Synthesis of fluorinated β-ketosulfones and gem-disulfones by nucleophilic fluoroalkylation of esters and sulfinates with di- and monofluoromethyl sulfones

Article abstract of DOI:10.1021/jo900320b

(Chemical Equation Presented) An efficient and practically useful method for the preparation of α-functionalized mono- and difluoro(phenylsulfonyl) methanes by using a nucleophilic fluoroalkylation methodology was developed. α,α-Difluoro-β-ketosulfones, α

Full text of DOI:10.1021/jo900320b

Synthesis of Fluorinated ꢀ-Ketosulfones and gem-Disulfones by
Nucleophilic Fluoroalkylation of Esters and Sulfinates with Di- and
Monofluoromethyl Sulfones
Chuanfa Ni, Laijun Zhang, and Jinbo Hu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, 345 Ling-Ling Road, Shanghai 200032, China
jinbohu@mail.sioc.ac.cn
ReceiVed February 13, 2009
An efficient and practically useful method for the preparation of R-functionalized mono- and
difluoro(phenylsulfonyl)methanes by using a nucleophilic fluoroalkylation methodology was developed.
R,R-Difluoro-ꢀ-ketosulfones, R-monofluoro-ꢀ-ketosulfones, and R-fluoro disulfones were successfully
prepared in excellent yields by nucleophilic fluoroalkylation of esters and sulfinates with PhSO2CF2H
and PhSO2CH2F reagents.
Introduction
addition reactions to esters often result in the double-addition
products (tertiary alcohols) as undesired byproduct.6d,7a Gassman
and O’Reilly have shown that the nature of the products formed
from the nucleophilic perfluoroalkylation of esters using fluo-
roorganometallic reagents was a function of both the structure
of the ester and the reaction conditions.6d Prakash and co-
workers reported a one-step conversion of various methyl esters
to trifluoromethyl ketones using the Ruppert-Prakash reagent
Nucleophilic fluoroalkylation, typically involving the transfer
of a fluorine-bearing carbanion (Rf-) to an electrophile, repre-
sents one of the major synthetic methods to synthesize orga-
nofluorine compounds.1-5 During the past three decades,
nucleophilic fluoroalkylation using organometallic reagents
(RfM) and organosilicon reagents (RfSiR3) have been extensively
studied.1,2 Among these reactions, the nucleophilic fluoroalky-
lation of carboxylic esters (to give fluoroalkyl ketones) generally
needs well-controlled reaction conditions, and the yields vary
widely.6,7 Although nucleophilic perfluoroalkylation of Weinreb
and morpholine amides with perfluoroalkyllithium reagents
usually produces perfluoroalkyl ketones in high yields,8 similar
(6) (a) Wiedemann, J.; Heiner, T.; Mloston, G.; Prakash, G. K. S.; Olah,
G. A. Angew. Chem., Int. Ed. 1998, 37, 820–821. (b) Singh, R. P.; Cao, G.;
Kirchmeier, R. L.; Shreeve, J. M. J. Org. Chem. 1999, 64, 2873–2876. (c)
Yokoyama, Y.; Mochida, K. Synlett 1997, 907–908. Perfluoroalkylation of esters
with lithium reagents: (d) Gassman, P. G.; O’Reilly, N. J. J. Org. Chem. 1987,
52, 2481–2490. (e) Cregge, R. J.; Curran, T. T.; Metz, W. A. J. Fluorine Chem.
1998, 88, 71–77. (f) Roques, N.; Russell, J. PCT Int. Appl. WO 9719038, 1997.
(g) Roques, N.; Russell, J. Tetrahedron 1998, 54, 13771–13782.
(1) (a) Uneyama, K. Organofluorine Chemistry; Blackwell: Oxford, U.K.,
2006. (b) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, ReactiVity,
Applications; Wiley-VCH: Weinheim, 2004. (c) Chambers, R. D. Fluorine in
Organic Chemistry; Blackwell: Oxford, U.K., 2004. (d) Organofluorine Com-
pounds: Chemistry and Applications; Hiyama, T., Ed.; Springer: New York, 2000.
(2) (a) Prakash, G. K. S.; Hu, J. New Nucleophilic Fluoroalkylation
Chemistry. In Fluorine-Containing Synthons; Soloshonok, V. A., Ed.; American
Chemical Society: Washington, DC, 2005. (b) Prakash, G. K. S.; Hu, J.
Trihalomethyl Compounds. In Science of Synthesis; Charette, A. B., Ed.; Thieme:
New York, 2005; Vol. 22. (c) Prakash, G. K. S.; Yudin, A. K. Chem. ReV. 1997,
97, 757–786. (d) Prakash, G. K. S.; Mandal, M. J. Fluorine Chem. 2001, 112,
123–131.
(7) (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. (c) Berkowitz, D. B.; Eggen, M.; Shen, Q. R.; Shoemaker, R. K.
J. Org. Chem. 1996, 61, 4666–4675. (d) Phillion, D. P.; Cleary, D. G. J. Org.
Chem. 1992, 57, 2763–2764.
(8) (a) Kokotos, C. G.; Baskakis, C.; Kokotos, G. J. Org. Chem. 2008, 73,
8623–8626. (b) Durham, S. L.; Hare, C. M.; Huber, E. W.; Janusz, M. J.; Koehl,
J. R.; Marquart, A. L.; Mehdi, S.; Peet, N. P. J. Med. Chem. 1994, 37, 4538–
4554. (c) Johansson, A.; Poliakov, A.; Akerblom, E.; Wiklund, K.; Lindeberg,
G.; Winiwarter, S.; Danielson, U. H.; Samuelsson, B.; Hallberg, A. Bioorg. Med.
Chem. 2003, 11, 2551–2568. (d) Perni, R. B.; Pitlik, J.; Britt, S. D.; Court, J. J.;
Courtney, L. F.; Deininger, D. D.; Farmer, L. J.; Gates, C. A.; Harbeson, S. L.;
Levin, R. B.; Lin, C.; Lin, K.; Moon, Y.-C.; Luong, Y.-P.; O’Malley, E. T.;
Rao, B. G.; Thomson, J. A.; Tung, R. D.; Van Drie, J. H.; Wei, Y. Bioorg. Med.
Chem. Lett. 2004, 14, 1441–1446.
(3) Prakash, G. K. S.; Hu, J. Acc. Chem. Res. 2007, 40, 921–930.
(4) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56, 7613–7632.
(5) Langlois, B. R.; Billard, T. Synthesis 2003, 185–194.
10.1021/jo900320b CCC: $40.75
Published on Web 04/17/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3767–3771 3767

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

Synthesis of ꢀ-Ketosulfones and gem-Disulfones
TABLE 2. (Phenylsulfonyl)difluoromethylation of Various Esters
SCHEME 2. Proposed Mechanism for
(Phenylsulfonyl)difluoromethylation of Esters
entry
R1
R2
product
yielda (%)
1
2
3
4
5
6
7
8
9
Ph
CH3 8a
CH3 8b
CH3 8c
92 (86)
96 (88)
95 (87)
85 (76)
92 (84)
87
4-Cl-C6H4
4-Br-C6H4
4-MeO-C6H4 CH3 8d
CH3
C2H5
CH2dCH
PhCt
COOC2H5
C2H5 8e
C2H5 8f
C2H5 8g
C2H5 8h
0
C
80 (72)
93
C2H5 PhSO2CF2C(OH)2CO2C2H5
8i
a Isolated yield when the reaction was carried out on a 0.5-1.0 mmol
scale. Number in parentheses refers to the isolated yield when the
reaction was carried out on a 10-20 mmol scale.
SCHEME 3. Various Transformations of 8a
(entry 4). During the nucleophilic difluoromethylation of alde-
hydes and ketones with PhSO2CF2H,15 it was found that the
addition of hexamethylphosphoramide (HMPA) as a cosolvent
could significantly improve the yields. Much to our delight, with
HMPA as an additive, the reaction of 2 with 7a and LHMDS
in a molar ratio of 2:1:2 at -98 °C gave 8a in 92% yield (entry
7). It seems that HMPA played an important role in the
stabilization of the tetrahedral intermediate, the (phenylsulfo-
nyl)difluoromethylated lithiated hemiketal. Furthermore, de-
creasing the temperature was found to be beneficial to the
product yield, probably because of the enhanced stability of the
lithiated hemiketal at a low temperature (entries 5 and 6).
By applying the optimized reaction condition (Table 1, entry
7), we turned our attention to the efficient synthesis of R,R-
difluoro-ꢀ-ketosulfones from various esters, and the results are
shown in Table 2. The reactions with different methyl and ethyl
esters gave the corresponding ketones 8 in good-to-excellent
yields (entries 1-6). When ethyl acrylate was used as an
electrophile, no desired product was obtained, probably because
of the high reactivity of this less hindered R,ꢀ-unsaturated ester
toward LHMDS (entry 7). However, the reaction with ethyl
3-phenylpropiolate could afford the desired product 8h in good
yield, without the formation of Michael addition product (entry
8). For diethyl oxalate, the PhSO2CF2- anion selectively attacked
one of the two ester groups, and the desired product 8i was
obtained in 93% yield as a hydrate form after acidic quenching
(entry 9). As shown in Table 2, this preparative procedure was
able to be scaled up with high product yields.
a Determined by 19FMR using PhCHF3 as an internal standard.
act as a precursor for the synthesis of difluoromethyl substituted
tri- and tetrasubstituted oxiranes and tetrasubstituted alkenes16
(Scheme 3, eq 1). In addition, we found that magnesium metal-
promoted reductive desulfonylation of the ketosulfones 8a and
8e in the presence of TMSCl afforded 2,2-difluoro enol silyl
ethers 11a and 11e in 70-80% yields (Scheme 3, eq 2), which
provides an alternative method for the preparation of 2,2-difluoro
enol silyl ethers.17
Nucleophilic (phenylsulfonyl)monofluoromethylation of es-
ters18 with fluoromethyl phenyl sulfone 4 was also investigated.
Reactions between 4 and esters in the presence of LHMDS
readily took place, providing the corresponding R-fluoro-ꢀ-
ketosulfones 13 in excellent yields (Table 3). Different from
the above-mentioned difluoromethylation of esters, the monof-
luoromethylation was able to proceed smoothly even at -78
°C, and no additional HMPA was necessary to promote the
formation of the lithiated hemiketals. However, in the case of
carbonate, there was an equilibrium between the reactant and
the lithiated hemiketal intermediate, and 2.0 equiv of diethyl
carbonate was required for a complete consumption of the
sulfone reagent 4 (Table 3, entry 8).
It should be noted that in all cases that no double addition
product (that is, the bis[(phenylsulfonyl)difluoromethyl]-
substituted carbinol) was observed. This suggests that before
acidic quenching, the decomposition of the tetrahedral inter-
mediate 9 to ꢀ-ketosulfones 8 via loss of R2OLi was not
occurring (Scheme 2). ꢀ-Ketosulfones 8 was likely formed from
the dealcoholation of hemiketal intermediate 10, which was
formed during acidic quenching of 9.
The efficient nucleophilic fluoroalkylation method was also
extended to arylsulfinates. When excess methyl benzenesulfinate
14 (1.2 equiv) reacted with PhSO2CH2F (4) in the presence of
LHMDS at -78 °C, monofluorinated R-sulfonyl sulfoxide 15
was obtained as a mixture of two diastereomers in the ratio of
1:2 (Scheme 4). Subsequent oxidation of the sulfoxide 15
As one of the highly useful fluorinated building blocks, R,R-
difluoro-ꢀ-ketosulfones can undergo many organic transforma-
tions. For example, treatment of the ketosulfone 8a with
dichloromethyllithium in THF at -98 °C in the presence of
HMPA afforded dichlorohydrin 11 in good yield, which can
(16) (a) Shimizu, M.; Fujimoto, T.; Minezaki, H.; Hata, T.; Hiyama, T. J. Am.
Chem. Soc. 2001, 123, 6947–6948. (b) Liu, X.; Shimizu, M.; Hiyama, T. Angew.
Chem., Int. Ed. 2004, 43, 879–882.
(17) Amii, H.; Kobaiyashi, T.; Hatamoto, Y.; Uneyama, K. Chem. Commun.
1999, 1323–1324, and the references cited therein.
(18) Examples for the acylation of monofluorinated ester enolates: (a) Turner,
J. A.; Jacks, W. S. J. Org. Chem. 1989, 54, 4229–4231. (b) Bergmann, E. D.;
Cohen, S. J. Chem. Soc. 1961, 4669–4671. (c) Shahak, I.; Bergmann, E. D.
J. Chem. Soc. 1960, 3225–3229. (d) Bergmann, E. D.; Cohen, S.; Shahak, I.
J. Chem. Soc. 1959, 3278–3285.
(15) Prakash, G. K. S.; Hu, J.; Wang, Y.; Olah, G. A. Eur. J. Org. Chem.
2005, 2218–2223.
J. Org. Chem. Vol. 74, No. 10, 2009 3769

Ni et al.
TABLE 4. Comparison of Fluorinated and Chlorinated Sulfones
TABLE 3. (Phenylsulfonyl)monofluoromethylation of Various
Esters
entrya
halogenated sulfone
product
yieldb (%)
entrya
R1
R2
monofluoroproduct
yieldb (%)
1
2
3
4
2: X ) F, Y ) F
4: X ) F, Y ) H
18: X ) Cl, Y ) H
20: X ) Cl, Y ) Cl
8a
13a
19
92
98
50 (48)c
0 (97)
1
2
3
4
5
6
7
8c
Ph
CH3
CH3
CH3
CH3
C2H5
C2H5
C2H5
C2H5
13a
13b
13c
13d
13e
13f
98
97
92
95
96
93
94
93
4-Cl-C6H4
4-Br-C6H4
4-MeO-C6H4
CH3
21
a Reaction conditions: for entries 1 and 4, 7a/sulfone/LHMDS )
2:1:2, THF/HMPA ) 10:1, -98 °C; for entries 2 and 3, 7a/sulfone/
LHMDS ) 1.2:1:1.2, -78 °C. b Isolated yield. Number in parentheses
refers to the recovery yield of the unreacted sulfone. c The yield was
C2H5
PhCt
C
13g
13h
1
determined by H NMR analysis of the mixture of 18 and 19.
OCH2CH3
a Unless otherwise noted, the reaction was carried out with 7/4/
LHMDS ) 1.2:1.0:1.2 on a 0.5-1.0 mmol scale. b Isolated yield.
c Reactant ratio was 7/4/LHMDS ) 2:1:2.
halogenated sulfone carbanions toward esters may arise from
the different stability of the lithiated hemiketals. It is expected
that the chlorinated sulfone carbanions possess better leaving
ability than the fluorinated ones, so the lithiated mono- or
dichloromethylphenylsulfonyl substituted hemiketals would be
less stable than the corresponding mono- and difluorometh-
ylphenylsulfonyl substituted ones.
SCHEME 4. Preparation of 16 by Monofluoromethylation
of 14
Conclusions
In conclusion, we have shown an efficient and practically
useful method for the preparation of R-functionalized mono-
and difluoro(phenylsulfonyl)methanes by using a nucleophilic
fluoroalkylation methodology. R,R-Difluoro-ꢀ-ketosulfones,
R-monofluoro-ꢀ-ketosulfones, and R-fluoro disulfones could be
prepared in excellent yields by nucleophilic fluoroalkylation of
esters and sulfinates with PhSO2CF2H and PhSO2CH2F as
reagents. The fluorinated products are expected to be useful
fluorinated building blocks, as exemplified by the conversion
of R,R-difluoro-ꢀ-ketosulfones to the corresponding 2,2-difluoro
enol silyl ethers promoted by magnesium metal in the presence
of TMSCl. Efforts are underway to extend the scope of the
fluorinated sulfones to fluorinated heteroaromatic sulfones and
to apply these R-functionalized fluorinated sulfones for other
transformations.
afforded fluorobis(phenylsulfonyl)methane 16 with 91% overall
yield. This sulfination and oxidation procedure provides a highly
useful and practical method for the preparation of R-fluoro
disulfones such as 16. It should be mentioned that compound
16 is an excellent and widely used monofluoromethide equiva-
lent for the synthesis of a series of achiral and chiral monof-
luoromethylated compounds.10
In addition, we also attempted the nucleophilic monofluoro-
alkylation of benzenesulfonate 17 using 4 and LHMDS, but no
desired R-fluoro disulfone 16 was formed (Scheme 4). The
reaction between benzenesulfinate, PhSO2CF2H (2), and LH-
MDS under the similar conditions was attempted but failed to
give the desired difluorinated R-sulfonyl sulfoxide (PhSO2-
CF2SOPh).
Although the nucleophilic fluoroalkylation of esters with di-
and monofluoromethyl sulfones is a useful method for the
synthesis of fluorinated ꢀ-ketosulfones, reactions with chlori-
nated sulfones are rare.19 For a comparison of the reactivity of
different halogenated sulfone carbanions toward esters, we
examined the reactions of mono- and dichlorinated sulfones with
methyl benzoate. As shown in Table 4, monochlorinated sulfone
18 could give a moderate yield of R-chloro-ꢀ-ketosulfone
product 19 (entry 3). However, dichlorinated sulfone 20 could
not react with methyl benzoate 7a, and the starting material 20
was recovered (see entry 4). The reactivity differences between
Experimental Section
General Procedure for the Preparation of r,r-Difluoro-ꢀ-
ketosulfone 8: 2,2-Difluoro-1-phenyl-2-(phenylsulfonyl)ethanone
(8a).14 Under N2 atmosphere, into a Schlenk tube containing methyl
benzoate 7a (136 mg, 1.0 mmol) and PhSO2CF2H (2) (96 mg, 0.5
mmol) in THF-HMPA (2.5 mL/0.25 mL) at -98 °C was added
dropwise 1.0 M LHMDS in THF (1.0 mL, 1.0 mmol). The reaction
mixture was then stirred vigorously at -98 °C for 30 min, followed
by adding concentrated aqueous HCl solution (1 mL) at this
temperature. The reaction mixture was slowly warmed to room
temperature and then extracted with EtOAc (10 mL × 3). The
combined organic phase was dried over MgSO4. After the removal
of volatile solvents under vacuum, the crude product was further
purified by silica gel column chromatography (10:1 PE/EtOAc v/v
as eluent) to afford product 8a (137 mg, 92% yield). White solid,
mp 80-81 °C, 92% yield. 1H NMR (300 MHz, CDCl3): δ 7.55 (t,
J ) 7.8 Hz, 2H), 7.64-7.73 (m, 3H), 7.82 (t, J ) 7.5 Hz, 1H),
8.03 (d, J ) 7.6 Hz, 2H), 8.18 (d, J ) 7.6 Hz, 2H). 19F NMR (282
MHz, CDCl3): δ -101.9 (s). 13C NMR (75 MHz, CDCl3): δ 116.5
(t, J ) 299 Hz), 128.9, 129.6, 130.8, 130.9, 132.0, 132.6, 135.4,
136.0, 183.8 (t, J ) 24 Hz). MS (ESI, m/z): 314.0 (M + NH4+),
319.0 (M + Na+), 351.0 (M + MeOH + Na+). Anal. Calcd for
(19) We noticed that there is only one example reported on the nucleophilic
addition of chlorinated sulfone carbanion to the carbonyl group of dimethyl
chloromaleate with low yield. See: Makosza, M.; Nizamov, S.; Kwast, A.
Tetrahedron 2004, 60, 5413–5421.
3770 J. Org. Chem. Vol. 74, No. 10, 2009

Synthesis of ꢀ-Ketosulfones and gem-Disulfones
C14H10F2O3S: C, 56.75; H, 3.40. Found: C, 56.70; H, 3.75. IR (KBr):
7.7 Hz, 2H). 19F NMR (282 MHz, CDCl3): δ -180.2 (d, J ) 48
Hz, 1F). 13C NMR (100 MHz, CDCl3): δ 100.1 (d, J ) 233 Hz),
128.8, 129.4, 129.7 (d, J ) 3.0 Hz), 129.8 (d, J ) 1.5 Hz), 133.9,
134.6, 135.0, 135.3, 186.5 (d, J ) 18 Hz). MS (ESI, m/z): 295.9
(M + NH4+).
1703, 1594, 1449, 1350, 1272, 1143 cm-1
.
General Procedure for the Preparation of r-Monofluoro-ꢀ-
ketosulfone 13: 2-Fluoro-1-phenyl-2-(phenylsulfonyl)ethanone (13a).
Under N2 atmosphere, into a Schlenk tube containing methyl
benzoate 7a (163 mg, 1.2 mmol) and PhSO2CH2F (4) (174 mg,
1.0 mmol) in THF (5.0 mL) at -78 °C was added dropwise 1.0 M
LHMDS in THF (1.2 mL, 1.2 mmol). The reaction mixture was
then stirred at -78 °C for 30 min, followed by adding saturated
HCl water solution (2 mL) at this temperature. The solution mixture
was extracted with EtOAc (20 mL × 3), and the combined organic
phase was dried over MgSO4. After the removal of volatile solvents
under vacuum, the crude product was further purified by silica gel
column chromatography (4:1 PE/EtOAc as eluent) to afford product
Acknowledgment. Support of our work by the National
Natural Science Foundation of China (20502029, 20772144,
20825209, 20832008) and the Chinese Academy of Sciences
(Hundreds-Talent Program and Knowledge Innovation Program)
is gratefully acknowledged.
Supporting Information Available: Experimental details and
characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
1
13a (273 mg, 98% yield). White solid, mp 94-96 °C. H NMR
(300 MHz, CDCl3): δ 6.39 (d, J ) 48 Hz, 1H), 7.45-7.61 (m,
4H), 7.62-7.76 (m, 2H), 7.87 (d, J ) 7.6 Hz, 2H), 8.01 (d, J )
JO900320B
J. Org. Chem. Vol. 74, No. 10, 2009 3771