Direct S-difluoromethylation of thiols using the Ruppert-Prakash reagent Dedicated to Prof. Veronique Gouverneur on the occasion of receiving the ACS Award for Creative Work in Fluorine Chemistry.

Article abstract of DOI:10.1016/j.jfluchem.2015.09.011

Direct S-difluoromethylation of aryl and aliphatic thiols using the Ruppert-Prakash reagent is demonstrated. The reaction produces trimethylsilyldifluoromethyl sulfides, which upon cleavage with fluoride produces the difluoromethyl sulfides. The key reaction features are the use of relatively inexpensive and commercially available starting materials, shorter reaction times, ambient temperatures, easy reaction procedure, and selective S-difluoromethylation in the presence of -OH, -NH₂ and -CO₂H functional groups. Furthermore, one-pot arylthiodifluoromethyl transfer to PhCHO is also demonstrated.

Full text of DOI:10.1016/j.jfluchem.2015.09.011

Accepted Manuscript
Title: Direct S-Difluoromethylation of Thiols Using the
Ruppert-Prakash Reagent
Author: G. K. Surya Prakash Sankarganesh Krishnamoorthy
Sayan Kar George A. Olah.
PII:
S0022-1139(15)00287-0
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2015.09.011
FLUOR 8663
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
4-8-2015
19-9-2015
22-9-2015
Please cite this article as: G.K.S. Prakash, S. Krishnamoorthy, S. Kar, G.A. Olah.,
Direct S-Difluoromethylation of Thiols Using the Ruppert-Prakash Reagent, Journal
of Fluorine Chemistry (2015), http://dx.doi.org/10.1016/j.jfluchem.2015.09.011
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Graphical Abstract
Page 1 of 17

Direct S-Difluoromethylation of Thiols Using the Ruppert-Prakash
Reagent
G. K. Surya Prakash,* Sankarganesh Krishnamoorthy, Sayan Kar and George A. Olah.
Direct S-difluoromethylation of aryl and aliphatic thiols using the Rupert-Prakash
reagent is demonstrated. The reaction produces trimethylsilyldifluoromethyl sulfide,
which upon cleavage with fluoride produces the difluoromethyl sulfides. The key
reaction features are use of relatively inexpensive and commercially available starting
materials, shorter reaction times, ambient temperatures, easy reaction procedure and
selective S-difluoromethylation in the presence of -OH, -NH and -CO H functional
2
2
groups. Furthermore, one-pot arylthiodifluoromethyl transfer to PhCHO is also
demonstrated.
2
Page 2 of 17

Direct S-Difluoromethylation of Thiols Using the Ruppert-Prakash
Reagent
G. K. Surya Prakash,* Sankarganesh Krishnamoorthy, Sayan Kar, George A. Olah.
Loker Hydrocarbon Research Institute and Department of Chemistry, University of
Southern California, Los Angeles, CA 90089-1661, United States
E-mail: gprakash@usc.edu
Highlights
•
•
Direct S-difluoromethylation of aliphatic and aromatic thiols using TMSCF3
Selective S-difluoromethylation in presence of -OH, -NH and -CO H functional
2
2
groups
•
•
One-pot nucleophilic (arylsulfanyl)difluoromethylation of PhCHO
Short reaction times and ambient temperatures.
Direct S-Difluoromethylation of Thiols Using the Ruppert-Prakash
Reagent
G. K. Surya Prakash,* Sankarganesh Krishnamoorthy, Sayan Kar, George A. Olah.
Loker Hydrocarbon Research Institute and Department of Chemistry, University of
Southern California, Los Angeles, CA 90089-1661, United States
E-mail: gprakash@usc.edu
Dedicated to Prof. Veronique Gouverneur on the occasion of receiving the ACS Award
for Creative Work in Fluorine Chemistry
Abstract
Direct S-difluoromethylation of aryl and aliphatic thiols using the Rupert-Prakash
reagent is demonstrated. The reaction produces trimethylsilyldifluoromethyl sulfide,
which upon cleavage with fluoride produces the difluoromethyl sulfides. The key
reaction features are the use of relatively inexpensive and commercially available starting
materials, shorter reaction times, ambient temperatures, easy reaction procedure and
selective S-difluoromethylation in the presence of -OH, -NH and -CO H functional
2
2
groups. Furthermore, one-pot arylthiodifluoromethyl transfer to PhCHO is also
demonstrated.
3
Page 3 of 17

Keywords: Ruppert-Prakash reagent, TMSCF3, Difluoromethylation, thiols,
siladifluoromethylation, difluoromethyl thioethers, nucleophilic
arylsulfanyl)difluoromethylation, RSCF H, RSCF TMS
(
2
2
1
. Introduction
Analogues to aryl and alphatic trifluoromethyl thioethers [1], difluoromethyl
thioethers are promising synthons in medicinal chemistry and materials science. The
SCF H group has attracted considerable attention recently as it promises a unique
2
lipophilic weak hydrogen bond donor property. Its popularity is also associated with the
more acidic nature of the SCF -H proton compared to its carbon analog [2].
2
A common approach to synthesize difluoromethyl thioethers is to use
difluorocarbene based reagents such as ClCF CO Na [3], CF HCl [4], CF H [5],
2
2
2
3
+
-
BrCF PO(OEt) [6], and ArSONRCF H [7] and Ph P CF CO [8]. An electrophilic
2
2
2
3
2
2
+
reagent, ArSONR CF H , transferring -CF H to nucleophiles has also been used [9]. In
2
2
2
contrast, Goosen et al showed nucleophilic transfer of -CF H to in situ formed
2
+
electrophiles, RSCN, generated from RBr/ROMs or ArN2 [10] In an alternative
.
approach, a nucleophilic -SCF H group from (NHC)AgSCF H is transferred to
2
2
diazonium salts [11]; conversely, Shen and co-workers electrophilically transfer–SCF H
2
from N-difluoromethylthiothalimide to boronic acids, alkynes, amines, thiols and electron
4
Page 4 of 17

rich aromatics [12] giving access to a wide variety of -SCF H compounds. In the process
2
of discovery, drug or material, easy access to reagents in terms of the cost and handling
and simple procedures are highly desired.
Easy commercial and economical access, and ease of handling make the Ruppert-
Prakash reagent (TMSCF ) a popular nucleophilic trifluoromethylating agent [13].
3
Moreover, useful difluoromethyl [14] and difluoromethylene transfer reagents [15] have
also been prepared from TMSCF and employed to make difluoromethylene (CF )
3
2
containing compounds. Others and us have been exploring its direct use and reactivity as
a difluoromethylene transfer reagent as we can reduce the cost and efforts associated with
additional synthetic steps (Scheme 1) [16]. So far only a handful of examples of direct
difluoromethylene (CF ) transfer from TMSCF has been demonstrated to synthesize
2
3
difluorocyclopropane and propene [16a], alkyl and aryl-difluoromethylstannnes [15b], α-
siladifluoromethyl carbonyl compounds [16b], gem-difluoroolefins [16c], N-
difluoromethyl imidazoles and benzimidazoles [16d] and difluoromethyl containing
amines [16e]. To best of our knowledge, though the reagents derived from TMSCF such
3
as TfOCF H [17 ], TMSCF Br [18] and TMSCF H [10] have been utilized for the S-
2
2
2
difluoromethylation of thiols, TMSCF has never been directly employed until now.
3
Derived reagents
TMSCF H, TfOCF H
2
2
Products
Products
TMSCF3
TMSCF Br, TMSCF Cl
2
2
Bu SnCF H
3
2
Scheme 1. Difluorormethylene transfer from TMSCF3.
2
. Results and discussion
Table 1. Screening conditions
a
a
a
Entry MX (1.2 equiv) A% B%
Unreacted TMSCF (equiv)
3
1
2
3
LiI
KI
0
0
0
0
0
0
1.2
2.2
2.1
NaI
5
Page 5 of 17

4
5
6
7
CaI2
MgI2
LiBr
LiCl
9
24
0
0
9
0
0
1.2
1
1.5
1
40
Conditions: Reactions were carried out on 0.25 mmol scale with DMA (2.5 mL) and TMSCF (3
equiv). Determined by trifluorotoluene internal standard.
3
d
Following our base free difluoromethylation of imidazoles and benzimidazoles
with TMSCF [13b], we investigated difluoromethylation of thiols under similar reaction
3
conditions using naphthalene-2-thiol as a model substrate. For instance, LiI in triglyme or
diglyme produced less than 15% of the difluoromethylated product with complete
consumption of TMSCF at 120 °C. In order to prevent the decomposition TMSCF , we
3
3
opted relatively lower temperatures. TMSCF can be activated with alkali and alkaline
3
earth metal halides in polar solvents such as DMF, DMA or NMP. With DMA as a
solvent, different MX salts were examined at 70 °C (Table 1). Interestingly, MgI2
produced siladifluoromethylated product (A) along with difluoromethylated product (B),
whereas LiCl offered only A in 40% conversion. Further reactions were explored with
LiCl at various temperatures. The maximum conversion obtained was 50%; attempts to
increase the conversion by leaving the reaction for longer time or heating at higher
temperature resulted in decomposition of the product with the reaction mixture turning
orange. Attempts to arrest the reaction before decomposition of the product were not
always successful.
We propose that the lithium arylthiolate produced in situ by trifluoromethanide
anion from TMSCF and LiCl is the active species that reacts with TMSCF (Table 1,
3
3
Entry 7). However, the TMSCF3 activation by LiCl for the generation of
trifluoromethanide anion requires temperature above 60 °C. But the resulting product
decomposes overtime under the reaction conditions. Therefore, we decided to start from a
lithium thiolate. For easy handling, LiH was selected as a base to deprotonate the thiols.
When the reaction was carried out with LiH in DMA at room temperature, the reaction
proceeded in less than a minute, giving the S-siladifluormethylated product in 50%
conversion (Table 2, Entry 1). Similar results were obtained in DMF. Interestingly, when
the reaction was carried out without the LiCl additive, the reaction failed to produce any
+
product (Entry 8). Furthermore, we speculated that the Li acts as a fluoride trap,
6
Page 6 of 17

allowing the siladifluoromethyl product and the TMSCF to survive under the reaction
3
conditions. We also hypothesized that the more cationic nature of the lithium may assist
in the fluoride abstraction. As expected, lithium salts of weakly coordinating anions
-
-
-
-
increasingly produced the product in the following order OTf = NTf < PF < BF .
2
6
4
When the amount LiBF was optimized, we observed that use of sub-stoichiometric
4
amount (15 or 50 mol%) of LiBF produced 72% conversion. Superior conversion (84%)
4
was obtained when slightly over an equivalent amount of LiBF was employed.
4
An optimum conversion was obtained with LiH (1.2 equiv), TMSCF (2.5 equiv),
3
5
min for deprotonation and 10 min for reaction time (Table 3). The resulting
siladifluoromethyl sulfides can be conveniently cleaved with either TBAF or aqueous
KF.
Table 2. Optimization and screening conditions
Conversion
Entry
LiX
Solvent
a
(%)
1
2
3
4
5
6
7
8
9
LiCl
LiCl
LiCl
LiBr
LiI
LiPF6
LiF
DMA
DMF
THF
DMA
DMA
DMF
DMF
DMF
DMF
50
53
0
33
33
74
0
-
0
67
LiN(SO CF )
2
3 2
1
0
LiBF4
LiBF4
LiBF4
LiOTf
LiOAc
DMF
DMF
DMF
DMF
DMF
78
72
84
67
44
b
1
1
1
2
c
1
1
3
4
7
Page 7 of 17

Conditions: Reactions were carried out on 0.25 mmol scale with 2.2 equiv of LiH, 3 equiv TMSCF and 1.5
3
a
19
b
equiv LiX. Determined by F NMR using trifluorotoluene as an internal standard. 15 or 50 mol% of
C
LiBF was used. 1.2 equiv of LiBF was used.
4
4
Thiols with electron donating groups such as methyl and methoxy groups
provided excellent conversions. In general, the pKa of -SH is lower than -OH and -NH2,
therefore with the present conditions; we predicted that -SH could be selectively
deprotonated and difluoromethylated. Gratifyingly, -OH and -NH substituents, typically
2
considered sensitive functional groups, produced 60% and 50% conversions,
respectively. In the halosubstituted thiols, 4-fluoro gave greater than 86% conversion,
whereas -Cl and -Br were over 60%. We hypothesized that by employing two equivalent
of LiH, the ionized carboxylic acid group can be made less electron-withdrawing and less
sensitive. To our delight, thiosalicylic acid produced 75% conversion. However, electron-
withdrawing substituents such as trifluoromethyl and nitro produced 25% and 0%
products, respectively.
Table 3. Optimized conditions and substrate scope
8
Page 8 of 17

Conditions: For convenient isolation, the substrate scope was explored on 0.5 mmol scale with LiH (1.2
a
b
equiv), LiBF (1.2 equiv) and TMSCF (2.5 equiv) in dry DMF (2.5 ml). KF or TBAF was used. The
4
3
1
9
c
yields in parentheses were determined by F NMR using trifluorotoluene as an internal standard. Isolated
yield.
2
.2. Aliphatic thiols
Similar reaction conditions were extended to aliphatic thiols with 1-dodecanethiol
as a model substrate, the conversions were over 20%, which was associated to higher
reactivity of aliphatic thiols over aromatic thiols. Consequently, lower reaction
o
temperatures were examined. No reaction was observed at 0 C or lower temperatures.
When the reaction was allowed to come to room temperature from 0 °C, the conversion
improved to 56%. With the modified conditions, 1-butanethiol and benzylthiol gave 71%
and 51% conversions, respectively.
Table 4. Aliphatic difluoromethyl thioethers.
9
Page 9 of 17

Conditions: Reactions were carried out on 0.5 mmol scale with LiH (1.2 equiv), LiBF (1.2 equiv) and
4
a
b
TMSCF (2.5 equiv) in dry DMF (2.5 ml). KF or TBAF was used. The yields in parentheses were
3
1
9
determined by F NMR using trifluorotoluene as an internal standard.
2
.3 One-pot tolyllthiodifluoromethyl transfer to benzaldehyde
RSCF - transfer to organic molecules is an important area of research, as the
2
resulting products’ –SR group can be modified into several other useful functionalities.
The widely used PhSCF TMS was first developed and employed by us [19] and
2
subsequently by others [20]. Moreover, recently ArSCF H have also been used to transfer
2
-
ArSCF in the presence of bases [21].
2
Scheme 2.
Under the present conditions, we surmised that the resulting
siladifluoromethylated product could be made to react with electrophiles in the same pot.
To demonstrate that a one-pot transfer of the arylthiodifluoromethylene from the
intermediate, S-siladifluoromethyl thioether to electrophiles, tolylthiol was
siladifluoromethylated and the reaction mixture was subjected to vacuum to remove
excess TMSCF and benzaldehyde was subsequently added and the reaction mixture was
3
stirred at room temperature for 12 hours to give 3a in 62% yield. We employed 4Å MS to
keep the reaction dry and to avoid formation of any ArSCF H. The reaction also occurs in
2
the absence of molecular sieves, however, with 15% of ArSCF H formation leading to
2
10
Page 10 of 17

slight decrease in the yield of 3a. Similar approach can be extended to other carbonyl
compounds to make useful products in one-pot.
2
.3. Mechanism
Scheme 3. Proposed mechanism.
Based on the experimental observations, a plausible mechanism can be proposed
(Scheme 3). Lithium thiolate is generated in the presence of lithium hydride, which
attacks silicon to produce a pentavalent intermediate; the pentavalent intermediate
+
eliminates a fluoride with help of Lewis acidic Li to give the product. When the reaction
of naphthalene-2-thiol was performed in the presence of 1,1-diphenylethylene (Scheme
4
), initially no difluorocyclopropane was observed, only the expected product A was
obtained. However, leaving the reaction mixture over an hour slowly formed small
amount of difluorocyclopropane (C), which can be a background reaction with the excess
TMSCF . When the reaction was performed with TIPSCF , where the Si center is
3
3
sterically congested, no product formation was observed and the TIPSCF (Scheme 4)
3
remained unreactive. Additionally, use of sodium hydride as a base instead of LiH, led to
decomposition of TMSCF into several unidentified signals along with CF H and TMSF,
3
3
and no product was formed. Moreover, no tetrafluoroethylene and related products was
observed under the reaction conditions, clearly ruling out the involvement of free singlet
difluoromethylene.
Scheme 4. 1,1-diphenylethylene to trap difluorocarbene.
11
Page 11 of 17

Scheme 5. Reaction with TIPSCF3.
3
. Conclusion
Direct use of TMSCF for difluoromethylation of aliphatic and aromatic thiols has
3
been developed. As the reaction produces siladifluoromethylated products in one-step,
without the need for use of CF Br or the consecutive use of Mg/TMSCl to generate the
2
2
reagent, one can directly use the present conditions to make diverse products from
various electrophiles. Similar, results can be achieved by preforming the lithium thiolates
using mild bases such as Li CO when the use of strong base such as LiH is detrimental
2
3
for the substrate. Given the unique acidity and nucleophilicity of thiolates, a
chemoselective S-difluoromethylation is easily adaptable to thiols with various functional
groups.
4
. Experimental
4
.1 General information
1
13
19
H, C and F NMR spectra were recorded on Varian 500 MHz or 400 MHz
1
NMR spectrometers. H NMR chemical shifts were determined relative to the signal of a
1
3
residual protonated solvent, CDCl (δ 7.24 ppm) or DMSO-d (2.5 ppm). C NMR
3
6
1
3
chemical shifts were determined relative to the C signal of solvent, CDCl (δ 77.23
3
1
9
ppm) or DMSO-d (39.52 ppm). F NMR chemical shifts were determined relative to
6
CFCl as an internal standard (δ 0.0 ppm). HRMS data was obtained from University of
3
Illinois urbana-champaign’s mass spectrometry laboratory. Typically all reactions
mixtures were prepared and carried out under inert atmosphere in a Schlenk flask or a
sealed microwave vial. Unless otherwise mentioned, all the reactants, reagents and
solvents were purchased from commercial sources.
4
.2 Synthesis of aryldifluoromethyl thioethers
To a mixture of LiBF (1.2 equiv; 0.6 mmol, 56.2 mg), LiH (1.2 equiv; 0.6 mmol,
4
4
.7 mg) and DMF (dry; 2.5 mL) was added, the required substrate (1 equiv; 0.5 mmol).
The mixture was stirred for 5 min under inert atmosphere in a microwave vial or a
Schlenk flask. To the vigorously stirring mixture, TMSCF (180 µL) was quickly injected
3
and stirring continued for 10 more min. Aqueous KF (150 µL, 10M) or TBAF in THF
(2mL, 1M) was added and stirred for 10 min. Unreacted LiH was quenched with water (5
12
Page 12 of 17

mL) (H evolution; extra care must be taken for large scale reactions!) and extracted
2
in EtOAc or Et O (2 x 5 mL) and these layers were combined and washed with water (3 x
2
1
0 mL) and brine (10 mL). The combined organic layers were then dried over anhydrous
MgSO , filtered and dried in a rotary evaporator. The resulting residue was purified by
4
silica flash column chromatography using pentane or hexane/EtOAc gradient and the
pure fractions were combined and rotary evaporated to obtain the pure difluoromethyl
thioethers.
4
.2.1. (difluoromethyl)(p-tolyl)sulfane (1b)
1
Colorless oil (65.3 mg; 75% yield). H NMR (399 MHz, CDCl ) δ 7.48 (d, J = 8.1
3
1
9
Hz, 2H), 7.21 (d, J = 7.8 Hz, 2H), 6.79 (t, J = 57.2 Hz, 1H), 2.38 (s, 3H). F NMR (376
1
3
MHz, CDCl ) δ -92.18 (d, J = 57.1 Hz). C NMR (100 MHz, CDCl ) δ 140.4, 135.7,
3
3
1
30.3, 122.5 (t, J = 3.0 Hz), 121.2 (t, J = 268.8 Hz), 21.4. The data corroborate with the
literature report [3, 5].
4
.2.2. (difluoromethyl)(2,6-dimethylphenyl)sulfane (1c)
1
Colorless oil (77.1 mg; 82% yield). H NMR (399 MHz, CDCl ) 7.25-7.21 (m,
3
1
3
1
H), 7.17-7.15 (m, 2H), 6.67 (t, J = 57.0 Hz), 2.55 (s, 6H). C NMR (100 MHz, CDCl )
3
1
9
δ 145.1, 130.4, 128.7, 125.0, 121.7 (t, J = 275.9 Hz), 22.5. F NMR (376 MHz, CDCl ) δ
3
-90.96 (d, J = 57.0 Hz). The data corroborate with the literature report [3].
4
.2.3. (difluoromethyl)(4-methoxyphenyl)sulfane (1d)
1
Colorless oil (78 mg; 82% yield). H NMR (399 MHz, CDCl ) δ 7.53 (d, J = 8.8
3
1
3
Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 6.74 (t, J = 57.1, 1H), 3.83 (s, 3H). C NMR (126
MHz, CDCl ) δ 161.3, 137.7, 121.1 (t, J = 276.7 Hz), 116.2 (t, J = 3.1 Hz) 115.0, 55.5.
3
1
9
F NMR (376 MHz, CDCl ) δ -92.79 (d, J = 57.1 Hz. The data corroborate with the
3
literature report [3].
4
.2.4. 4-((difluoromethyl)thio)phenol (1e)
1
White solid (29.0 mg; 33%). H NMR (500 MHz, CDCl ) δ 7.48 (d, J = 8.1 Hz,
3
1
3
1
H), 6.84 (d, J = 7.9 Hz, 1H), 6.74 (t, J = 56.8 Hz, 1H), 5.27 (s, 1H). C NMR (126
1
9
MHz, CDCl ) δ 157.5, 138.0, 126.4, 121.0 (t, J = 275.6 Hz), 116.5. F NMR (470 MHz,
3
+
-
CDCl ) δ -92.82 (d, J = 57.2 Hz). ESI-HRMS: m/z calculated for C H F OS [(M-H ) ]:
3
7
6 2
+
-
1
75.0029, Found: 175.0033 [(M-H ) ].
4
.2.5. 4-((difluoromethyl)thio)aniline (1f)
13
Page 13 of 17

1
Colorless Oil (24%, 20.6 mg). H NMR (399 MHz, CDCl ) δ 7.40 – 7.31 (m, 2H),
3
1
3
6
.71 (t, J = 57.3 Hz, 1H), 6.69 – 6.63 (m, 2H), 3.87 (bs, 2H). C NMR (100 MHz,
1
9
CDCl ) δ 148.5, 137.8, 121.4 (t, J = 274.0 Hz), 115.6, 112.9. F NMR (376 MHz,
3
CDCl ) δ -93.03 (d, J = 57.4 Hz). ESI-HRMS: m/z calculated for C H F NS: 176.0346
3
7
7 2
+
Found: 176.0354 [(M+H) ].
4
.2.6. (4-chlorophenyl)(difluoromethyl)sulfane (1i)
1
Colorless Liquid. (53.6 mg, 55%). H NMR (400 MHz, CDCl ) δ 7.53 (d, J = 8.3
3
1
3
Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 6.82 (t, J = 56.7, 1H). C NMR (126 MHz, CDCl ) δ
3
1
9
1
36.9, 136.7 , 129.8 , 124.4 (t, J = 3.1 Hz), 120.5 (t, J = 275.7 Hz). F NMR (376 MHz,
CDCl ) δ -92.22 (d, J = 56.7 Hz). The data corroborate with the literature report [3].
3
4
.2.7. (4-bromophenyl)(difluoromethyl)sulfane (1j)
1
Colorless Oil (70.5 mg, 59%). H NMR (500 MHz, CDCl ) δ 7.53 – 7.49 (m, 2H),
3
1
9
7
.48 – 7.42 (m, 2H), 6.81 (t, J = 56.6 Hz, 1H). F NMR (470 MHz, CDCl ) δ -92.15 (d, J
3
1
3
=
56.6 Hz). C NMR (126 MHz, CDCl ) δ 137.0, 132.7, 125.0 (t, J = 3.3 Hz), 124.9,
3
1
20.4 (t, J = 274.1 Hz). The data corroborate with the literature report [10].
4
.2.8. (2-bromophenyl)(difluoromethyl)sulfane (1l)
1
Colorless Oil (55 mg, 46%) H NMR (500 MHz, CDCl ) δ 7.72-7.65 (m, 2H),
3
1
9
7
.41 – 7.32 (m, 1H), 7.32 – 7.23 (m, 2H), 6.93 (t, J = 57.0, 1H). F NMR (470 MHz,
1
3
CDCl ) δ -92.72 (d, J = 57.0 Hz). C NMR (126 MHz, CDCl ) δ 136.57, 133.93, 131.14,
3
3
1
29.30, 128.54, 128.39, 120.63. The data corroborate with the literature report [22].
4
.2.9. (difluoromethyl)(naphthalen-1-yl)sulfane (1m)
1
1
Colorless liquid (75.7mg, 72%). H NMR (500 MHz, CDCl ) H NMR (500
3
MHz, Chloroform-d) δ 8.53 (d, J = 8.6 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 7.7
1
9
Hz, 2H), 7.69 – 7.42 (m, 3H), 6.83 (t, J = 57.1 Hz, 1H). F NMR (470 MHz, CDCl ) δ -
3
1
3
9
1
1.30 (d, J = 57.2 Hz). (t, J = 273.6 Hz). C NMR (126 MHz, CDCl ) δ 136.5, 135.4,
3
34.4, 131.4, 128.7, 127.6, 126.8, 125.9, 125.8, 123.6, 121.5 (t, J = 273.6 Hz). The data
corroborate with the reported literature [11].
4
.2.10. (difluoromethyl)(naphthalen-2-yl)sulfane (1n)
1
Colorless oil (80.6 mg; 76% yield) H NMR (399 MHz, CDCl ) δ 8.13 (s, 1H),
3
7
.91 – 7.82 (m, 3H), 7.63 (d, J = 8.6, 1H), 7.60 – 7.53 (m, 2H), 6.92 (t, J = 56.9 Hz, 1H).
1
3
C NMR (100 MHz, CDCl ) δ 135.5, 133.6, 133.5, 131.5, 129.1, 128.0, 127.8, 127.5,
3
14
Page 14 of 17

1
9
1
27.0, 123.3 (t, J = 3.0 Hz), 121.2 (t, J = 274.5 Hz). F NMR (376 MHz, CDCl ) δ -
3
9
1.67 (d, J = 57.1 Hz). The data corroborate with the reported literature [11].
4
.2.11. 2-((difluoromethyl)thio)benzoic acid (1q)
Purified by acid base extraction. No column chromatography was performed.
1
White solid (49.8 mg, 49%). H NMR (500 MHz, CDCl ) δ 8.09 (d, J = 7.9 Hz, 1H), 7.64
3
(d, J = 7.9 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.03 (t, J = 56.2 Hz,
1
9
13
1
H). F NMR (470 MHz, CDCl ) δ -93.51 (d, J = 56.2 Hz). C NMR (126 MHz,
3
DMSO-d6) δ 167.4, 132.6, 131.3, 130.9, 130.8 (t, J = 3.7 Hz), 129.7, 127.4, 121.2 (d, J =
+
-
2
2
4
70.7 Hz). ESI-HRMS: m/z calculated for C H F O S (M-H ) : 202.9978, found:
8 6 2 2
+
-
02.9975 (M-H ) .
.2.12. benzyl(difluoromethyl)sulfane (2b)
1
Colorless Liquid (40%, 34.8 mg). H NMR (399 MHz,CDCl ) δ 7.52 – 7.11 (m,
3
1
3
5
1
5
4
H), 6.73 (t, J = 56.6 Hz, 1H), 4.02 (s, 2H). C NMR (100 MHz, CDCl ) δ 136.4, 129.0,
3
1
9
28.9, 127.8, 120.4 (t, J = 271.9 Hz), 31.9. F NMR (376 MHz, CDCl ) δ -94.98 (d, J =
3
6.6 Hz). The data corroborate with the reported literature [10].
.2.13. (2,2-difluoro-1-phenyl-2-(p-tolylthio)ethoxy)trimethylsilane (3a)
To a mixture of LiBF (1.2 equiv; 0.6 mmol, 56.2 mg), LiH (1.2 equiv; 0.6 mmol,
4
4
.7 mg), DMF (dry; 2.5 mL), 4A MS (250 mg, beads) and 4-methylbenzenethiol (1
equiv; 0.5 mmol) was added and the mixture stirred for 5 min under inert atmosphere in a
schlenk flask. TMSCF (180 µL) was quickly injected and the mixture stirred vigorously
3
for 10 min. The reaction mixture was subjected to vacuum to remove unreacted TMSCF3
that may be present and PhCHO (2 equiv) was added and stirred overnight. Unreacted
LiH was quenched with water (5 mL) (H evolution; extra care must be taken for
2
large scale reactions!) and extracted in EtOAc (2 x 5 mL) and these layers were
combined and washed with water (3 x 10 mL) and brine (10 mL). The combined organic
layers were then dried over anhydrous MgSO , filtered and dried under rotary evaporator.
4
The resulting residue was purified by silica flash column chromatography using
hexane/EtOAc gradient (0-10%) and the pure fractions were combined and rotary
1
evaporated to obtain the pure 3a as an off-white solid (62%, 109.2 mg). H NMR (500
MHz, CDCl ) δ 7.51 – 7.40 (m, 4H), 7.40 – 7.30 (m, 3H), 7.19 – 7.08 (m, 2H), 4.98 (dd,
3
15
Page 15 of 17

1
3
J = 10.9, 7.5 Hz, 1H), 2.58 – 2.11 (m, 3H), 0.12 (s, 9H). C NMR (126 MHz, CDCl ) δ
3
1
39.72, 136.86, 136.41, 135.65, 133.42, 129.62, 128.82 (t, J = 284.0 Hz), 128.62, 127.95,
1
9
1
22.94, 21.23, -0.07. F NMR (470 MHz, CDCl ) δ -80.59 (dd, J = 204.0, 7.5 Hz), -
3
8
3.83 (dd, J = 204.2, 11.0 Hz). EI-HRMS: m/z calculated for C H F OSSi: 352.1129;
1
8
22 2
Found: 352.1128.
Acknowledgements
Support of our work by the Loker Hydrocarbon Research Institute is gratefully
acknowledged.
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