Efficient nucleophilic fluoromethylation and subsequent transformation of alkyl and benzyl halides using fluorobis(phenylsulfonyl)methane

Article abstract of DOI:10.1021/ol8029627

An efficient methodology for the nucleophilic fluoromethylation of alkyl and benzyl halides using r-fluoro-α-(phenylsulfonyl)methane (1) as a highly versatile reagent is reported. Using benzyl halides, stereospecific one-pot synthesis of α-fluorovinyl com

Full text of DOI:10.1021/ol8029627

ORGANIC
LETTERS
2009
Vol. 11, No. 5
1127-1130
Efficient Nucleophilic Fluoromethylation
and Subsequent Transformation of Alkyl
and Benzyl Halides Using
Fluorobis(phenylsulfonyl)methane
G. K. Surya Prakash,* Sujith Chacko, Habiba Vaghoo, Nan Shao,
Laxman Gurung,† Thomas Mathew, and George A. Olah*
Loker Hydrocarbon Research Institute and Department of Chemistry,
UniVersity of Southern California, Los Angeles, California 90089-1661
gprakash@usc.edu; olah@usc.edu
Received December 23, 2008
ABSTRACT
An efficient methodology for the nucleophilic fluoromethylation of alkyl and benzyl halides using r-fluoro-r-(phenylsulfonyl)methane (1) as
a highly versatile reagent is reported. Using benzyl halides, stereospecific one-pot synthesis of r-fluorovinyl compounds such as
r-fluorostyrylsulfones, r-fluorocinnamates, and r-fluorochalcones has been achieved. The methodology has been extended toward the synthesis
of r-substituted fluoroalkane derivatives using selective reductive desulfonylation conditions.
The introduction of a monofluoromethyl group into organic
molecules has been the subject of numerous articles and
has more recently sparked interest in the life sciences.1
7R-(Fluoromethyl)dihydroxytestosterone,2 3-fluoro-5-(2-
(2-(fluoromethyl)thiazol-4-yl)ethynyl)benzonitrile,3and6-(flu-
oromethyl)purine4 are a few examples of monofluorom-
ethyl analogues of biologically important compounds
synthesized recently. As is already well-known, incorpora-
tion of fluorine in drug molecules can highly affect their
physicochemical properties such as bond strength, lipo-
philicity, bioavailability, conformation, electrostatic po-
tential, dipole moment, pKa, etc.; pharmacokinetic prop-
erties such as tissue distribution and rate of metabolism;
or pharmacological consequences such as pharmacody-
namics and toxicology. In addition, vinyl fluorides play
† REU Research Participant, Summer 2007, University of Southern
California.
(1) (a) Prakash, G. K. S.; Chacko, S.; Alconcel, S.; Stewart, T.; Mathew,
T.; Olah, G. A. Angew. Chem., Int. Ed. 2007, 46, 4933. (b) Prakash, G. K. S.;
Ledneczki, I.; Chacko, S.; Olah, G. A. Org. Lett. 2008, 10, 557. (c)
Fukuzumi, T.; Shibata, N.; Sugiura, M.; Yasui, H.; Nakamura, S.; Toru, T.
Angew. Chem., Int. Ed. 2006, 45, 4973. (d) Li, Y.; Ni, C.; Liu, J.; Zhang,
L.; Zhang, J.; Hu, J. Org. Lett. 2006, 8, 1693. (e) Mizuta, S.; Shibata, N.;
Goto, Y.; Furukawa, T.; Nakamura, S.; Toru, T. J. Am. Chem. Soc. 2007,
129, 6394.
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R. B.; Pike, V. W. J. Med. Chem. 2007, 50, 3256.
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3, 3001.
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10.1021/ol8029627 CCC: $40.75
Published on Web 01/30/2009
2009 American Chemical Society

an important role in biological sciences as peptidomimics5
and enzyme inhibitors6 and are also key synthons for
various organic synthetic transformations.7,8
alkylated R-fluoro(phenylsulfonyl)methanes in moderate to
excellent yields (Table 1).
Olah and co-workers first reported the use of fluorometha-
nol9 for electrophilic monofluoromethylation. The use of
fluoromethyl halides, fluoromethyl triflates, and chlorofluo-
romethane has also been reported.10 Recently, our group has
shown that direct electrophilic monofluoromethylation can
be carried out using S-(monofluoromethyl)-diarylsulfonium
tetrafluoroborate.1b Prakash, Shibata, and Hu have indepen-
dently reported the use of fluorobis(phenylsulfonyl)methane
as monofluoromethide equivalent for the transfer of a
monofluoromethyl group to alcohols,1a allylic acetates,1c and
epoxides1d and also for 1,4-addition reactions to various
Michael acceptors.11 Fluoromethyl phenylsulfone and mag-
nesium benzyl fluoromalonates were also used for nucleo-
philic monofluoromethylation.12 Previously, we have reported
the use of fluoroiodobis(phenylsulfonyl)methane for radical
fluoroalkylations of terminal alkenes.13 Herein, we disclose
a simple and efficient new method for the preparation of
terminal monofluorobis(phenylsulfonyl)alkanes (2a-f) with
varying chain lengths from readily available primary halides
and their subsequent transformations.
Table 1. Nucleophilic Monofluoromethylation of Alkyl Halides
Using R-Fluorobis(phenylsulfonyl)methane (1a)
starting
material
product
(2a-j)
yield
(%)a
entry
a
b
c
d
e
f
g
h
i
Ph(CH2)3I
Ph(CH2)4I
PhCH2CH2CH2CF(SO2Ph)2 83
Ph(CH2)4CF(SO2Ph)2
CH3(CH2)6CF(SO2Ph)2
CH3(CH2)5CF(SO2Ph)2
PhCH2CF(SO2Ph)2
85
90
81
87
82
60
40
20b
60c
CH3(CH2)6I
CH3(CH2)5I
PhCH2Br
Ph(CH2)2Br
CH3CHICH3
CH3CHBr(CH2)2CH3 CH3CH(n-Pr)CF(SO2Ph)2
CH3(CH2)6Cl
PhCH2Cl
Ph(CH2)2CF(SO2Ph)2
CH3CHCF(SO2Ph)2CH3
CH3(CH2)6CF(SO2Ph)2
PhCH2CF(SO2Ph)2
j
a Isolated yield. b No NaI used. c In the presence of NaI.
One of the crucial factors for the nucleophilic substitution
of primary halides is to match the softness of the nucleophile
with that of the electrophilic center. We have previously
reported the nucleophilic difluoromethylation of alkyl halides
using difluoromethyl phenyl sulfone with potassium tert-
butoxide as the base.14 However, we found that using mild
bases such as stoichiometric amounts of potassium carbonate
in DMF or cesium carbonate in acetonitrile, the soft
carbanion [R-fluorobis(phenylsulfonyl)methide] can be gen-
erated from R-fluorobis(phenylsulfonyl)methane at room
temperature. The reaction proceeds smoothly for both
primary alkyl iodides and alkyl bromides to provide the
However, in the case of primary alkyl chlorides, the
reaction was found to be sluggish and yield was low. With
the addition of a catalytic amount of NaI, the reaction of
benzyl chloride provided the desired product in 60% yield.
With secondary alkyl iodide (Table 1, entry g), the reaction
was found to be rather slow compared to that of primary
alkyl iodides.
Interestingly, when the reactions of benzyl halides were
carefully examined, formation of fluorovinyl sulfones was
observed indicating that a second elimination step occurred
after the initial substitution reaction. Vinyl fluorides can be
prepared from electrophilic fluorination of vinyllithiums15,16
or stannanes17,18 via the Horner-Wadsworth-Emmons
condensation of R-fluorophosphonates with carbonyls,19-21
desulfonylation,22,23 stannyldesulfonylation,24-26 silyl and
germyldesulfonylation27,28 of fluorovinyl sulfones, as well
as Peterson29 and Julia30 olefination. Fluorovinyl sulfones,
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Org. Lett., Vol. 11, No. 5, 2009

precursors of vinyl fluorides, are commonly synthesized
using the Horner-Wittig reaction. In addition, direct alky-
lation of halides and subsequent elimination using phenyl-
sulfonyl-substituted fluorinated carbanions for the synthesis
of fluorovinyl sulfones is quite rare in the literature.31 We
found that when nucleophilic monofluoromethylation of
benzyl halides using R-fluorobis(phenylsulfonyl)methane (1a)
was carried out in the presence of cesium carbonate in
acetonitrile, monofluoromethylation followed by subsequent
elimination occurs leading to the corresponding fluorovinyl
sulfones in moderate to excellent yields (Table 2).
lower (Table 2, entry f). Both substituted benzyl bromides
and chlorides work well in this reaction. However, in the
case of benzyl chlorides, addition of a small amount of NaI
is needed to make the reaction more facile. When we
compared the reactivity of o-, m-, and p-nitrobenyl bromides,
we found that ortho- and para-substituted derivatives react
immediately to give the corresponding fluorovinyl sulfones
in excellent yield. However, the reaction of m-nitrobenzyl
bromide was sluggish even at 70 °C, resulting in comparably
lower yield.
We further extended this methodology to include R-sub-
stituted fluoro(phenylsulfonyl)methane derivatives 1b and 1c
to afford the corresponding R-fluorochalcones and R-fluo-
rocinnamate in one step (Table 2 entries h-j). Unlike in the
previous case, the reaction with the R-substituted fluoro(phe-
nylsulfonyl)methane derivatives requires heating. At room
temperature, only the SN2 reaction occurs as manifested by
19F NMR analysis. On heating, the intermediate undergoes
elimination to afford the vinyl fluoride as evident by the
disappearance of the triplet at -146 ppm and emergence of
a doublet at -120 ppm in 19F NMR. (Table 2, entries 3 h-j).
With allyl and propargyl bromides the reaction proceeded
as expected to give the corresponding products in moderate
yields (Table 2, entries k and l). On the other hand, in the
case of alkyl halides, the alkylated R-fluoro(phenylsulfonyl)-
methane products did not undergo R-eliminations.
Table 2. Cs2CO3/CH3CN-Catalyzed Synthesis of Fluorovinyl
Sulfones and R-Fluoro-R,ꢀ-unsaturated Carbonyls
The exclusive formation of the E-isomer in the benzyl
halides (3a-j) is most likely due to the proximity of the
phenyl group. After the initial formation of the benzyl-
substituted R-fluoro-R-bis(sulfonyl)methane, the aromatic
ring in proximity at the ꢀ-position can function as a
neighboring group, which assists the exclusive formation of
the E-isomer. However, in 3k and 3l, the effect is less
prominent than the other cases and some amount of Z-isomer
is also formed.
One of the major transformations using sulfone-based
organic reactions is its replacement with hydrogen by
reductive desulfonylation. Efforts have been directed at
developing various reducing agents, including metal amal-
gams, samarium diiodide, sodium dithionite, hydrides in the
presence of transition metal catalysts, and tributyltinhydride
(under free radical conditions).32
Geminal bis-sulfones are widely used in organic syntheses,
as they can be easily deprotonated and used in various
nucleophilic substitution and cyclization reactions. One of
the challenges involved in this chemistry is the stepwise
desulfonylation reaction. Falck and co-workers reported the
use of lithium naphthalenide in THF as well as samarium
iodide for the reductive monodesulfonylation of gem-bis-
sulfones.33Tuttle et al. reported the use of neutral organic
super-electron-donor (S.E.D) reagent for the synthesis of
monosulfones from gem-disulfones.34
a Isolated yield. b Relative ratios determined by 19F NMR.
In all cases, the reaction was found to be highly stereospe-
cific and formation of only the E-isomer was observed on
the basis of 19F NMR analysis. Benzyl halides with both
electron-donating and electron-withdrawing groups on the
phenyl ring were tolerated. With electron-withdrawing
groups, the yields of the corresponding fluorovinyl sulfones
were considerably higher in most cases and the reaction
proceeded at room temperature. Electron-rich benzyl systems
required heating (120 °C), and the yields were relatively
(32) (a) Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon
Press: Oxford, England, 1993. (b) Najera, C.; Jus, M. Tetrahedron 1999,
55, 10547. (c) Magnus, P. D. Tetrahedron 1977, 33, 2019.
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Lett. 1994, 35, 5437.
(34) Schoenebeck, F.; Murphy, J. A.; Zhou, S.; Uenoyama, Y.; Miclo,
Y.; Tuttle, T. J. Am. Chem. Soc. 2007, 129, 13368.
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Org. Lett., Vol. 11, No. 5, 2009
1129

Our aim was to find a system that is more environmentally
friendly and economical. We used a Mg/HOAc/NaOAc
system for the reductive desulfonylation of the gem-disul-
fones, and to our delight the reaction stopped at monodes-
ulfonylation, enabling us to isolate the products in moderate
to excellent yields (Table 3). Hu et al. also reported the use
(Table 4). Furthermore, under these reaction conditions, we
did not detect any monodesulfonylated product.
Table 4. Synthesis of Monofluromethyl Alkanes Using Mg/
MeOH System
Table 3. Reductive Monodesulfonylation Using a Mg/HOAc/
NaOAc System
entry
starting material
product (5a-f)
yield (%)a
a
b
c
d
e
f
Ph(CH2)2CF(SO2Ph)2
Ph(CH2)3CF(SO2Ph)2
Ph(CH2)4CF(SO2Ph)2
Ph(CH2)5CF(SO2Ph)2
PhO(CH2)3CF(SO2Ph)2 PhO(CH2)3CH2F
PhO(CH2)4CF(SO2Ph)2 PhO(CH2)4CH2F
Ph(CH2)2CH2F
Ph(CH2)3CH2F
Ph(CH2)4CH2F
Ph(CH2)5CH2F
71
48
56
75
83
77
entry
starting material
product (4a-g)
yield (%)a
a
b
c
d
e
f
CH3(CH2)5CF(SO2Ph)2 CH3(CH2)5CHFSO2Ph
CH3(CH2)6CF(SO2Ph)2 CH3(CH2)6CHFSO2Ph
70
65
63
65
60
62
63
a Isolated yield.
PhCH2CF(SO2Ph)2
Ph(CH2)2CF(SO2Ph)2
Ph(CH2)3CF(SO2Ph)2
Ph(CH2)4CF(SO2Ph)2
PhCH2CHFSO2Ph
Ph(CH2)2CHFSO2Ph
Ph(CH2)3CHFSO2Ph
Ph(CH2)4CHFSO2Ph
In conclusion, we have developed an efficient methodology
for the synthesis of alkyl(benzyl) R-fluoro-R-bis(phenylsul-
fonyl)methanes by nucleophilic substitution of the corre-
sponding alkyl/benzyl halides with R-fluorobis(phenylsul-
fonyl)methane (1a). We have also developed an efficient one-
pot stereospecific synthesis of fluorovinyl sulfones. By using
different R-substituted fluoro(phenylsulfonyl)methane deriva-
tives, a variety of vinyl fluorides (3a-l) can be obtained.
With proper choice of reductive desulfonylating reagent
system, we were also able to perform the stepwise desulfo-
nylation reaction to yield the R-fluoro-R-(phenylsulfonyl)-
alkanes (4a-g) and R-fluoroalkanes (5a-f), respectively.
g
PhO(CH2)4CF(SO2Ph)2 PhO(CH2)4CHFSO2Ph
a Isolated yield.
of the same system for the reductive desulfonylation of
difluoromethyl phenylsulfonyl derivatives.35
Inspired by this result, we turned our attention to the
reductive di-desulfonylation of R-fluorobis(phenylsulfonyl)-
alkanes. Mg/CH3OH is a well-established reductive desulfo-
nylation system and has been widely exploited in organic
synthesis.32,36
We have previously reported the use of a Mg/CH3OH
system for the reductive desulfonylation of bis-sulfones for
the synthesis of monofluoromethyl-substituted compounds.1a
Application of this reagent system provided the desired
didesulfonylated products in good yields in these cases also
Acknowledgment. Support of our work by Loker Hydro-
carbon Research Institute is gratefully acknowledged.
Supporting Information Available: General experimental
procedure and spectroscopic data of all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(35) (a) Ni, C.; Hu, J. Tetrahedron Lett. 2005, 46, 8273. (b) Liu, J.; Ni,
C.; Wang, F.; Hu, J. Tetrahedron Lett. 2008, 49, 1605.
(36) Brown, A. C.; Caprino, L. A. J. Org. Chem. 1985, 50, 1749
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