New electrophilic bromodifluoromethylation and pentafluoroethylation reagents

Article abstract of DOI:10.1055/s-0029-1219579

S-(fluoroalkyl)diphenylsulfonium salts have been successfully synthesized from the reaction between fluoroalkylsul-finates and triflic anhydride in dichloromethane through a one-pot procedure. These S-(fluoroalkyl) diphenylsulfonium salts have been demonstrated to be effective reagents to fluoroalkylate C-nucleophilic substrates. Ionic substitution and radical or halogenophilic mechanism might be all involved in the reactions. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1219579

LETTER
1089
New Electrophilic Bromodifluoromethylation and Pentafluoroethylation
Reagents
N
ew Electrophili
h
Bromodiflu
e
oromethyla
n
tion Reage
n
g
ts -Pan Zhang,a Hai-Ping Cao,a Zong-Ling Wang,a,b Chun-Tao Zhang,b Qing-Yun Chen,a Ji-Chang Xiao*a
a
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: jchxiao@mail.sioc.ac.cn
Hunan University of Chinese Medicine, Changsha, Hunan Province 410208, P. R. of China
b
Received 5 January 2010
analogous trifluoromethyl sulfonium salts from inexpen-
sive reagents and improved their electrophilic power by
introducing electron-withdrawing substituents on the
benzene rings.3b Recently, Prakash reported two new
Abstract: S-(fluoroalkyl)diphenylsulfonium salts have been suc-
cessfully synthesized from the reaction between fluoroalkylsul-
finates and triflic anhydride in dichloromethane through a one-pot
procedure. These S-(fluoroalkyl)diphenylsulfonium salts have been
demonstrated to be effective reagents to fluoroalkylate C-nucleo- electrophilic fluoromethylating reagents, S-(difluorome-
philic substrates. Ionic substitution and radical or halogenophilic
mechanism might be all involved in the reactions.
thyl)diaryl-sulfonium tetrafluoroborate and S-(monofluo-
romethyl)diarylsulfonium tetrafluoroborate, which were
Key words: fluorine,
alkyl)diphenylsulfonium salts, fluoroalkylation
nucleophiles,
sulfoxides,
S-(fluoro-
shown to be effective for the introduction of difluorome-
thyl or monofluoromethyl group into C, S, O, N, and P nu-
cleophiles.7 Although these reagents are very useful, they
are always prepared by multistep and laborious synthetic
Compounds containing the fluoroalkyl group have been procedures. In 2006, E. Magnier et al. developed a very
confirmed to be very important in organic chemistry. The short and efficient method to synthesize aryl trifluorome-
introduction of the fluoroalkyl group into organic mole- thyl sulfonium salts in one pot.8 Then they extended this
cules often changes their physical, chemical, and physio- method and successfully synthesized some new trifluo-
logical properties.1 Due to the recent progress in these romethyl dibenzothiophenium salts such as Umemoto-
fields, methodologies for the direct introduction of the type reagents.9 So far, most studies are limited to simple
perfluoroalkyl group are now available through nucleo- fluoroalkyl sulfonium salts. In order to acquire more in-
philic, free radical, and electrophilic approaches.2 Electro- formation about the electrophilicity of bromodi-
philic perfluoroalkylation, one of the three fundamental fluoroalkyl and long fluoroalkyl sulfonium salts, we
fluoroalkylation methods, has become increasingly im- investigated the synthesis and reaction of these fluoro-
portant in organic synthesis. However, it is not a trivial alkyl sulfonium salts.
task. The formation of the fluoroalkyl cation in these elec-
Based on the previous reports,3b,8,9 S-(fluoroalkyl)diphe-
trophilic fluoroalkylation reagents is quite difficult due to
nylsulfonium salts were synthesized from the simple and
the highest electronegativity of the fluorine atoms.3 Even
inexpensive material in a one-pot procedure (Table 1).
so, many reagents have been developed to introduce the
Reactivity was tuned successfully via trifluoromethane-
fluoroalkyl group into organic molecules. In 1970’s,
sulfonylation of fluoroalkylsulfinates with triflic anhy-
Yagupolskii reported a method for perfluoroalkylation us-
dride in dichloromethane. For example, (bromo-
ing (perfluoroalkyl)-p-tolyl-iodonium salts as the first
difluoromethyl)diphenylsulfonium
trifluoromethane-
electrophilic perfluoroalkylation reagent in polar solvent
under mild conditions.4 In 1984, two trifluoromethyl sul-
fonium salts were prepared as another class of electro-
philic perfluoroalkylation reagent, which could react with
sodium p-nitrothiophenolate in DMF to give p-nitrophe-
nyltrifluoromethyl sulfide in high yield.5 Umemoto
further extended these methods to the synthesis of (per-
fluoroalkyl)phenyliodonium trifluoromethanesulfonates,
(perfluoroalkyl)-phenyliodonium hydrogensulfates, and
some powerful electrophilic perfluoroalkyl sulfonium
agents that could transfer the perfluoroalkyl group to dif-
ferent kinds of organic molecules.6 In 1998, Shreeve and
co-workers developed an alternative route to prepare the
sulfonate (1a) was formed in 44% yield when sodium bro-
modifluoromethanesulfinate reacted with benzene and
triflic anhydride in dichloromethane at 0 °C for 2 hours
and then at room temperature for 22 hours (Table 1, entry
1). Its structure was confirmed by single-crystal X-ray dif-
fraction analysis (Figure 1).10 The reaction became com-
plicated, and the expected sulfonium salts were obtained
in a minor amount with longer fluoroalkyl chains. As
shown in Table 1, only 20% of (pentafluoroethyl)diphe-
nylsulfonium triflate (1b) was formed even after 4 days
(entry 2). 19F NMR analysis of the reaction mixture
showed that many side reactions occurred. Oxidation of
fluoroalkyl sulfinate happened during the reaction. Simi-
lar results were obtained in the case of sodium 2-chloro-
1,1,2,2-tetrafluoroethanesulfinate (entry 3).
SYNLETT 2010, No. 7, pp 1089–1092
x
x.
x
x.
2
0
1
0
Advanced online publication: 10.03.2010
DOI: 10.1055/s-0029-1219579; Art ID: W00210ST
© Georg Thieme Verlag Stuttgart · New York

1090
C.-P. Zhang et al.
LETTER
alkylsulfinates. Otherwise, only trace amount of the prod-
uct was obtained.
With these new S-(fluoroalkyl)diphenylsulfonium salts in
hand, we investigated their potential to act as electrophiles
in alkylation reactions. Sulfonium salts 1a and 1b were
taken as examples. Bromodifluoromethylation of (2-phe-
nylethynyl)lithium with 1a proceeded smoothly (Table 2,
entry 1). (2-Phenylethynyl)lithium was prepared in situ
before 1a was added in this reaction. Arylethynyl lithium
with electron-donating or electron-withdrawing substitu-
ent at para position of the phenyl ring was bromodifluo-
romethylated equally well under this reaction condition
(entries 2 and 3). Both 2b and 2c were formed in moderate
yield. Similar result was obtained while treating 1a with
hept-1-ynyllithium (entry 4). Other C-nucleophiles were
also successfully bromodifluoromethylated with 1a.
Compound 2e was satisfactorily produced when 1a react-
ed with ethyl 2-methyl-3-oxobutanoate in DMF at –50 °C
to room temperature (entry 5).
Figure 1 X-ray Crystallographic Structure of 1a
Table 1 One-Pot Synthesis of S-(Fluoroalkyl)diphenylsulfonium
Salts11
CH2Cl2
RFSO2Na
+
Tf2O
+
S+
RF
0 °C to r.t.
A comparison of these results with the previous reports
led us to think that an electrophilic mechanism might be
involved in this bromodifluoromethylation reaction.3b,6c
However, when ethyl 2-methyl-3-oxo-butanoate was re-
placed by 2-methylcyclopentane-1,3-dione in this reac-
tion, 3-(difluoromethoxy)-2-methyl-cyclopent-2-enone
(2f) was obtained in 50% yield (entry 6). Trace of bro-
modifluorinated product could be detected by 19F NMR
but not isolated due to its low yield. This indicated that the
radical or halogenophilic mechanism could not be exclud-
ed in this reaction system.6c These mechanisms might co-
exist and compete with each other. The predominant
pathway might depend on the nucleophiles and the reac-
tion conditions.
L–
1a–d
Entry RF
RFSO2Na/ Time
L
Yield
(%)b
Tf2O
1:2.4
1:2.4
1:2.4
(d)a
1
2
3
BrCF2
1
CF3SO3
CF3SO3
1a 44
1b 20
1c 8
CF3CF2
4
Cl(CF2)2
4
Cl(CF2)2SO3,
CF3SO3
4
Cl(CF2)4
1:2.4
5
Cl(CF2)4SO3
1d 4.5
a Reacted first at 0 °C for 2 h and then at r.t.
b Isolated yield.
Pentafluoroethylated product was similarly formed in the
reaction of sulfonium salt 1b with phenylacetylene or eth-
yl 2-methyl-3-oxobutanoate (entries 7 and 8). 19F NMR
measurement of the reaction course (entries 7 and 8)
showed the simultaneous formation of undesired 1H-pen-
tafluoroethanes (CF3CF2H). This might be another evi-
dence for the coexistence of the radical and ionic
substitution mechanism in these reactions.
Trifluoromethanesulfonate and 2-chloro-1,1,2,2-tetra-
fluoroethanesulfonate anions were both involved in the
sulfonium salts 1c. Efforts to isolate the two salts failed.
In addition, when sodium 4-chloro-1,1,2,2,3,3,4,4-octa-
fluorobutanesulfinate reacted with benzene and triflic an-
hydride in dichloromethane, (4-chloro-1,1,2,2,3,3,4,4-
octafluorobutyl)diphenylsulfonium salt (1d) with only
one anion was obtained, but the yield was extremely poor
(entry 4). Oxidation of 4-chloro-1,1,2,2,3,3,4,4-octafluo-
robutanesulfinate to the corresponding sulfonate also hap-
pened. Triflic anhydride has been known for its oxidative
properties,12 yet there is no explanation proposed. Tri-
fluoromethanesulfonate anions existing in sulfonium salts
became easier to be replaced by the oxidized sulfonate
with increasing length of the fluoroalkyl chain. The purity
of the sodium fluoroalkylsulfinate is an essential factor for
the success of this reaction, just as the literature reported.9
Lower purity of the sodium 2-chloro-1,1,2,2-tetrafluoro-
ethanesulfinate always resulted in the failure of prepara-
tion of the desired sulfonium salts. The temperature also
has an influence on the yield of the reaction. At the begin-
ning of the reaction, lower reaction temperature had to be
employed to assure the mild transformation of fluoro-
In summary, we have successfully synthesized S-(bro-
modifluoromethyl)- and S-(pentafluoroethyl)diphenylsul-
fonium salts by using a slightly modified Magnier’s
approach. Because of the strong electronegativity of the
fluorine atoms, sulfonium salts with long fluoroalkyl
chain are very difficult to synthesize. The purity of the so-
dium fluoroalkylsulfinate as well as the temperature used
at the beginning of the reaction has great influence on the
reaction. These S-(fluoroalkyl)-diphenyl-sulfonium salts
have been demonstrated to be effective electrophilic fluo-
roalkylating agents of C-nucleophilic substrates. Ionic
substitution and radical or halogenophilic mechanism
might be all involved in these fluoroalkylation reactions.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2010, No. 7, 1089–1092 © Thieme Stuttgart · New York

LETTER
New Electrophilic Bromodifluoromethylation Reagents
1091
Table 2 Electrophilic Fluoroalkylation of Sulfonium Salts13,14
+
R
Li
R
H
R
RF
S
TfO–
or
RF
or
or
COOEt
base
COOEt
COOEt
solvent
temp
(1a or 1b)
RF
Na+
COOEt
COOEt
COOEt
Entry
1
Substrates
Conditions (base, temp, solvent)a
Products
Yield (%)b
BuLi, –78 °C, 1a, then r.t., THF
2a 47
CF2Br
2
3
4
BuLi, –78 °C, 1a, then r.t., THF
BuLi, –78 °C, 1a, then r.t., THF
BuLi, –78 °C, 1a, then r.t., THF
2b 52
2c 57
2d 45
MeO
Br
CF2Br
MeO
Br
CF2Br
CF2Br
O
O
O
COOEt
CF2Br
5
NaH, –50 °C, 1a, then r.t., DMF
2e 55
O
6
7
8
NaH, –50 °C, 1a, then r.t., DMF
BuLi, –78 °C, 1b, then r.t., THF
NaH, –50 °C, 1b, then r.t., DMF
2f 50
2g 25
2h 33
O
Ο
OCF2H
O
CF2CF3
O
O
O
COOEt
CF2CF3
O
a Anions was first generated in the reaction with BuLi or NaH at –78 or –50 °C. Then the fluoroalkylating agents were added. The cooling bath
was removed, and the reaction system was warmed to r.t.
b Isolated yield.
(5) Yagupolskii, L. M.; Kondratenko, N. V.; Timofeeva, G. N.
Acknowledgment
J. Org. Chem. USSR 1984, 20, 103.
We thank the Chinese Academy of Sciences (Hundreds of Talents
(6) (a) Umemoto, T.; Kuriu, Y.; Shuyama, H.; Miyano, O.;
Program) and the National Natural Science Foundation (20772147,
20972179) for financial support.
Nakayama, S.-I. J. Fluorine Chem. 1982, 20, 695.
(b) Umemoto, T.; Kuriu, Y.; Shuyama, H.; Miyano, O.;
Nakayama, S.-I. J. Fluorine Chem. 1986, 31, 37.
(c) Umemoto, T.; Ishihara, S. J. Am. Chem. Soc. 1993, 115,
2156.
References and Notes
(7) (a) Prakash, G. K. S.; Weber, C.; Chacko, S.; Olah, G. A.
Org. Lett. 2007, 9, 1863. (b) Prakash, G. K. S.; Ledneczki,
I.; Chacko, S.; Olah, G. A. Org. Lett. 2007, 10, 557.
(8) Magnier, E.; Blazejewski, J.-C.; Tordeux, M.; Wakselman,
C. Angew. Chem. Int. Ed. 2006, 45, 1279.
(1) (a) Chambers, R. D. In Fluorine in Organic Chemistry; John
Wiley and Sons: New York, 1973. (b) In Organofluorine
Chemistry, Principles and Commercial Applications; Banks,
R. E.; Smart, B. E.; Tatlow, J. C., Eds.; Plenum Press: New
York, 1994. (c) In Fluorine-Containing Amino Acids,
Synthesis and Properties; Kukhar, V. P.; Soloshonok, V. A.,
Eds.; John Wiley and Sons: Chichester, 1995. (d) Matsnev,
A.; Noritake, S.; Nomura, Y.; Tokunaga, E.; Nakamura, S.;
Shibata, N. Angew. Chem. Int. Ed. 2010, 49, 572.
(2) Umemoto, T. Chem. Rev. 1996, 96, 1757.
(9) Macé, Y.; Raymondeau, B.; Pradet, C.; Blazejewski, J.-C.;
Magnier, E. Eur. J. Org. Chem. 2009, 1390.
(10) CCDC 759656 contains the supplementary crystallographic
data for the compound 1a. This data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif.
(11) Typical Procedure for the Preparation of 1a–d
Under nitrogen atmosphere, benzene (7.5 mL, 84.0 mmol)
and trifluoromethanesulfonic anhydride (6.0 mL, 35.5
mmol) were added into a suspension of sodium pentafluoro-
ethanesulfinate15 (3.18 g, 15.4 mmol) in CH2Cl2 (5 mL),
which was well cooled by ice bath. After vigorously stirring
at 0 °C for 2 h, the reaction mixture was warmed to r.t. and
continued to react for 4 d. Then the reaction mixture was
(3) (a) Huheey, J. E. J. Phys. Chem. 1965, 69, 3284. (b) Yang,
J.-J.; Kirchmeier, R. L.; Shreeve, J. M. J. Org. Chem. 1998,
63, 2656.
(4) (a) Yagupolskii, L. M.; Maletina, I. I.; Kondratenko, N. V.;
Orda, V. V. Synthesis 1978, 835. (b) Yagupol’skii, L. M.;
Mironova, A. A.; Maletina, I. I.; Orda, V. V. Zh. Org. Khim.
1980, 16, 232. (c) Yagupolskii, L. M. J. Fluorine Chem.
1987, 36, 1.
Synlett 2010, No. 7, 1089–1092 © Thieme Stuttgart · New York

1092
C.-P. Zhang et al.
LETTER
diluted with CH2Cl2 (60 mL) and filtered. The filtrate was
concentrated under reduced pressure, and the residue was
purified by column chromatography on silica gel using
CH2Cl2–MeCN (4:1) as the eluent. After recrystallization
from pentane–EtOAc, 1.40 g of 1b (20%) was obtained as a
white solid. 1H NMR (300 MHz, CDCl3): d = 7.84 (t, J = 7.7
Hz, 2 H), 7.95 (t, J = 8.2 Hz, 1 H), 8.34 (d, J = 8.2 Hz, 2 H).
19F NMR (282 MHz, CDCl3): d = –94.5 (s, 2 F), –75.7 (s, 3
F), –76.8 (s, 3 F). 13C NMR (100 MHz, CDCl3): d = 137.4,
133.9, 132.3, 120.7 (q, J = 318.5 Hz, CF3), 117.0. ESI-MS:
m/z = 305.0 [M+]. IR (KBr): 3067, 1477, 1455, 1331, 1288,
1254, 1234, 1160, 1128, 1031, 938, 757, 639, 517, 504 cm–1.
Anal. Calcd for C15H10F8O3S2: C, 39.65, H, 2.22. Found: C,
39.64, H, 2.51.
7.57 (d, J = 7.7 Hz, 2 H), 7.49 (t, J = 7.3 Hz, 1 H), 7.40 (t,
J = 7.7 Hz, 2 H). 19F NMR: d = –101.2 (q, J = 4.2 Hz, 2 F),
–85.3 (t, J = 4.2 Hz, 3 F).
(14) Typical Procedure for the Fluoroalkylation of 2e–f,h
To a 25 mL round-bottomed flask, ethyl 2-methyl-3-
oxobutanoate (70 mg, 0.49 mmol) was dissolved in anhyd
DMF (4 mL). NaH (24 mg, 56%, 0.56 mmol) was added
under a N2 atmosphere. The reaction mixture was stirred at
r.t. for 30 min then cooled to –50 °C. Compound 1b (226 mg
in 2 mL of anhyd DMF, 0.50 mmol) was added, and the
cooling bath was removed. After warming naturally to r.t.,
the reaction mixture was poured into H2O (30 mL), extracted
with Et2O (30 mL), washed with brine (3 × 20 mL), and
dried over anhyd Na2SO4. The ether layer was evaporated
under reduced pressure. The residue was purified by column
chromatography on silica gel using PE–EtOAc (10:1) as the
eluent; 42 mg of 2h (33%) was obtained as a colorless liquid.
1H NMR (300 MHz, CDCl3): d = 4.29 (q, J = 7.3 Hz, 2 H),
2.34 (s, 3 H), 1.61 (s, 3 H), 1.30 (t, J = 7.3 Hz, 3 H). 19F NMR
(282 MHz, CDCl3): d = –113.5 (dd, AB, 2JFF = 282.5 Hz, 2
F), –78.8 (s, 3 F). 13C NMR (100 MHz, CDCl3): d = 197.1,
166.1, 63.3 (t, J = 19.5 Hz), 62.8, 27.9, 15.6, 13.7. MS (EI):
m/z = 43 (100), 44 (5.3), 73 (3.0), 77 (2.9), 105 (7.3), 123
(6.1), 192 (3.4), 220 (7.3). IR (KBr): 2988, 2942, 1734,
1466, 1389, 1365, 1338, 1260, 1209, 1107, 1004, 745 cm–1.
HRMS: m/z calcd for C9H11O3F5: 262.0628; found:
262.0625.
(12) (a) Maas, G.; Stang, P. J. Org. Chem. 1981, 46, 1606.
(b) Baraznenok, I. L.; Nenajdenko, V. G.; Balenkova, E. S.
Tetrahedron 2000, 56, 3077.
(13) Typical Procedure for the Fluoroalkylation of 2a–d,g
To a 25 mL round-bottomed flask, 1-ethynylbenzene (50
mg, 0.49 mmol) and anhyd THF (4 mL) were added and
maintained under a N2 atmosphere at –78 °C. n-BuLi (0.22
mL of a 2.5 mol L–1 solution in hexane, 0.55 mmol) was
added, and the reaction mixture was stirred at –78 °C for 30
min. Then 1b (226 mg in 2 mL of anhyd THF, 0.50 mmol)
was added. After 1 h, the cooling bath was removed, and the
reaction was warmed naturally to r.t. Then the reaction
mixture was poured into H2O (30 mL), extracted with Et2O
(30 mL), washed with brine (3 × 20 mL), and dried over
anhyd Na2SO4. Et2O was evaporated under reduced
pressure, and the residue was purified by column chroma-
tography on silica gel using pentane as the eluent; 28 mg of
2g (25%) was obtained as a colorless liquid. 1H NMR: d =
(15) For the preparation of sodium fluoroalkylsulfinates, see:
(a) Huang, W.-Y.; Zhang, H.-Z. Chin. J. Chem. 1992, 10,
274. (b) Hu, L.-Q.; DesMarteau, D. D. Inorg. Chem. 1993,
32, 5007. (c) Huang, W.-Y.; Huang, B.-N.; Wang, W.
Huaxue Xuebao 1985, 663.
Synlett 2010, No. 7, 1089–1092 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.