Ni et al.
SCHEME 1. Nucleophilic Fluoroalkylations of Methyl Cinnamate 1
TABLE 1. Survey of Reaction Conditions for
(Phenylsulfonyl)difluoromethylation
(Me3SiCF3) and a catalytic amount of fluoride initiator.6a The
method has been further extended by Shreeve and co-workers
using CsF as an initiator.6b Percy and co-workers found that
the cerium mediated reaction between (EtO)2(O)PCF2Li and
various esters gave R,R-difluoro-ꢀ-ketophosphonates in moder-
ate-to-good yields.9 Recently, fluorinated sulfones such as
PhSO2CF2H, PhSO2CF2SiMe3, and PhSO2CH2F have been
extensively used as useful reagents in nucleophilic difluorom-
ethylation, difluoromethylenation, and monofluoromethylation
reactions.3 However, both nucleophilic (phenylsulfonyl)difluo-
romethylation and (phenylsulfonyl)monofluoromethylation of
esters have not been reported.
On the other hand, R-functionalized fluorinated sulfones
such as (PhSO2)2CHF, PhSO2CHFCOPh, and PhSO2CF2-
COPh are of great interest in organic synthesis, since they
can be used as “soft” fluoroalkylation reagents and also be
subject to a range of transformations.10 Currently, these
R-functionalized fluorinated sulfones were commonly pre-
pared by electrophilic fluorination with Selectfluor or an NFSI
reagent (NFSI ) N-fluorodibenzenesulfonimide)10,11 or by
oxidation of corresponding sulfides12 or alcohols13 through
a two-step procedure. However, the electrophilic monoflu-
orination procedure often leads to an undesired overfluori-
nation (difluorination), and it is usually inconvenient to
separate the mono- and difluorinated sulfones. Furthermore,
electrophilic gem-difluorination of ketosulfones with an
excess amount of Selectfluor sometimes only gives a moder-
ate yield of difluorinated products.14 Therefore, a more
efficient and practical method for the preparation of various
R-functionalized di- and monofluorinated sulfones is desired.
entry base molar ratio (7a:2:base) additivea temp (°C) yieldb (%)
1
2
3
LHMDS
t-BuOK
LHMDS
1.2:1:1.2
1.2:1:1.2
2:1:2
1.2:1:1.2
1.2:1:1.2
1.2:1:1.2
2:1:2
-98
-98
-98
-98
-98
-78
-98
70
71
70
0
82
75
92
4c LHMDS
5
6
7
LHMDS
LHMDS
LHMDS
HMPA
HMPA
HMPA
a THF/HMPA ) 10:1 (v/v). b Isolated yield. c 4-Benzoylmorpholine
(instead of 7a) was used as the electrophile.
Previously, in the course of our investigation of nucleophilic
fluoroalkylation of R,ꢀ-enones with fluorinated sulfones, we
found that for acylic R,ꢀ-enones, the hard or soft nature of the
carbanions played a major role on the regioselectivity.10f When
methyl cinnamate 1 was tested as a Michael acceptor, the
regioselectivity of di- and monofluoromethylation are similar
to the cases with R,ꢀ-enones, giving the fluorinated ꢀ-ketosul-
fones 3 and 5 as the major product, respectively (Scheme 1,
eqs 1 and 2).10f These results encouraged us to develop a general
procedure for the synthesis of fluorinated R-ketosulfones and
gem-disulfones by nucleophilic fluoroalkylation of esters and
sulfinates with PhSO2CF2H and PhSO2CH2F reagents.
(9) (a) Lequeux, T. P.; Percy, J. M. J. Chem. Soc., Chem. Commun. 1995,
2111–2112. (b) Blades, K.; Lequeux, T. P.; Percy, J. M. Tetrahedron 1997, 53,
10623–10632.
Results and Discussion
(10) (a) Ni, C.; Li, Y.; Hu, J. J. Org. Chem. 2006, 71, 6829–6833. (b)
Fukuzumi, T.; Shibata, N.; Sugiura, M.; Yasui, H.; Nakamura, S.; Toru, T. Angew.
Chem., Int. Ed. 2006, 45, 4973–4977. (c) Prakash, G. K. S.; Chacko, S.; Alconcel,
S.; Stewart, T.; Mathew, T.; Olah, G. A. Angew. Chem., Int. Ed. 2007, 46, 4933–
4936. (d) Mizuta, S.; Shibata, N.; Goto, Y.; Furukawa, T.; Nakamura, S.; Toru,
T. J. Am. Chem. Soc. 2007, 129, 6394–6395. (e) Prakash, G. K. S.; Zhao, X.;
Chacko, S.; Wang, F.; Vaghoo, H.; Olah, G. A. Beilstein J. Org. Chem. 2008,
4, 17. (f) Ni, C.; Zhang, L.; Hu, J. J. Org. Chem. 2008, 73, 5699–5713. (g)
Furukawa, T.; Shibata, N.; Mizuta, S.; Nakamura, S.; Toru, T.; Shiro, M. Angew.
Chem., Int. Ed. 2008, 47, 8051–8054.
(11) (a) Zajc, B.; Kake, S. Org. Lett. 2006, 8, 4457–4460. (b) Alonso, D. A.;
Fuensanta, M.; Ga´mez-Bengoa, E.; Na´jera, C. AdV. Synth. Catal. 2008, 350,
1823–1829. (c) Davis, F. A.; Han, W.; Murphy, C. K. J. Org. Chem. 1995, 60,
4730–4737.
(12) (a) Pfund, E.; Lebargy, C.; Rouden, J.; Lequeux, T. J. Org. Chem. 2007,
72, 7871–7877. (b) Nagura, H.; Fuchigami, T. Synlett 2008, 1714–1718. (c) He,
M.; Ghost, A. K.; Zajc, B. Synlett 2008, 999–1004. (d) Motherwell, W. B.;
Greaney, M. F.; Tocher, D. A. J. Chem. Soc., Perkin Trans. 1 2002, 2809–
2815. (e) Takeuchi, Y.; Asahina, K. H.; Koizumi, T. J. Chem. Soc., Perkin Trans.
1 1988, 1149–1153.
We began our investigation with the goal to search for
optimized reaction conditions for the preparation of R,R-
difluoro-ꢀ-ketosulfones from difluoromethyl sulfone 2 (Table
1). First, lithium hexamethyldisilazide (LHMDS) was chosen
as the base to generate PhSO2CF2Li in situ from PhSO2CF2H
(2) at -98 °C. Thus, the reaction mixture of methyl benzoate
7a (1.2 equiv) and PhSO2CF2H (2) (1.0 equiv) was cooled to
-98 °C and then treated with LHMDS (1.2 equiv). After 0.5 h,
the reaction mixture was quenched with aqueous HCl solution
at -98 °C. Simple workup and chromatography purification of
the crude product gave R,R-difluoro-ꢀ-ketosulfone 8a in 70%
yield (entry 1). When tBuOK was used as the base, a similar
result was obtained (entry 2). Change in the reactant ratio from
1.2:1:1.2 to 2:1:2 did not significantly affect the product yield
(entries 1 and 3). Interestingly, when morpholine amide (4-
benzoylmorpholine) was used as the electrophile, we did not
obtain the carbinolamine or the corresponding ketone product
(13) Stahly, G. P. J. Fluorine Chem. 1989, 43, 53–66.
(14) Loghmani-Khouzani, H.; Poorheravi, M. R.; Sadeghi, M. M. M.;
Caggiano, L.; Jackson, R. F. W. Tetrahedron 2008, 64, 7419–7425.
3768 J. Org. Chem. Vol. 74, No. 10, 2009