Highly regioselective Pd-catalyzed allylic alkylation of fluorobis(phenylsulfonyl)methane

Article abstract of DOI:10.1016/j.tetlet.2010.11.132

A highly regioselective palladium-catalyzed allylic alkylation of fluorobis(phenylsulfonyl)methane has been studied. Using different allylic carbonates, a variety of terminal mono-fluoromethylated compounds were achieved in 85-99% yields with high regiose

Full text of DOI:10.1016/j.tetlet.2010.11.132

Tetrahedron Letters 52 (2011) 665–667
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Tetrahedron Letters
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Highly regioselective Pd-catalyzed allylic alkylation
of fluorobis(phenylsulfonyl)methane
⇑
Xiaoming Zhao , Dongge Liu, Shengcai Zheng, Ning Gao
Department of Chemistry, Tongji University, 1239 Siping Road, Shanghai 200092, PR China
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly regioselective palladium-catalyzed allylic alkylation of fluorobis(phenylsulfonyl)methane has
been studied. Using different allylic carbonates, a variety of terminal mono-fluoromethylated compounds
were achieved in 85–99% yields with high regioselectivities.
Received 28 September 2010
Revised 11 November 2010
Accepted 26 November 2010
Available online 3 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Regioselectivity
Palladium
Allylic alkylation
Fluorobis(phenylsulfonyl)methane
Mono-fluoromethylated compounds are of great importance in
the field of medicinal1 and material2 chemistry. Therefore, new
synthetic methods for highly stereo-selective introduction of
CFH2 group into organic compounds, using convenient starting
materials, are still desirable. Fuorobis(phenylsulfonyl)methane3
(FBSM) has successfully been demonstrated as a synthetic equiva-
lent of a fluoromethide species.4 Using the fluorinated carbanion
generated from FBSM, thermally unstable species,4 as a nucleo-
phile, transition metal such as palladium4 and iridium5 catalyzed
allylic alkylations of allylic alcohol derivatives has attracted con-
siderable attention since 2006. This type of the reactions,6 which
usually lead to a mixture of the linear product and the branch
product, is one of the powerful methods for preparation of
mono-fluoromethylated compounds. It is possible to control regi-
oselectivity through adjusting catalyst system.5 More recently,
we have successfully developed a methodology for synthesis of
mono-fluoromethylated branch product from allylation of FBSM
catalyzed by iridium.5 In addition, introduction of a fluorine atom
into the aliphatic moiety of liquid crystal compounds dramatically
leads to the change of the physical property.7,2c We envision using
allylic alkylation of FBSM to synthesize mono-fluoromethylated
linear compounds. Herein, we report Pd-catalyzed allylic alkylation
of mono-substituted allylic alcohol derivatives with FBSM and its
potential in synthesis of liquid crystal compounds with a mono-
fluorinated aliphatic group.
We began our investigations with a reaction of (E)-cinnamyl
methyl carbonate (1a) with 2a in the presence of 2 mol % of
Pd(OAc)2 and 4 mol % of DPPE9 in THF at room temperature. To
8
our delight, after 36 h, a mixture of the linear product (3a) and
the branched product (4a)2 was obtained in 91% yield with a ratio
of 3a/4a in 99/1 (entry 1). The use of 4 Å MS led to somewhat the
improvement of the yield but long reaction time (36 h) (entry 2).
When Cs2CO3 was employed as a base, both the rate and yield were
improved (entry 3). Encouraged by these, a series of bases such as
K3PO4, K2CO3, DBACO, BSA, and DBU were screened. Interestingly,
all of Cs2CO3, K3PO4, K2CO3, and BSA gave the excellent results
without significantly influencing the regioselectivity (entries 4–
6). However, DBASO gave only 15% yield and DBU could not pro-
mote the reaction (entries 7–8). Consequently, we chose K2CO3
as the suitable base since it is more economic. Loading Pd(OAc)2
was decreased from 2% to 1.5%; the yield was reduced as well (en-
try 10). Notably, this reaction could not proceed in the absence of
DPPE, thus, the ligand DPPE is required to assist this AAA reaction
(entry 11). Furthermore, other solvents including DCM and toluene
were screened and we found that DCM gave 86% of 3a along with
4a with an excellent regioselectivity but longer reaction time (en-
try 12). Both THF and toluene resulted in excellent yield and high
regioselectivity (entry 5 vs entry 13). THF was chosen as the suit-
able solvent because of the economic reason and convenient
workout.
With the optimal reaction conditions listed in entry 5 of Table 1,
we further explored the scope of this finding and the preliminary
results were demonstrated in Table 2. All allyl methyl carbonates
including aliphatic, phenyl, aromatic with an electronic-donating
⇑
Corresponding author. Tel./fax: +86 21 65981376.
E-mail address: xmzhao08@mail.tongji.edu.cn (X. Zhao).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.132

666
X. Zhao et al. / Tetrahedron Letters 52 (2011) 665–667
Table 1
Optimizing reaction conditions for Pd-catalyzed allylation of fluorobis(phenylsulfonyl)methane (FBSM)a
O
F
OMe
SO2Ph
O
PhO2S
SO2Ph
F
SO2Ph
1a
Pd(OAc)2 / DPPE
K2CO3, THF, rt
+
+
3a
F
4a
H
PhO2S
SO2Ph
2a
Entry
Base
Cat. loading (%)
Solvent
t (h)
Yieldb (%)
3a/4ac
d
1
2e
3
4
5
6
7
8
9
10
11f
12
13
—
2
2
2
2
2
2
2
2
2
1.5
2
2
2
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DCM
Toluene
36
36
0.5
0.5
0.5
0.5
10
10
0.5
6
91
98
95
99
96
99
15
NR
94
86
NR
94
99
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
—
>99/1
>99/1
—
>99/1
>99/1
4 Å MS
Cs2CO3
K3PO4
K2CO3
BSA
DBACO
DBU
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
24
10
0.5
a
b
c
d
e
f
Reaction conditions: 2 mol % Pd(OAc)2, 4 mol % DPPE, 100 mol % of 1a, 100% of base and 105 mol % 2a at room temperature.
Isolated yields.
Determined by 19F NMR.
No base was added.
100 mg 4 Å MS were used.
No ligand was employed.
or electronic-withdrawing group, and heterocyclic substrates gave
the corresponding linear product in excellent yield with high reg-
ioselectivity (entries 1–11, Table 2). Notably, ethyl 2-fluoro-2-
(phenylsultonyl)acetate 2b in racemic form was used instead of
FBSM 2a under the optimized conditions and it also gave the cor-
responding linear product 3l in 85% yield with a ratio of 3l/4l in
99/1 (entry 12).
Attempt to study on Pd-catalyzed asymmetric alkylation (AAA)
of 2b in racemic form, a combination of [Pd(C3H5)Cl]2 and Trost’s
ligand was employed as a catalyst and this AAA reaction of 2b
was conducted under a similar condition. As a result, compound
5 was obtained in 60% yield with 18% ee (Eq. 1). The detailed stud-
ies on Pd-catalyzed AAA of 2b are currently under way.
was produced in 99% yield.3 Also, 3ka may be converted into
3kb according to the known procedure.12 Compared with a
known liquid crystal compound 40-butylbiphenyl-4-carboni-
trile,13 3kb may exhibit good physical property of liquid crystal
(Eq. 2).
1) I2, HIO3
CH3CO2H
SO2Ph
SO2Ph
F
F
Mg, CH3OH
0°C
3ka
2) CuCN
3k
Ph
Ph
NC
ð2Þ
99%
F
3kb
In conclusion, we have developed a convenient method for
preparation of mono-fluoromethylated compounds via a highly
F
F
∗
[Pd(C3H5)Cl]2 / L*
H
CO2Et
OCO2Me
SO2Ph
CO2Et
1a
PhO2S
O
5
K2CO3, THF, rt
2b
18% ee
60% yield
ð1Þ
O
N
N
L*:
PPh2Ph2P
To explore the synthetic utility of the product obtained, a
representative example was illustrated in Eq. 2. The phenylsulfo-
nyl groups and double bond on 3k10 were readily removed and
reduced in one-pot by using activated magnesium11 and 3ka10
regioselective palladium-catalyzed alkylation of FBMS with various
allyl methyl carbonates. This method will be able to apply to syn-
thesize liquid crystal compounds containing terminal mono-fluori-
nated aliphatic group.

X. Zhao et al. / Tetrahedron Letters 52 (2011) 665–667
667
Table 2
4. (a) Mizuta, S.; Shibata, N.; Goto, Y.; Furukawa, T.; Nakamura, S.; Toru, T. J. Am.
Chem. Soc. 2007, 129, 6394–6395; (b) Prakash, G. K. S.; Chacko, S.; Alconcel, S.;
Stewart, T.; Mathew, T.; Olah, G. A. Angew. Chem., Int. Ed. 2007, 46, 4933–4936;
(c) Furukawa, T.; Shibata, N.; Mizuta, S.; Nakamura, S.; Toru, T.; Shiro, M.
Angew. Chem., Int. Ed. 2008, 47, 8051–8054; (d) Prakash, G. K. S.; Ledneczki, I.;
Chacko, S.; Olah, G. A. Org. Lett. 2008, 10, 557–560; (e) Ni, C.; Zhang, L.; Hu, J. J.
Org. Chem. 2008, 73, 5699–5713; (f) Prakash, G. K. S.; Zhao, X.; Chacko, S.;
Wang, F.; Vaghoo, H.; Olah, G. A. Beilstein J. Org. Chem. 2008, 4, 17; (g) Alba, A.-
N.; Companyó, X.; Moyano, A.; Rios, R. Chem. Eur. J. 2009, 15, 7035–7038; (h)
Moon, H. W.; Cho, M. J.; Kim, D. Y. Tetrahedron Lett. 2009, 50, 4896–4898; (i)
Zhang, S.; Zhang, Y.; Ji, Y.; Li, H.; Wang, W. Chem. Commun. 2009, 4886–4888;
(j) Ullah, F.; Zhao, G.-L.; Deiana, L.; Zhu, M.; Dziedzic, P.; Ibrahem, I.; Hammar,
P.; Sun, J.; Crdova, A. Chem. Eur. J. 2009, 15, 10013–10017; (k) Prakash, G. K. S.;
Chacko, S.; Vaghoo, H.; Shao, N.; Gurung, L.; Mathew, T.; Olah, G. A. Org. Lett.
2009, 11, 1127–1130.
Regioselective Pd-catalyzed allylations of FBSM with allyl methyl carbonatesa
O
OMe
R
O
H
F
SO2Ph
PhO2S
SO2Ph
Pd(OAc)2 / DPPE
K2CO3, THF, rt
1
+
R
F
+
F
R
3
SO2Ph
4
PhO2S
SO2Ph
2
Entry
R
NuH
Product
Yieldb (%)
3/4c
1
2
3
4
5
6
7
8
9
10
11
12
13
Ph
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2bd
2a
3a
3b
3c
3d
3e
3f
3g
3h
3i
96
99
99
99
95
93
90
99
99
96
99
85
86
>99/1 (99/1)e
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
3-MeOC6H4
4-MeOC6H4
4-MeC6H4
4-BrC6H4
3-CF3C6H4
2-ClC6H4
4-ClC6H4
2-Thienyl
Cyclohexyl
4-PhC6H4
Ph
5. Liu, W.; Zheng, S.; He, H.; Zhao, X.; Dai, L.; You, S. Chem. Commun. 2009, 43,
6604–6606.
6. (a) Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965, 3488–4387; (b)
Trost, B. M.; Fullerton, T. J. J. Am. Chem. Soc. 1973, 95, 292–294; For reviews, see:
(c) Trost, B. M. Chem. Rev. 1996, 96, 395–422; (d) Trost, B. M. Chem. Pharm. Bull.
2002, 50, 1; (e) Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 258–297.
7. (a) Bondi, A. J. Phys. Chem. 1964, 68, 441; (b) Nagel, J. K. J. Am. Chem. Soc. 1990,
112, 4740.
8. (a) [Pd(allyl)Cl]2 was also tested as a catalyst in this AAA reaction and it lad to
the formation of the allyl by-product. In the process of our investigation, an
example of Pd(PPh3)4 -catalyzed allylic alkylation of FBSM was reported by the
group of Jinbo Hu.; For details, see: (b) Ni, C.; Hu, J. Tetrahedron Lett. 2009, 50,
7252–7255.
3j
>99/1
>99/1
3k
3l
>99/1
Me
3mg
84/16 (88/12)f
9. (a) Van Haaren, R. J.; Goubitz, K.; Fraanje, J.; Van Strijdonck, G. P. F.; Oevering,
H.; Coussens, B.; Reek, J. N. H.; Kramer, P. C. J.; Van Leeuwen, P. W. N. M. Inorg.
Chem. 2001, 40, 3363–3372; (b) Tromp, M.; Van Bokhoven, J. A.; Van Haaren, R.
J.; Van Strijdonck, G. P. F.; Van der Eerden, A. M. J.; Van Leeuwen, P. W. N. M.;
Koningsberger, D. C. J. Am. Chem. Soc. 2002, 124, 14814–14815.
a
Reaction conditions: 2 mol % Pd(OAc)2, 4 mol % DPPE, 105 mol % of 1, 100 mol %
K2CO3, and 100 mol % 2 at room temperature.
b
Isolated yields.
c
Determined by 19F NMR.
d
Compound 2b was used instead of 2a in this case.
10. (a) Typical procedure for the preparation of 3k. To
a mixture of allylic
e
Determined by HPLC.
carbonates 1k (0.21 mmol, 105%), FBSM 2a (0.2 mmol, 100%), Pd(OAc)2
(0.02 mmol, 2%) and DPPE (0.04 mmol, 4%) in dry THF (2 mL) was added
K2CO3 (0.2 mmol, 100%), and the mixture was stirred at room temperature
under Ar2 atmosphere. After completion of the reaction, the reaction mixture
was filtered through a core with kieselguhr using methylene dichloride as an
eluent. Then the filtrate was concentrated and purified by flash
chromatography with silica gel (PE/EtOAc = 5:1) to give the desired product,
f
Determined by 1H NMR.
g
A mixture of (E)-isomer and (Z)-isomer in a ratio of 91/9 determined by 1H
NMR.
1H
NMR
Acknowledgments
(E)-4-(4-fluro-4,4-bis(phenylsulfonyl)but-1-enyl)biphenyl
(3k).
(300 MHz, CDCl3) d 7.93 (d, J = 8.4 Hz, 4H), 7.70–7.61 (m, 2H), 7.61–7.24 (m,
13H), 6.37 (d, J = 15.8 Hz, 1H), 6.01 (dt, J = 7.2 Hz, 15.6 Hz, 1H), 3.36 (dd,
J = 6.9 Hz, J = 18.0 Hz, 2H). 13C NMR (75 MHz, CDCl3) d 140.6, 140.4, 135.6,
135.3, 135.2, 130.9, 130.8, 129.0, 128.7, 127.3, 127.1, 126.8, 117.8 (d,
J = 6.5 Hz), 114.7 (d, J = 265.7 Hz), 33.9 (d, J = 18.0 Hz). 19F NMR (282 MHz,
CDCl3) d ꢀ141.9 (dd, J = 12.1 Hz, J = 16.3 Hz). MS (ESI, m/z): 529.1 (M+Na+).
HRMS (EI): calcd for C28H23FO4S2 (M+) 506.1022, found 506.1027. IR (KBr):
3526, 3060, 3030, 1484, 1446, 1346, 1310, 1150, 1076, 965, 752, 728,
We gratefully acknowledge the NSFC (20342003), Innovative
Program of Shanghai Education Committee (09ZZ36), Pu Jiang Pro-
gram of Shanghai (2010), 985 Program of Tongji University, Key
Laboratory of Fluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, State Key Laboratory of
Fine Chemicals, Dalian University of Technology for generous
financial support.
628 cmꢀ1
.
(b) Typical procedure for the synthesis of 3ka: 3k (73.1 mg, 0.14 mmol), Mg
(69 mg, 2.88 mmol), and MeOH (3 mL) was added in a dry Schlenk tube under
argon atmosphere. The reaction mixture was stirred overnight at room
temperature. When 3k was fully consumed, monitoring by TLC, the reaction
was quenched with sat. NH4Cl aq and extracted with Et2O (4 ꢁ 10 mL). The
combined organic phase was washed with brine, dried over Na2SO4 and
concentrated under reduced pressure. The crude product was purified by
column chromatography on silica gel (PE/EtOAc = 1/10) to give 4-(4-
fluorobuty)biphenyl (3ka) (31.6 mg, 99% yield) as yellow liquid. 1H NMR
(300 MHz, CDCl3) d 7.55 (dd, J = 18.5, J = 7.5 Hz, 4H), 7.42 (t, J = 7.2 Hz, 2H),
7.34–7.24 (m, 3H), 4.47 (dt, J = 47.4 Hz, J = 5.7 Hz, 2H), 2.70 (t, J = 6.9 Hz, 2H),
1.88–1.65 (m, 4H). 13C NMR (151 MHz, CDCl3) d 141.10, 141.06, 138.80, 128.82,
128.71, 127.09, 127.02, 127.00, 84.00 (d, J = 163.5 Hz), 35.04, 30.11, 27.00 (d,
J = 5.2 Hz). 19F NMR (282 MHz, CDCl3) d ꢀ218.17 (tt, J = 47.4 Hz, J = 25.4 Hz).
MS (EI, m/z): 228. HRMS (EI): calcd for C16H17F (M+) 228.1314, found 228.1316.
IR (KBr): 3443, 3021, 2928, 2852, 1486, 1383, 1260, 1005, 836, 763, 695.
11. (a) Brown, A. C.; Carpino, L. A. J. Org. Chem. 1985, 50, 1749–1750; (b) Kundig, E.
P., ; Cunningham, A. F., Jr. Tetrahedron 1988, 44, 6855–6860; For a review, see:
(c) Lee, G. H.; Youn, I. K.; Choi, E. B.; Lee, H. K.; Yon, G. H.; Yang, H. C.; Pak, C. S.
Curr. Org. Chem. 2004, 8, 1263–1287.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.132.
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