Fluoride ion-mediated nucleophilic fluoroalkylation of alkyl halides with Me3SiCF2SPh: Synthesis of PhSCF2- and CF2H-containing compounds

Article abstract of DOI:10.1016/j.jfluchem.2008.01.010

A facile and highly efficient nucleophilic (phenylthio)difluoromethylation of alkyl halides has been achieved via fluoride ion-mediated substitution reaction using [difluoro(phenylthio)methyl]trimethylsilane (Me₃SiCF₂SPh). The reaction proceeds well with primary alkyl bromides (or alkyl iodides) in DME solvent when CsF/15-crown-5 was used as the fluoride source/additive. The PhSCF₂-containing products can be readily transformed into CF₂H-containing compounds via a free-radical desulfurization method.

Full text of DOI:10.1016/j.jfluchem.2008.01.010

Available online at www.sciencedirect.com
Journal of Fluorine Chemistry 129 (2008) 382–385
www.elsevier.com/locate/fluor
Fluoride ion-mediated nucleophilic fluoroalkylation of alkyl halides
with Me3SiCF2SPh: Synthesis of PhSCF2- and
CF2H-containing compounds
*
Ya Li, Jinbo Hu
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
Received 10 January 2008; received in revised form 21 January 2008; accepted 22 January 2008
Available online 2 February 2008
Abstract
A facile and highly efficient nucleophilic (phenylthio)difluoromethylation of alkyl halides has been achieved via fluoride ion-mediated
substitution reaction using [difluoro(phenylthio)methyl]trimethylsilane (Me3SiCF2SPh). The reaction proceeds well with primary alkyl bromides
(or alkyl iodides) in DME solvent when CsF/15-crown-5 was used as the fluoride source/additive. The PhSCF2-containing products can be readily
transformed into CF2H-containing compounds via a free-radical desulfurization method.
# 2008 Elsevier B.V. All rights reserved.
Keywords: (Phenylthio)difluoromethylation; Difluoromethylation; Selective fluoroalkylation; Nucleophilic substitution; Alkyl halides
1. Introduction
addition of CBr2F2 to double bonds [22], (e) SRN1 reaction
between a nucleophile and CHClF2 [5,23], and (f) nucleophilic
introduction of a CF2H moiety into carbonyl compounds using
(difluoromethyl)dimethylphenylsilane [24] or difluoro[bis(tri-
methylsilyl)]methane [10]. More recently, both difluoromethyl
phenyl sulfone (PhSO2CF2H) and [difluoro(phenylsulfonyl)-
methyl]trimethylsilane (Me3SiCF2SO2Ph) were used as effi-
cient nucleophilic difluoromethylating agents for a variety of
electrophiles [25].
Selective incorporation of fluorine atom(s) or a fluorinated
moiety into an organic molecule can often bring profound
effects on its chemical and biological properties, including
changes in stability, lipophilicity, and bioavailability [1–7]. As
a result, organofluorine chemistry has attracted enormous
attention in the field of pharmaceutical and agricultural
chemistry, as exemplified by the fact that fluorine substituents
have become widespread and important drug components [8,9].
Among fluorine-containing moities, the difluoromethyl group
(CF2H) is of significant interest [10–13], since the latter one is
believed to act as an isopolar and isosteric analog of the CH2OH
group [14,15]. Moreover, CF2H is able to act as a lipophilic
hydrogen bond donor through hydrogen bonding [11].
Recently, Tyrra et al. reported a fluoride ion-mediated cross-
coupling of alkyl halides RX (X = Br, I) and Me3SiRf
(Rf = CF3, C2F5) to give perfluoroalkylated products R–Rf
[26]. Inspired by their work and based on our own experience
with Me3SiCF2SPh (1) [27e], we envisioned that a similar
fluoride ion-mediated nucleophilic fluoroalkylation of alkyl
halides might be possible with reagent 1, which could be used to
prepare both PhSCF2- and CF2H-containing compounds. In this
paper, we disclose our results on this study.
There are several methods for introducing the CF2H moiety
[4,5,7,16], including (a) the deoxofluorination of aldehydes
using SF4, DAST, or SeF4 reagent [17,18], (b) nucleophilic
fluorination of gem-bistriflates using TBAF [19], (c) fluorina-
tion of 1,2- or 1,3-dithianes using BrF3 [12,20,21], (d) the
2. Results and discussion
First, we carried out the nucleophilic (phenylthio)difluoro-
methylation of ethyl iodide 2a with Me3SiCF2SPh (1) [27] in
the presence of a fluoride source. The reaction conditions
* Corresponding author. Tel.: +86 21 54925174; fax: +86 21 64166128.
E-mail address: jinbohu@mail.sioc.ac.cn (J. Hu).
0022-1139/$ – see front matter # 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.01.010

Y. Li, J. Hu / Journal of Fluorine Chemistry 129 (2008) 382–385
383
Table 1
Optimization of the reaction conditions
Entry
‘‘Fꢀ’’
Solvent
Additive
Yield (%)a
1
2
TBAT
TBAT
TBAT
KF
CH2Cl2
DME
–
0
28
0
–
3
DMF
–
4
DME
–
0
5
CsF
CH3CN
CH2Cl2
THF
–
0
6
CsF
–
0
7
CsF
–
21
37
32
43
23
16
20
8
CsF
DME
–
9
CsF
DME
18-Crown-6
15-Crown-5
15-Crown-5
15-Crown-5
15-Crown-5
10
11
12
13
CsF
DME
CsF
Diglyme
Et2O
CsF
CsF
Toluene
aThe yield was determined by 19F NMR spectroscopy and GC–MS. bThe molar ratio of 1/2a/CsF/additive = 1:3:1:1.
were carefully tuned (see Table 1). It is apparent that
the reaction was significantly influenced by both the fluo-
ride source and the reaction solvent. When the reactions were
carried out in DMF, CH3CN, or CH2Cl2 solvent, and
different fluoride sources [such as tetrabutylammonium
triphenyldifluorosilicate (TBAT), KF, and CsF] were
applied, no expected product 3a was formed (Table 1,
entries 1 and 3–6). In these cases, the only detectable
fluorine-containing product was PhSCF2H. After several
trials, we found that the combination of 1,2-dimethoxyethane
(DME) and CsF could give better results (entries 8–10),
while reactions in THF, diglyme, Et2O, and toluene resulted
in lower yields (entries 7 and 11–13). Moreover, the addition
of the crown ether to the reaction mixture was found to be
beneficial, and 15-crown-5 gave better result than 18-crown-
6 (entries 9 and 10).
Then we tried the less reactive electrophiles—ethyl bromide
4a and ethyl chloride 5a—to test their reaction with 1/CsF/15-
crown-5 under the optimized reaction conditions (as those for
Table 2, entry 4). To our delight, when ethyl bromides 4a was
used as an electrophile, the reaction worked well and product
3a was obtained in 85% isolated yield (see Scheme 1). Since
alkyl bromides are relatively more available than alkyl iodides,
it represents a practical advantage that alkyl bromides can be
used in this reaction. However, when ethyl chloride was used,
only trace amount of product 3a was detected by 19F NMR
(Scheme 1).
We used the reaction conditions shown in Scheme 1 as the
standard condition, and studied the scope of the reaction between
reagent 1 and different alkyl bromides. The results are shown in
Table 3. In all cases (phenylthio)difluoromethylated products 3
were obtained in good to excellent isolated yields, and the major
detectable fluorine-containing by-product was PhSCF2H.
Products 3 are useful precursors for the preparation of
difluoromethyl compounds. For instance, compound 3d was
treated with Bu3SnH/AIBN in toluene at 90 8C, and the mixture
was subject to a routine workup to afford difluoromethyl
compound 6 in 95% yield (Scheme 2). Indeed, the present
(phenylthio)difluoromethylation of primary alkyl bromides
with 1 provides an alternative approach for the preparation of
CF2H-containing compounds, which were previously synthe-
sized by using PhSO2CF2H reagent under strongly basic
conditions [13].
Further studies (see Table 2, entry 4) revealed that, when
2.0 equiv. of Me3SiCF2SPh (1) was used (relative to the amount
of ethyl iodide 2a), the yield of product 3a was dramatically
increased (93%). However, excess amount of ethyl iodide 2a
contributed little to the product yields, and the yield
improvement was negligibly small even when 4.0 equivalent
of ethyl iodide was applied (Table 2, entries 1–3). It is also
worthwhile to mention that, no alkyl fluorides was detected as
by-products in these reactions, which indicates that the rate of
the reaction between ethyl iodide 2a and CsF was much lower
under the given reaction conditions.
Table 2
Influence of the reactant ratio (1/2a) on the product yields
Entry
Molar ratio (1/2a)
Yield (%)a
1
2
3
4
1:1
1:3
1:4
2:1
42
43
47
93
aIsolated yield. b1/CsF/15-crown-5 = 1:1:1.

384
Y. Li, J. Hu / Journal of Fluorine Chemistry 129 (2008) 382–385
4.1. Typical procedure for the fluoride ion-mediated
nucleophilic (phenylthio)difluoromethylation of alkyl
halides
Under a nitrogen atmosphere, a mixture of dried CsF
(182 mg, 1.2 mmol), 15-crown-5 (264 mg, 1.2 mmol), and
freshly distilled DME (3.5 mL) was stirred for 5 min at ꢀ20 8C.
Scheme 1.
Table 3
Preparation of PhSCF2-containing compounds 3 by fluoride-mediated substitution reactions between Me3SiCF2SPh (1) and alkyl bromides (4)
Entrya
Alkyl bromide
Product
Yield (%)b
1
2
3
4
5
6
CH3CH2Br (4a)
CH3(CH2)5Br (4b)
PhCH2Br (4c)
CH3CH2CF2SPh (3a)
CH3(CH2)5CF2SPh (3b)
PhCH2CF2SPh (3c)
85
92
88
85
94
84
PhOCH2CH2CH2Br (4d)
p-CH3C6H4OCH2CH2CH2Br (4e)
p-CH3OC6H4OCH2CH2Br (4f)
PhOCH2CH2CH2CF2SPh (3d)
p-CH3C6H4OCH2CH2CH2CF2SPh (3e)
p-CH3OC6H4OCH2CH2CF2SPh (3f)
a
Molar ratio 1/4/CsF/15-crown-5 = 2:1:2:2.
Isolated yield based on the amount of 4 that was used.
b
Scheme 2.
3. Conclusions
Then a mixture of Me3SiCF2SPh (1) (280 mg, 1.2 mmol) and
ethyl bromide (65 mg, 0.6 mmol) in DME (0.5 mL) was slowly
added to the reaction flask. The reaction temperature was raised
to 10 8C in 4 h, followed by adding H2O (5 mL) to the reaction
mixture. The solution mixture was extracted with Et2O (15 mL
3ꢁ), and the combined organic phase was dried over MgSO4.
After the removal of volatile solvents under vacuum, the crude
product was purified by silica gel column chromatography with
petroleum ether to give product 3a as an oily liquid, yield 85%
(96 mg).
In conclusion, a facile and highly efficient nucleophilic
(phenylthio)difluoromethylation of alkyl halides has been
achieved via fluoride-mediated substitution reaction using
[difluoro(phenylthio)methyl]trimethylsilane (Me3SiCF2SPh)
reagent. The reaction proceeds well with primary alkyl
bromides (or alkyl iodides) in DME solvent when CsF/15-
crown-5 was used as the fluoride source/additive. The PhSCF2-
containing products can be readily transformed into CF2H-
containing compounds via a free-radical desulfurization
method.
4.1.1. 1,1-Difluoropropyl phenyl sulfide (3a)
(CH3CH2CF2SPh)
4. Experimental
Liquid; IR (film): 2987, 1477, 1442, 1227, 1174, 1140, 1027,
973 cmꢀ1; 1H NMR (CDCl3): d 7.59–7.62 (m, 2H), 7.34–7.42
(m, 3H), 2.03–2.18 (m, 2H), 1.12 (t, J = 7.5 Hz, 3H); 19F NMR
(CDCl3): d ꢀ74.8 (t, J = 14.7 Hz, 2F); 13C NMR (CDCl3): d
136.0, 130.4 (t, J = 276.6 Hz), 129.6, 129.0, 127.2, 32.1 (t,
J = 24.5 Hz), 7.46 (t, J = 4.2 Hz); EI (m/z %) 188 (M+, 37.7),
110 (100.0); HRMS (EI) calcd. For C9H10F2S: 188.0471; found
188.0461.
Unless otherwise mentioned, solvents and reagents were
purchased from commercial sources and used as received.
DME was freshly distilled over sodium and stored under
nitrogen atmosphere. Me3SiCF2SPh reagent was prepared
according to the previous report [27a]. 1H NMR spectra were
recorded on a 300-MHz NMR spectrometer using Me4Si as
an internal standard. 19F NMR spectra were recorded on a
300-MHz NMR spectrometer using CFCl3 as an external
standard. 13C NMR spectra were recorded on a 500-MHz or a
400-MHz NMR spectrometer. Mass spectra were obtained on
a HP5989A spectrometer. High-resolution mass data were
recorded on a high-resolution mass spectrometer in the EI or
MALDI mode.
4.1.2. 1,1-Difluoroheptyl phenyl sulfide (3b)
(CH3(CH2)5CF2SPh)
Liquid; IR (film): 2959, 1475, 1442, 1172, 1042, 1025,
944 cmꢀ1; 1H NMR (CDCl3): d 7.58–7.61 (m, 2H), 7.33–7.40
(m, 3H), 2.00–2.15 (m, 2H), 1.52–1.61 (m, 2H), 1.25–1.35 (m,
6H), 0.88 (t, J = 6.9 Hz); 19F NMR (CDCl3): d ꢀ72.7 (t,

Y. Li, J. Hu / Journal of Fluorine Chemistry 129 (2008) 382–385
385
J = 14.6 Hz, 2F); 13C NMR (CDCl3): d 136.1, 130.1 (t,
Acknowledgements
J = 276.6 Hz), 129.6, 128.9, 127.3, 38.7 (t, J = 24.3 Hz), 31.4,
28.6, 23.0 (t, J = 6.2 Hz), 22.4, 14.0; EI (m/z %) 244 (M+, 2.6),
110 (100.0); HRMS (EI) calcd. For C13H18F2S: 244.1097;
found 244.1102.
We gratefully acknowledge the National Natural Science
Foundation of China (20502029, 20772144), Shanghai Rising-
Star Program (06QA14063), and the Chinese Academy of
Sciences (Hundreds-Talent Program and Knowledge Innova-
tion Program) for financial support.
4.1.3. 1,1-Difluoro-2-phenylethyl phenyl sulfide (3c)
(PhCH2CF2SPh)
References
Liquid; IR (film): 3066, 1498, 1475, 1442, 1224, 1155, 1031,
977 cmꢀ1; 1H NMR (CDCl3): d 7.42–7.58 (m, 2H), 7.27–7.42
(m, 8H), 3.41 (t, J = 15.0 Hz, 2H); 19F NMR (CDCl3): d ꢀ72.0
(t, J = 14.7 Hz, 2F); 13C NMR (CDCl3): d 136.1, 131.9 (t,
J = 3.8 Hz), 130.5, 129.6, 128.9, 128.6 (t, J = 277.9 Hz), 128.4,
127.7, 126.8, 45.1 (t, J = 23.9 Hz); EI (m/z %): 250 (M+, 74.4),
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Liquid; IR (film): 3064, 1601, 1498, 1475, 1442, 1246, 1172,
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7.34–7.45 (m, 3H), 7.08 (d, J = 8.1 Hz, 2H), 6.78 (d, J = 7.8 Hz,
2H), 3.96 (t, J = 6.3 Hz, 2H), 2.28 (s, 3H), 2.23–2.38 (m, 2H),
2.02–2.12 (m, 2H); 19F NMR (CDCl3): d ꢀ73.1 (t, J = 15.2 Hz,
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66.6, 35.5 (t, J = 23.3 Hz), 23.3 (t, J = 2.3 Hz), 20.5; EI (m/z %)
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7.43 (m, 3H), 6.84–6.87 (m, 4H), 4.17 (t, J = 6.9 Hz, 2H), 3.76
(s, 3H), 2.56–2.66 (m, 2H); 19F NMR (CDCl3): d ꢀ71.9 (t,
J = 15.5 Hz, 2F); EI (m/z %) 310 (M+, 25.1), 123 (100.0);
HRMS (EI) calcd. For C16H16F2O2S: 310.0839; found
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