoroborate (1).
subsequent methylation of 2 was first performed under the one-
pot procedure described by Johnson [11], which resulted in the
rapid decomposition of the parent sulfoximine. Further attempts
to transform 2 via an established methylation protocol [4d],
however, only gave the title products with unsatisfactory yields.
Eventually, the methylation of 2 was achieved through a stepwise
route utilizing trimethyloxonium tetrafluoroborate as the methyl-
ating reagent (Scheme 1). Obtained in high yields, salt 1 is a white
solid possessing reasonable stability that allows its storage for
several hours at room temperature [12]. Interestingly, in contrast
to its trifluoromethylated analogue that was inert in MeOH [4d], a
rapid reaction between 1 and CD3OD has been observed via 1H and
19F NMR spectroscopy implying its remarkable reactivity [13].
Noticeably, despite the slight lability of sulfoximinium 1, its
precursor 3 has exhibited sufficient stability under ambient
conditions permitting a facile access to 1.
Having the difluoromethylated Johnson reagent 1 on hand, we
were able to systematically investigate its difluoromethyl-transfer
ability to an arsenal of nucleophilic species. An examination of
various reaction media revealed that anhydrous dichloromethane
is the optimal solvent for the difluoromethylation of triphenylpho-
sphine (Table 1). Other solvents such as tetrahydrofuran (THF) and
dimethylformaldehyde (DMF) were found to promote the decom-
position of the reagent presumably due to their slight nucleophi-
licity. After a careful modification of the reaction parameters such
as the addition sequences of the reagents and the proportions of
substrates, the optimized yields were achieved by the treatment of
1 with 1.5 equiv. of various nucleophiles in dichloromethane at
room temperature.
Intriguingly, the electrophilic difluoromethylating reagent 1
was also found to act as an ambident species capable of oxidizing
phosphorous nucleophiles. Because the transformation from 3 to 1
was performed under heterogeneous conditions, control experi-
ments have been performed to exclude the possible involvement of
Me3O+BF4À residue that can account for the observed side reaction.
As depicted in Fig. 1B, the reaction between 3 and Me3O+BF4À, in a
Table 2
Difluoromethylation of phosphines using 1.
1. Me3O+BF4-, CH2Cl2
O
NMe
-
.
R3P CF2H BF4
S
2. phosphine (4), CH2Cl2
Ph
CF2H
5a-i
Entry Phosphine (4)
Product (5)
Yield (%)a
90/57
1
Ph3P
-
Ph3P CF2H BF4
4a
5a
2
(n-Bu)3P
64/53
84/49
-
(n-Bu)3P CF2H BF4
4b
5b
3
4
Me
Me
Ph
Me
-
P
Ph
P+ CF H
BF4
2
Me
4c
5c
87/49
-
P
P CF2H BF4
3
3
We subsequently explored the scope of current protocol with a
wide range of phosphorus nucleophiles. As depicted in Table 2, the
difluoromethylation reaction underwent smoothly with both
aromatic and aliphatic phosphines to afford the corresponding
difluoromethyl phosphonium salts in moderate to good yields
(Entries 1–6 and 8, Table 2). Intriguingly, the steric characters of
phosphorus nucleophiles seem to be crucial to the outcome of the
reaction (Entry 7, Table 2). Although the meta- and the para-
substituted aryl phosphines exhibited satisfactory reactivity
toward sulfoximinium 1, the presence of ortho substituents on
the aromatic rings dramatically inhibits the reactivity of the
phosphines.
4d
5d
5
6
65/43
80/56
-
P
P
CF H
BF4
2
3
3
4e
5e
-
P
P CF2H BF4
3
3
3
4f
5f
7
0/0
-
P
P
CF2H
BF4
Table 1
Optimization of the reaction conditions.
3
4g
5g
BF4
O
Me2N
Ph
Solvent
N2, rt
Ph3P+CF2H BF4
-
+
Ph3P
8
50/35
S
-
CF2H
MeO
P
MeO
P
3
CF2H
BF4
1
3
4h
5h
a
CH3CN
THF
DMF
CH2Cl2
19F NMR yields/isolated yields based on 1. The NMR yields were determined by
19F NMR using PhCF3 as the internal standard. The isolated yields were based on
pure phosphonium salts, as the isolated products were found to be mixtures of
phosphonium salts and the corresponding phosphine oxides in ca. 3:1 ratios,
respectively.
Conv. (%)a
Yield (%)a
100
0
100
0
100
0
100
90
Monitored by 19F NMR using PhCF3 as internal standard.
a

794
G.K.S. Prakash et al. / Journal of Fluorine Chemistry 132 (2011) 792–798
Fig. 1. Investigation of the difluoromethylation and oxidation ability of 1 with Ph3P. (A) 19F NMR spectrum of 3; (B) 19F NMR spectrum of the reaction mixture of 3 and
Me3O+BF4À in 2:1 ratio; (C) 19F NMR spectrum of the reaction mixture of 3 and Me3O+BF4À in 1:1 ratio; (D) 31P NMR spectrum of the reaction mixture B and Ph3P. All the
spectra were taken in CD3CN.
Me
Ph
Me
Me
Me
corresponding phosphine oxide in a ratio of approximately 3:1,
which was similar to the observation in the reaction employing a
slightly excess amount of Me3O+BF4À. This striking observation
was found to resemble the previously described oxidation of
phosphines with sulfoxides in the presence of Lewis acids, and a
similar mechanism has been proposed (Scheme 2) [14].
Me
Me
N
S
O
N
S
N
S
Ph
HF2C
PPh3
O
Ph3P O
CF2H
Ph
HF2C
PPh3
O
PPh3
Scheme 2. Plausible mechanism of the oxidation of Ph3P.
In addition to the phosphorus nucleophiles, a series of amines
and several nitrogen-containing heterocyclic compounds were
subjected to the reaction expecting the formation of difluoro-
methyl ammonium salts. Gratifyingly, tertiary amines were also
found to readily react with 1 under the optimized reaction
conditions. As shown in Table 3, the difluoromethylation of the
tertiary amines generally gave the corresponding ammonium salts
molar ratio of 2:1, gave a mixture of 3, 1, and a small amount of
impurities in 4.1:2.7:0.7 ratio according to the 19F NMR spectrum,
which provides cÀompelling evidence for the complete consump-
tion of Me3O+BF4 under the present reaction conditions. Further
treatment of the same mixture with a stoichiometric amount of
Ph3P afforded the difluoromethyl phosphonium salt and the
Difluorocarbene Pathway
B
Nu
Me2N O
H+/D+
Me2N O
S
H
CF2
Nu CF2H/D
Nu CF2
S
Ph
C
Ph
CF2
F2
Electrophilic Difluoromethylation Pathway
Me2N O
S
Nu
Nu CF2H
H
Ph
C
F2
Et3N (1.5 equiv)
CD3OD (1.5 equiv)
-
BF4
Me2N O
S
-
-
Et3NCF2H BF4
Et3NCF2D BF4
+
+
CH2Cl2, rt
Ph
CF2H
Ph3P (1.5 equiv)
CD3OD (1.5 equiv)
-
BF4
Me2N O
S
-
-
Ph3PCF2H BF4
Ph3PCF2D BF4
CH2Cl2, rt
Ph
CF2H
-
CD3OD (solvent)
rt
Me2N O BF4
S
CD3OCF2D
CD3OCF2H +
Ph
CF2H
Scheme 3. Mechanistic studies based on isotope-labeling experiments.

G.K.S. Prakash et al. / Journal of Fluorine Chemistry 132 (2011) 792–798
795
Table 3
Table 4
Difluoromethylation of nitrogen nucleophiles using 1.
Difluoromethylation of sulfur and oxygen nucleophiles using 1.
1. Me3O+BF4-, CH2Cl2
1. Me3O+BF4-, CH2Cl2
O NMe
O NMe
-
BF4
R3N CF2H
7a-j
.
R
XCF2H
9a-9h
S
S
.
6
2. Amines ( ), CH2Cl2
2. RXM (8), CH2Cl2
Ph
CF2H
Ph
CF2H
XM = SNa and OH
X = S and O
Entry Substrate
Product
Yield (%)a,b
99/69
Entry
1
Substrate
Product
Yield (%)a
1
2
Et3N
-
Et3N CF2H BF4
7a
6a
Ph–SNa
Ph–SCF2H
78
8a
9a
2
45 (42)b
MeO
SNa
MeO
SCF2H
76/71
72/70
-
CF2H BF4
N
N
Ph
Ph
6b
7b
8b
9b
3
4
5
3
4
19
25
SNa
SCF2H
-
CF2H BF4
N
N
N
OMe
OMe
8c
9c
6c
6d
7c
SNa
SCF2H
90/83
-
CF2H BF4
N
Br
Br
8d
8e
9d
9e
5
48 (32)b,c
OH
OCF2H
7d
20/–c
-
CF2HBF 4
N
N
6
7
45
25
OH
8f
OCF2H
6e
7e
9f
6
0/0
iPr
iPr
-
CF2HBF 4
OH
15
OCF2H
15
N
N
8g
9g
iPr
iPr
6f
7f
8
37
OH
OCF2H
7
8
74/53
50/47
87/68
-
CF2H BF4
MeO
N
MeO
N
7
7
8h
9h
Yields were determined by 19F NMR using PhCF3 as the internal standard.
The numbers in parentheses are isolated yields based on 1.
a
6g
7g
b
c
2-Phenylethyl ether was found to be an inseparable impurity with the title
-
CF2H BF4
product.
N
N
Cl
Cl
6h
7h
however, has not been rationalized yet. In particular, substantially
differing from the reaction between 1 and phosphorous nucleo-
philes, oxidation of amines was not observed under the current
reaction conditions.
9
Ph
N
Ph
N
-
BF
CF2H
N
N
4
6i
6i
We further investigated the reaction of reagent 1 with various
oxygen and sulfur nucleophiles. Derived from the corresponding
aryl thiols and NaH, sodium aryl thiolates displayed low to
moderate reactivity toward sulfoximinium 1 (Entries 1–4, Table 4).
In contrast, it has been observed that the treatment of 1 with
sodium alkoxides and phenolates led to the rapid decomposition of
the reagent instead of affording the corresponding difluoromethyl
ethers. Surprisingly, the desired difluoromethyl ethers were
achieved, when sulfoximinium 1 was reacted with a large excess
amount of aliphatic alcohols (10 equiv.) under neutral conditions
(Entries 5–8, Table 4). As depicted in Table 4, the current synthetic
approach was applicable not only for the difluoromethylation of
primary alcohols, but also for secondary and tertiary alcohols. It is
worth noting that, in addition to (2-difluoromethoxyethyl)ben-
zene, 2-phenylethyl ether was also isolated as the side product
when 2-phenylethanol was employed as the substrate. Such an
a
The conversions of all the entries were monitored by 19F NMR, and found to be
100%.
b
19F NMR yields/isolated yields based on 1, the NMR yields were determined by
19F NMR using PhCF3 as the internal standard.
c
Not isolated.
in moderate to good yields as monitored by 19F NMR spectroscopy
(Entries 1–4 and 7–10, Table 3). Similar to the difluoromethylation
of the phosphines, the reactivity of the amines toward 1 was also
affected by the steric demand of the ortho-substituents. In
particular, when highly bulky 2,2-diisopropyl aniline was sub-
jected to the reaction, 1 was found to be intact. Noticeably,
although 1-phenyl-1H-imidazole reacted with sulfoximinium 1
smoothly, the similar difluoromethylation of 1H-imidazole and
pyridine was found to be rather sluggish. This observation,

796
G.K.S. Prakash et al. / Journal of Fluorine Chemistry 132 (2011) 792–798
outcome evidently indicates that the coupling reaction of
nucleophiles toward the formation of the corresponding ethers
is one of the significant competing reactions of the difluoromethy-
lation process, which may account for the low yields observed in
the reaction of 1 with alcohols. In particular, phenols were found to
be inert under the present reaction conditions.
product was further purified by flash column chromatography
(silicon gel) using hexane and ethyl acetate (4:1) as the eluent to
afford an colorless oil (3.80 g, 99%). 1H NMR (CDCl3):
d
6.14 (t,
J = 54.8 Hz, 1H), 7.57–7.66 (m, 2H), 7.73–7.77 (m, 1H), 8.06–8.08
(m, 2H). 19F NMR (CDCl3):
d
À119.3 (dd, J = 258.5 Hz, J = 54.8 Hz,
1F), À122.4 (dd, J = 258.5, Hz J = 54.8 Hz, 1F). 13C NMR (CDCl3):
d
In an effort to gain the mechanistic insight into the protocol,
isotope-labeling experiments have been performed to determine
the pathway involved in the present reaction (Scheme 3). In theory,
the difluoromethyl group is believed to undergo a deprotonation-
protonation process in the difluorocarbene pathway. Hence,
significant amounts of deuterated products (CF2D) are anticipated
in the presence of deuterated methanol under such mechanism. In
contrast, such a proton–deuterium exchange is presumably unable
to take place under the electrophilic difluoromethylation pathway
due to the absence of the C–H cleavage. As demonstrated in
Scheme 3, the results have ruled out difluorocarbene as a plausible
intermediate under the current reaction conditions since no
deuterated difluoromethyl group was detectable via 19F NMR
spectroscopy, which experimentally confirmed sulfoximinium 1 as
a de facto electrophilic difluoromethylating reagent [15].
115.4 (t, J = 287.1 Hz), 129.5, 130.6, 133.3, 135.0. HRMS: calculated
for C7H8F2NOS+ (MH+) 192.0289, found: 192.0289.
4.2. Typical procedure for the preparation of N-methyl-S-
difluoromethyl-S-phenyl sulfoximine (3)
S-Difluoromethyl-S-phenylsulfoximine 2 (3.80 g, 19.9 mmol)
was dissolved in anhydrous dichloromethane (20 mL) under N2.
Trimethyloxonium tetrafluoroborate (3.25 g, 22 mmol) was added
into the stirred solution in small portions. The reaction was
monitored by thin layer chromatography until the completion. The
resulting mixture was then quenched with saturated NaHCO3
aqueous solution and extracted with dichloromethane
(50 Â 3 mL). The combined organic layer was dried over Na2SO4
before evaporation of the solvent. The crude product was purified
by column chromatography (silica gel) using hexane and ethyl
acetate (5:1) as the eluent to accommodate 2 as a colorless oil
3. Conclusion
(2.8 g, 68%). 1H NMR (CDCl3):
7.55–7.65 (m, 2H), 7.68–7.78 (m, 1H), 7.95–8.05 (m, 2H). 19F NMR
(CDCl3):
À118.0 (dd, J = 259.8 Hz, J = 54.3 Hz, 1F), À120.5 (dd,
J = 259.7 Hz, J = 54.5 Hz, 1F). 13C NMR (CDCl3):
29.3, 115.6 (t,
J = 287.8 Hz), 129.6, 130.8, 132.3, 134.7. HRMS: calculated for
C8H10F2NOS+ (MH+) 206.0446, found: 206.0447.
d 2.98 (s, 3H), 6.20 (t, J = 54.4 Hz, 1H),
In conclusion, we have successfully prepared the unprecedented
N,N-dimethyl-S-difluoromethyl-S-phenylsulfoximinium tetrafluor-
oborate as a versatile electrophilic difluoromethylating reagent. In
situ generated from the shelf-stable N-methyl-S-difluoromethyl-S-
phenylsulfoximine, difluoromethylated sulfoximinium salt has
d
d
enabled
a feasible synthetic approach toward a variety of
4.3. Typical procedure for the preparation of N,N-dimethyl-S-
difluoromethylated compounds. As a difluoromethylated analogue
of the Johnson reagents, the compound has been found to transfer
the difluoromethyl group via an electrophilic alkylation fashion
instead of the commonly adopted difluorocarbene pathway.
difluoromethyl-S-phenyl sulfoximinium tetrafluoroborate (1)
To a stirred solution of N-methyl-S-difluoromethyl-S-phenyl-
sulfoximine 2 (3.08 g, 15 mmol) in anhydrous dichloromethane
(15 mL), trimethyloxonium tetrafluoroborate (2.43 g, 16.5 mmol)
was added all at once under N2. The reaction mixture was stirred
for 30 min before the removal of volatile substances under
4. Experimental
Unless otherwise mentioned, all chemicals were purchased from
commercial sources. The NMR spectra were recorded on 400 MHz
and500 MHzsuperconducting NMR spectrometers, respectively. All
the unknown compounds have been fully characterized by NMR
spectroscopy and high resolution MS analysis, whereas structures of
all known products were confirmed by comparison of their 1H NMR
vacuum.
difluoromethylations reaction without further purification (4.3 g,
99%). 1H NMR (CD3CN):
3.24 (s, 6H), 7.70 (t, J = 51.5 Hz, 1H), 7.94–
8.00 (m, 2H), 8.14–8.21 (m, 3H). 19F NMR (CD3CN):
À108.9 (dd,
A white solid was obtained and subject to the
d
d
J = 249.4 Hz, J = 51.9 Hz, 1F), À115.3 (dd, J = 248.5 Hz, J = 51.1 Hz,
and 19F NMR spectra with reported data. 1H NMR chemical shifts (
were determined relative to internal tetramethylsilane at 0.0 ppm
or to the signal of a residual solvent in CDCl3 (
7.26 ppm). 13C NMR
chemical shifts were determined relative to internal tetramethylsi-
lane at
0.0 ppm or to the 13C signal of CDCl3 at 77.16 ppm. 19F
NMR chemical shifts were determined relative to internal CFCl3 at
0.0 ppm. 31P NMR chemical shifts were determined relative to
internal H3PO4 (85%) at 0.0 ppm.
d)
1F), À154.0 (b, 4F). 13C NMR (CD3CN):
d 40.3, 117.2 (t, J = 295.8 Hz),
d
121.2, 132.6, 133.0, 141.0. HRMS calculated for C9H12F2NOS+ (M+)
220.0602, found: 220.0601.
d
d
d
4.4. Typical procedure for difluoromethylations of phosphorus
nucleophiles
d
d
To the in situ generated 1 (0.2 mmol), a solution of phosphines
(4a–4i) (0.3 mmol) in anhydrous CH2Cl2 (0.5 mL) was quickly
added under N2 protection and the reaction mixture was stirred for
1 h. The reaction was monitored via 19F NMR spectroscopy with
PhCF3 as an internal standard. The solvent was then evaporated
under vacuum and the residue was purified by flash column
chromatography or thin layer chromatography (silica gel) using
CH2Cl2 and MeOH as the eluent.
4.1. Typical procedure for the preparation of S-difluoromethyl-S-
phenylsulfoximine (2)
PhSOCF2H (3.52 g, 20 mmol) was mixed with sodium azide
(NaN3, 2.6 g, 40 mmol) in dichloromethane (20 mL) under N2. To
the stirred reaction mixture, oleum (20%, 7.5 mL) was added
dropwise within 15 min at À10 8C. The reaction was slowly
warmed to room temperature and stirred over night. The resulting
suspension was slowly poured into ice water (ca. 100 mL) and
neutralized with NaOH (solid, 4.73 g, 120 mmol). NaHCO3 was
subsequently added in small portions until bubbling ceased. The
mixture was then extracted with dichloromethane (50 Â 3 mL).
The combined organic phase was washed with water (20 mL) and
dried over Na2SO4 before the removal of the solvent. The crude
P-(Difluoromethyl)triphenylphosphonium
(5a). Yield = 82%. 1H NMR (DMSO-d6):
tetrafluoroborate
7.85–7.93 (m, 12H),
8.04–8.06 (m, 3H), 8.40 (dt, J = 47.1 Hz, J = 29.3 Hz, 1H). 19F NMR
d
(DMSO-d6):
d
À125.7 (dd, J = 77.3 Hz, J = 47.1 Hz, 2F), À147.65 (s,
1F), À147.70 (s, 3F).
P-(Difluoromethyl)tri(n-butyl)phosphonium Tetrafluoroborate
(5b). Yield = 53%. 1H NMR (CD3OD):
d
1.01 (t, J = 7.2 Hz, 9H), 1.54
(sextet, J = 7.1 Hz, 6H), 1.65 (quintet, J = 7.1 Hz, 6H), 2.50–2.57 (m,

G.K.S. Prakash et al. / Journal of Fluorine Chemistry 132 (2011) 792–798
797
6H), 7.16 (dt, J = 47.3 Hz, J = 26.8 Hz, 1H). 19F NMR (CD3OD):
À129.30 (dd, J = 68.9 Hz, J = 47.4 Hz, 2F), À153.95 (s, 1F), À154.00
(s, 3F). 31P NMR (CD3OD): 38.2 (t, J = 68.9 Hz). 13C NMR (CD3OD):
12.1 (d, J = 0.8 Hz), 15.0 (d, J = 41.9 Hz), 22.7 (d, J = 5.0 Hz), 23.6 (d,
d
N-(Difluoromethyl)-N,N-dimethylanilinium tetrafluoroborate
(7b). Yield: 71%. 1H NMR (DMSO-d6):
3.77 (s, 6H), 7.56 (t,
J = 58.6 Hz, 1H), 7.61–7.62 (m, 3H), 7.86–7.88 (m, 2H). 19F NMR
d
d
d
(DMSO-d6):
(s, 3F).
d
À115.04 (d, J = 61.0 Hz, 2F), À153.95 (s, 1F), À154.00
J = 16.2 Hz), 113.95 (dt, J = 265.4 Hz, J = 75.4 Hz). HRMS calculated
for C13H28F2P+ (M+) Expected: 253.1891. Found: 253.1894.
P-(Difluoromethyl)dimethylphenylphosphonium tetrafluoro-
N-(Difluoromethyl)-N,N-dimethyl-p-toluenedinium tetrafluor-
oborate (7c). Yield: 70%. 1H NMR (DMSO-d6):
2.40 (s, 3H), 3.78 (s,
d
borate (5c). Yield = 70%. 1H NMR (CD3OD):
d
2.54 (d, J = 14.7 Hz,
6H), 7.41–7.52 (m, 2H), 7.55 (t, J = 60.0 Hz, 1H), 7.81–7.87 (m, 2H).
6H), 7.10 (dt, J = 48.5 Hz, J = 28.8 Hz, 1H), 7.78–7.83 (m, 2H), 7.94 (t,
J = 7.8 Hz, 1H), 8.04 (dd, J = 13.3 Hz, J = 8.2 Hz, 1H). 19F NMR
19F NMR (DMSO-d6):
À154.00 (s, 3F).
d
À117.10 (d, 2F, J = 56 Hz), À153.95 (s, 1F),
(CD3OD):
d
À126.55 (dd, J = 77.7 Hz, J = 47.3 Hz, 2F), À153.95 (s,
N-(Difluoromethyl)-N,N-dimethyl-m-toluenedinium
fluoroborate (7d). Yield: 83%. 1H NMR (DMSO-d6):
tetra-
1F), À154.00 (s, 3F). 31P NMR (CD3OD):
d
28.0 (t, J = 77.9 Hz). 13C
d
3.02 (s,
NMR (CD3OD):
d
2.54 (d, J = 52.2 Hz), 114.9 (dt, J = 265.3 Hz,
3H), 4.25 (t, J = 1.5 Hz, 6H), 7.60 (t, J = 58.8 Hz, 1H), 8.06–8.09 (m,
1H), 8.11–8.16 (m, 1H), 8.20–8.23 (m, 1H). 19F NMR (DMSO-d6):
À114.5 (dt, J = 58.8 Hz, J = 1.5, Hz, 2F), À153.95 (s, 1F), À154.00 (s,
J = 84.4 Hz), 123.3 (d, J = 87.5 Hz), 131.4 (d, J = 13.1 Hz), 134.0 (d,
J = 10.4 Hz), 137.2 (d, J = 3.3 Hz). HRMS calculated for C9H12F2P+
(M+) Expected: 189.0639. Found: 189.0639.
d
3F). 13C NMR (CD3OD):
d 21.4, 49.1, 117.0 (t, J = 277.6 Hz), 120.2,
P-(Difluoromethyl)tricyclohexylphosphonium tetrafluorobo-
123.6, 131.7, 133.6, 141.4, 143.1. HRMS calculated for C10H14F2N+
(M+) Expected: 186.1089. Found: 186.1089.
rate (5d). Yield = 69%. 1H NMR (CD3OD):
d
2.59 3.00 (m, 30H),
2.93 (m, 3H), 7.32 (dt, J = 46.8 Hz, J = 26.3 Hz, 1H). 19F NMR
(CD3OD):
N-(Difluoromethyl)-N,N-dimethyl-m-aminoanisolium
tetra-
d
À126.9 (dd, J = 61.1 Hz, J = 47.0 Hz, 2F), À153.95 (s, 1F),
fluoroborate (7 g). Yield: 53%. 1H NMR (CD3OD):
d
3.83 (s, 6H),
À154.00 (s, 3F).
3.92 (s, 3H), 7.29 (d, J = 8.4 Hz, 1H), 7.44 (t, J = 58.9 Hz, 1H, partially
overlapping with aromatic signals), 7.43–7.50 (m, 2H), 7.63 (t,
P-(Difluoromethyl)tri(p-tolyl)phosphonium tetrafluoroborate
(5e). Yield = 61%. 1H NMR (CD3OD):
d
2.54 (s, 9H), 7.34–7.71 (m,
12H), 7.95 (dt, J = 47.3 Hz, J = 29.6 Hz). 19F NMR (CD3OD):
À126.72 (dd, J = 76.9 Hz, J = 47.4 Hz, 2F), À153.95 (s, 1F), À154.00
(s, 3F). 31P NMR (CD3OD): 18.7 (t, J = 77.0 Hz). 13C NMR (CD3OD):
21.9, 110.2 (d, J = 88.8 Hz), 115.9 (dt, J = 268.3 Hz, J = 87.0 Hz),
J = 8.4 Hz, 1H). 19F NMR (CD3OD):
d
À112.16 (d, J = 58.7 Hz, 2F),
d
À153.95 (s, 1F), À154.00 (s, 3F). 13C NMR (CD3OD):
d 49.2 (partially
overlapping with solvent signal), 56.7, 109.8, 114.8, 117.0 (t,
J = 277.5 Hz, partially overlapping with aromatic signals), 142.4,
162.7. HRMS calculated for C10H14F2NO+ (M+) Expected: 202.1038.
Found: 202.1038.
d
d
132.8 (d, J = 13.6 Hz), 135.8 (d, J = 10.8 Hz), 150.1 (d, J = 3.2 Hz).
HRMS calculated for C22H22F2P+ (M+) Expected: 355.1422. Found:
355.1421.
N-(Difluoromethyl)-N,N-dimethyl-m-chloroanilinium
fluoroborate (7h). Yield: 47%. 1H NMR (CD3OD):
tetra-
3.87 (t,
d
P-(Difluoromethyl)tri(m-tolyl)phosphonium tetrafluoroborate
J = 2.4 Hz, 6H), 7.45 (t, J = 58.6 Hz, 1H), 7.71–7.79 (m, 2H), 7.93
(d, J = 8.1 Hz, 1H), 8.11 (pseudo t, J = 2.1 Hz, 1H). 19F NMR (CD3OD):
d
(5f). Yield = 78%. 1H NMR (CD3OD):
d
2.47 (s, 9H), 7.58–7.65 (m,
6H), 7.70–7.74 (m, 3H), 7.84–7.85 (m, 3H), 7.96 (dt, J = 47.3 Hz,
À111.2 (d, J = 58.6 Hz, 2F), À153.95 (s, 1F), À154.00 (s, 3F). 13C
J = 29.6 Hz, 1H). 19F NMR (CD3OD):
d
À126.24 (dd, J = 77.0 Hz,
NMR (CD3OD): d 49.2, 109.8, 114.8, 117.0 (t, J = 280.7 Hz), 118.1,
J = 47.3 Hz, 2F), À153.95 (s, 1F), À154.00 (s, 3F). 31P NMR (CD3OD):
132.8, 142.4, 162.7. HRMS calculated for C9H11ClF2N+ (M+)
Expected: 206.0543. Found: 206.0543.
d
19.1 (t, J = 77.0 Hz). 13C NMR (CD3OD):
d 21.3, 113.6 (d,
J = 85.0 Hz), 115.9 (dt, J = 272.0 Hz, J = 89.5 Hz), 132.0 (d,
J = 14.1 Hz), 133.2 (d, J = 10.3 Hz), 135.7 (d, J = 10.3 Hz), 138.8 (d,
J = 3.2 Hz), 143.0 (d, J = 13.3 Hz). HRMS calculated for C22H22F2P+
(M+) Expected: 355.1422. Found: 355.1423.
N-(Difluoromethyl)-3-phenylimidazolium
tetrafluoroborate
(7i). Yield: 68%. 1H NMR (CD3CN): 7.61 (t, J = 59.1 Hz, 1H), 7.66
(5H), 7.94 (s, 1H), 7.96 (s, 1H), 9.41 (s, 1H). 19F NMR (CD3CN): 95.5
(d, J = 59.0 Hz), À153.95 (s, 1F), À154.00 (s, 3F).
P-(Difluoromethyl)tri(p-methoxyphenyl)phosphonium tetra-
fluoroborate (5 h). Yield = 48%. 1H NMR (CD3OD):
d
3.96 (s, 9H),
4.6. Typical procedure for difluoromethylations of sulfur nucleophiles
7.33–7.36 (m, 6H), 7.69–7.74 (m, 6H), 7.76 (dt, J = 47.7 Hz,
J = 29.1 Hz, 1H). 19F NMR (CD3OD):
d
À127.62 (dd, J = 76.5 Hz,
To a stirred solution of aryl thiols (8a–8d) (0.3 mmol) in
anhydrous THF, NaH (0.3 mmol) was added in small portions
under N2. The solvent was evaporated under vacuum until the
bubbling ceased. The residue was added to freshly prepared 1
(0.2 mmol) in one portion under N2 and the reaction mixture was
stirred for 1 h. The reaction was monitored via 19F NMR
spectroscopy with PhCF3 as an internal standard, and the yields
were calculated on the basis of substrate 1 used.
J = 47.6 Hz, 2F), À153.95 (s, 1F), À154.00 (s, 3F). 31P NMR (CD3OD):
d
17.7 (t, JP-F = 76.5 Hz). 13C NMR (CD3OD):
d 56.7, 103.8 (d,
J = 95.3 Hz), 115.9 (dt, J = 266.8 Hz, J = 88.5 Hz), 117.8 (d,
J = 14.3 Hz), 137.9 (d, J = 12.1 Hz), 167.7 (d, J = 3.1 Hz). HRMS
calculated for C22H22F2O3P+ (M+) Expected: 403.1269. Found:
403.1268.
4.5. Typical procedure for difluoromethylations of nitrogen
nucleophiles
4.7. Typical procedure for difluoromethylations of oxygen
nucleophiles
To the in situ generated 1 (0.2 mmol), a solution of amines or
nitrogen-containing heterocyclics (6a–6j) (0.3 mmol) in anhy-
drous CH2Cl2 (0.5 mL) was quickly added under N2 protection and
the reaction mixture was stirred for 1 h. The reaction was
monitored via 19F NMR spectroscopy with PhCF3 as an internal
standard. The solvent was then evaporated under vacuum and the
residue was purified by flash column chromatography or thin layer
chromatography (silica gel) using CH2Cl2 and MeOH as the eluent.
N-(Difluoromethyl)triethylammonium tetrafluoroborate (7a).
To the in situ generated 1 (0.2 mmol), a solution of alcohols (8e–
8h) (2 mmol) in anhydrous CH2Cl2 (0.5 mL) was quickly added
under N2 protection and the reaction mixture was stirred for 1 h.
The reaction was monitored via 19F NMR spectroscopy with PhCF3
as an internal standard, and the yields were calculated on the basis
of substrate 1 used.
Acknowledgement
Yield: 69%. 1H NMR (CD3OD):
d 1.42 (q, J = 5 Hz, 9H), 3.67(t,
J = 5 Hz, 6H), 7.14 (t, J = 55.0 Hz, 1H). 19F NMR (CD3OD):
(d, J = 56.0 Hz, 2F), À153.95 (s, 1F), À154.00 (s, 3F).
d
À112.97
Financial Support of our work by the Loker Hydrocarbon
Research Institute is gratefully acknowledged.

798
G.K.S. Prakash et al. / Journal of Fluorine Chemistry 132 (2011) 792–798
[6] C.R. Johnson, E.R. Janiga, M. Haake, J. Am. Chem. Soc. 90 (1968) 3890–3891.
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