Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate, a difluorocarbene reagent with reactivity comparable to that of trimethylsilyl 2,2-difluoro-2- (fluorosulfonyl)acetate (TFDA)

Article abstract of DOI:10.1021/jo300876z

Under specific high concentration, high temperature conditions, methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (MDFA) has been found to act as a very efficient source of difluorocarbene, exhibiting carbene reactivity characteristics comparable to those exhibited by trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (TFDA). For example, in reaction with highly unreactive n-butyl acrylate and using only 2 equiv of MDFA, a yield of 76% of difluorocyclopropane product was obtained after 2 days.

Full text of DOI:10.1021/jo300876z

Note
pubs.acs.org/joc
Methyl 2,2-Difluoro-2-(fluorosulfonyl)acetate, a Difluorocarbene
Reagent with Reactivity Comparable to That of Trimethylsilyl 2,2-
Difluoro-2-(fluorosulfonyl)acetate (TFDA)
Steffen Eusterwiemann, Henry Martinez, and William R. Dolbier, Jr.*
Department of Chemistry, University of Florida, Gainesville, Florida 32611-7200, United States
S
* Supporting Information
ABSTRACT: Under specific high concentration, high temper-
ature conditions, methyl 2,2-difluoro-2-(fluorosulfonyl)acetate
(MDFA) has been found to act as a very efficient source of
difluorocarbene, exhibiting carbene reactivity characteristics
comparable to those exhibited by trimethylsilyl 2,2-difluoro-2-
(fluorosulfonyl)acetate (TFDA). For example, in reaction with
highly unreactive n-butyl acrylate and using only 2 equiv of MDFA, a yield of 76% of difluorocyclopropane product was obtained
after 2 days.
ithin the pharmaceutical and agrochemical community,
preparing gem-difluorocyclopropanes3−6 and for preparing
difluoromethyl ethers or amines.7−15 The most recent report
involving the use of the Ruppert−Prakash reagent6 was
particularly useful, since it allowed reactions to be carried out
at relatively low temperatures with relatively sensitive alkene
substrates (Scheme 2).
W
gem-difluorocyclopropanes1 are of considerable current
interest, as witnessed by the number of patents filed over the
past 7 years that include this structural feature. A SciFinder
search for three major 2,2-difluorocyclopropyl building blocks
(1a−c) provided 66 hits for patents or patent applications since
our 2005 full paper appeared reporting the use of the
difluorocarbene reagent trimethylsilyl 2,2-difluoro-2-
(fluorosulfonyl)acetate (TFDA) to prepare such compounds.2
There is little mention of these compounds in the journal or
patent literature prior to the discovery of TFDA, and to this day
TFDA remains the only difluorocarbene reagent that has
sufficient reactivity to prepare the precursors of these building
blocks in high yield. The reactions of TFDA to make the two
precursors from which these three compounds can be readily
prepared are given in Scheme 1.
Scheme 2. Recent Hu/Prakash Difluorocarbene
Methodology
However, none of these new methods has been reported to
react efficiently with the two relatively electron-deficient alkene
substrates shown in Scheme 1 or with other relatively
unreactive substrates, such as 1-alkenes. To accomplish that,
one must use TFDA, which has remained a relatively expensive
reagent that must be handled with great care. It is highly
moisture-sensitive with a poor shelf life and is most effective
when prepared immediately before use. Therefore we have
sought an alternative reagent that might avoid these
disadvantages but will still provide a highly reactive source of
difluorocarbene. Somewhat surprisingly an “old friend” ended
up providing the answer to our search.
Scheme 1. Key Difluorocyclopropane Syntheses Using
TFDA
Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (MDFA) is
arguably the very best precursor for in situ generation of
trifluoromethylcopper in a process reported first by Chen in
1989 and finding great use ever since.16−19 His original recipe
remains sufficient for most substrates, but when necessary it can
be enhanced by PdII catalysis.20−22
Development and/or invention of new difluorocarbene
reagents has remained an area of great interest and importance
in the years following our report of TFDA, and a number of
good, new reagents have been reported, both for use in
Received: May 1, 2012
Published: May 21, 2012
© 2012 American Chemical Society
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Note
Mechanistically the formation of CF3Cu proceeds via initial
formation of difluorocarbene, which then combines with
fluoride and Cu+ to form the CF3Cu (Scheme 3), and there
stirring the reaction mixture as the reaction progressed.
Diglyme proved better than either tetraglyme or dioxane,
when used alone, but in the end a combination of diglyme and
dioxane led to the most consistently advantageous results. The
conditions that were eventually settled upon as optimal
included using MDFA in 2-fold excess over substrate alkene,
a reaction temperature of 110−120 °C, and a time of reaction
of 2 days, which was required in order to ensure full conversion
of the MDFA. Because of the slow rate of reaction, it was
possible to simply mix all of the ingredients together prior to
heating the reaction vessel to initiate the reaction. This is much
more convenient than using a syringe pump, as was required for
the TFDA reactions.
Scheme 3. Use of Methyl 2,2-Difluoro-2-
(fluorosulfonyl)acetate To Prepare in Situ CF3Cu
has been mention of difluorocarbene being able to be trapped
by the classic, highly reactive carbene trap 2,3-dimethylbu-
tene,23 although to our knowledge until the present work no
determined attempt has been made to actually use methyl 2,2-
difluoro-2-(fluorosulfonyl)acetate as a reagent for the synthesis
of gem-difluorocyclopropanes.
The crux of our plan was to initiate difluorocarbene
formation from MDFA via its demethylation by iodide ion
and then to limit the production of trifluoromethyl anion by
removing the fluoride ion produced via trapping with
trimethylsilyl chloride (TMSCl), as depicted in Scheme 4.
A broad selection of alkenes, of varying reactivity, was
screened using the optimal conditions chosen for MDFA
reaction, with the results being given in Table 1. The identities
Table 1. Synthesis of gem-Difluorocyclopropanes Using
a
MDFA as Difluorocarbene Source
Scheme 4. Generation of Difluorocarbene from MDFA
In optimizing this process, two important factors remained
relatively invariable on the basis of our experience with TFDA:
high temperature and high concentration. Because of the
relatively low reactivity of difluorocarbene, TFDA reactions
were optimally carried out between 90 and 120 °C and neat or
with minimal solvent present. In the case of our experiments
with MDFA, it was found that, because of the use of KI as an at
least stoichiometric reagent, small quantities of solvent were
required, in order to allow the mixtures to be stirred. The
choice of solvent turned out to be important. The relatively
unreactive alkene allyl benzoate was chosen as the substrate
with which to test the use of MDFA as a difluorocarbene source
under various conditions.
Initial experiments at 95 °C, neat or with small amounts of
diglyme added, led to promising results as exemplified in
Scheme 5, but even after 4 days considerable MDFA remained,
Scheme 5. Early MDFA Experiment
a
Yields reported are by NMR, with isolated yields also being obtained
for 2a, 2j, and 2k, . All products are known,2,6,24−26 except for 2k
b
of known compounds 2a−2j were initially determined on the
basis of the characteristic AB system observed in their fluorine
NMR spectra but were also confirmed by examination of their
proton spectra. New compound 2k was fully characterized on
and yields of cyclopropane product were modest. KI proved
superior to NaI as a source of iodide, whereas attempts to use
the more soluble tetrabutylammonium bromide led to rapid,
total destruction of the MDFA, with little or no cyclopropane
product being formed. In such early experiments, the MDFA
was added slowly, using a syringe pump, as was required when
TFDA was used as the carbene precursor.
Optimization experiments determined that use of additional
solvent led to more rapid consumption of MDFA, but lower
yields of product. Use of too little solvent led to problems with
1
the basis of its H, 13C, and 19F NMR spectra, its IR spectrum,
and its exact mass as determined by HRMS.
On the basis of the results given in the Table, it can be seen
that the level of reactivity attained by the use of MDFA as the
source of difluorocarbene is very similar to that reported for
TFDA. Although all of the examples given in the table were
carried out at the 10.4 mmol scale (i.e., starting with 1.7 g of
allyl benzoate), with NMR yields being reported, successful
scale-up of the reaction was possible. When starting with 47.1
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Note
NMR δ 166.4 (s), 133.2 (s), 129.9 (d, JFC = 7.4 Hz), 129.8 (s), 128.5
mmol (7.6 g) of allyl benzoate, the observed yield actually
increased to 80%, with 79% of product 2a (7.9 g) able to be
isolated after 3 days.
It was also found that hexamethyldisiloxane (HMDSO)
could be used as the fluoride trap in place of trimethylsilyl
chloride. Unlike TMSCl, HMDSO is neither corrosive nor
volatile. Unfortunately, in order to obtain similar conversions,
much longer reaction times were required when using HMDSO
(Scheme 6).
3
(s), 113.1 (t, 1JFC = 283.0 Hz), 61.7 (d, JFC = 5.5 Hz), 21.2 (t, 2JFC
=
=
11.2 Hz), 15.1 (t, 2JFC = 11.2 Hz); 19F NMR δ −129.61 (dddm, 2JFF
3
2
160 Hz, JFH = 13.0 and 11.6 Hz, 1F), −143.76 (ddm, JFF = 160 Hz,
3JFH = 13.3 Hz, 1F). The observed data are in accord with those
reported in the literature.2
n-Butyl 2,2-Difluorocyclopropanecarboxylate (2b). When n-butyl
acrylate was used as substrate according to the general procedure, the
product was purified by column chromatography to provide a colorless
to yellow liquid: NMR yield, 76%; 1H NMR δ 4.08 (t, J = 6.6 Hz, 2H),
2.36 (m, 1H), 1.98 (m, 1H), 1.66 (m, 1H), 1.57 (m, 2H), 1.33 (m,
3
2H), 0.87 (t, J = 7.3 Hz, 3H); 13C NMR δ 166.8 (d, JFC = 1.7 Hz),
Scheme 6. MFDA Reaction Using HMDSO in Place of
TMSCl
110.6 (dd, 1JFC = 283.0 and 288.1 Hz), 65.6 (s), 30.7 (s), 25.8 (t, 2JFC
2
= 11.0 Hz), 19.2 (s), 16.6 (t, JFC = 11.1 Hz), 13.8 (s); 19F NMR δ
2
3
−126.54 (dtd, JFF = 153.6 Hz, JFH = 12.4 and 6.2 Hz, 1F), −141.33
(ddd, 2JFF = 153.6 Hz, 3JFH = 12.2 and 4.8 Hz, 1F). The observed data
are in accord with those reported in the literature.2
1,1-Difluoro-2-hexylcyclopropane (2c). From reaction with 1-
octene the product yield was determined by NMR: 88%; 19F NMR δ
2
2
−128.46 (dm, JFF = 155.5 Hz), 1F), −145.22 (ddd, JFF = 155.5 Hz,
3JFH = 12.8 and 3.6 Hz, 1F). The observed data are in accord with
those reported the literature.2,27
Although the time required for the difluorocarbene reactions
of MDFA (2−3 days) is considerably longer than the 5 h
generally required for the analogous difluorocarbene reactions
of TFDA, the overall advantages of the MDFA reaction in
terms of cost, safety, and ease of reaction should in most cases
outweigh the time factor advantage of TFDA.
(2,2-Difluoro-1-methylcyclopropyl)benzene (2d). From reaction
with α-methyl styrene, a colorless liquid was obtained: NMR yield,
1
82%; H NMR δ 7.28 (m, 5H), 1.64 (m, 1H), 1.49 (s, 3H), 1.34 (m,
1H); 13C NMR δ 139.3 (t, JFC = 2.1 Hz), 128.7 (s), 128.5 (d, JFC = 2.1
Hz), 127.3 (s), 114.7 (dd, 1JFC = 289.5 and 287.2 Hz), 31.4 (dd, 2JFC
10.9 and 9.9 Hz), 22.6 (t, J = 9.9 Hz), 21.5 (dd, 3JFC = 6.5, 1.9 Hz); 19
=
F
NMR δ −132.92 (dd, 2JFF = 149.9, 3JFH = 13.4 Hz, 1F), −137.96 (dd,
EXPERIMENTAL SECTION
3
2JFF = 149.9, JFH = 12.4 Hz, 1F). The observed data were in accord
■
1
General Considerations. The NMR spectra for H, 13C and 19F
with those reported in the literature.6
were recorded in CDCl3 at 300, 75.46, and 282 MHz, respectively,
with chemical shifts being reported in ppm downfield from the
respective internal standards (TMS for proton and carbon and CFCl3
for fluorine spectra).
Ethyl 2,2-Difluoro-3-phenylcyclopropanecarboxylate (2e). When
ethyl cinnamate was used as substrate in the above general procedure,
the crude product was purified by column chromatography to obtain a
2
yellow liquid: NMR yield, 64%; 19F NMR δ −133.5 (dd, JFF = 152
General Procedure for the Synthesis of gem-Difluorocyclo-
propanes. A 100 mL three-necked, round-bottomed flask equipped
with reflux condenser, rubber septum, and a magnetic stir bar was
flame-dried under a nitrogen atmosphere. Then 3.88 g of oven-dried
potassium iodide (23.4 mmol, 2.25 equiv) was added, and the flask
allowed to cool to room temperature. A nitrogen atmosphere was
maintained until the end of the reaction via a slow N2 flow through a
T-tube attached above the reflux condenser. Using a syringe, the
alkene substrate (10.4 mmol, 1.0 equivalent), 1.5 mL of dioxane (17.6
mmol, 1.7 equiv), and 0.15 mL of diglyme (1.0 mmol, 0.1 equiv) were
added in that order via injection through the rubber septum. The
mixture was then heated by an oil bath maintained between 115 and
120 °C. At this temperature 2.26 g of trimethylsilyl chloride (20.8
mmol, 2.0 equiv) was added by syringe, followed by analogous
addition of 4.0 g of MDFA (20.8 mmol, 2.0 equiv). The mixture was
then stirred at 115−120 °C for 2 days. After the mixture cooled to
approximately 40 °C, 30 mL of diethyl ether and 30 mL of distilled
water were added, and the mixture was stirred for 30 min while cooling
to room temperature. The two phases were then separated, and the
aqueous layer was washed two times with 20 mL of diethyl ether. After
drying the combined organic layers over anhydrous magnesium sulfate
and filtering the mixture, the solvent was removed under reduced
pressure to obtain a dark red residue. Yields were then determined
directly by 19F NMR of the residue in CDCl3 using an appropriate
amount of trifluoromethylbenzene as internal standard. When isolating
a pure product from these small scale reactions it was most convenient
to do so via column chromatography using silica gel and a 50:1
mixture of hexane and diethyl ether as eluent.
Hz, 3JFH = 13.2 Hz, 1F), −134.70 (ddd, 2JFF = 152 Hz, 3JFH = 12.9 and
3.3 Hz, 1F). The observed data were in accord with those reported in
the literature.2
9,9-Difluorobicyclo[6.1.0]nonane (2f). When cis-cyclooctene was
used in the above general procedure, the crude product was purified by
column chromatography, with the product being isolated as a colorless
1
liquid: NMR yield, 65%; H NMR δ 1.82 (d, J = 11.4 Hz, 2H), 1.52
(m, 4H), 1.29 (m, 8H); 19F NMR δ −125.3 (dt, 2JFF = 157.2 Hz, 3JFH
2
= 13.8 Hz, 1F), −153.4 (d, JFF = 157.0 Hz, 1F). The spectral data
were in accord with those in the literature.25
trans-3,3-Difluoro-1,2-diphenylcyclopropane (2g). When trans-
stilbene was used as substrate according to the general procedure, the
crude product was purified by column chromatography, with the
1
product being isolated as a white solid: NMR yield, 71%; H NMR δ
7.23 (m, 10H), 2.95 (t, 3JFH = 7.6 Hz, 2H); 19F NMR δ −134.6 (t, 3JFH
= 7.6 Hz, 2F). The spectral data were in accord with those in the
literature.2
2,2-Difluoro-1,1-diphenylcyclopropane (2h). When 1,1-diphenyl-
ethylene was used as substrate according to the general procedure, the
crude product was purified by column chromatography, with the
1
product being isolated as a white solid: NMR yield, 87%, H NMR δ
7.32 (m, 4H), 7.23 (m, 4H), 7.15 (m, 2H), 1.99 (m, 2H); 19F NMR δ
3
−130.4 (t, JFH = 8.6 Hz, 2F). The spectral data were in accord with
those in the literature.6
7,7-Difluoro-1-phenylbicyclo[4.1.0]heptanes (2i). When 1-phenyl-
cyclohexene was used according to the general procedure, the crude
product was purified by column chromatography, with the product
1
being isolated as a colorless liquid: NMR yield, 98%; H NMR δ 7.20
2,2-Difluorocyclopropylmethyl Benzoate (2a). When allyl ben-
zoate was used as substrate according to the general procedure, the
product was purified by column chromatography, and after removal of
the solvent under vacuum the desired compound was obtained as a
colorless liquid: NMR yield, 70%, (isolated yield, 1.48 g, 6.97 mmol,
67%); 1H NMR δ 8.06 (m, 2H), 7.56 (m, 1H), 7.44 (m, 2H), 4.46 (m,
1H), 4.30 (m, 1H), 2.08 (m, 1H), 1.55 (m, 1H), 1.29 (m, 1H); 13C
(m, 5H), 2.09 (m, 1H), 1.91 (m, 1H), 1.72 (m, 3H), 1.30 (m, 4H);
13C NMR δ 142.0 (d, JFC = 2.1 Hz), 128.6 (s), 128.4 (d, JFC = 2.1 Hz),
127.0 (s), 115.8 (t, 1JFC = 290.7 Hz), 31.2 (t, 2JFC = 10.2 Hz), 27.5 (t,
2
JFC = 2.7 Hz), 23.5 (dd, JFC = 10.6 and 9.4 Hz), 21.3 (dd, JFC = 2.6
and 1.7 Hz), 20.9 (dd, JFC = 2.0, 1.1 Hz), 17.1 (d, JFC = 1.0 Hz); 19F
NMR δ −128.3 (dd, 2JFF = 149.7 Hz, 3JFH = 14.7 Hz, 1F), −143.5 (d,
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Note
2JFF = 149.7 Hz, 1F). The spectral data were in accord with those in
the literature.,6
Notes
The authors declare no competing financial interest.
1,1-Difluoro-1,1a,6,6a-tetrahydrocyclopropa[a]indene (2j). When
indene was used as substrate according to the general procedure, the
crude product was purified by column chromatography, with the
product being isolated as a pale yellow liquid: NMR yield, 80%
(isolated yield, 1.279 g, 74%); 1H NMR δ 7.22 (m, 1H), 7.10 (m, 3H),
ACKNOWLEDGMENTS
The assistance of Dr. Fei Wang and Mr. Zhaoyun Zheng in
obtaining NMR and IR spectra is gratefully acknowledged.
■
3
3.14 (m, 3H), 2.38 (m, 1H); 13C NMR δ 143.3 (dd, JFC = 5.1, 2.8
REFERENCES
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■
1
2
113.1 (dd, JFC = 295.5, 280.7 Hz), 35.5 (t, JFC = 12.9 Hz), 32.0 (d,
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1
a colorless liquid: NMR yield, 80% (isolated yield, 1.26 g,72%); H
2
3
NMR δ 7.30 (m, 5H), 2.87 (dd, JHH = 15.3 Hz, JHH = 8.1 Hz, 1H),
2
3
2.76 (ddd, JHH = 15.0 Hz, JHH = 6.8 Hz, J = 3.0 Hz, 1H), 1.71 (m,
1H), 1.39 (m, 1H), 0.99 (m, 1H); 13C NMR, δ 139.9 (d, 4JFC = 1.5 Hz,
Ar), 128.9 (s, Ar), 128.5 (d, 5JFC = 1.1 Hz, Ar), 126.7 (s, Ar), 114.6 (t,
1JFC = 289 Hz, CF2), 33.1 (dd, 3JFC = 4.2 and 1.2 Hz, CH2), 23.6 (dd,
2JFC = 11.2 and 9.7 Hz, cyclopropyl CH), 16.6 (t, JFC = 10.5 Hz,
2
cyclopropyl CH2); 19F NMR δ −128.7 (dtt, 2JFF = 155 Hz, 3JHF = 13.2,
2
3
JHF = 3.6 Hz, 1F), −143.5 (ddd, JFF = 155 Hz, JHF = 13.0 Hz, JHF
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Benzoate (2a). A 250 mL three-necked, round-bottomed flask,
equipped as described earlier with reflux condenser, rubber septum,
and a large magnetic stir bar, was flame-dried under a nitrogen
atmosphere. Then 17.6 g of oven-dried potassium iodide (106 mmol,
2.25 equiv) was added, and the flask allowed to cool to room
temperature. A nitrogen atmosphere was maintained until the end of
the reaction via a slow N2 flow through a T-tube attached above the
reflux condenser. Using a syringe, 7.64 g of allyl benzoate (47.1 mmol,
1.0 equiv), 7.0 mL of dioxane (79.7 mmol, 1.7 equiv), and 0.63 g of
diglyme (4.7 mmol, 0.1 equiv) were added in that order via injection
through the septum. The mixture was heated up to 115 °C (oil bath
temperature). At this temperature 20.2 g of trimethylsilyl chloride
(94.2 mmol, 2.0 equiv) was added, followed by addition of 18.1 g of
MDFA (94.2 mmol, 2.0 equiv). For 3 days the mixture was stirred at
120 °C. After the mixture cooled to approximately 40 °C, 90 mL of
diethyl ether and 90 mL of distilled water were added, and the mixture
was stirred for 30 min as the reaction cooled to room temperature.
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times with 50 mL of diethyl ether. After drying the combined organic
layers over anhydrous magnesium sulfate and filtering the mixture, the
solvent was removed under reduced pressure to obtain a dark red
residue. The product was isolated by column chromatography
(hexanes/Et2O, 50:1) to provide a pale yellow liquid: NMR yield,
80% (isolated yield, 7.90 g, 37.2 mmol, 79%).
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ASSOCIATED CONTENT
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S
* Supporting Information
1H, 13C, and 19F NMR spectra and IR spectrum of new
1
compound 2k; H spectra of 2a, 2b, 2d, 2f, 2g, 2h, 2i, and 2j,
and 19F NMR spectra of 2c and 2e. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: wrd@chem.ufl.edu.
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dx.doi.org/10.1021/jo300876z | J. Org. Chem. 2012, 77, 5461−5464