Nucleophilic (phenylsulfonyl)difluoromethylation of alkyl halides using PhSO2CF2SiMe3: Preparation of gem-difluoroalkenes and trifluoromethyl compounds

Article abstract of DOI:10.1016/j.tetlet.2010.09.068

Nucleophilic (phenylsulfonyl)difluoromethylation of both alkyl iodides and bromides was successfully accomplished by using CsF/15-crown-5 as an initiating system in DME, and the amount of 15-crown-5 was found to be critical to the yield of the product. The prepared (phenylsulfonyl)difluoromethylated alkanes were converted into gem-difluoroalkenes by a base-mediated 1,2-elimination reaction, and the latter species could be further transformed into trifluoromethyl compounds in the presence of KF/18-crown-6 or TBAF.

Full text of DOI:10.1016/j.tetlet.2010.09.068

Tetrahedron Letters 51 (2010) 6150–6152
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Tetrahedron Letters
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Nucleophilic (phenylsulfonyl)difluoromethylation of alkyl halides using
PhSO2CF2SiMe3: preparation of gem-difluoroalkenes
and trifluoromethyl compounds
⇑
Lingui Zhu, Ya Li, Yanchuan Zhao, Jinbo Hu
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling-ling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Nucleophilic (phenylsulfonyl)difluoromethylation of both alkyl iodides and bromides was successfully
accomplished by using CsF/15-crown-5 as an initiating system in DME, and the amount of 15-crown-5
was found to be critical to the yield of the product. The prepared (phenylsulfonyl)difluoromethylated
alkanes were converted into gem-difluoroalkenes by a base-mediated 1,2-elimination reaction, and the
latter species could be further transformed into trifluoromethyl compounds in the presence of KF/18-
crown-6 or TBAF.
Received 13 August 2010
Revised 14 September 2010
Accepted 17 September 2010
Available online 22 September 2010
Keywords:
Fluorine
Ó 2010 Elsevier Ltd. All rights reserved.
(Phenylsulfonyl)difluoromethylation
Difluoroalkene
Trifluoromethylation
Nucleophilic substitution
Fluoroalkylation
Selective incorporation of fluorine atom(s) or fluorine-contain-
ing moieties into organic molecules can often bring about many
profound changes in their physical, chemical, and biological
properties.1,2 Among the fluorine-containing moieties, gem-
difluorovinyl group is of particular interest owing to its high
electrophilicity, isosteric property as a carbonyl group,3,4 as well
as its critical role in some enzyme inhibitors.5 Moreover, gem-
difluoroalkenes are also important synthetic precursors to prepare
other fluorinated compounds and polymers.6
At present, there are several methods to prepare gem-
difluoroalkenes,7 including Wittig-type reactions,8 elimination reac-
tions,9 and Julia–Kocienski olefination.10 Previously, Prakash et al.
reported the preparation of gem-difluoroalkenes by a substitution-
elimination method using primary alkyl halides and difluoromethyl
phenyl sulfone (PhSO2CF2Y).11 Due to the use of a strong base such
as t-BuOK, this method is not compatible with activated alkyl halides
such as benzyl bromides.11 On the other hand, as an alternative re-
agent to PhSO2CF2Y, [(phenylsulfonyl)difluoromethyl]trimethylsi-
lane (PhSO2CF2SiMe3, 1) was successfully applied by us in the
nucleophilic (phenylsulfonyl)difluoromethylation of some base-
sensitive substrates such as enolizable aldehydes under mild condi-
tions.12 Recently, fluoride-initiated cross-coupling reactions
between alkyl halides and RfSiMe3 (Rf = CF3, C2F5, PhSCF2) reagents
were reported by Tyrra et al.13a and us.13b Inspired by these results,
we envisioned that a nucleophilic substitution reaction between an
alkyl halide and PhSO2CF2SiMe3 reagent in the presence of a fluoride
ion source could also be possible. More importantly, the prepared
PhSO2CF2-containing alkanes could be further transformed into
trifluoromethyl compounds through gem-difluoroalkene inter-
mediates.14
First of all, we examined the reaction conditions of the nucleo-
philic (phenylsulfonyl)difluormethylation reaction with PhSO2CF2-
SiMe (1) by using iodoethane (2a) as a model substrate. The results
are shown in Table 1. It was found that, when tetrabutylammo-
nium (triphenylsilyl)-difluorosilicate (TBAT) was used as an initiat-
ing system in THF,15 the (phenylsulfonyl)difluormethylation
reaction between reagent 1 and substrate 2a hardly proceeded
(Table 1, entry 1). When KF (2.0 equiv)/DMF or CsF (2.0 equiv)/
15-crown-5 (4.0 equiv)/1,2-dimethoxyethane (DME) was used,13a
product 3a was obtained in 23% and 84% yield, respectively
(Table 1, entries 2 and 3). Although the yield of 3a was satisfactory,
the amount of 15-crown-5 was still too high (4.0 equiv relative to
2a). Therefore, we decided to explore the effect of the amount of
15-crown-5 on the yield of the product. After testing various
amounts from 1.0 to 4.0 equiv (Table 1, entries 3À7), we found that
the amount of 15-crown-5 was critical to the yield of the product.
As shown in Table 1, when the amount of 15-crown-5 was below
2.0 equiv, the yields linearly increased with the amounts of
15-crown-5; however, when the amount of 15-crown-5 was above
2.0 equiv, the yields almost kept intact.
⇑
Corresponding author. Tel.: +86 21 54925174; fax: +86 21 64166128.
E-mail address: jinbohu@sioc.ac.cn (J. Hu).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.068

L. Zhu et al. / Tetrahedron Letters 51 (2010) 6150–6152
6151
Table 1
gem-difluoroalkenes was observed probably owing to the weak
basicity of CsF.
The optimization of reaction condition
conditionsa
Having achieved nucleophilic substitution of alkyl halides with
PhSO2CF2SiMe3, we turned our interest into the preparation of
gem-difluoroalkenes by a base-mediated 1,2-elimination reaction
from product 3. According to the modified procedure using
LiHMDS as a base,17 gem-difluoroalkenes 4aÀe were obtained in
moderate to excellent yields from 3f and 3jÀm (Table 3).
With gem-difluoroalkenes 4 in hand, their further transfor-
mations were taken into account. In the presence of wet KF and
18-crown-6,18 gem-difluoroalkenes such as 4bÀe gave trifluorom-
ethylated products 5bÀe in moderate yields, but gem-difluoroalk-
ene-containing aliphatic chain 4a failed to give the CF3-containing
product 5a (Table 4, entries 1À5). Considering that tetrabutylam-
monium fluoride (TBAF) can act both as a good nucleophilic fluori-
nating agent and as a phase-transfer catalyst (PTC), we applied
TBAF to replace wet KF/18-crown-6 system in the reaction. Much
to our delight, it was found that in the presence of TBAF, the trans-
formation could smoothly proceed at ambient temperature to af-
ford the desired products 5bÀe in satisfactory yields (Table 4,
entries 2À5).19
PhSO2CF2SiMe3
CH3CH2I
2a
CH3CH2CF2SO2Ph
3a
1
(2.0 equiv)
(1.0 equiv)
Entry
Conditions
15-Crown-5 (equiv)
Yieldb (%)
1
2
3
4
5
6
7
8
9
TBAT/THF/0 °C
KF/DMF/À20 °C
CsF/DMEÀ20 °C
CsF/DME/À20 °C
CSF/DME/À20 °C
CSF/DME/À20 °C
CSF/DME/À20 °C
CsF/DME/À78 °C
CsF/DME/0 °C
None
None
4.0
3.0
2.0
1.5
1.0
2.0
2.0
<10
23
84
85
85
65
44
77
24
10
11
CsF/DME/À20 °C
2.0
2.0
34c
<10d
CsF/DME/À20 °C
a
In all cases, the amount of fluoride source was 2.0 equiv relative to that of 2a.
b
Yields were determined by 19F NMR spectroscopy using PhCF3 as an internal
standard.
c
CH3CH2Br was used as a substrate instead of 2a.
CH3CH2OTs was used as a substrate instead of 2a.
d
In conclusion, an improved protocol to prepare gem-difluoroalk-
enes has been achieved by (phenylsulfonyl)difluoromethylation of
alkyl halides using PhSO2CF2SiMe3 (1) and subsequent base-
mediated 1,2-elimination. Taking CsF/15-crown-5 as an initiating
system in DME, (phenylsulfonyl)difluoromethylation of both
simple alkyl iodides and activated alkyl bromides smoothly
proceeded. It was found that the amount of additive 15-crown-5
was critical to the yield of the product. The prepared (phenylsulfo-
nyl)difluoromethylated alkanes were converted into gem-
difluoroalkenes by a base-mediated elimination reaction, and the
latter species could be further transformed into trifluoromethyl
compounds in the presence of wet KF/18-crown-6 or TBAF reagent.
Furthermore, an investigation on reaction temperature indi-
cated that the reaction proceeded best at À20 °C (Table 1, entries
5, 8, and 9). In addition, when bromoethane and ethyl tosylate
were used as substrates instead of iodoethane, the product yields
were sharply decreased (Table 1, entries 10 and 11). Finally, the
optimal reaction condition was chosen as follows: using CsF/15-
crown-5 as an initiating system in DME solvent and running the
reaction at temperatures ranging from À20 °C to ambient temper-
ature (Table 1, entry 5).16
By using the optimized condition as standard, we extended the
reaction scope to a variety of alkyl halides to give corresponding
(phenylsulfonyl)difluoromethylated products 3. As illustrated in
Table 2, not only could primary alkyl iodides bearing different chain
length afford products 3aÀf in moderate to good yields (Table 2,
entries 1À6), activated bromides such as allyl bromide and benzyl
bromides could also give the corresponding products 3g and
3iÀm in similar yields (Table 2, entries 7 and 9À13). However,
the reactions with alkylhalides bearing strongelectron-withdrawing
groups, such as ethyl 2-bromoacetate and p-nitrobenzyl bromide,
were not successful (Table 2, entries 8 and 14). It should be
mentioned that, in all cases as shown in Table 2, no formation of
Table 3
Preparation of gem-difluoroalkenes 4aÀe
LiHMDS (1.5 equiv)
RCH2CF2SO2Ph
RCH CF2
THF (or DMF), 0 o
C
3
4
Entry RCH2CF2SO2Ph (3)
RCH@CF2 (4)
C6H5(CH2)2CH@CF2 (4a)
Yielda (%)
68b
1
2
3
4
5
C6H5(CH2)2CH2CF2SO2Ph (3f)
4-MeO-C6H4CH2CF2SO2Ph (3j) 4-MeO-C6H4CH@CF2 (4b) 78b
4-Ph-C6H4CH2CF2SO2Ph (3k)
1-Naphth-CH2CF2SO2Ph (3l)
4-Br-C6H4CH2CF2SO2Ph (3m)
4-Ph-C6H4CH@CF2 (4c)
1-Naphth-CH@CF2 (4d)
4-Br-C6H4CH@CF2 (4e)
90
76
77
a
Isolated yield.
The reactions were carried out in DMF.
b
Table 2
Nucleophilic (phenylsulfonyl)difluormethylation of alkyl halides 2
CsF/15-crown-5
RCH2CF2SO2Ph
PhSO2CF SiMe3
2
RCH2X
DME, 20 oC
−
1
2
3
Table 4
Further transformations of gem-difluoroalkenes 4
Entry RCH2X (2)
RCH2CF2SO2Ph (3)
Yielda (%)
Condition A
or Condition B
RCH CF2
RCH2CF3
5
1
2
3
4
5
6
7
8
9
CH3CH2I (2a)
CH3CH2CF2SO2Ph (3a)
CH3CH2CH2CF2SO2Ph (3b)
79
65
4
CH3CH2CH2I (2b)
CH3(CH2)2CH2I (2c)
CH3(CH2)4CH2I (2d)
CH3(CH2)5CH2I (2e)
C6H5(CH2)2CH2I (2f)
CH2@CHCH2Br (2g)
EtOOCCH2Br (2h)
C6H5CH2Br (2i)
CH3(CH2)2CH2CF2SO2Ph (3c)
CH3(CH2)4CH2CF2SO2Ph (3d)
CH3(CH2)5CH2CF2SO2Ph (3e)
C6H5(CH2)2CH2CF2SO2Ph (3f)
CH2@CHCH2CF2SO2Ph (3g)
EtOOCCH2CF2SO2Ph (3h)
C6H5CH2CF2SO2Ph (3i)
62
71
72
73
57
0
KF, 18-crown-6, DMF(wet), 80−140 oC
Condition A:
Condition B: TBAF, THF, rt.
Entry
RCH@CF2 (4)
RCH2CF3 (5)
Yielda (%)
1
2
3
4
5
C6H5(CH2)2CH@CF2 (4a)
4-MeO-C6H4CH@CF2 (4b)
4-Ph-C6H4CH@CF2 (4c)
1-Naphth-CH@CF2 (4d)
4-Br-C6H4CH@CF2 (4e)
C6H5(CH2)2CH2CF3 (5a)
4-MeO-C6H4CH2CF3 (5b)
4-Ph-C6H4CH2CF3 (5c)
1-Naphth-CH2CF3 (5d)
4-Br-C6H4CH2CF3 (5e)
0 (0)
57b (56)
58 (66)
60 (55)
64b (61b)
84
10
11
12
13
14
4-MeO-C6H4CH2Br (2j) 4-MeO-C6H4CH2CF2SO2Ph (3j) 83
4-Ph-C6H4CH2Br (2k)
1-Naphth-CH2Br (2l)
4-Br-C6H4CH2Br (2m)
4-Ph-C6H4CH2CF2SO2Ph (3k)
1-Naphth-CH2CF2SO2Ph (3l)
4-Br-C6H4CH2CF2SO2Ph (3m)
79
77
51
a
Isolated yield obtained by using either condition A or condition B (data in
parentheses).
4-O2N-C6H4CH2Br (2n) 4-O2N-C6H4CH2CF2SO2Ph (3n) Trace
b
Determined by 19F NMR using PhCF3 as an internal standard.
a
Isolated yield.

6152
L. Zhu et al. / Tetrahedron Letters 51 (2010) 6150–6152
9. (a) McDonald, I. A.; Lacoste, J. M.; Bey, P.; Palfreyman, M. G.; Zreika, M. J. Med.
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11. Prakash, G. K. S.; Hu, J.; Wang, Y.; Olah, G. A. Angew. Chem., Int. Ed. 2004, 43,
5203–5206.
Therefore, in certain cases, the (phenylsulfonyl)difluoromethyl
functionality (in combination of an additional fluoride ion source)
can be considered as a synthetic equivalent of trifluoromethyl
group.
Acknowledgments
12. (a) Ni, C.; Hu, J. Tetrahedron Lett. 2005, 46, 8273–8277; (b) Liu, J.; Ni, C.; Wang,
F.; Hu, J. Tetrahedron Lett. 2008, 49, 1605–1608.
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M. J. Fluorine Chem. 2007, 128, 813–817; (b) Li, Y.; Hu, J. J. Fluorine Chem. 2008,
129, 382–385.
14. Previously, PhSO2CF2 group was known to act as synthetic equivalents of
difluoromethyl (CF2H), difluoromethylene (ÀCF2À) and difluoromethylidene
(@CF2) functionalities. See reviews: (a) Hu, J. J. Fluorine Chem. 2009, 130, 1130–
1139; (b) Prakash, G. K. S.; Hu, J. Acc. Chem. Soc. 2007, 40, 921–930; (c) Hu, J.;
Zhang, W.; Wang, F. Chem. Commun. 2009, 7465–7478.
This work was supported by the National Natural Science
Foundation of China (20502029, 20772144, 20825209, 20832008)
and the Chinese Academy of Sciences (Hundreds-Talent Program
and Knowledge Innovation Program) for financial support.
Supplementary data
15. Prakash, G. K. S.; Mandal, M.; Olah, G. A. Synlett 2001, 77–78.
16. Typical experimental procedure for nucleophilic substitution of alkyl halides with
PhSO2CF2SiMe3 (1): The reaction was carried out in a Schlenk flask under a
nitrogen atmosphere. A solution of CsF (205 mg, 1.349 mmol) and 15-crown-5
(300 mg, 1.36 mmol) in DME (2 mL) was cooled to À20 °C (ice-sodium
chloride) after stirring at room temperature for 10 min, then a mixture of
PhSO2CF2SiMe3 (1) (356 mg, 1.347 mmol) and ethyl iodide (105 mg,
0.675 mmol) in DME (1.2 mL) was slowly added to the reaction flask. The
reaction temperature was allowed to warm to room temperature. When the
reaction was completed by TLC, water (5 mL) was added to the mixture and the
aqueous layer was extracted with EtOAc (3 Â 5 mL). The combined organic
layers was dried over Na2SO4 and concentrated under vacuum. The residue was
purified by silica gel column chromatography (EtOAc/PE = 1:50) to give
product 3a as colorless oil, 79% yield (117 mg). 1H NMR (300 MHz, CDCl3): d
7.99 (d, J = 2.4 Hz, 2H), 7.80À7.75 (m, 1H), 7.66À7.61 (m, 2H), 2.48À2.49 (m,
2H), 1.20 (t, J = 7.5 Hz, 3H). 19F NMR (282 MHz, CDCl3): d À106.0 (t, J = 19.2 Hz,
2F) lit.10
Supplementary data (experimental procedures and spectro-
scopic data for all isolated new compounds) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.09.068.
References and notes
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19. Typical procedure for the preparation of compound 5: Condition A: A mixture of
4d (151 mg, 0.794 mmol), KF (140 mg, 2.547 mmol), and 18-crown-6 ether in
DMF (3 mL) containing water (0.15 mL) was stirred in sealed tube and heated
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.
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