Trimethylsilyl fluorosulfonyldifluoroacetate (TFDA): A new, highly efficient difluorocarbene reagent

Article abstract of DOI:10.1016/j.jfluchem.2003.12.002

TFDA is readily prepared from the reaction of fluorosulfonyldifluoroacetic acid with trimethylsilyl chloride, and it is a very effective and efficient source of difluorocarbene for use in addition reactions to alkenes of a broad scope of reactivities. Acid-sensitive substrates may require an additional purification step involving treatment of the distilled TFDA with sufficient Et₃N to remove the acid impurity. Other trialkylsilyl fluorosulfonyldifluoroacetates can also be prepared, and they have been found to have reactivities similar to TFDA. The triethyl derivative, TEFDA is more convenient to prepare in a pure state and has similar reactivity to TFDA. Thus, it may prove to be a superior reagent.

Full text of DOI:10.1016/j.jfluchem.2003.12.002

Journal of Fluorine Chemistry 125 (2004) 459–469
Trimethylsilyl fluorosulfonyldifluoroacetate (TFDA):
a new, highly efficient difluorocarbene reagent
William R. Dolbier Jr.a,*, Feng Tiana, Jian-Xin Duana, An-Rong Lia, Samia Ait-Mohanda,
Olivia Bautistaa, Saiwan Buathonga, J. Marshall Bakera, Jen Crawforda, Pauline Anselmea,
Xiao Hong Caia, Aneta Modzelewskab, Henryk Koroniakb,
Merle A. Battistea, Qing-Yun Chenc
aDepartment of Chemistry, University of Florida, P.O. Box 117200, Gainesville, FL 32611-7200, USA
bChemistry Department, Adam Mickiewicz University, Poznan, Poland
cShanghai Institute of Organic Chemistry, 354 Fenglin Lu, Shanghai 200032, China
Received 9 October 2003; received in revised form 2 December 2003; accepted 2 December 2003
Abstract
TFDA is readily prepared from the reaction of fluorosulfonyldifluoroacetic acid with trimethylsilyl chloride, and it is a very effective and
efficient source of difluorocarbene for use in addition reactions to alkenes of a broad scope of reactivities. Acid-sensitive substrates may
require an additional purification step involving treatment of the distilled TFDA with sufficient Et3N to remove the acid impurity. Other
trialkylsilyl fluorosulfonyldifluoroacetates can also be prepared, and they have been found to have reactivities similar to TFDA. The triethyl
derivative, TEFDA is more convenient to prepare in a pure state and has similar reactivity to TFDA. Thus, it may prove to be a superior
reagent.
# 2003 Elsevier B.V. All rights reserved.
Keywords: Trimethylsilyl fluorosulfonyldifluoroacetate; Difluorocarbene reagent; Addition reactions
1. Introduction
only modest excess, leads to good yields with a great variety
of alkenes, including 1-octene, as in the example given
below. Unfortunately, despite its excellent reactivity char-
acteristics, Seyferth’s reagent is only rarely used today,
because of its toxicity and consequent lack of commercial
availability. Its preparation is also both difficult and hazar-
dous.
Fluorocyclopropanes first appeared on the chemical scene
in 1952 with the inadvertent preparation of hexafluorocy-
clopropane by Atkinson [1], but since the advent of pre-
parative difluorocarbene chemistry in 1960 [2], the methods
for synthesis of gem-difluorocyclopropanes have generally
involved the addition of difluorocarbene to alkenes [3–6].
Because of the interaction of the lone pairs of its two fluorine
substituents with the carbene center, difluorocarbene is a
relatively stabilized carbene, and it is, therefore, less reactive
than other dihalocarbenes. Thus, although electron-rich
alkenes react readily with :CF2 under mild conditions,
even modestly electron-deficient alkenes, such as 1-octene
or cyclohexene, are reluctant substrates in reaction with
:CF2. In practice, there are only a few difluorocarbene
reagents that have been found to react efficiently with such
less-nucleophilic substrates.
A second useful method for generating reactive difluor-
ocarbene, and one that has been popular commercially, is the
thermal decarboxylative elimination reaction of sodium
chlorodifluoroacetate [2], which is optimally carried out
at the high temperatures derived from refluxing solvents
such as diglyme. The main practical problem associated
with this difluorocyclopropanation procedure is the require-
ment that large excesses of Naþ-O2CCF2Cl must be used in
order to obtain decent yields when using less-reactive sub-
strates. (Note the 11 equivalents used in the example that is
provided) [8].
Perhaps the best of the early :CF2 reagents was Seyferth’s
phenyl-(trifluoromethyl)mercury reagent [7], which used in
* Corresponding author. Tel.: þ1-352-392-0591; fax: þ1-352-846-1962.
E-mail address: wrd@chem.ufl.edu (W.R. Dolbier Jr.).
0022-1139/$ – see front matter # 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2003.12.002

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W.R. Dolbier Jr. et al. / Journal of Fluorine Chemistry 125 (2004) 459–469
are lost as gases from the reaction mixture.
FSO2CF2CO2TMS þ FÀ ! FSO2CF2CO2À þ TMSF
FSO2CF2CO2 !: CF2 þ CO2 þ SO2 þ FÀ
À
Hexafluoropropyleneoxide (HFPO) provides a third (gas-
When the reaction is carried out as prescribed, using
alkene substrate neat or with a minimal amount of a some-
times specific diluent/solvent, at temperatures > 100 ꢀC,
and adding TFDA very slowly, difluorocyclopropanation
can be very clean and efficient, with 2 equivalents of TFDA
generally being sufficient to produce high yields with most
alkenes. In this paper, we will present recent work directed at
definition of the scope of use of TFDA to prepare 1,1-
difluorocyclopropanes via addition of difluorocarbene to
carbon–carbon double bonds [20,21].
eous) source of reactive :CF2 when it is pyrolyzed in the
presence of an alkene substrate at temperatures > 180 ꢀC
[9,10]. The use of this difluorocarbene precursor is, of
course, limited by availability of the reagent and the fact
that HFPO reactions must be carried out in an autoclave.
A number of other very nice difluorocarbene reagents
have been developed over the years in the hope of discover-
ing a convenient, generally useful, room temperature
difluorocyclopropanation procedure [11–13]. However, as
witnessed by the above examples of ‘‘reactive’’ sources of
:CF2, it has finally been recognized that any generally-useful
difluorocarbene reagent must be capable of generating the
:CF2 at a sufficiently high temperature (>80 8C) to overcome
the apparently substantial energy barrier for :CF2 addition to
all but the most reactive of alkenes.
2. Results and discussion
Table 1 contains a representative list of alkenes to which
this process has been successfully applied.
Experiments directed at optimization, some of which are
included in Table 1, indicated that the choice of (a) diluent/
solvent, (b) fluoride source, (c) temperature, and (d) rate of
addition of the TFDA can strongly affect the yields of
reactions with individual substrates. One thing that is appar-
ent is that no single ‘‘recipe’’ can provide optimal results for
all alkene substrates.
Recently, we reported the discovery of a new difluoro-
carbene reagent, TFDA, that allows :CF2 to be generated
under conditions where it can add efficiently to even quite
unreactive alkenes, such as acrylate esters [14,15].
Data in Table 1 indicate clearly that choice of diluent/
solvent can be of great importance in determining the out-
come of TFDA reactions. For example toluene (T) diluent
gives good results for the benzoate ester examples, but poor
results for purely hydrocarbon substrates, whereas methyl
benzoate (MB) enhances the reactivity of the hydrocarbon
substrates. Although not usually being the optimal solvent,
3-pentanone (DEK), appears to be a generally useful solvent
for TFDA reactions. Dilution is not generally an attribute,
with minimal quantities of solvent usually proving optimal.
One example to the contrary is the large scale reaction of
TFDA with n-butyl acrylate (example: 17 equivalents) in
which 200 ml of toluene (12 equivalents) is used with 20 g of
substrate. The larger quantity of solvent in this case appeared
to help minimize competitive polymerization of the acrylate
ester.
TFDA, trimethylsilyl fluorosulfonyldifluoroacetate [16–
18], can be conveniently prepared via the reaction of fluor-
osulfonyldifluoroacetic acid with trimethylsilylchloride
[14,15]. The fluorosulfonyldifluoroacetic acid precursor
remains expensive, but as shown below, deriving ultimately
from the sultone formed by reaction of SO3 with TFE [19], it
can itself be prepared from the considerably less expensive
fluorosulfonyldifluoroacetyl fluoride by treatment with
water in a hydrocarbon solvent [19].
In experiments designed to determine the best fluoride
initiator (catalyst), a series of reactions of TFDA with neat
allyl benzoate demonstrated that NaF is superior to both CsF
and KF as an initiator. This result may actually derive from
NaF’s poorer solubility characteristics.
pet
FO2SCF2COF þ H2O ! FO2SCF2CO2H
ether
FO2SCF2CO2H þ Me3SiCl n!eat FO2SCF2CO2SiMe3
reflux
TFDA
TFDA undergoes catalytic desilation with a fluoride
source, followed by subsequent decarboxylation and loss
of SO2 to form :CF2 plus FÀ, which is quickly consumed via
its desilative attack of another TFDA molecule. All of the
products of this thermal, fluoride ion catalyzed decomposi-
tion of TFDA, other than the :CF2 and the recycled fluoride,
The temperature of the reaction greatly affected the
efficiency of conversion of the substrate, as indicated by

W.R. Dolbier Jr. et al. / Journal of Fluorine Chemistry 125 (2004) 459–469
461
Table 1
Reactions of TFDA with alkenes
Example
Alkene substrate
1-Octene
TFDA (equivalent)
T (8C)
Diluenta
Yield (%)
Refs.
1
2
2
110
110
110
105
110
115
120
120
105
115
120
105
120
120
105
105
110
105
97
0.5 MB
1.0 MB
10 MB
1.5 DEK
Neat
74
[14,22]
2
63
24
3
2
4
2
62
5
2
0
6
trans-1-Phenylpropene
2
1.0 T
0
[13]
7
2
1.0 MB
1.0 BA
1.6 DEK
1.0 T
91
8
2
Equivalent quantity
9
2
90
67
63
81
87
94
73
52
55
78
49
89
86
76bb
66c
36
92
a
a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Ethyl cinnamate
2
2
1.0 MB
2.5 DEK
1.0 T
5
Cinnamyl benzoate
Butyl acrylate
2
2.5
1.5
2
1.0 MB
2.0 MB
1.75 DEK
12.0 T
Neat
[14]
a
2
[15]
Allyl benzoate
2
[14]
Allyl p-nitrobenzoate
3-Butenyl benzoate
4-Pentenyl benzoate
trans-2-Butenyl benzoate
3-Buten-2-yl benzoate
trans-Stilbene
2
Neat
[23]
1.5
1.5
2
105
105
120
120
105
120
Neat
Neat
[14,23]
[14,23]
[23]
Neat
1.5
2
neat
[23]
a
2 DEK
BA
a
1-Pentyl-1-hexenyl acetate
1.5
a T: toluene; MB: methyl benzoate; DEK: 3-pentanone; BA: n-butyl acetate.
b Mixture of cis:trans: 1:9.
c 1:1 mixture of diastereomers.
the comparative data given below. Obviously, higher
2.1. Comparative reactivity/selectivity of TFDA-derived
difluorocarbene intermediate
Examples of additions of difluorocarbene to substrates as
electron deficient as a,b-unsaturated carbonyl compounds
are few and far between [24,25]. Therefore, studies were
carried out in order to obtain comparative reactivity data
for this new difluorocarbene reagent. First, it was deter-
mined, in a direct competition study, that the :CF2 generated
from TFDA was not unique in adding to butyl acrylate; the
:CF2 generated from sodium chlorodifluoroacetate was also
sufficiently reactive to accomplish this addition, and, con-
sidering the differences in temperature for the two experi-
ments, the observed relative reactivities for acrylate versus
1-octene addition for the two reagents must be considered
similar.
temperatures favor the addition of difluorocarbene to the
relatively unreactive substrate, allyl benzoate, although
there does not appear to be any advantage to using tem-
peratures above 125 8C.
It was also shown that slow addition of the TFDA to the
reaction mixture favors good cyclopropanation results.
For most substrates, 2 equivalents of TFDA were suffi-
cient to provide optimal cyclopropanation yields, as indi-
cated by the data below:

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Likewise, the relative reactivities of allyl and 3-butenyl
2.2. Limitations and cautions
benzoate were consistent with expectations for an electro-
philic carbene and exhibiting the kind of selectivities nor-
mally observed for addition of difluorocarbene [26].
2.2.1. Residual acid
Limitations with respect to the utility of the TFDA reagent
appear to derive almost entirely from the presence of trace
amounts of residual acid (fluorosulfonyldifluoroacetic acid)
in the reagent. This strong acid can lead to destruction of
acid-sensitive alkene substrates, such as enol ethers. For
example, the attempted reaction of TFDA (containing less
than 3% acid), under the usual conditions, with the very acid
sensitive enol ether, t-pentyl vinyl ether, led to no observable
difluorocyclopropane product.
On the other hand, enol acetates were not so sensitive to
the presence of small amounts of acid, and they proved to be
satisfactory alkene substrates:
Lastly, a quantitative Hammett study of addition of :CF2
generated from TFDA in its addition reactions to p-sub-
stituted a-methylstyrenes was carried out. As determined by
a series of competition experiments, the relative reactivities
of the different a-methylstyrenes were: p-CH3, 1.3; H, 1.00;
p-F, 0.84; p-Cl, 0.85; p-CF3, 0.35. When these relative
reactivities are plotted against the s constants of the various
substituents, the derived value of r (þ0.58) can be compared
favorably with that obtained (however, plotted against sþ
values) by Moss and Mallon for the reaction of Seyferth’s
reagent with a series of substituted styrenes in benzene at
80 8C (r ¼ þ0:57) [27].
2.2.2. Shelf life
TFDA is very susceptible to hydrolysis, hydrolyzing
virtually immediately when added to water, and therefore
its ‘‘shelf-life’’ is not great. Indeed, it is always best to use
freshly prepared (or at least freshly distilled) TFDA in
reactions. If one needs to store TFDA, it is best stored in
plastic bottles in a dry box. Refrigeration is unnecessary.
2.2.3. Skin sensitivity
Because of its ready hydrolysis back to its strong acid
precursor, care should be taken to avoid all contact of TFDA
with skin.
2.3. Improvement of TFDA reagent by removal of
traces of acid
Earlier there arose a mechanistic question as to whether
the :CF2 might in some manner be ‘‘delivered’’ by the
carbonyl function in the benzoate ester substrates (presum-
ably via a carbonyl ylide intermediate). In order to test this
hypothesis, the reaction of TFDA with cyclohex-2-enyl
benzoate was carried out, with the expectation that, if the
:CF2 were indeed delivered via the carbonyl ylide inter-
mediate, a preference for the cis-product should be
observed. However, no exceptional diastereoselectivity
was observed in this reaction; hence there is no evidence
for such exceptional mechanistic:
Although multiple redistillations of TFDA can virtually
eliminate detectable amounts of acid, a more efficient and
less tedious procedure for accomplishing this is to, first,
determine the amount of residual acid by 19F NMR, then add
approximately 1 equivalent of triethylamine, filter the pre-
cipitated salt, and immediately carry on with the cyclopro-
panation procedure using the filtered TFDA.
Using such ‘‘acid-free’’ TFDA (TFDAÃ), the reaction with
the acid-sensitive enol ethers was able to be carried out
satisfactorily, as exemplified by the reaction with t-pentyl
vinyl ether and as shown in Table 2.
intervention in the TFDA difluorocarbene reactions. The
observed 5:1 trans:cis ratio can be compared to that
observed by Schlosser (9:1) using a different difluorocar-
bene method [28].
Note the temperature sensitivity of the reaction with
n-butyl vinyl ether. The observed higher yields at the
lower temperatures may be due to the propensity of

W.R. Dolbier Jr. et al. / Journal of Fluorine Chemistry 125 (2004) 459–469
463
Table 2
Cyclopropanations using TFDAÃ (acid free)
Table 3
Preparation of trialkylsilyl fluorosulfonyldifluoroacetates
Vinyl enol ether
T (8C)
Solvent
Yield (%)
45
Silane used
Substrate/
silane
ratio
Time of
reflux
Yield
(%)
Acid
CH2–CHOR
impurity
(%)
R: t-pentyl
105
Toluene
ClSi(CH3)3
1:4
1:3
1:2
1:2.5
1:3
1:3
1:3
12 h
80
2.0
0.4
3.0
3.3
8.0
18.5
94
R: n-C4H9
105
95
Toluene
Toluene
Benzene
Trace
36
ClSi(CH2CH3)3
ClSi(CH3)2CH2CH3
ClSi(CH3)2CH2Cl
ClSi(CH3)2CH(CH3)2
ClSi(CH3)2C(CH3)3
ClSi(CH3)2Ph
2 days
7 days
4 days
7 days
7 days
7 days
80
64
69
80
44
67
70
N/A
difluorocyclopropyl ethers to undergo thermal decomposi-
tion, with ring opening, to form mixtures of products [3].
The scope and limitations of the use of acid-free TFDAÃ to
difluorocyclopropanate acid-sensitive alkene substrates is
currently being examined in detail.
2.4. An alternative reagent, TEFDA
it could generally be obtained in a greater state of purity (less
residual acid) after distillation. It also proved to be essen-
tially equivalent to TFDA as a difluorocarbene source.
Hoping that use of a sterically larger trialkylsilyl group in
place of trimethylsilyl might create a carbene source with
improved shelf life and reactivity characteristics, a number
of trialkylsilyl fluorosulfonyldifluoroacetates were prepared
and tested as difluorocarbene reagents. As Tables 3 and 4
indicate, most could be prepared using procedures similar to
that used for TFDA, and most of these trialkylsilyl esters
proved to be satisfactory sources of :CF2. However, none of
them exhibited the superior shelf life or reactivity character-
istics that had been hoped for, although the preparation of the
triethyl derivative, triethylsilyl fluorosulfonyldifluoroacetate,
TEFDA, proved somewhat easier than that of TFDA, and
If base/moisture-induced decomposition of the trialkylsi-
lyl esters had proceeded via attack at silicon, then one would
have expected improved stability and shelf life as one placed
bulkier alkyl substituents on the silicon. Since shelf life nor
stability were so-enhanced, we concluded that the two a-
fluorine substituents in TFDA, TEFDA, and the other trialk-
ylsilyl esters must enhance carbonyl addition reactivity to
such an extent that the mechanism of their reaction with oxy-
nucleophiles involves C–O cleavage with attack at the
carbonyl, rather than Si–O cleavage via attack at silicon.
Table 4
Syntheses of gem-difluorocyclopropanes using trialkylsilylfluorosulfonyldifluoroacetates
R3Si
Alkene substituent
T (8C)
Solvent
Yield (%)
–Si(CH2CH3)3
–CO2C4H9
–n-C6H13
105
105
105
105
105
Toluene
80
–Si(CH2CH3)3
Methylbenzoate
Toluene
77a
78
–Si(CH3)2CH2CH3
–Si(CH3)2CH2Cl
–CH2CH2Si(CH3)3
–CO2C4H9
–CO2C4H9
–CO2C4H9
Toluene
63
64a
Toluene
b
–Si(CH2CH3)3
105
Toluene
51
a
19F NMR yield.
b Acid free.

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W.R. Dolbier Jr. et al. / Journal of Fluorine Chemistry 125 (2004) 459–469
This was borne out in an experiment where TEFDA was
allowed to react with methanol. This reaction was shown to
occur to preferentially form methyl fluorosulfonyldifluor-
oacetate, rather than
4.2. Synthesis of trialkylsilyl fluorosulfonyldifluoroacetates
4.2.1. The reaction of 2-fluorosulfonyl-2,2-difluoroacetic
acid with chlorosilanes general reaction set-up
methoxytriethylsilane, which would have resulted from
attack on silicon. Thus, it would appear that there is no
advantage to the use of trialkylsilyl esters other than TFDA
and TEFDA.
Unless otherwise indicated, reactions were carried out in
25 or 50 ml three-necked, round-bottomed flasks equipped
with a magnetic stirrer, an addition funnel with nitrogen (N2)
inlet, and a water-cooled condenser with gas outlet. The gas
outlet was connected by Tygon tubing to an empty 500 ml
backup trap, and then to an inverted glass funnel outlet
positioned just above a 500 ml beaker containing 15 g of
sodium bicarbonate in 100 ml water.
3. Summary
In summary, TFDA has been found to be a very effective
and efficient source of difluorocarbene for use in addition
reactions to alkenes of a broad scope of reactivities. For most
applications, TFDA may be used without problem after
purification by careful distillation, which will usually lead
to the presence of up to 3–4% of residual acid impurity. In
order to obtain satisfactory results, acid-sensitive substrates
will usually require an additional purification step involving
treatment of the distilled TFDA with sufficient Et3N to
remove the acid impurity. In spite of taking such measures
to purify TFDA, there may still be substrates too sensitive to
allow effective use. Further studies are ongoing to: (a)
identify such substrate types, and (b) find ways to overcome
the problems observed.Other trialkylsilyl fluorosulfonyldi-
fluoroacetates can be prepared and have been found to have
similar stabilities and reactivities as those of TFDA. The
triethyl derivative, TEFDA is more convenient to prepare in
a pure state and has similar reactivity to TFDA, and it may
thus prove to be a superior reagent.
4.2.2. Trimethylsilyl fluorosulfonyldifluoroacetate
[14–16] (TFDA) (improved synthesis)
A 1 l, three-necked, round-bottomed flask, equipped
with a magnetic stirrer, addition funnel with nitrogen
(N2) inlet, and a water-cooled condenser with gas outlet
was set-up. The gas outlet was connected by Tygon tubing
to an empty 500 ml backup trap, and then to an inverted
glass funnel outlet positioned just above a 1 l beaker,
which contained 60 g of NaHCO3 in 300 ml of water.
The flask was charged with 204.0 g (1.15 mol) of 2-
fluorosulfonyl-2,2-difluoroacetic acid, and chlorotri-
methylsilane (500 g, 4.6 mol, 4 equivalents) was added
dropwise, with stirring and cooling with an ice bath over a
3 h period. Upon completion of addition, the mixture was
allowed to warm to RT over a 3 h period, and then the
mixture was refluxed overnight. Excess chlorotrimethylsi-
lane was then recovered by simple distillation at atmo-
spheric pressure, and the residue was finally distilled at
reduced pressure to give 230 g of TFDA (80%) (bp: 73–74
at 35 mm) as a colorless liquid. Analysis by 19F NMR
indicated the presence of 2.0% residual acid in the distilled
product.
4. Experimental section
4.1. General experimental procedures
1H, and 13C NMR spectra were determined at 300 MHz
(1H), 75 MHz (13C) using CDCl3 as solvent, unless other-
wise indicated, and tetramethylsilane as an internal stan-
dard; 19F NMR spectra were measured at 282 MHz,
referenced to external CFCl3 in CDCl3. Toluene was
distilled under nitrogen immediately before use from
sodium. Sodium fluoride (NaF) was dried in the oven.
All other reagents and solvents were obtained from com-
mercial sources and were used without additional purifica-
tion.
4.2.3. Triethylsilyl fluorosulfonyldifluoroacetate (TEFDA)
Chlorotriethylsilane (27.0 g, 179 mmol, 3.0 equivalents)
is added dropwise to 2-fluorosulfonyl-2,2-difluoroacetic
acid (10.5 g, 59 mmol) during 1 h at 0 8C. The mixture
is allowed to warm to RT for 2 h, and is heated at 100 8C
for 48 h. Then the product mixture is distilled to give
triethylsilyl fluorosulfonyldifluoroacetate (13.8 g, 80%)

W.R. Dolbier Jr. et al. / Journal of Fluorine Chemistry 125 (2004) 459–469
465
(bp: 108–110 8C at 25 mm) as a colorless liquid: 1H NMR
4.3. Preparation of 2-(trimethylsilyl)ethyl
fluorosulfonyldifluoroacetate
d 0.84–0.97 (m, 9H), 0.98–1.06 (m, 6H); 13C NMR d 4.1,
5.8, 112.2 (dt, J ¼ 31:5, 300.3 Hz), 155.1 (t, J ¼ 28:6 Hz);
19F NMR d 40.39 (s, 1F), À103.41 (s, 2F).
2-Fluorosulfonyl-2,2-difluoroacetic acid (17.8 g, 100
mmol) is added dropwise to phosphorus pentachloride
(23.0 g, 110 mmol) at 0 8C and then is allowed to warm to
RT for 30 min. After the mixture is heated to 60 8C for 2 h, 2-
fluorosulfonyl-2,2-difluoroacetyl chloride isobtained(18.7 g,
95%) by fractionation as a colorless liquid: 13C NMR d 111.7
(dt, J ¼ 33:3, 305.0 Hz), 160.2 (t, J ¼ 34:2 Hz); 19F NMR d
40.44 (s, 1F), À100.08 (s, 2F).
4.2.4. Ethyldimethylsilyl fluorosulfonyldifluoroacetate
Chloroethyldimethylsilane (5.0 g, 40.7 mmol, 2.0 equiva-
lents) is added dropwise to 2-fluorosulfonyl-2,2-difluoroa-
cetic acid (3.6 g, 20.2 mmol) during 1 h at 0 8C. The mixture
is allowed to warm to RT for 2 h, and is heated at 100 8C for
7 days. The product mixture is then distilled to give ethyl-
dimethylsilyl fluorosulfonyldifluoroacetate (3.4 g, 64%)
(bp: 89–91 8C at 38 mm): 19F NMR d 40.55(s, 1F),
À103.59 (s, 2F).
2-(Trimethylsilyl)ethanol (5.92 g, 50 mmol) is added
dropwise to 2-fluorosulfonyl-2,2-difluoroacetyl chloride
(9.83 g, 50 mmol) during 30 min at 0 8C. The mixture is
allowed to warm to RT for 1 h, and is heated at 80 8C for 2 h.
The product mixture is distilled to give 2-(trimethylsily-
l)ethyl fluorosulfonyldifluoroacetate (5.8 g, 42%) (bp: 78–
80 8C at 46 mm) as a colorless liquid (3.3% residual 2-
fluorosulfonyl-2,2-difluoroacetic acid was observed by 19F
NMR): 19F NMR d 40.59 (s, 1F), À103.71 (s, 2F).
4.2.5. Chloromethyldimethylsilyl
fluorosulfonyldifluoroacetate
Chloro(chloromethyl)dimethylsilane (32.7 g, 228.5 mmol,
2.5 equivalents) is added dropwise to 2-fluorosulfonyl-2,2-
difluoroacetic acid (16.5 g, 91 mmol) during 1 h at 0 8C.
The mixture is allowed to warm to RT for 2 h, and is heated
at 100 8C for 7 days. The product mixture is distilled to
give chloromethyldimethylsilylfluorosulfonyldifluoroacetate
(18.0 g, 69%) (bp: 111–112 8C at 43 mm) as a colorless
4.4. Synthesis of gem-difluorocyclopropanes
4.4.1. 3-(2,2-Difluorocyclopropyl)propyl benzoate [14]
A 25 ml dry two-neck round bottom flask, equipped with a
magneticstirringbar,waschargedwith2.3 mgofinitiatorNaF
and 0.900 g (4.8 mmol) of 4-pentenyl benzoate. Under N2 and
at 105 8C, 1.8 g (7.2 mmol, 1.5 equivalents) of TFDA was
addedslowlyusingasyringepumpviaaTeflon1 needleovera
period of 5 h. (When 1.3 equivalents of TFDAwas added, the
conversion is 97% and after 1.5 equivalents of carbene pre-
cursorwasadded,nostartingmaterialremainedinthereaction
mixture.) Upon the completion of the addition, the reaction
mixturewasstirredfor20 minandcooledtoroomtemperature
and diluted with 30 ml of diethyl ether. The solution was
washed with water, 5% sodium bicarbonate, water and brine
anddriedoversodiumsulfate. Thesolventwasremovedunder
reduced pressure. Purification of the products on flash column
chromatography (10% diethyl ether/hexanes) provided 0.98 g
1
liquid: H NMR d 0.22 (s, 6H), 2.74 (s, 2H); 13C NMR
d À3.9, 27.0, 112.0 (dt, J ¼ 32:8, 300.9 Hz), 155.1 (t,
J ¼ 28:0 Hz); 19F NMR d 40.99 (s, 1F), À103.73 (s, 2F).
4.2.6. Dimethylisopropylsilyl fluorosulfonyldifluoroacetate
Chlorodimethyl isopropyl silane (5.0 g, 36.6 mmol,
3.0 equivalents) is added dropwise to 2-fluorosulfonyl-
2,2-difluoroacetic acid (2.17 g, 12.2 mmol) during 1 h at
0 8C. The mixture is allowed to warm to RT for 2 h, and is
heated at 110 8C for 7 days. The product mixture is distilled
to give dimethylisopropylsilyl fluorosulfonyldifluoroacetate
(2.27 g, 67%) (bp: 88–91 8C at 52 mm) as a colorless liquid:
19F NMR d 40.61 (s, 1F), À103.51 (s, 2F).
4.2.7. tert-Butyldimethylsilyl fluorosulfonyldifluoroacetate
tert-Butyldimethylchlorosilane (5.1 g, 33.8 mmol, 3.0
equivalents) is added dropwise to 2-fluorosulfonyl-2,2-
difluoroacetic acid (2.00 g, 11.3 mmol) during 1 h at 0 8C.
The mixture is allowed to warm to RT for 2 h, and is refluxed
for 7 days. The product mixture is distilled to give tert-
butyldimethylsilyl fluorosulfonyldifluoroacetate (2.31 g,
70%) (bp: 94–98 8C at 41 mm) as a colorless liquid: 19F
NMR d 40.64 (s, 1F), À103.55 (s, 2F).
1
of colorless liquid (yield, 86%): H NMR d 8.02 (2H, d,
Jd ¼ 7:8 Hz), 7.53 (1H, t, Jt ¼ 7:3 Hz), 7.41 (2H, t,
Jt ¼ 7:6 Hz), 4.33 (2H, t, Jt ¼ 6:4 Hz), 1.88 (2H, p,
Jp ¼ 6:8 Hz), 1.60 (2H, m), 1.52 (1H, m), 1.36 (1H, tdd,
Jt ¼ 11:1 Hz, Jd ¼ 7:5 Hz, Jd ¼ 4:0 Hz), 0.90 (1H, dtd,
Jd ¼ 13:2 Hz, Jt ¼ 7:1 Hz, Jd ¼ 3:5 Hz); 13CNMR d 166.4,
132.85, 130.1, 129.4, 128.3, 114.3 (t, JtðFÀCÞ ¼ 283:5 Hz),
64.0, 27.9 (d, JdðFÀCÞ ¼ 1:5 Hz), 23.5 (d, JdðFÀCÞ ¼ 3:5 Hz,
21.9 (t, JtðFÀCÞ ¼ 10:6 Hz), 16.0 (t, JtðFÀCÞ ¼ 10:6 Hz); 19F
4.2.8. Dimethylphenylsilyl fluorosulfonyldifluoroacetate
Chlorodimethylphenylsilane (10.0 g, 58.6 mmol, 3.0
equivalents) is added dropwise to 2-fluorosulfonyl-2,2-
difluoroacetic acid (3.47 g, 19.5 mmol) during 1 h at 0 8C.
The mixture is allowed to warm to RT for 2 h, and is refluxed
for 7 days. The 19F NMR spectrum indicated that the
reaction mixture still contained 94% 2-fluorosulfonyl-2,2-
difluoroacetic acid, so the mixture was not distilled.
NMR d À128.6 (1F, dt, JdðFÀFÞ ¼ 155:8 Hz, JtðFÀHÞ
12:7 Hz), À145.2 (1F, dd, JdðFÀFÞ ¼ 155:8 Hz, JdðFÀHÞ
¼
¼
12:7 Hz); HRMS (CI) calculated: C13H15O2F2, (M þ 1)þ,
241.1040, found: 241.1000.
4.4.2. 2,2-Difluorocyclopropylmethyl benzoate [14]
As described above, a neat reaction with allyl benzoate,
followed by purification by column chromatography (10%

466
W.R. Dolbier Jr. et al. / Journal of Fluorine Chemistry 125 (2004) 459–469
1
1
diethyl ether/hexanes): Colorless liquid; H NMR d 8.04
(2H, m), 7.56 (1H, tt, Jt ¼ 7:5 Hz, Jt ¼ 1:5 Hz), 7.44 (2H,
m), 4.45 (1H, dddd, JdðHÀHÞ ¼ 12:0 Hz, JdðHÀHÞ ¼ 7:5 Hz,
anti isomer: H NMR d 8.073 (2H, dm, Jd ¼ 7:5 Hz),
7.575 (1H, tt, Jt ¼ 7:5 Hz), 7.451 (2H, tm, Jt ¼ 7:5 Hz),
5.362 (1H, t, Jt ¼ 4:2 Hz), 1.932 (1H, m), 1.84 ꢁ 1.50 (6H,
m), 1.401 (1H, m); 13C NMR d 165.780, 133.042, 130.297,
129.576, 128.368, 113.331 (t, JtðFÀCÞ ¼ 284:5 Hz), 64.921,
26.981 (t, JtðFÀCÞ ¼ 2:5 Hz), 22.474 (t, JtðFÀCÞ ¼ 10:9 Hz),
18.094(t, JtðFÀCÞ ¼ 10:6 Hz), 16.478, 15.917; 19F NMR d
125.994 (1F, dt, JdðFÀFÞ ¼ 162:3 Hz, JtðFÀHÞ ¼ 15:0 Hz),
149.677 (1F, d, JdðFÀFÞ ¼ 162:3 Hz); HRMS (CI), calcu-
lated: C14H15O2F2, (M þ 1)þ, 253.1040, found: 253.1039.
JdðFÀHÞ ¼ 2:7 Hz, Jd ¼ 1:5 Hz), 4.29 (1H, ddd, JdðHÀHÞ
¼
12:0 Hz, JdðHÀHÞ ¼ 8:1 Hz, Jd ¼ 1:8 Hz), 2.08 (1H, dddt,
Jd ¼ 13:2 Hz, Jd ¼ 11:4 Hz, Jd ¼ 7:8 Hz, Jt ¼ 7:8 Hz),
1.56 (1H, tdd, Jt ¼ 11:4 Hz, Jd ¼ 7:8 Hz, Jd ¼ 4:5 Hz),
1.29 (1H, dtd, Jd ¼ 13:2 Hz, Jt ¼ 7:8 Hz, Jd ¼ 3:9 Hz);
13C NMR d 166.4, 133.2, 129.8, 129.7, 128.4, 113.0 (t,
JtðCÀFÞ ¼ 282:5 Hz), 61.6 (d, JdðCÀFÞ ¼ 5:5 Hz), 21.2
(t, JtðCÀFÞ ¼ 11:6 Hz), 15.0 (t, Jt(CÀF) Jt(CÀF) JtðCÀFÞ
11:1 Hz); 19F NMR d 129.6 (1F, ddddd, JdðFÀFÞ
160:0 Hz, JdðFÀHÞ ¼ 13:0 Hz, JdðFÀHÞ ¼ 11:6 Hz, JdðFÀHÞ
¼
¼
¼
4.4.5. Ethyl trans-3-phenyl-2,2-
difluorocyclopropylcarboxylate
4:0 Hz, JdðFÀHÞ ¼ 2:5 Hz, JdðFÀHÞ ¼ 0:6 Hz), 143.8 (1F,
As described above, reaction of ethyl cinnamate in 2.5
equivalents 3-pentanone solvent, using 2 equivalents of
TFDA with the reaction temperature being 105 8C (yield,
ddddd, JdðFÀFÞ ¼ 160:0 Hz, JdðFÀHÞ ¼ 13:3 Hz, JdðFÀHÞ
¼
4:8 Hz, JdðFÀHÞ ¼ 2:0 Hz, JdðFÀHÞ ¼ 0:6 Hz); HRMS (CI)
C11H11O2F2 (M þ 1)þ, calculated: 213.0727, found:
213.0752.
1
81%): H NMR d 1.33 (t, J ¼ 7:4 Hz, 3H), 2.75 (m, 1H),
3.50 (m, 1H), 4.3 (q, J ¼ 7:4 Hz, 2H), 7.30 (m, 5H); 19F
NMR, d À133.5 (dd, J ¼ 151:4 and 14.9 Hz), À134.6 (dd,
J ¼ 151:4 and 12.7 Hz). HRMS (Mþ): calculated for
C12H12O2F2: 226.0805; found: 226.0816.
4.4.3. 2-(2,2-Difluorocyclopropyl)ethyl benzoate [14]
As described above, a neat reaction with 3-butenyl benzo-
ate, followed by column chromatography purification. (10%
1
diethyl ether/hexanes). Colorless liquid. H NMR d 8.04
4.4.6. trans-1,1-Difluoro-2-methyl-3-phenylcyclopropane
As described above, reaction of trans-1-phenylpropene in
2.5 equivalents 3-pentanone solvent, using 2 equivalents of
TFDA with the reaction temperature being 105 8C (yield,
90%): 1H NMR, d 1.40 (m, 3H), 1.90 (m, 1H), 2.35 (m, 1H),
7.5 (m, 5H); 19F NMR, d À137.7 (dd, J ¼ 153:4 and
12.8 Hz), À138.7 (dd, J ¼ 153:4 and 12.8 Hz) (Table 5).
(2H, m), 7.55 (1H, m), 7.43 (2H, m), 4.39 (2H, m), 1.96 (1H,
m), 1.88 (1H, m), 1.65 (1H, ddq, Jd ¼ 13:8 Hz,
Jd ¼ 11:1 Hz, Jq ¼ 7:2 Hz), 1.44 (1H, tdd, Jt ¼ 11:7 Hz,
Jd ¼ 7:8 Hz, Jd ¼ 4:2 Hz), 1.00 (1H, dtd, Jd ¼ 12:9 Hz,
Jt ¼ 7:5 Hz, Jd ¼ 2:4 Hz); 13C NMR d 166.5, 133.0,
130.1, 129.6, 128.4,113.9 (t, JtðFÀCÞ ¼ 283:5 Hz), 63.7 (d,
JdðFÀCÞ ¼ 2:0 Hz), 26.4 (d, Jd ¼ 4:1 Hz), 19.7 (t,
JtðFÀCÞ ¼ 11:1 Hz), 15.9 (t, JtðFÀCÞ ¼ 10:6 Hz); 19F NMR
4.4.7. trans-2,2-Difluoro-3-phenylcyclopropylmethyl
benzoate
d
À129.4 (1F, dddtd, JdðFÀFÞ ¼ 155:8 Hz, JdðFÀHÞ
¼
¼
¼
13:8 Hz, JdðFÀHÞ ¼ 12:7 Hz, JtðFÀHÞ ¼ 3:7 Hz, JdðFÀHÞ
As described above, reaction of trans-cinnamyl benzoate in
1 equivalent methyl benzoate solvent, using 2 equivalents of
TFDA with the reaction temperature being 120 8C (yield,
1:1 Hz), À144.3 (1F, dddt, JdðFÀFÞ ¼ 155:8 Hz, JdðFÀHÞ
12:7 Hz, JdðFÀHÞ ¼ 4:2 Hz, JtðFÀHÞ ¼ 1:4 Hz); HRMS (CI),
C12H13O2F2 (M þ 1)þ, calculated: 227.0884, found:
227.0889.
1
94%): H NMR, d 2.43 (m, 1H), 2.80 (m, 1H), 4.60 (m,
2H), 7.5 (m, 10H); 19F NMR, d À135.6 (dd, J ¼ 157:9 and
13.8 Hz), À137.4 (dd, J ¼ 157:9 and 13.8 Hz); HRMS (Mþ):
calculated for C17H14O2F2: 288.0962; found: 288.0971.
4.4.4. syn- and anti-7,7-difluoro-2-bicyclo[4.1.0]heptyl
benzoate [28]
As described above, a neat reaction with cyclohexen-3-yl
benzoate, followed by purification by column chromatogra-
phy (10% diethyl ether/hexanes) resulted in a 5:1 ratio of
anti to syn product (total yield, 65%): syn isomer, a colorless
4.4.8. trans-1,1-Difluoro-2-bromomethyl-3-
phenylcyclopropane
As described above, reaction of trans-cinnamyl benzoate
in 1 equivalent methyl benzoate solvent, using 2 equivalents
of TFDA with the reaction temperature being 120 8C (yield,
32%): 1H NMR, d 7.25 (m, 5H), 3.68 (m, 1H), 3.54 (m, 1H),
2.63 (m, 1H), 2.34 (m, 1H); 13C NMR, d 132.6, 128.9, 128.5,
127.9, 35.4 (t, J ¼ 11 Hz), 32.2 (t, J ¼ 11 Hz), 28.26; 19F
NMR, d À134.5 (dd, J ¼ 158 and 12 Hz), À136.8 (dd,
J ¼ 158 and 12 Hz); HRMS (Mþ): calculated for C10H10-
BrF2: 246.9934, found: 246.9937.
1
liquid; H NMR d 8.07 (2H, d, Jd ¼ 7:5 Hz), 7.57 (1H, t,
Jt ¼ 7:5 Hz), 7.45 (2H, t, Jt ¼ 7:5 Hz), 5.44 (1H, dtd,
Jd ¼ 10:2 Hz, Jt ¼ 6:6 Hz, Jd ¼ 3:0 Hz), 2.10 ꢁ 1.86 (3H,
m), 1.76 ꢁ 1.18 (5H, m); 13C NMR d 166.3, 133.0, 130.3,
129.7, 128.3, 115.0 (t, Jt ¼ 285:1 Hz), 67.8 (t, JtðFÀCÞ
¼
2:0 Hz), 26.7 (dd, JdðFÀCÞ ¼ 3:5 Hz, JdðFÀCÞ ¼ 1:1 Hz), 22.1
(t, JtðFÀCÞ ¼ 11:1 Hz), 21.6 (d, JdðFÀCÞ ¼ 3:5 Hz), 20.9 (dd,
JdðFÀCÞ ¼ 12:1 Hz, JdðFÀCÞ ¼ 9:1 Hz), 15.7 (d, JdðFÀCÞ
¼
2:5 Hz); 19F NMR d À123.5 (1F, dt, JdðFÀFÞ ¼ 160:0 Hz,
JdðFÀHÞ ¼ 12:7 Hz), À148.2 (1F, d, JdðFÀFÞ ¼ 160:0 Hz);
4.4.9. trans-1,1-Difluoro-2,3-diphenylcyclopropane
As described above, reaction of trans-stilbene in 2.5
equivalents 3-pentanone solvent, using 2 equivalents of
TFDA with the reaction temperature being 105 8C (yield,
HRMS (CI), calculated: C14H15O2F2, (M
253.1040, found: 253.1008.
þ
1)þ,

W.R. Dolbier Jr. et al. / Journal of Fluorine Chemistry 125 (2004) 459–469
467
Table 5
Summary of 19F NMR data for 1,1-difluorocyclopropane products
R1
R2
R3
R4
d (ppm)
JAB (Hz)
Ref.
[22]
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
n-C6H13
À128.4, À145.0
À137.8, À138.7
À133.4, À134.6
À126.5, À141.7
À135.6, À137.4
À134.5, À136.8
À129.6, À143.8
À129.8, À143.7
À129.4, À144.3
À128.6, À145.2
155
CH3
Ph
H
Ph
CO2Et
CO2nBu
152.3
151.4
154
[13]
a
[15]
a
Ph
Ph
H
CH2O2CPh
CH2Br
157.9
158
a
a
CH2O2CPh
CH2O2CPh-p-NO2
(CH2)2O2CPh
(CH2)3O2CPh
160.0
161.1
155.8
155.8
H
[23]
[23]
[23]
H
H
CH3
H
H
CH2O2CPh
cis: À126.0, À153.7
160.2
160.0
[23]
[23]
trans: À140.3, À141.5
H
H
H
CH(CH3)O2CPh
(a) À127.7, À142.4
162
162
[23]
[23]
(b) À129.0, À144.3
a
a
a
a
H
H
H
H
H
H
H
H
H
O-n-Bu
À131.8, À149.5
À131.8, À146.3
À134.0, À142.7
trans: 134.5
164.5
163.3
163.3
–
H
O-t-pentyl
Phthalimidyl
Ph
H
Ph
a This work.
36%): 1H NMR, d 3.05 (t, 2H), 7.35 (m, 10H); 19F NMR, d
À134.5 (t, J ¼ 8:5 Hz).
of TFDA was added slowly to the mixture at 100 8C and the
mixture maintained at 100 8C for one additional hour. After
the mixture was cooled to RT, trifluoromethylbenzene was
added as an internal standard, and the ratio of products
determined by 19F NMR. On the basis of the ratios that were
obtained, the following relative reactivities were obtained:
CH3 (1.3), H (1), F (0.84), Cl (0.85), CF3 (0.35). A plot of the
log of these relative reactivities versus sp resulted in Fig. 1.
4.5. General procedure for preparation of 1,1-difluoro-2-
methyl-2-p-X-phenylcyclopropanes (for Hammett study)
The reactions were carried out as described above, except
that 1 equivalent of methyl benzoate was added as solvent, 2
equivalents of TFDAwere used, and the reaction was carried
out at 120 8C. The yields reported are NMR yields, using
trifluoromethylbenzene as an internal standard.
4.6. General procedure for preparation of n-butyl
2,2-difluorocyclopropanecarboxylate [14,15]
ꢂ X ¼ Cl: 89% yield; 19F NMR
d
À136.4 (dd,
A three-necked, round-bottomed flask was equipped with
a magnetic stirrer, an addition funnel, and a water-cooled
condenser bearing a nitrogen (N2) inlet. The flask was
charged with toluene, sodium fluoride (0.06 equivalent)
and n-butyl acrylate. The solution was heated to reflux
and slow N2 bubbling was initiated for 1 h. The appropriate
trialkylsilyl fluorosulfonyldifluoroacetate (1.5–1.6 equiva-
lents) was added dropwise, and the mixture was heated
3
2JF;F¼ 149:5 Hz, JH;F¼ 12:1 Hz, 1F), À138.1 (dd,
3
2JF;F¼ 149:5 Hz, JH;F ¼ 12:1 Hz, 1F).
ꢂ X ¼ CH3: 60% yield; 19F NMR d À136.9 (dd,
3
2JF;F ¼ 149:5 Hz, JH;F ¼ 12:1 Hz, 1F), À138.0 (dd,
3
2JF;F ¼ 149:5 Hz, JH;F ¼ 12:1 Hz, 1F).
ꢂ X ¼ CF3: 34% yield; 19F NMR d À62.8 (s, 3F), À132.2
(dd, 2JF;F ¼ 149:2 Hz, 3JH;F ¼ 12:7 Hz, 1F), À136.0 (dd,
3
2JF;F ¼ 149:2 Hz, JH;F ¼ 12:7 Hz, 1F).
ꢂ X ¼ F: 55% yield; 19F NMR
d
À132.7 (dd,
3
p
2JF;F ¼ 151:2 Hz, JH;F ¼ 13:8 Hz, 1F), À137.9 (dd,
Correlation of
with log k(X)/k(H)
0.2
0.1
0
3
2JF;F ¼ 151:2 Hz, JH;F ¼ 12:1 Hz, 1F).
y = -0.5757x + 0.006
R2 = 0.9457
ꢂ X ¼ H: 85% yield; 19F NMR
d
À132.8 (dd,
3
2JF;F ¼ 149:5 Hz, JH;F ¼ 15:2 Hz, 1F), À137.8 (dd,
-0.1
-0.2
-0.3
-0.4
3
2JF;F ¼ 149:5 Hz, JH;F ¼ 12:1 Hz, 1F).
4.5.1. Procedure for the Hammett Study
-0.3
-0.2
-0.1
0
0.1
0.2
0.3
0.4
0.5
0.6
The binary mixture of two different p-substituted a-
methylstyrenes (equimolar, 1.1 mmol) in methyl benzoate
(2 equivalents, 300 mg, 2.2 mmol) with 3 mg of NaF was
stirred under N2 and heated to 100 8C. Then 0.2 equivalent
p
Fig. 1. Hammett plot for difluorocyclopropanation of p-substituted a-
methylstyrenes.

468
W.R. Dolbier Jr. et al. / Journal of Fluorine Chemistry 125 (2004) 459–469
overnight. Toluene was removed by simple distillation at
atmospheric pressure, and the residue distilled at reduced
pressure to obtain n-butyl 2,2-difluorcyclopropanecarboxy-
Then triethylsilyl fluorosulfonyldifluoroacetate (0.44 g,
1.5 mmol, 1.5 equivalents) in a plastic syringe was added
dropwise via a Teflon needle at the rate of 0.25 ml/h (con-
trolled by syringe pump). The reaction mixture was heated at
105 8C overnight and then cooled to RT. An amount of
36.0 mg of trifluorotoluene was added as a internal standard.
19F NMR indicated that 1,1-difluoro-2-hexylcyclopropane
was obtained (77%): 19F NMR d À128.5 (dm, J ¼ 155:6 Hz,
1F), À142.5 (dm, J ¼ 155:6 Hz, 1F).
1
late: bp 93–95 8C at 50 mm; a colorless liquid; H NMR d
0.88 (t, J ¼ 7:4 Hz, 1H), 1.26–1.42 (m, 1H), 1.50–1.69 (m,
3H), 1.89–2.02 (m, 1H), 2.27–2.43 (m, 1H), 4.08 (t,
J ¼ 6:6 Hz, 1H); 13C NMR d 13.4, 16.2 (t, J ¼ 11:1 Hz),
18.9, 25.5 (t, J ¼ 11:1 Hz), 30.4, 65.2, 110.6 (dd, J ¼ 283:0,
288.1 Hz), 166.5; 19F NMR d À126.6 (dm, J ¼ 152:6 Hz,
1F), À141.3 (dm, J ¼ 152:6 Hz, 1F).
4.6.6. N-(2,2-Difluorocyclopropyl)phthalimide
4.6.1. Using ethyldimethylsilyl
fluorosulfonyldifluoroacetate
A three-neck round bottomed flask bearing a reflux con-
denser with N2 inlet was charged with dry toluene (1.2 ml),
sodium fluoride (2.6 mg, 0.06 equivalent) and N-vinylphtha-
limide (0.17 g, 1.0 mmol). The mixture was heated in a
105 8C oil bath for 1 h. Fresh TEFDA (0.6 g, 2 mmol, 2.0
equivalents) (free of acid according to 19F NMR) was added
slowly using a syringe with a Teflon needle at the rate of
0.30 ml/h. After 3 h, an additional amount of fresh TEFDA
(0.3 g, 1 mmol) was added to achieve complete conversion.
The reaction mixture was heated at 105 8C overnight. After
the solvent was removed under reduced pressure, the residue
was purified by column chromatography on silica gel
(hexanes/AcOEt: 10/1) to give N-(2,2-difluorocyclopro-
pyl)phthalimide (0.115 g, 51%) as white solid: mp 150–
152 8C; 1H NMR d 2.02–2.24 (m, 2H), 3.22–3.32 (m, 1H),
7.72–7.79 (m, 2H), 7.84–7.92 (m, 2H); 13C NMR d 16.6 (t,
J ¼ 11:2 Hz), 28.4 (m), 109.3 (dd, J ¼ 283:4, 286.4 Hz),
123.6, 131.6, 134.4, 167.6; 19F NMR d À134.0 (dm,
J ¼ 163:3 Hz, 1F), À142.7 (dm, J ¼ 163:3 Hz, 1F); analy-
tically calculated for C11H7F2NO2: C, 59.20; H, 3.16; N,
6.28; Found: C, 59.04; H, 3.03; N, 6.08.
The flask was charged with dry toluene (6.4 ml), NaF
(12.6 mg, 0.06 equivalent) and n-butyl acrylate (0.64 g,
5.0 mmol). Ethyldimethylsilyl fluorosulfonyldifluoroacetate
(2.0 g, 7.5 mmol) was added, and the above procedure
followed to give 0.69 g of n-butyl 2,2-difluorocyclopropa-
necarboxylate (78%).
4.6.2. Using chloromethyldimethylsilyl
fluorosulfonyldifluoroacetate
The flask was charged with dry toluene (12.8 ml), NaF
(25.2 mg, 0.06 equivalent), n-butyl acrylate (1.28 g,
10.0 mmol), and chloromethyldimethylsilyl fluorosulfonyl-
difluoroacetate (4.55 g, 16.0 mmol, 1.6 equivalents) added,
and the above procedure followed to give 1.12 g of n-butyl
2,2-difluorocyclopropanecarboxylate (63%).
4.6.3. Using triethylsilyl fluorosulfonyldifluoroacetate
(TEFDA)
The flask was charged with dry toluene (6.4 ml),
NaF (12.6 mg, 0.06 equivalent) and n-butyl acrylate
(0.64 g, 5.0 mmol). Triethylsilyl fluorosulfonyldifluoroace-
tate (TEFDA) (2.2 g, 7.5 mmol, 1.5 equivalents) was added.
n-Butyl 2,2-difluorcyclopropanecarboxylate was obtained
(0.70 g, 80%).
4.7. Procedure for removal of traces of acid from
trialkylsilyl fluorosulfonyldifluoroacetates
A 10 ml, one-necked, round-bottomed flask equipped
with a magnetic stirrer and a nitrogen (N2) inlet was used.
The flask was charged with 3.0 g of TFDA that contained
3.6% 2-fluorosulfonyl-2,2-difluoroacetic acid according to
its 19F NMR spectrum. Triethylamine (60.0 ml, 0.43 mmol)
(1.0 equivalent relative to residual acid) was added dropwise
at room temperature using a syringe. The mixture was stirred
for 5 min, and then the solid was filtered by a pipette with
some cotton to obtain a colorless liquid. No residual 2-
fluorosulfonyl-2,2-difluoroacetic acid could be observed by
19FNMR after this treatment.
4.6.4. Using 2-(trimethylsilyl)ethyl
fluorosulfonyldifluoroacetate
A two-neck round bottom was charged dry toluene
(1.2 ml), NaF (2.5 mg, 0.06 equivalent) and n-butyl acry-
late (0.13 g, 1.0 mmol). Then 2-(trimethylsilyl)ethyl
fluorosulfonyldifluoroacetate (0.56 g, 2.0 mmol, 2.0 equi-
valents) in a plastic syringe was added dropwise via a
Teflon needle at the rate of 0.4 ml/h (controlled by syringe
pump). The reaction mixture was heated at 105 8C over-
night and then cooled to RT. An amount of 35.0 mg of
trifluorotoluene was added as a internal standard. 19F NMR
indicated that 64% of n-butyl 2,2-difluorocyclopropane-
carboxylate was obtained.
4.7.1. 2,2-Difluorocyclopropyl tert-pentyl ether
A three-neck round bottomed flask bearing a reflux con-
denser and N2 inlet was charged with dry toluene (6.0 ml),
sodium fluoride (12.6 mg, 0.06 equivalent) and tert-pentyl
vinyl ether (0.73 ml, 5.0 mmol). The mixture was heated in a
105 8C oil bath. TFDA (2.5 g, 10 mmol, 2.0 equivalents)
(treated as described above by Et3N) was added slowly using
a syringe with a Teflon needle at the rate of 0.4 ml/h. After
4.6.5. 1,1-Difluoro-2-hexylcyclopropane
A two-neck round bottomed flask was charged with
methyl benzoate (0.06 ml, 0.5 equivalent), sodium fluoride
(2.5 mg, 0.06 equivalent) and 1-octene (0.16 ml, 1.0 mmol).

W.R. Dolbier Jr. et al. / Journal of Fluorine Chemistry 125 (2004) 459–469
469
the addition was complete, the reaction mixture was heated
at 105 8C for 3 h. The residue was then distilled at reduced
pressure to obtain 2,2-difluorocyclopropyl tert-pentyl ether
(containing toluene) (bp, 65–70 8C; 230 mm) (purity, 19.3%
in toluene; yield, 45%) as a colorless liquid: 1H NMR d 1.29
(t, J ¼ 7:4 Hz, 3H), 1.59 (s, 3H), 1.60 (s, 3H), 1.62–1.76 (m,
1H), 1.78–2.20 (m, 3H), 3.81–3.91 (m, 1H); 13C NMR d 8.3,
18.1 (t, J ¼ 11:1 Hz), 24.7 (d, J ¼ 1:1 Hz), 24.9, 33.3,
50.9(m), 111.2 (dd, J ¼ 289:1, 292.2 Hz); 19F NMR d
À131.81 (dm, J ¼ 163:3 Hz, 1F), À146.34 (dm, J ¼
163:3 Hz, 1F).
33.2 Hz), 157.7 (t, J ¼ 24:8 Hz); 19F NMR (acetone-d6) d
40.58 (t, J ¼ 6:1 Hz, 1F), À103.41 (d, J ¼ 6:1 Hz, 1F).
Acknowledgements
The support of this work in part by the National Science
Foundation (CHE-9982587 and CHE-0239884) and by an
NSF-REU grant to the University of Florida is gratefully
acknowledged.
4.7.2. N-Butyl-2,2-difluorocyclopropyl ether
References
A three-necked, round bottomed flask bearing a reflux
condenser and N2 inlet was charged with dry toluene
(6.4 ml), sodium fluoride (12.6 mg, 0.06 equivalent) and
n-butyl vinyl ether (distilled) (0.65 ml, 5.0 mmol). The
mixture was heated in a 95 8C oil bath. TFDA (2.5 g,
10 mmol, 2.0 equivalents) (treated as described above by
Et3N) was added slowly using a syringe with a Teflon needle
at the rate of 0.4 ml/h. The reaction mixture was heated at
95 8C for 4 h, and the residue then distilled at atmospheric
pressure to obtain n-butyl-2,2-difluorcyclopropyl ether in
toluene (yield, 36%) as a colorless liquid: 1H NMR d 1.14 (t,
J ¼ 7:3 Hz, 3H), 1.50–1.68 (m, 4H), 1.72–1.84 (m, 2H),
3.66–3.79 (m, 3H); 13C NMR d 13.7, 17.9 (t, J ¼ 10:6 Hz),
19.1, 31.4, 56.8 (m), 71.4 (d, J ¼ 2:0 Hz) 111.4 (dd,
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