Preparation and synthetic applications of aryl tetraflates (ArOSO 2CF2CF2H)

Article abstract of DOI:10.1021/jo701630a

(Chemical Equation Presented) We have recently developed an improved synthetic route to 1,1,2,2-tetrafluoroethanesulfonic acid (HCF ₂CF₂SO₃H, TFESA) and explored the applications of this newly available superacid in catalysis. Low volatility, ease of handling, and a convenient ¹H NMR handle make this acid an attractive alternative to triflic acid. TFESA can also be converted to several of its derivatives: anhydride, sulfonyl chloride, and sulfonyl fluoride, which provide a good entry point for the synlhesis of aryl sulfonates. We prepared several aryl esters of 1,1,2,2-tetrafluoroethanesulfonic acid (aryl tetraflates) and showed that they can be used in a number of palladium-catalyzed coupling reactions (Suzuki, Heck, and Buchwald-Hartwig couplings). While the reactivity of tetraflates lies between that of triflates and chlorides, tetraflates appear to be more thermally stable. Additionally, the presence of a hydrogen atom in the tetraflate group facilitates monitoring of reactions and characterization of derivatives.

Full text of DOI:10.1021/jo701630a

SCHEME 1. Preparation of TFESA
Preparation and Synthetic Applications of Aryl
Tetraflates (ArOSO2CF2CF2H)
Vsevolod V. Rostovtsev,* Lois M. Bryman,
Christopher P. Junk, Mark A. Harmer, and Liane G. Carcani
palladium-catalyzed reactions such as Suzuki coupling,7 Heck
reaction,8,9 and Buchwald-Hartwig aminations.10 The reactivity
of these derivatives in coupling reactions falls somewhere
between that of aryl chlorides and aryl bromides.1
Derivatives of longer chain perfluoroalkanesulfonic acids
show similar reactivity and were explored for use in fluorous
technologies.11,12
DuPont Central Research and DeVelopment,
Experimental Station,† Wilmington, Delaware, 19880
VseVolod.rostoVtseV@usa.dupont.com
ReceiVed July 30, 2007
We have recently reported the synthesis of a series of fluori-
nated sulfonate salts and sulfonic acids.13-15 Addition of sulfites
to a variety of fluoroolefins and perfluorovinyl ethers provides
a convenient and practical preparation of the corresponding salts,
which can be further converted to sulfonic acids. For example,
potassium 1,1,2,2-tetrafluoroethanesulfonate (or tetraflate) was
prepared from tetrafluoroethylene in a buffered aqueous solution
of potassium sulfite and bisulfite and then converted to 1,1,2,2-
tetrafluoroethanesulfonic acid (TFESA) in 90% overall yield
by distillation from oleum (Scheme 1).15
TFESA is a convenient starting point for the preparation of
a number of acid derivatives. Here, we report the preparation
of 1,1,2,2-tetrafluoroethanesulfonyl chloride (1), fluoride (2),
anhydride (3), and aryl esters of TFESA (aryl tetraflates). We
also examined the utility of aryl tetraflates in Suzuki, Heck,
and Buchwald-Hartwig reactions.
1,1,2,2-Tetrafluoroethanesulfonic acid anhydride (TFESAA)
was prepared in moderate yields by distillation from P4O10,
following the procedure reported for triflic anhydride (Scheme
1).16 TFESAA is a colorless liquid that starts to decompose when
heated above 105 °C.17 It can be distilled at 80-100 °C under
reduced pressure.
Synthesis of the chloride was disclosed in a Hoechst patent18
and the same method was used in this work to obtain sulfonyl
chloride 1 from TFESA in excellent yields (Scheme 2). The
product is a colorless liquid with a boiling point of 104 °C at
1 atm. Treatment of 1 with CsF in sulfolane solvent, followed
by distillation afforded sulfonyl fluoride 2 in 83% yield. Fluoride
We have recently developed an improved synthetic route
to 1,1,2,2-tetrafluoroethanesulfonic acid (HCF2CF2SO3H,
TFESA) and explored the applications of this newly available
superacid in catalysis. Low volatility, ease of handling, and
1
a convenient H NMR handle make this acid an attractive
alternative to triflic acid. TFESA can also be converted to
several of its derivatives: anhydride, sulfonyl chloride, and
sulfonyl fluoride, which provide a good entry point for the
synthesis of aryl sulfonates. We prepared several aryl esters
of 1,1,2,2-tetrafluoroethanesulfonic acid (aryl tetraflates) and
showed that they can be used in a number of palladium-
catalyzed coupling reactions (Suzuki, Heck, and Buchwald-
Hartwig couplings). While the reactivity of tetraflates lies
between that of triflates and chlorides, tetraflates appear to
be more thermally stable. Additionally, the presence of a
hydrogen atom in the tetraflate group facilitates monitoring
of reactions and characterization of derivatives.
Triflate (CF3SO2-) and nonaflate (C4F9SO2-) derivatives are
widely used in organic chemistry as synthetic intermediates.1-4
Aryl triflates and nonaflates can be conveniently prepared from
phenols and sulfonic acid anhydrides or fluorides. Perfluoro-
alkanesulfonyl esters of 4-nitrophenol can also be used as
sulfonyl transfer agents for the synthesis of aryl triflates and
nonaflates.5,6 The presence of a fluorinated sulfonate ester
activates the carbon-oxygen bond of the phenol, so that aryl
trifaltes and nonaflates become substrates for a number of
(7) Suzuki, A. In Modern Arene Chemistry; Astruc, D., Ed.; Wiley-
VCH: Weinheim, Germany, 2002; pp 53-106.
(8) Zeni, G.; Larock, R. C. Chem. ReV. 2006, 106 (11), 4644-4680.
(9) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100 (8), 3009-
3066.
(10) Hartwig, J. F. In Modern Arene Chemistry; Astruc, D., Ed.; Wiley-
VCH: Weinheim, Germany, 2002; pp 107-168.
(11) Zhang, W.; Nagashima, T. J. Fluorine Chem. 2006, 127 (4-5),
588-591.
(12) Zhang, X.; Sui, Z. Tetrahedron Lett. 2003, 44 (15), 3071-3073.
(13) Harmer, M. A.; Junk, C. P.; Schnepp, Z. U.S. Patent Appl. 2006-
447713, 2006.
† Contribution No. 8807.
(1) Ritter, K. Synthesis 1993, 735-62.
(2) Stang, P. J.; Hanack, M.; Subramanian, L. R. Synthesis 1982, 85-
(14) Junk, C. P.; Harmer, M. A.; Feiring, A. E.; Schadt, F. L.; Schnepp,
Z. U.S. Patent Appl. 2006-447825, 2006.
126.
(3) Howells, R. D.; Mc Cown, J. D. Chem. ReV. 1977, 77(1), 69-92.
(4) Huang, W.-Y.; Chen, Q.-Y. In The Chemistry of Sulfonic Acids, Esters
and Their DeriVatiVes; Patai, S., Rappoport, Z., Eds.; John Wiley & Sons
Ltd: New York, 1991.
(5) Neuville, L.; Bigot, A.; Dau, M. E. T. H.; Zhu, J. J. Org. Chem.
1999, 64 (20), 7638-7642.
(6) Zhu, J.; Bigot, A.; Elise, M.; Dau, T. H. Tetrahedron Lett. 1997, 38
(7), 1181-1182.
(15) Harmer, M. A.; Junk, C.; Rostovtsev, V.; Carcani, L. G.; Vickery,
J.; Schnepp, Z. Green Chem. 2007, 9 (1), 30-37. TFESA has recently
become commercially available.
(16) Burdon, J.; Farazmand, I.; Stacey, M.; Tatlow, J. C. J. Chem. Soc.
1957, 2574-2578.
(17) Hassani, M. O.; Germain, A.; Brunel, D.; Commeyras, A. Tetra-
hedron Lett. 1981, 22 (1), 65-68.
(18) Siegemund, G.; Schwertfeger, W. U.S. Patent 4343749, 1982.
10.1021/jo701630a CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/18/2007
J. Org. Chem. 2008, 73, 711-714
711

SCHEME 2. Preparation of Tetraflate Derivatives
The proton of the tetraflate group appears to be stable in the
presence of strong bases.19,20 4-tert-Butylphenyl tetraflate was
treated with n-BuLi in Et2O for 30 min at -78 °C followed
by methanol-d4 quench. Starting tetraflate was recovered in
1
40% yield. By H and 19F NMR, the balance consisted of
4-tert-butylphenol and lithium 1,1,2,2-tetrafluoroethanesulfo-
nate. No deuterium incorporation into the HCF2CF2- group or
traces of other fluorine-containing byproducts was observed,
implying that sulfonate ester hydrolysis happens before depro-
tonation.
Suzuki coupling of aryl sulfonates with aryl boronic acids is
used widely for the formation of carbon-carbon bonds.7 Tri-
flates,21 nonaflates,22 and perfluorooctylsulfonates23 can all be
used successfully for this transformation. We found that aryl
tetraflates behave similarly to triflates in these reactions (Table
3). Under conditions reported by Fu and co-workers (Pd(OAc)2/
PCy3/CsF in THF at 55 °C),21 4′-substituted 2-methylbiphenyls
were obtained in good yields (86-94%). However, sterically
hindered 2,6-dimethylphenyl tetraflate gave only traces of the
product.
Fluorinated aryl sulfonates such as triflates, nonaflates, or
perfluorooctylsulfonates have also been extensively used in
palladium-catalyzed aminations.11,24-26 In our hands, amination
of aryl tetraflates with aniline afforded diarylamines in good
yields (57-86%, Table 4). The yield was highest for 4-tert-
butylphenyl tetraflate, while 4-nitro- and 4-methoxyphenyl
tetraflates gave lower yields of the desired products. We also
found that the Xanthos ligand had to be used for the coupling
of 4-nitrophenyltetraflate.
Aryl tetraflates can also be used in Heck coupling (Table 5).
We employed conditions reported by Norrby and co-workers
for reactions of aryl triflates (5 mol % Pd2(dba)3, 10 mol %
1,3-bis(diphenylphosphino)propane or dppp, Et3N, DMF, 80
°C)27 and compared yields and selectivities of triflate couplings
with those for aryl tetraflates. With 4-nitrophenyl tetraflate,
Xanthphos and DBU were used instead of dppp and Et3N,
respectively. In all cases we obtained good to excellent yields
of substituted styrenes. 4-Nitro- and 4-tert-butylphenyl tetraflates
gave mostly â-substituted styrenes, while 4-methoxyphenyl
tetraflate afforded a 1:1 mixture of R and â isomers. Norrby
and co-workers reported that reaction between phenyl triflate
and several 4-substituted styrenes also gave a mixture of
isomers: 1:0.81 and 1:0.89 for 4-methoxy and 4-methyl,
respectively, at low conversions.27 Interestingly, 4-trifluoro-
methylstyrene gave predominantly the 1,2-isomer (1:0.23 at low
TABLE 1. Preparation of Tetraflates
X
R (product)
base
Et3N
Et3N
Et3N
DBU
DBU
Pyridine
time, h
yield, %
Cl
Cl
Cl
F
4-t-Bu, 5
4-NO2, 6
4-OMe, 4
2,6-(Me)2, 7
4-t-Bu, 5
4-t-Bu, 5
17
4
2
3.5
1
4
94
92
94
93
99
84
F
OSO2CF2CF2H
2 can also be prepared by treatment with KF/KHF2 in aceto-
nitrile, as reported by Hoechst researchers.18
We
used
HCF2CF2SO2Cl,
HCF2CF2SO2F,
and
(HCF2CF2SO2)2O to prepare aryl tetraflates from phenols using
methods typically used for the preparation of aryl triflates (Table
1).1,2 Sulfonyl chloride 1 worked well with both electron-poor
and electron-rich phenols (p-nitro and p-methoxy, respectively),
but gave very low yields with sterically crowded 2,6-dimeth-
ylphenol. The latter was successfully converted to its tetraflate
with HCF2CF2SO2F. All three derivatives can be used with
4-tert-butylphenol to give 4-tert-butylphenyltetraflate in good
to excellent yields.
The presence of hydrogen in the 1,1,2,2-tetrafluoroethane
1
sulfonyl group allows the use of H NMR for characterization
1
of tetraflate derivatives. A fragment of the H NMR spectrum
of 4-methoxyphenyl tetraflate is shown in Figure 1. In addition
to peaks in the aromatic region, which belong to the substituted
phenyl group, there is a triplet of triplets centered at 6.22 ppm.
This signal was assigned to the proton of the tetraflate group
and it is split by two sets of CF2 groups. In contrast to triflate
and other perfluoroalkylsulfonate groups, we found that the
1
presence of this H NMR feature greatly facilitates not only
characterization of tetraflate derivatives but also monitoring of
their reactions.
(19) Okano, T.; Chokai, M.; Hiraishi, M.; Yoshizawa, M.; Kusukawa,
T.; Fujita, M. Tetrahedron 2004, 60 (18), 4031-4035.
(20) Prakash, G. K. S.; Hu, J.; Mathew, T.; Olah, G. A. Angew. Chem.,
Int. Ed. 2003, 42 (42), 5216-5219.
We compared thermal properties of 4-nitrophenylfluorosul-
fonates derived from trifluoromethanesulfonic, nonafluorobu-
tanesulfonic, and 1,1,2,2-tetrafluoroethanesulfonic acids by
thermogravimetric analysis (Table 2).28 We found that 10% and
50% weight losses for tetraflate occur at considerably higher
temperatures compared to nonaflate and triflate esters. For
example, 4-nitrophenyl triflate loses 10% of its weight at 105
°C, 4-nitrophenyl nonaflate loses 10% at 125 °C, but tetraflate
only reaches the same weight loss at 150 °C. A similar trend is
seen for 50% weight loss. To better understand thermal
properties of these materials, we also measured their melting
points. Surprisingly, tetraflate has the lowest melting point
(Table 2). This unexpected property of aryl tetraflates, which
might be due to lower volatility of these derivatives, opens up
the possibility of using higher temperatures for their transforma-
tions.
(21) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122 (17),
4020-4028.
(22) Rottlaender, M.; Knochel, P. J. Org. Chem. 1998, 63 (1), 203-
208.
(23) Zhang, W.; Chen, C. H.-T.; Lu, Y.; Nagashima, T. Org. Lett. 2004,
6 (9), 1473-1476.
(24) Anderson, K. W.; Mendez-Perez, M.; Priego, J.; Buchwald, S. L.
J. Org. Chem. 2003, 68 (25), 9563-9573.
(25) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J.
Org. Chem. 2000, 65 (4), 1158-1174.
(26) Tundel, R. E.; Anderson, K. W.; Buchwald, S. L. J. Org. Chem.
2006, 71 (1), 430-433.
(27) Fristrup, P.; Le Quement, S.; Tanner, D.; Norrby, P.-O. Organo-
metallics 2004, 23 (26), 6160-616
(28) Thermogravimetric analysis (TGA) is an analytical technique that
records the changes in mass of a sample as a function of changes in
temperature. Testing is typically done under the flow of nitrogen.
712 J. Org. Chem., Vol. 73, No. 2, 2008

1
FIGURE 1. Part of the H NMR spectrum of 4-methoxyphenyltetraflate in CDCl3.
TABLE 2. Thermal Properties of 4-Nitrophenylsulfonates,
TABLE 5. Heck Coupling with Aryl Tetraflates
a
ArOSO2RF
RF
T10%
T50%
mp, °C
CF3
HCF2CF2
CF3CF2CF2CF2
105
150
125
128
190
158
52-535
24
705
a Temperatures of 10% and 50% weight loss, by TGA.
entry
R
ligand L
base
time, h
yield, %
1
2
3
4-t-Bu
4-NO2
4-OMe
dppp
XantPhos
dppp
Et3N
DBU
Et3N
21
42
21
68 (6:1)a
71 (50:1)a
89 (1:1)a
TABLE 3. Suzuki Coupling with Aryl Tetraflates
a Ratio of 1,2- to 1,1-isomers; see the Supporting Information for ligand
structures.
Experimental Procedures
entry
R
time, h
yield, %
Preparation of 1,1,2,2-Tetrafluoroethanesulfonyl Chloride
(1).18 This procedure was carried out in a drybox (TFESA is
hygroscopic). To an oven-dried 250-mL round-bottomed flask
charged with 57.25 g of catechylphosphorous trichloride (0.233 mol,
1.2 equiv) was added 35.4 g of 1,1,2,2-tetrafluoroethanesulfonic
acid (0.194 mol, 1.0 equiv) slowly to keep the gas evolution under
control. After 1 h, the gas evolution had ceased but undissolved
catechylphosphorous trichloride remained. The reaction flask was
removed from the drybox, and a distillation head was attached under
nitrogen atmosphere. The reaction mixture was heated in an 80 °C
oil bath for 2 h. A clear, light-brown solution was obtained after
30 min of heating. The oil bath temperature was raised to 140 °C
to begin the distillation and slowly increased to 190 °C. One
fraction, with a boiling point range of 84-88 °C (lit.18 90 °C),
yielded 36.73 g (94%) of a clear colorless liquid. Identity was
1
2
3
4
4-t-Bu
4-NO2
4-OMe
2,6-(Me)2
17
17
16
40
86
94
90
4
TABLE 4. Catalytic Amination of Aryl Tetraflatesa
entry
R
L
temp, °C
time, h
yield, %
1
2
3
4-t-Bu
4-NO2
4-OMe
BPCy2
XantPhos
BPCy2
80
105
80
18
40
16
86
57
60
1
confirmed by H and 19F NMR.18 1H NMR (400 MHz, CDCl3) δ
2
a See the Supporting Information for ligand strucutres.
6.27 (1H, tt, JHF ) 51.9 Hz). 19F NMR (400 MHz, CDCl3) δ
2
-111.9 (2F, m), -133.6 (2F, dt, JHF ) 51.9 Hz).
Preparation of 1,1,2,2-Tetrafluoroethanesulfonyl Fluoride
(2).18 In a drybox, an oven-dried two-necked 100-mL round-
bottomed flask was charged with 15.0 g of 1,1,2,2-tetrafluoro-
ethanesulfonyl chloride (74.8 mmol) and 17.9 g of dry cesium
fluoride (112.2 mmol). The flask was brought out of the drybox
and a short-path distillation head was attached under nitrogen
atmosphere. To this was added 25 mL of dry sulfolane, warmed in
a 55 °C oil bath, using a hot syringe to prevent the sulfolane from
solidifying. The reaction mixture was stirred at room temperature
for 88 h until reaction was complete as judged by 19F NMR
monitoring. The receiving flask was cooled with a dry ice/acetone
bath and product was transferred out of the reaction mixture under
conversion). It appears that the presence of electron-withdrawing
groups favors the formation of the 1,2-regioisomer.
In summary, it has been demonstrated that aryl esters of
1,1,2,2-tetrafluoroethanesulfonic acid (aryl tetraflates) can be
used in a number of palladium-catalyzed coupling reactions.
While the reactivity of tetraflates is similar to that of triflates
and chlorides, tetraflates appear to be more thermally stable.
Additionally, the presence of the hydrogen atom in the tetraflate
group facilitates monitoring of reactions and characterization
of derivatives.
J. Org. Chem, Vol. 73, No. 2, 2008 713

reduced pressure and with vigorous stirring. 1,1,2,2-Tetrafluoro-
ethanesulfonyl fluoride (11.4 g, 82.6%) was collected as a clear
of 3.01 g of 1,1,2,2-tetrafluoroethanesulfonyl chloride (15 mmol,
1.25 equiv) in 5 mL of dichloromethane was added portion wise.
The reaction mixture was allowed to stir cold and then was left to
gradually warm to room temperature overnight. Diethyl ether (100
mL) was added and reaction mixture was transferred to a separatory
funnel. The organic layer was washed twice with water and once
with brine, dried over MgSO4, and concentrated. The crude product
was passed through a 4 in. plug of silica gel, using 400 mL of
ether. Ether was removed under reduced pressure to yield 3.56 g
(94.4%) of 4-tert-butylphenyl-1,1,2,2-tetrafluoroethane sulfonate as
colorless liquid. Identity was confirmed by 1H and 19F NMR.18 1
H
2
NMR (400 MHz, CDCl3) δ 6.21 (1H, tt, JHF ) 51.75 Hz). 19F
NMR (400 MHz, CDCl3) δ 44.4 (1F, m), -114.9 (2F, m), -135.1
2
(2F, dq, JHF ) 51.9 Hz).
Preparation of 1,1,2,2-Tetrafluoroethanesulfonic Acid An-
hydride (3). An oven-dried 500-mL round-bottomed flask was
charged with 40 g of sand, 82.0 g (57.7 mmol) of phosphorus
pentoxide, and a magnetic stir bar. The flask was swirled by hand,
and was warm to the touch. A short-path distillation column was
attached and the reaction flask was twice evacuated and filled with
nitrogen atmosphere. 1,1,2,2-Tetrafluoroethanesulfonic acid (41.09
g, 23.0 mmol) was added and the flask was evacuated and filled
with nitrogen once more. The reaction mixture was warmed in a
65 °C oil bath and began to turn dark brown. The reaction mixture
was kept at 65 °C for 3 h, followed by 16 h at room temperature.
Distillation was carried out at 75 °C under vacuum (60 mT, vapor
pressure of 3 is 15 Torr at 72 °C) giving 20.44 g of 1,1,2,2-
tetrafluoroethanesulfonic acid anhydride (44%) as a clear colorless
1
a pale yellow liquid. H NMR (400 MHz, CDCl3) δ 1.32 (9H, s),
2
6.23 (1H, tt, JHF ) 52.3 Hz), 7.19 (2H, app d), 7.43 (2H, app d).
19F NMR (400 MHz, CDCl3) δ -117.15 (2F, m), -135.3 (2F, dt,
2JHF ) 52.3 Hz). 13C NMR (100 MHz, CDCl3) δ 31.05, 34.67,
2
108.02 (1JCF ) 256 Hz, JCF ) 29.5 Hz), 114.99 (1JCF ) 294 Hz,
2JCF ) 28.4 Hz), 120.94, 127.18, 147.72, 151.83. IR (KBr pellet)
2968 (m), 1504 (m), 1416 (s), 1209 (s), 1190 (m), 1165 (s), 1137
(s), 888 (s). Anal. Calcd for C12H14F4O3S: C 45.86; H 4.49; F,
24.18. Found: C, 46.04; H, 4.69; F, 24.14.
1
liquid. The product was stored in a drybox. H NMR (400 MHz,
2
CDCl3) δ 6.24 (1H, tt, JHF ) 51.7 Hz). 19F NMR (400 MHz,
Acknowledgment. The authors would like to thank the
DuPont NMR group for technical assistance and Drs. V. Petrov,
M. Tisack, A. Sievert, and L. Sprague for many helpful
discussions.
CDCl3) δ -112.7 (4F, m), -134.3 (4F, dq, 2JHF ) 51.7 Hz). Anal.
Calcd for C4H2F8O5S2: C, 13.88; H, 0.58; F, 43.91. Found: C,
13.85; H, 0.53; F, 44.16.
Preparation of 4-tert-Butylphenyl-1,1,2,2-tetrafluoroethane-
sulfonate (5). An oven-dried three-necked 250-mL round-bottomed
flask was charged with 1.8 g (12.0 mmol, 1.0 equiv) of 4-tert-
butylphenol, 20 mL of dichloromethane, and 2.2 mL (15.6 mmol,
1.3 equiv) of triethylamine under nitrogen atmosphere. The mixture
was cooled with a dry ice/acetone bath to -40 °C and a solution
Supporting Information Available: General information for
synthetic procedures and compound characterization. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO701630A
714 J. Org. Chem., Vol. 73, No. 2, 2008