Palladium-catalyzed allylation of 2,2,2-trifluoroethyl phenyl sulfone, a potential 2,2,2-trifluoroethyl pronucleophile

Article abstract of DOI:10.1016/j.tetlet.2012.09.094

A palladium-catalyzed allylation reaction of PhSO₂CH ₂CF₃ (2) with a variety of allyl carbonates has been successfully developed for selective 2,2,2-trifluoroethylation under neutral conditions. With this method, the 1-phe

Full text of DOI:10.1016/j.tetlet.2012.09.094

Tetrahedron Letters 53 (2012) 6565–6568
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Palladium-catalyzed allylation of 2,2,2-trifluoroethyl phenyl sulfone,
a potential 2,2,2-trifluoroethyl pronucleophile
Wei Zhang a, Yanchuan Zhao a, Chuanfa Ni a, Thomas Mathew a,b, , Jinbo Hu a,
⇑
⇑
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling-Ling Road, Shanghai 200032, China
b Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, CA 90089-1661, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A palladium-catalyzed allylation reaction of PhSO2CH2CF3 (2) with a variety of allyl carbonates has been
successfully developed for selective 2,2,2-trifluoroethylation under neutral conditions. With this method,
the 1-phenylsulfonyl-2,2,2-trifluoroethyl moiety was efficiently transferred into organic compounds
without the competing b-elimination of fluoride, to afford a range of mono-allylated and di-allylated
compounds.
Received 8 August 2012
Revised 16 September 2012
Accepted 21 September 2012
Available online 28 September 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Fluorine
Trifluoroethylation
Allylation
Palladium catalysis
Trifluoroethyl sulfone
Due to the high electronegativity and small size of fluorine, the
presence of fluorine atom(s) or fluorinated moieties in organic
molecules often modifies the latter’s bioactivity by changing the
metabolic stability, lipophilicity, and bioavailability.1,2 Among var-
ious fluorinated moieties, the trifluoromethyl group (CF3) has been
the focus of increasing attention owing to its diverse applications.3
In contrast to the tremendous progress that has been made toward
the direct introduction of a trifluoromethyl group into organic
compounds,4,5 the selective transfer of a 2,2,2-trifluoroethyl carb-
anion (CF3CH2À) has remained largely unexplored.6,7 Although
the electron-withdrawing effect of trifluoromethyl group may
stabilize the carbanion species, the 2,2,2-trifluoroethyl carbanion
is highly unstable and rapidly decomposes to give gem-difluoroalk-
enes by b-elimination of a fluoride ion.6
To stabilize the 2,2,2-trifluoroethyl carbanions by charge
delocalization, electron-withdrawing groups, such as sulfonyl, car-
bonyl, or phenyl groups were usually introduced. Therefore, the
presence of suitable substituents can make these substrates effec-
tive 2,2,2-trifluoroethyl pronucleophiles in the alkylation reac-
tions. In 1983, Ishikawa and Yokozawa reported that the
dimethyl(trifluoromethyl)malonate can react with alkyl halide by
using CsF as a proton sink, and they found that the Michael addi-
tion with dimethyl(trifluoromethyl)malonate was also successful.8
The alkylations of trifluoroethyl carbanions by using enolates were
also developed.9–11 In 1999, Kitazume demonstrated that palla-
dium-catalyzed allylation of trifluoroethyl ketones proceeded
smoothly without b-fluoride elimination.12 Similar allylation reac-
tions of related trifluoroethyl carbonyl compounds were also re-
ported by the research groups led by Konno et al.,13 Ando and
co-workers,14 and Shibata and Cahard.15 Recently, we reported
the first palladium-catalyzed trifluoroethylation of organoboronic
acids and esters by using the readily available reagent CF3CH2I.7
Since the phenylsulfonyl group can be regarded as a ‘chemical
chameleon’, during the past decade, we were extensively involved
in the nucleophilic, radical, and electrophilic fluoroalkylations
using a series of
a
-fluorinated organosulfur reagents.16–19 The
phenylsulfonyl group can not only stabilize the a-fluorocarbanion
(Scheme 1, reagents 1) by effective charge delocalization,16–20 it
can also stabilize the b-fluorocarbanion (derived from 2,2,2-trifluo-
roethyl phenyl sulfone, Scheme 1, reagent 2).6 Although the
Previous work
This work
F
O
O
O
O
F
F
S
S
R1
R2
H
H
F
(R1, R2 = H, F, SO2Ph)
2
1
Nucleophilic
Electrophilic
Nucleophilic
Radical
⇑
Corresponding authors. Tel./fax: +1 213 740 5983 (T.M.); tel.: +86 21 5492
5174; fax: +86 21 6416 6128 (J.H.).
Scheme 1. Different (phenylsulfonyl)fluoroalkylations.
E-mail addresses: tmathew@usc.edu (T. Mathew), jinbohu@sioc.ac.cn (J. Hu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.094

6566
W. Zhang et al. / Tetrahedron Letters 53 (2012) 6565–6568
H2O2, AcOH
100oC, 3 h
of the selectivity of the reaction by changing various reaction
NaH
DMF
PhSO2CH2CF3
PhSCH2CF3
PhSH + TsOCH2CF3
parameters such as the reagent/substrate ratio, temperature, cata-
lysts as well as catalyst loading, and the solvent system. By increas-
ing the amount of compound 2 or changing the solvent to toluene,
the amount of di-allylated product 5a was significantly reduced
(entries 3, 4, and 6). Among the catalysts screened, Pd(PPh3)4 gave
better yields than Pd(dba)2 or Pd(OAc)2 (entries 4, 7, and 8) while
solvents 1,4-dioxane and DMF were found to be not effective for
this reaction (entries 2 and 5). A threefold increase in substrate
concentration changed the course of the reaction significantly,
resulting in the reversal of the ratio of mono-allylated and di-
allylated products from 2:1 to 1:2. (Table 1, entries 1 and 14). Thus,
the yield of the di-allylated product increased to 48% yield and the
mono-allylated product decreased to 24%. An optimal product
yield (76%) of the mono-allylated product 4a (with only 7% of 5a)
was obtained when the reaction was conducted in THF at 60 °C
for 22 h with 4 equiv of reagent 2 and 10 mol % of Pd(PPh3)4 (entry
13).
2
Scheme 2. Preparation of 2,2,2-trifluoroethyl phenyl sulfone.
reagent 2 is a simple and easily available compound, which can re-
act with electrophilic reagents such as CH3I or I2, the reaction sub-
strates are very limited.21 To expand our fluorinated organosulfur
chemistry and develop the synthetic application of the reagent 2
for 2,2,2-trifluoroethylation, we carried out the palladium-
catalyzed allylation reaction of 2 with various allyl carbonates
under neutral conditions. We found that the method is very effective
for the 2,2,2-trifluoroethylation of a series of 3-aryl-substituted
allyl carbonates as well as the parent allyl carbonate. Herein, we
want to report our results of this efficient 2,2,2-trifluoroethylation
method.22
2,2,2-Trifluoroethyl phenyl sulfone (PhSO2CH2CF3, 2) was
obtained by the oxidation of PhSCH2CF3 (using H2O2 in AcOH),
which in turn was prepared from sodium thiophenolate and
2,2,2-trifluoroethyl p-toluenesulfonate (Scheme 2).23
With compound 2 in hand, we were able to explore its reactivity
with allyl carbonates by using palladium catalysis. As shown in Ta-
ble 1, initially, we chose cinnamyl ethyl carbonate (3a) as a model
compound and 10 mol % Pd(PPh3)4 as a catalyst. Under neutral
conditions, the allylation product 4a was obtained in 38% yield (en-
try 1). However, the di-allylated product 5a was also observed in
18% yield (Table 1, entry 1). Then, we focused on the improvement
Having established the optimized reaction conditions with re-
agent 2, we studied the scope of the current 2,2,2-trifluoroethyla-
tion protocol by Pd-catalyzed allylation reaction with a range of
allylic carbonates. It was found that a variety of structurally diverse
Table 2
Synthesis of allylated trifluoroethyl sulfones using various allyl ethyl carbonates
CF3
Pd(PPh3)4 (10 mol%)
THF, 60oC, 22h
R
PhSO2CH2CF3
+
R
OCO2Et
SO2Ph
2
3
4
Table 1
Yielda
(%)
Optimization of the reaction conditions for palladium-catalyzed allylation of 2,2,2-
trifluoroethyl phenyl sulfone using cinnamyl ethyl carbonate
Entry
Substrate
Product
CF3
OCO2Et
Pd catalyst
1
2
76
79
PhSO2CH2CF3
+
3a
Ph
OCO2Et
SO2Ph
CF3
Solvent, 60oC
4a
4a
2
3a
OCO2Et
CF3
SO2Ph
PhO2S CF3
SO2Ph
Ph
+
Ph
Ph
3aa
4a
CF3
SO2Ph
CF3
SO2Ph
5a
Et
OCO2
3
65
3b
Entry Ratio Pd
Pd
(mol %)
Solvent
Time
(h)
Yield (%)
4aa (5aa)
Me
4b
Me
catalyst
2:3a
OCO2Et
4
73
1
2
3
4
5
6
7
8
1:1
1:1
2:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
4:1
4:1
1:3
3:1
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(dba)2
10
10
10
10
10
10
10
10
20
5
THF
Dioxane
THF
7
7
38
0
(18)
(0)
3c
Me
4c
Me
CF3
20
11
11
11
11
18
11
22
22
11
22
22
24
39b (3)b
OCO2Et
OCO2Et
OCO2Et
5
70b
60c
65
THF
58
(5)
3d
SO2Ph
CF3
DMF
Toluene
THF
THF
THF
THF
THF
THF
THF
30b (2)b
MeO
4d
MeO
Br
47
53
(1)
(5)b
14b (0)b
c
6
Pd(OAc)2
3e
SO2Ph
Br
4e
9
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4 10
Pd(PPh3)4
Pd(PPh3)4
60
21
70
70
76
(8)
10
11
12
13
14
15
(1)b
(9)
CF3
10
10
7
3f
SO2Ph
(7)
F
4f
F
(7)b
CF3
10
10
THF
24b (48)
52
OCO2Et
OCO2Et
THF/
toluene
(2:3)
THF/
toluene
(5:1)
THF/
toluene
(10:1)
(1)
8
68
3g
SO2Ph
Cl
4g
Cl
CF3
SO2Ph
16
17
3:1
3:1
Pd(PPh3)4
Pd(PPh3)4
10
10
36
29
48b (3)b
62b (5)b
9
40
73
3h
OCO2Et
O2N
4h
O2N
CF3
SO2Ph
10
3i
4i
a
b
c
a
Isolated yield.
Isolated yield.
Determined 19F NMR spectroscopy.
PPh3 (20 mol %) was added.
b
c
Determined 19F NMR spectroscopy.
Stirring for 43 h.

W. Zhang et al. / Tetrahedron Letters 53 (2012) 6565–6568
6567
Table 3
Allylation of mono-allylated product 4a with allylic carbonates
Pd(PPh3)4 (10 mol%)
THF, 60oC, 22h
CF3
Ph
PhO2S CF3
+
R
OCO2Et
(2.0 equiv.)
R
Ph
SO2Ph
4a
Substrate
3
5
Entry
1
Product
Yielda (%)
PhO2S CF3
OCO2Et
Ph
Ph
86
84
85
3a
5a
PhO2S CF3
OCO2Et
p-PhMe
Ph
2
3b
Me
5b
PhO2S CF3
OCO2Et
3i
Ph
3
5c
a
Isolated yield.
CF3
is only a peak of reactant of PhSOCH2CF3 or PhSO2CH2CH2F, and
this may be due to the weaker acidity of the reagents and weaker
charge-stabilization of the carbanions.
R
OCO2Et
R
Pd(0)
SO2Ph
3
4
The reaction mechanism of the above palladium-catalyzed ally-
lation reaction of PhSO2CH2CF3 was proposed as shown in
Scheme 3. Under neutral reaction conditions, the p-allyl alkoxy
R
R
CF3
SO2Ph
O
Pd
palladium complex 7, which is derived from the decarboxylation
of complex 6, reacts with the active methylene group in the re-
agent 2 to give the intermediate 8 and EtOH. Then the mono-
allylated compounds 4 are obtained as main products by the
reductive elimination of 8. Meanwhile, the di-allylated product 5
may be produced in the presence of 3 and 4, through the same
reaction mechanism.
In conclusion, the palladium-catalyzed allylation reaction of
PhSO2CH2CF3 (2) with a variety of allyl carbonates has been suc-
cessfully developed for selective 1-phenylsulfonyl-2,2,2-trifluoroe-
thylation under neutral conditions. With this method, the
1-phenylsulfonyl-2,2,2-trifluoroethyl moiety was efficiently
transferred into organic compounds without the competing b-
elimination of fluoride, to afford a range of mono-allylated and
di-allylated compounds.24 Further investigations of asymmetric
trifluoroethylation chemistry are currently underway in our
laboratory.
Pd
O
OEt
6
8
EtOH
R
CO2
Pd
OEt
7
PhSO2CH2CF3
2
Scheme 3. Proposed reaction mechanism.
allylic carbonates showed good reactivity with reagent 2 under the
neutral conditions giving the allyl substituted trifluoroethyl sulf-
ones 4 in moderate to high yields (see Table 2). As shown in entries
1 and 2, the cinnamyl ethyl carbonate 3a and ethyl 1-phenylallyl
carbonate 3aa gave the same product 4, clearly manifesting the
excellent regioselectivity of the allylic reaction. Reactions of
cinnamyl ethyl carbonate bearing electron-donating groups 3b,
3c, and 3d also gave the corresponding products in good yields
(Table 2, entries 3–5), while those of allylic carbonate 3h bearing
strong electron-withdrawing group resulted in low yield (entry
9). Furthermore, the product 4i can be obtained in 73% yield from
the simple parent allyl ethyl carbonate 3i (entry 10).
As mentioned earlier, the Pd-catalyzed allylation reaction could
give the di-allylated products (see Table 1). Thus, we decided to
investigate the second allylation reaction between mono-allylated
product 4a and other allylic carbonates 3. It was found, by using
2 equiv of allylic carbonates, the di-allylated products 5a, 5b, and
5c were obtained in 86%, 84%, and 85% yields, respectively (Table 3,
entries 1–3). It indicates that, theoretically, it is possible to get a
variety of trifluoroethyl compounds with two different allylic
groups by choosing the suitable monoallylated product and the al-
lyl ethyl carbonate.
Acknowledgments
This work was supported by the National Basic Research Pro-
gram of China (2012CB215500 and 2012CB821600), the National
Natural Science Foundation of China (20825209 and 20832008),
and the Chinese Academy of Sciences (CAS). T.M. thanks the Chi-
nese Academy of Sciences for honoring him with the CAS Visiting
Professorship. Professor George A. Olah and Professor G. K. Surya
Prakash are thanked for their support for this collaborative work.
Supplementary data
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 http://dx.doi.org/
10.1016/j.tetlet.2012.09.094.
Under the same neutral reaction conditions (Pd(PPh3)4/
THF/60 °C/22 h), neither the trifluoroethyl sulfoxide PhSOCH2CF3,
nor the monofluoroethyl sulfone PhSO2CH2CH2F can react with
allylic carbonates. According to the 19F NMR spectroscopy, there
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