Preparation of and fluoroalkylation with (chlorodifluoromethyl)trimethylsilane, difluorobis(trimethylsilyl)methane, and 1,1,2,2-tetrafluoro-1,2-bis(trimethylsilyl)ethane

Article abstract of DOI:10.1021/ja962990n

CF₂BrCl reacts with aluminum/N-methylpyrrolidinone in the presence of chlorotrimethylsilane to give Me₃SiCF₂Cl in high yield. Similarly, CF₂Br₂ gives Me₃SiCF₂Br with bromotrimethylsilane. Chlorodifluoromethylation of aldehydes using Me₃SiCF₂Cl and a catalytic amount of TBAF in polar solvents occurs at room temperature, providing difluoromethylated alcohols in two steps. Electroreduction of Me₃SiCF₂Cl in the presence of chlorotrimethylsilane gives Me₃SiCF₂SiMe₃ (anion-derived product) and Me₃SiCF₂CF₂SiMe₃ (radical-derived product). Using THF/HMPA strongly favors the former, whereas THF/TDA-1 (tris(3,6-dioxaheptyl)amine) the latter. Me₃SiCF₂SiMe₃ difluoromethylates aldehydes acting as a difluoromethylene dianion ('CF₂^2-'/equivalent), whereas Me₃SiCF₂CF₂SiMe₃ acts at room temperature as an in situ source for the perfluorovinyl anion (due to β-elimination of fluorotrimethylsilane). However, at low temperature the elimination pathway is suppressed and tetrafluoroethylene dianion ('^-CF₂CF₂^-'/equivalent) behavior is observed. The structure of Me₃SiCF₂CF₂SiMe₃ was analyzed by X-ray diffraction. All of the studied fluoroalkylating reagents are moisture- and air-stable and can be readily obtained from a single convenient precursor (CF₂BrCl).

Full text of DOI:10.1021/ja962990n

1572
J. Am. Chem. Soc. 1997, 119, 1572-1581
Preparation of and Fluoroalkylation with
(Chlorodifluoromethyl)trimethylsilane,
Difluorobis(trimethylsilyl)methane, and
1,1,2,2-Tetrafluoro-1,2-bis(trimethylsilyl)ethane
Andrei K. Yudin, G. K. Surya Prakash,* Denis Deffieux,† Michael Bradley,
Robert Bau, and George A. Olah*
Contribution from the Donald P. and Katherine B. Loker Hydrocarbon Research Institute
and Department of Chemistry, UniVersity of Southern California, UniVersity Park,
Los Angeles, California 90089-1661
ReceiVed August 26, 1996X
Abstract: CF2BrCl reacts with aluminum/N-methylpyrrolidinone in the presence of chlorotrimethylsilane to give
Me3SiCF2Cl in high yield. Similarly, CF2Br2 gives Me3SiCF2Br with bromotrimethylsilane. Chlorodifluoromethy-
lation of aldehydes using Me3SiCF2Cl and a catalytic amount of TBAF in polar solvents occurs at room temperature,
providing difluoromethylated alcohols in two steps. Electroreduction of Me3SiCF2Cl in the presence of chlorotri-
methylsilane gives Me3SiCF2SiMe3 (anion-derived product) and Me3SiCF2CF2SiMe3 (radical-derived product). Using
THF/HMPA strongly favors the former, whereas THF/TDA-1 (tris(3,6-dioxaheptyl)amine) the latter. Me3SiCF2-
SiMe3 difluoromethylates aldehydes acting as a difluoromethylene dianion (“CF22-” equivalent), whereas Me3SiCF2-
CF2SiMe3 acts at room temperature as an in situ source for the perfluorovinyl anion (due to â-elimination of
fluorotrimethylsilane). However, at low temperature the elimination pathway is suppressed and tetrafluoroethylene
dianion (“-CF2CF2-” equivalent) behavior is observed. The structure of Me3SiCF2CF2SiMe3 was analyzed by X-ray
diffraction. All of the studied fluoroalkylating reagents are moisture- and air-stable and can be readily obtained
from a single convenient precursor (CF2BrCl).
Introduction
prostacyclin analog exhibits high stability along with the highest
known inhibitory activity on ADP-induced human platelet
aggregation.3
Partially fluorinated organic compounds often possess proper-
ties making them suitable for diverse applications in materials
science, agrochemistry, and the pharmaceutical industry.1
Generally, the unique behavior of fluorinated systems can be
attributed to the high electronegativity of the fluorine atom (4.0
on Pauling’s electronegativity scale) combined with its close
size to hydrogen (the van der Waal’s radii of F and H atoms
are 1.35 and 1.2 Å, respectively) leading to the increase in
oxidative, hydrolytic, and thermal stability (the C-F bond
energy averages about 116 kcal/mol). In many instances
fluorinated compounds were shown to have minimal steric
difference from their parent hydrido analogs. Among fluorine-
containing groups, trifluoromethyl, difluoromethylene, and
difluoromethyl groups are of the most interest and use. For
example, many trifluoromethylated compounds are known to
increase lipid solubility and, therefore, enhance in ViVo transport
rates.2 The replacement of the methylene for difluoromethylene
group has been shown to markedly increase the hydrolytic
stability of some labile biologically active molecules. At the
same time since very little steric perturbation takes place as
hydrogen is replaced for fluorine, the substitution preserves or
even increases the biological activity. In a recent example,
Matsumura et al. have demonstrated that the difluorinated
The CF2 group is also recognized for its isosteric and isopolar
relation to ethereal oxygen, a property which has been widely
investigated in the area of difluorinated analogs of sugars and
other oxygenated biomolecules.2 The difluoromethyl group
(CF2H) is believed to act as an isopolar and isosteric analog of
the hydroxyl group.4 The CF2H group was reported to act as a
hydrogen bond donor which is useful in applications where a
more lipophilic hydrogen bond donor other than OH is required.
For example, chiral secondary alcohols bearing the lipophilic
difluoromethyl group have been targeted as inhibitors of certain
enzymes5 and as precursors for the preparation of liquid
crystalline materials.6
Compared with interest in the development of trifluorom-
ethylation methods in recent years, introduction of the chlo-
rodifluoromethyl as well as difluoromethyl and difluorometh-
ylene groups has received less attention. Convenient procedures
for introducing these latter groups are particularly desirable.
Currently available methods are based on (a) synthesis of
difluoromethyl- and difluoromethylene-containing compounds
from the corresponding fluorinated building blocks, (b) nucleo-
philic difluorination of carbonyl compounds,7 and (c) electro-
(3) Nakano, T.; Makino, M.; Morizawa, Y.; Matsumura, Y. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1019.
(4) Erickson, J. A.; McLoughlin, J. I. J. Org. Chem. 1995, 60, 1626.
(5) Smith, F. A. Handbook of Experimental Pharmacology; Springer-
Verlag: Berlin, 1970; Vol. XX, Part 2, p 166.
(6) Yoshino, K.; Ozaki, M.; Taniguchi, H.; Ito, M.; Satoh, K.; Yamazaki,
N.; Kitazume, T. Jpn. J. Appl. Phys. 1987, 26, L77.
(7) For recent examples from this lab, see: (a) York, C.; Prakash, G. K.
S.; Olah, G. A. J. Org. Chem. 1994, 59, 6493. (b) York, C.; Prakash, G. K.
S.; Wang, Q.; Olah, G. A. Synlett 1994, 6, 425.
† Instiut du Pin, Universite Bordeaux I, 351 cours de la liberation,
F-33405 Talence, France.
X Abstract published in AdVance ACS Abstracts, February 1, 1997.
(1) (a) Liebman, J. F., Greenberg, A., Dolbier, W. R., Jr., Eds. Fluorine-
containing Molecules, Structure, ReactiVity, Synthesis; VCH: New York,
1988. (b) Welch, J. T., Eshwarakrishnan, S., Eds. Fluorine in Bioorganic
Chemistry; Wiley: New York, 1991.
(2) Filler, R.; Kobayashi, Y. Biomedical Aspects of Organofluorine
Chemistry; Kodansha and Elsevier Biomedical: Amsterdam, 1983.
S0002-7863(96)02990-3 CCC: $14.00 © 1997 American Chemical Society

Preparation of Fluoroalkylating Reagents
J. Am. Chem. Soc., Vol. 119, No. 7, 1997 1573
philic difluorination of carbanions and related nucleophiles.3 Our
interest in this field began with studies on the development of
(trifluoromethyl)trimethylsilane (Me3SiCF3) and other (perfluo-
roalkyl)(trialkyl)silanes as reagents for nucleophilic trifluorom-
ethylation and perfluoroalkylation.8 Organosilicon fluoroalky-
lating reagents are especially attractive due to their relative
nontoxicity, stability, ease of handling, and low cost. Since
little is known about nucleophilic difluoromethylation using
organosilicon reagents, we extended our investigations to these
systems. We now report on the preparation and use of
fluoroalkylating reagents of the general formula Me3SiCF2X (X
) Cl (1a), Br (1b), SiMe3 (2), CF2SiMe3 (3)) readily obtained
from bromochlorodifluoromethane (CF2BrCl) and dibromodi-
fluoromethane (CF2Br2), respectively. The use of 1a, 2, and 3
in fluoroalkylation reactions is also described .
Scheme 1
Table 1. Experimental Conditions for the Preparation of
Me3SiCF2Cl and Me3SiCF2Bra
difluoro-
dihalomethane
(equiv)
halosilane
(equiv)
Al
(equiv)
product
entry
(yield, %)b
1
2
3
4
5
6
7d
Me3SiCl (1.5)
Me3SiCl (1.5)
Me3SiCl (1.0)
Me3SiCl (1.5)
Me3SiCl (1.5)
Me3SiCl (1.5)
Me3SiCl (1.5)
0.7
1.0
1.5
0.7
1.0
0.7
1.0
CF2BrCl (1.0) Me3SiCF2Cl (80)
CF2BrCl (1.0) Me3SiCF2Cl (77)
CF2BrCl (2.0) Me3SiCF2Cl (15)
CF2BrCl (1.0) Me3SiCF2Br (30)c
CF2BrCl (1.0) Me3SiCF2Cl (65)
CF2BrCl (1.0) Me3SiCF2Br (55)
CF2BrCl (1.0) Me3SiCF2Br (5)
Results and Discussion
Preparation of Me3SiCF2X (X ) Cl (1a) and Br (1b)). Use
of Me3SiCF3 for the nucleophilic trifluoromethylation of various
electrophiles is well documented.8 Under initiation by tetrabu-
tylammonium fluoride (TBAF) or other nucleophiles such as
tris(dimethylamino)sulfur trimethylsilyl difluoride (TASF) or
potassium tert-butoxide, Me3SiCF3 transfers the CF3 group to
ketones, aldehydes, esters, acid halides, and other substrates.
Consequently, we investigated 1a under similar reaction condi-
tions in order to develop a convenient and mild protocol for
the chlorodifluoromethylation of aldehydes to afford the cor-
responding secondary alcohols bearing the chlorodifluoromethyl
group. The importance of these compounds for the preparation
of difluoromethylated enzyme inhibitors is well established.
Recently, the synthesis and microbial resolution of the CF2Cl-
containing alcohols from ethyl chlorodifluoroacetate were
reported by Kitazume et al.9 Reduction of the C-Cl bond of
the resulting carbinols proceeds readily, providing the corre-
sponding difluromethylated derivatives. The target compounds
could be obtained in 5-6 steps. The silylated reagents were
expected to provide a much simpler way.
Initially our efforts were directed to developing an efficient
synthesis of 1a, avoiding the complications associated with the
use of a Ruppert-type procedure.10 Recently aluminum-induced
reductive methods for the preparation of Me3SiCF3 were
reported, suggesting that readily available CF2BrCl could be
used similarly to CF3Br in the reactions with chlorotrimethyl-
silane (Me3SiCl) and aluminum.11 In fact, we have found that
the carbon-bromine bond of CF2BrCl was selectively reduced
by aluminum powder in N-methylpyrrolidinone (NMP) in the
presence of Me3SiCl, and 1a was obtained in 80% isolated yield
according to eq 1. No formation of 1b was observed under
a All reactions except entry 6 were carried out in sealed tubes at
room temperature. b Isolated yield after distillation. c A 4:1 mixture of
1a and 1b was obtained. d Ultrasound-promoted reaction.
electrons per mole of CF2BrCl, was needed for the reduction.
The use of excess aluminum led to the increase in the undesired
formation of fluorotrimethylsilane (Me3SiF), which lowered the
yield. Results of the optimization of the reaction parameters
are presented in Table 1.
Alternatively to the anionic pathway, reaction 1 can be
considered to be due to difluoromethylene insertion into the
silicon-chlorine bond (generation of the CF2 carbene via
R-elimination from the CF2Cl- anion is regarded as a facile
process12 ). However, this possibility was ruled out when Me3-
SiBr was used instead of Me3SiCl as an electrophile. No
formation of Me3SiCF2Br (an expected product of carbene
insertion) was observed, despite the fact that the silicon-
bromine bond is considerably more reactive than the silicon-
chlorine bond (Table 1, entry 5). This suggests that the reaction
does not follow the carbene insertion pathway. Considering
the high propensity of the CF2Cl- for an R-chloride elimina-
tion,12 the cationic aluminum species formed during the oxida-
tion of aluminum in the system must efficiently stabilize the
intermediate chlorodifluoromethyl anion CF2Cl-.
The byproducts of the preparation of 1a are CF2ClH, CF2-
BrH (formed from CF2ClH by Cl/Br exchange), and Me3SiF.
CF2ClH arises from quenching the CF2Cl- by residual acid. Its
formation is minimized by using anhydrous NMP and acid-
free Me3SiCl. Some Me3SiF is always produced in this system
due to the thermodynamic preference for formation of the Si-F
bond (the Si-F bond energy averages 193 kcal/mol).
The preparation of 1a was carried out on a preparative scale
(50 mmol). In order to withstand the pressure of the gaseous
CF2BrCl, the thick-walled glass reaction tubes equipped with
magnetic stirrers were employed. The reaction tube was sealed,
and the reaction mixture was stirred at room temperature
overnight. After the volatile components were pumped off
followed by hydrolysis and distillation of the products, 1a was
obtained as a colorless liquid contaminated with a small amount
of disiloxane. Due to its inertness, disiloxane did not interfere
with the chemistry of 1a (Vide infra) and the mixture could be
further used without purification. Analytically pure samples
of 1a were obtained by washing the mixture with 98% sulfuric
acid that quantitatively removed any traces of the disiloxane
without affecting 1a.
these conditions. The process appears to involve a two-electron
reduction of the C-Br bond of CF2BrCl followed by trapping
of the resulting “CF2Cl-” anion by Me3SiCl (Scheme 1).
Aluminum powder, corresponding to a net consumption of two
(8) For a review, see: (a) Prakash, G. K. S. In Synthetic Fluorine
Chemistry; Olah, G. A., Chambers, R. D., Prakash, G. K. S., Eds.; Wiley:
New York, 1992; Chapter 10. (b) Prakash, G. K. S; Yudin, A. K. Chem.
ReV., in press.
(9) Kitazume, T.; Asai, M.; Tsukamoto, T.; Yamazaki, T. J. Fluorine
Chem. 1992, 56, 271.
(10) Broicher, V.; Geffken, D. J. Organomet. Chem. 1990, 381, 315.
(11) (a) Prakash, G. K. S.; Deffieux, D.; Yudin, A. K.; Olah, G. A. Synlett
1994, 12, 1057. (b) Aymard, F.; Nedelec, J. -Y.; Perichon, J. Tetrahedron
Lett. 1994, 46, 8623. (c) Grobe, J.; Hegge, J. Synlett 1995, 6, 642.
(12) Wheaton, G. A.; Burton, D. J. J. Org. Chem. 1978, 43, 2643.

1574 J. Am. Chem. Soc., Vol. 119, No. 7, 1997
Yudin et al.
Scheme 2
boiling point than NMP greatly simplifies the workup procedure.
Compared to trifluoromethylation, the chlorodifluoromethylation
requires higher amounts of initiator (10 mol % vs 2-3 mol %
TBAF) for efficient conversion.
The finding that strongly polar solvents are needed for the
nucleophilic activation of 1a is in agreement with our earlier
findings of the trans-trifluoromethylation of the disilyl sulfides
where NMP was more effective than THF.14 The polar solvents
help stabilize a putative pentavalent silicon intermediate (Scheme
3). Mechanistically, the reaction is considered to involve initial
formation of such a pentavalent complex via fluoride anion (of
TBAF) attack on the fluorophilic silicon center in 1a. Transfer
of the chlorodifluoromethyl group to the electrophilic carbon
center of the aldehyde then occurs. It is likely that precoordi-
nation of the aldehyde oxygen to the silicon center takes place
at this stage. This step yields gaseous Me3SiF and an alkoxide
adduct, stabilized by tetrabutylammonium cation. Only a
catalytic amount of TBAF is needed for the reaction because
the overall catalytic cycle is further maintained by the silicon’s
affinity to the anionic oxygen center in tetrabutylammonium
alkoxide obtained from an initial reaction between TBAF and
1a. The term “autocatalytic” in this case refers to the continuous
regeneration of the catalytic species that carries the whole
process.8
A series of aromatic and aliphatic aldehydes were chlorodi-
fluoromethylated (eq 3) at room temperature, providing an
efficient pathway to the valuable class of difluoromethyl-
containing secondary alcohols under mild conditions (Table 2).
Tetrabutylammonium fluoride (TBAF) was found to be superior
to KF and CsF as an initiating species. However, due to its
hygroscopic properties, TBAF should be dried beforehand by
azeotropic removal of water with 2-propanol or by other
methods in order to minimize the formation of CF2ClH during
the reaction.15 The mixture of 1a and disiloxane, obtained
directly upon the initial workup of the reaction mixture, is
generally suitable for use in the reactions since the byproduct
disiloxane is inert under the conditions. In some cases the
silylated adducts 4 turned out to be quite resistant toward
acidic workup (HCl, water) usually employed to remove the
trimethylsilyl group. In these cases a 40% HF solution in
acetonitrile was found suitable for the desilylation.16 Ketones
also reacted with 1a at room temperature under TBAF initia-
tion in the THF/NMP solvent system, furnishing the corre-
sponding chlorodifluoromethylated adducts. Not unexpectedly,
lower reactivity was observed compared to aldehydes (Table
2, entry 9).
Under similar conditions CF2Br2 gave 1b (Table 1, entry 6).
In this case, however, Cl/Br exchange between Me3SiCF2Br and
Me3SiCl also led to the concurrent formation of 1a. In a control
experiment, when 1b was heated with Me3SiCl, a quantitative
conversion into 1a and Me3SiBr took place (eq 2). In order to
eliminate this exchange, Me3SiBr was subsequently employed
instead of Me3SiCl in the reaction, giving a 55% isolated yield
of 1b (Table 1, entry 6).
Reactivity of 1a. Two major pathways for the synthetic use
of 1a can be considered. Nucleophilic activation of the silicon
atom (by fluoride ion) in the presence of a suitable electrophile
in polar media should result in transfer of the chlorodifluorom-
ethyl group to the electrophilic center (Scheme 2). Alternatively,
the presence of carbon-chlorine bond suggests the possibility
of reductive coupling to obtain new perfluoroalkylating agents
such as difluorobis(trimethylsilyl)methane and 1,1,2,2-tetrafluoro-
1,2-bis(trimethylsilyl)ethane.
Nucleophilic Activation of 1a. Me3SiCF2Cl was expected
to serve as a source for CF2Cl-, similar to Me3SiCF3 being a
- 8
convenient synthetic equivalent of CF3
. However, during its
preparation and subsequent purification, 1a was found to be
unaffected by water even upon prolonged exposure at more
elevated temperatures. This is surprising for a silane with a
highly polarized Si-CF2Cl bond. Similar results were reported
by Fuchikami et al. in their studies on the bromodifluorom-
ethylating properties of PhMe2SiCF2Br.13 In reactions with
aldehydes under TBAF initiation in THF (the conditions usually
employed in Me3SiCF3 chemistry), 1a turned out to be much
less reactive than Me3SiCF3. Only 30% of 1a was consumed
within the first 4 h of the reaction with benzaldehyde (Table 2,
entry 1). Arguably, this reflects the difference in polarity
between the Si-CF3 and Si-CF2Cl bonds which renders 1a
less susceptible to nucleophilic attack. We consequently
examined more polar and more coordinating solvents that could
further activate the silicon center toward nucleophilic attack and
at the same time help in stabilizing the anionic intermediates.
The addition of an equal volume of NMP to the reaction mixture
greatly accelerated the chlorodifluoromethylation process (eq
3) (the mechanistic pathway is presented in Scheme 3). 1,2-
Reduction of the Carbon-Halogen Bond of 1a,b. The
efficient preparation of 1a and 1b prompted us to study the
reactivity of the carbon-halogen bond of these compounds in
reductive coupling with electrophiles. The attachment of a
second trimethylsilyl group to the CF2 moiety of 1a furnishes
bis(trimethylsilyl)difluoromethane (2), a synthetic equivalent of
“CF22-”. Previously, preparation of 2 was briefly described
by Fritz et al.17 It was obtained via insertion of the singlet
CF2 (difluorocarbene), produced from (trifluoromethyl)(trim-
ethyl)tin at elevated temperatures, into the silicon-silicon
bond of FMe2SiSiMe2F (the absence of the silicon-bound
fluorine atoms renders the Si-Si bond in Me3SiSiMe3 unreactive
toward difluorocarbene). The resulting FMe2SiCF2SiMe2F,
isolated by gas chromatography, was reacted with methyl-
(14) Prakash, G. K. S.; Yudin, A. K.; Deffieux, D.; Olah, G. A. Synlett
1996, 151.
(15) Cox, D. P.; Tripinski, J.; Lawrynowicz, W. J. Org. Chem. 1984,
48, 3216.
(16) Wang, Z.; Ruan, B. J. Fluorine Chem. 1994, 69 , 271.
(17) Fritz, G.; Bauer, H. Angew. Chem., Int. Ed. Engl. 1983, 22, 730.
Dimethoxyethane (DME) was also found to be more suitable
than THF as the reaction medium (Table 2). Moreover, its lower
(13) Hagiwara, T.; Fuchikami, T. Synlett 1995, 7, 717.

Preparation of Fluoroalkylating Reagents
J. Am. Chem. Soc., Vol. 119, No. 7, 1997 1575
Table 2. Chlorodifluoromethylation of Carbonyl Compounds with Me3SiCF2Cl (1a)
entry
aldehyde
PhC(O)H
PhC(O)H
product
solvent
THF
THF/NMP (1:1)
DME
DME
NMP
DME
DME
DME
THF/NMP (1:1)
initiatorb
yieldc (%)
1
2
3
4
5
6
7
8
9
PhCH(OH)CF2Cl (5a)
PhCH(OH)CF2Cl (5a)
PhCH(OH)CF2Cl (5a)
PhCH2CH2CH(OH)CF2Cl (5b)
PhCH2CH2CH(OH)CF2Cl (5b)
PhCH2CH2CH(OH)CF2Cl (5b)
PhCH2CH(OH)CF2Cl (5c)
n-C6H13CH(OH)CF2Cl (5d)
Ph2C(OH)CF2Cl (5e)
TBAF
TBAF
TBAF
KF
35d
68
PhC(O)H
75d
30
PhCH2CH2C(O)H
PhCH2CH2C(O)H
PhCH2CH2C(O)H
PhCH2C(O)H
n-C6H13C(O)H
PhC(O)H
CsF
45
80
85
TBAF
TBAF
TBAF
TBAF
64
32d
a All reactions were carried out at room temperature for 24 h. b 10 mol% initiator was utilized. c Isolated yield after column chromatography.
d Based on 19F-NMR analysis.
Scheme 3
Scheme 4
unexpected 1,2-bis(trimethylsilyl)-1,1,2,2-tetrafluoroethane (3)
lithium to afford 2 as a product of Si-alkylation. The apparent
experimental difficulties in this procedure did not allow the
synthesis of 2 on a preparative scale, which would have
(according to eq 4).18 The results obtained in the electrochemi-
permitted investigation of its properties as a synthetic equivalent
2-
of CF2
.
During the aluminum-induced synthesis of 1a from CF2BrCl,
no products were formed derived from the reduction of the
carbon-chlorine bond. Apparently, the aluminum/NMP com-
bination was not sufficient to reach the reduction potential of
the C-Cl bond and convert 1a into anionic Me3SiCF22-. An
attempt to use magnesium/THF and magnesium/THF/HMPA
combinations resulted in very sluggish reactions between 1a
and Me3SiCl, giving the disilylated difluoromethane 2 not
exceeding 3-5% after one week (based on the NMR analysis).18
The relative ineffectiveness of these reagents, traditionally
employed for the reduction of alkyl halides, is not surprising in
view of the difficulties generally encountered in the preparation
of C1-perfluorinated organometallics (the strong metal-fluorine
bonds make these species extremely susceptible toward dispro-
portionation).19 This prompted us to study 1a under conditions
employed earlier by us in the electroreduction of CF3Br using
the sacrificial aluminum anode technique. The readily oxidiz-
able aluminum anode prevents the formation of elemental
chlorine (through the oxidation of chloride ions, Scheme 4).11,20
This ensures that halogenation and other side reactions of the
reduced species are largely suppressed, allowing the preparation
in an undivided cell.11a The reduction of 1a occurs on the
surface of a nickel cathode, wherein the anions, electrogenerated
from 1a, are coupled with Me3SiCl, present in the system. The
electrolysis of a mixture of 1a/Me3SiCl in the THF/HMPA
solvent system resulted in the formation of 2 along with that of
cal experiments are given in Table 3. Tetrabutylammonium
hexafluorophosphate or bromide (3-4 mol %) was used as an
electrolyte support to provide conductivity at the initial stages
of the reaction. A current density of 100 mA was applied until
NMR analysis of samples indicated the complete consumption
of 1a. The amount of electric current passed through the
solution was equivalent to a slight excess of two electrons per
mole of substrate, which is theoretically necessary to convert
1a into the corresponding anion. Formation of the homocoupled
byproduct 3 indicates the intermediacy of radicals in the course
of the reduction (Scheme 4). An alternative mechanism
suggested by one of the reviewers involving singlet diflurom-
ethylene insertion into Me3
SiCF - followed by trimethylsilyation
2
appears to be unlikely as no other difluoromethylene-derived
products are observed. We have found that using an excess of
Me3SiCl and a 15:1 THF/HMPA mixture results in a 15:2 molar
ratio of 2 and 3, thus strongly favoring the anionic pathway of
reduction. These conditions are optimal for the preparation of
1
2. The obtained products were fully characterized by
19F, H,
13C, and 29Si NMR. Table 4 summarizes these data on
compounds 2 and 3 as well the starting materials 1a and 1b.
Among the byproducts, Me3
SiCF H (formed via protonation
2
of Me3SiCF2- by residual acid) and Me3SiF were also detected.
3 is a low-melting solid compound (mp 38 °C) that crystallized
out of the mixture of 2 and 3 upon cooling. Large (1.5 × 2
in.!) transparent crystals were deposited on the walls of the flask
by slow room temperature sublimation of 3 from the mother
liquid. In contrast, related Me3SiCF3 is a volatile liquid (bp 45
°C). This intriguing difference warranted X-ray structure
analysis. Crystals of 3, suitable for a single-crystal X-ray
(18) The disilyl derivative PhMe2SiCF2CF2SiPhMe2, containing a per-
fluoroethylene unit, was obtained by Ojima et al. via nickel-catalyzed
reductive dimerization of PhMe2SiCF2Br: Fuchikami, T.; Ojima, I. J.
Organomet. Chem. 1982, 212, 195.
(19) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc.
1989, 111, 393 and references cited therein.
(20) For a review, see: Chaussard, J.; Folest, J.-C.; Nedelec, J.-Y.;
Perichon, J.; Sibille, S.; Troupel, M. Synthesis 1990, 369.

1576 J. Am. Chem. Soc., Vol. 119, No. 7, 1997
Yudin et al.
Table 3. Experimental Conditions for the Electrocoupling between Me3SiCF2X (X ) Cl, Br) and Me3SiCla
Me3SiCF2X
(equiv)
Me3SiCl
(equiv)
supporting electrolyte
(equiv)
electron density
(mA)
yield (%)
(ratio of 2 to 3)
entry
solvent mixture
1
2
3
4b
5
6
7
1a (1.0)
1a (1.0)
1a (1.0)
1a (1.0)
1a (1.0)
1a (1.0)
1a (1.0)
6.0
6.0
6.0
18.0
10.0
0.0
THF/HMPA (15:1)
DMF
NMP
THF/HMPA (6:1)
THF/HMPA (12:1)
THF/HMPA (10:1)
THF/TDA-1 (1:1)
NBu4PF6 (0.04)
NBu4PF6 (0.04)
NBu4PF6 (0.04)
NBu4PF6 (0.1)
NBu4PF6 (0.03)
NBu4PF6 (0.03)
NBu4Br (0.03)
100
100
50
150
100
100
100
80 (10:1)
0
0
27 (3.5:1)
56 (6:1)
0
3.0
75 (1:8.5)
a All reactions were carried out in a 100 mL undivided cell equipped with an aluminum (rod) anode and nickel grid cathode. b A syringe pump
was used to introduce the 1a/Me3SiCl mixture.
Table 4. NMR Parameters of 1a, 1b, 2, and 3
silane δ(1H)
δ(19F)
δ(13C)
δ(29Si)
1a
1b
2
0.27 (s) -63.8 (s) -4.71 (s)
10.21 (t)
135.20 (t)
2J(Si-F) 32.0 Hz
1J(C-F) 327.0 Hz
0.27 (s) -58.0 (s) -4.45 (s)
12.30 (t)
132.11 (t)
2J(Si-F) 29.3 Hz
1J(C-F) 338.5 Hz
0.13 (s) -137.3 (s) -4.12 (t)
1.65 (t)
1J(C-F) 2.9 Hz
2J(Si-F) 29.0 Hz
138.73 (t)
1J(C-F) 260.7 Hz
3
0.22 (s) -122.2 (s) -400 (m)
5.18 (tt)
126.63 (tt)
2J(Si-F) 34.3 Hz
1J(C-F) 264.5 Hz 3J(Si-F) 17.2 Hz
2J(C-F) 45.8 Hz
Table 5. (a, top) Experimental Details of the X-ray Analysis of 3
and (b, bottom) Geometric Parameters of 3
crystal size, 0.6 × 0.48 × V, Å3
644.0(3)
1.271
Cu KR (λ )
1.541 78 Å)
mm
chem form
fw
0.26
d
calc, gm cm-3
C8H18F4Si2
246.4
radiation
cyst syst
space group P21/n
a, Å
b, Å
c, Å
â, deg
Z
monoclinic
no. of data colltd 1852
no. of data used
641 (F > 4.0σ(F))
0.0456
0.0517
6.474(2)
R
Rw
Figure 1. ORTEP drawing of 3 (the methyl hydrogens are not shown
for clarity).
10.024(2)
9.924(2)
90.33(2)
2
largest peak, e/Å3 0.24
no. of parameters 64
Bond Distances (Å)
Si(1)-C(3)
Si(1)-C(5)
F(1)-C(3)
C(3)-C(3A)
1.935(4)
Si(1)-C(4)
Si(1)-C(6)
F(2)-C(3)
1.847(4)
1.846(5)
1.394(4)
1.857(5)
1.393(5)
1.499(8)
Bond Angles (deg)
C(3)-Si(1)-C(4)
C(4)-Si(1)-C(5)
C(4)-Si(1)-C(6)
Si(1)-C(3)-F(1)
F(1)-C(3)-F(2)
F(1)-C(3)-C(3A)
103.3(2)
112.2
C(3)-Si(1)-C(5)
108.7(2)
108.9(2)
111.8(2)
108.0(3)
123.6(4)
105.6(4)
C(3)-Si(1)-C(6)
C(5)-Si(1)-C(6)
Si(1)-C(3)-F(2)
Si(1)-C(3)-C(3A)
F(2)-C(3)-C(3A)
111.6(2)
108.3(2)
104.0(3)
105.7(4)
analysis, were grown by recrystallization. The details of the
X-ray structure analysis are given in the Experimental Section.
Table 5 gives the structural parameters of 3. An ORTEP
diagram and a packing diagram of the monoclinic cell of 3 are
presented in Figures 1 and 2, respectively. Experimental details
of the structure analysis, and selected distances and angles in
3, are given in parts a and b, respectively of Table 5. The
unusually large value of 123.6° for the Si-C-C bond angle is
possibly caused by the repulsion between the fluorine atoms
and trimethylsilyl groups. The dihedral angle Si-C-C-Si of
180° indicates the perfect trans arrangement. The bond length
as well as other bond angle values in the observed trans
conformation of 3 are within the normal range. No intermo-
lecular distances that would be indicative of the presence of
stabilizing hydrogen contacts (C-H-F) that could result in
Figure 2. Packing diagrams along the a-axis of 3.
crystallinity were detected. The shortest nonbonded distance
between a fluorine atom and methyl hydrogen of a trimethylsilyl
group is 2.88 Å, which is 0.33 Å longer than the van der Waals
distance of 2.55 Å for the hydrogen-fluorine contact. Appar-

Preparation of Fluoroalkylating Reagents
J. Am. Chem. Soc., Vol. 119, No. 7, 1997 1577
ently, the rigidity of the tetrafluoroethylene subunit within the
trans conformation of 3 is responsible for efficient packing. A
quite long value of 1.935 Å for the Si-CF2 bond is indicative
of its relative weakness. In comparison, a value of 1.923 Å
was obtained by Burger et al. for the Si-CF3 bond in CF3SiH3
using the electron diffraction study combined with the normal
coordinate analysis.21
in the constant current method used in our study, one assumes
that the presence of a bromodifluoromethyl group in 1b should
facilitate the dimerization process since the brominated com-
pounds generally have lower E1 values.23 However, we have
found that when 1b was treated under similar conditions, a
complicated mixture of products was obtained, resulting in a
very low isolated yield of 3. It was reported that, in the
electroreduction of alkyl halides even when a coupling process
does result in a preferential formation of a dimer, the SN2
reaction between the intermediate carbanion and alkyl halide
is the actual mechanistic path.24 For organofluorine compounds
this path, however, is unlikely due to their known resistance to
nucleophilic substitution. Therefore, to obtain high yields of
the dimer 3, the local concentration of the radicals near the
electrode surface as well as their lifetime should be enhanced.
An increase in the current density and, therefore, the concentra-
tion of the starting material (1a) near the electrode surface would
be a step toward favoring dimerization. We have indeed found
that under these conditions the formation of 3 increased based
on the NMR analysis (Table 3, entry 4). Further, optimization
of the reaction conditions for the formation of 2 and 3 led to
the realization of a profound solvent effect on the ratio between
2 and 3. Tris(3,6-dioxaheptyl)amine (TDA-1) as a cosolvent
with THF highly favored the formation of the homocoupled
product 3 (Scheme 4, path a), whereas when HMPA was used,
the anionic product 2 was dominant (Scheme 4, path b). Both
experiments were conducted under identical conditions. Thus,
by choosing a different solVent mixture during electroreduction,
the reaction could be funneled through a predominantly anionic
or radical pathway. We believe that the solvent TDA-1
increases the lifetime of the radical cage formed during the first
electron transfer step of the reduction, permitting the dominance
of the radical-derived product 3, whereas HMPA, well known
for its great stabilizing effect on the anionic species, favors the
formation of anion-derived product 2.12 Although the exact
nature of the involved processes is speculative, the correlation
with a donor number (DN) of the solvent is, nevertheless,
conceivable. The dependence of the radical cage stability on
the DN parameter was noted by Chen et al.24 It was shown
that, in copper-mediated reductions of perfluorinated alkyl
iodides, solvents with small DN (DN < 17) led to diffusional
control of the caged ion pair, permitting the trapping of a radical
by an appropriate olefin. On the other hand, in solvents with
DN higher than 31 (such as HMPA) the collapse of the ion
pair led to further reduction of radicals, absorbed on the surface
of the copper metal, giving anionic products.
The preparative separation of 2 and 3 by distillation turned
out to be rather tedious and impractical. Since our initial goal
was the preparation of 2, the experimental conditions were
tailored toward its selective preparation, giving 3 as an
insignificant byproduct. In order to obtain analytically pure 2
for synthetic purposes, the products collected following the
workup of the electroreduction mixture (2, 3, and disiloxane)
were treated with a catalytic amount of tetrabutylammonium
fluoride to remove 3 (Vide infra) and partitioned between 98%
sulfuric acid and pentane to remove traces of disiloxane.
Evaporation of pentane yielded 2 as an analytically pure
colorless liquid. Using the conditions where formation of 3 is
minimized (Table 3, entry 1) allows the preparation of 2 on a
preparative scale and in high yield. Similar to 1a, the
remarkable hydrolytic and thermal stabilities of the silylated
derivatives 2 and 3 are noteworthy. They do not show any
tendency for hydrolysis to give disiloxane and the corresponding
gaseous CF2HX (X ) H, Cl).22 Thermal stability of these
molecules with respect to fluorine migration from carbon to
silicon is also rather unusual. 3 does not show any tendency
to extrude Me3SiF even at high temperatures.
The described notable properties of the SiCF2Si moiety
deserve further investigation. We believe that since the dif-
luoromethylene group is considered isosteric with ethereal
oxygen, CF2 incorporation into an oxygenated polysiloxane
framework might yield novel materials with unexpected and
useful properties.21 The rigidity of the backbone is one of the
parameters that the difluoromethylene group is expected to alter.
It should be noted, however, that the observed stability is most
probably of kinetic, rather than thermodynamic origin due to
the anticipated electrophilic character of the silicon atom
adjacent to the highly electron-withdrawing difluoromethylene
group.
In its own right, disilylated 3 is attractive for synthetic
purposes as a source of the tetrafluoroethylene unit. Therefore,
we needed conditions that would yield 3 as a major, rather than
side, product. Conditions preferring the homocoupling were
expected to provide a preferential path to 3.
Preferential Preparation of 3. The behavior of alkyl halides
with respect to electrochemical homocoupling has been previ-
ously investigated by Fry et al.23 It is recognized that the first
electron transfer in the reduction process is usually potential-
determining. Dimerization of radicals occurs to some extent,
but it is generally difficult to control since the second electron
transfer to the radical generating the corresponding anion
proceeds more readily. In other words, for alkyl halides E1
(potential of the first electron transfer) is the negatiVe of E2
(potential of the second electron transfer). This fact precludes
the efficient use of the controlled potential method which could
otherwise be applied to provide the amount of electric current
which is theoretically required in order to reach the first
reduction potential and, therefore, favor dimerization. Similarly,
The direct electrochemical conversion of CF2BrCl or CF2-
Br2 into Me3SiCF2SiMe3 without the isolation of 1a would be
the easiest for the preparation of 2. However, in an attempted
direct electrocoupling of CF2Br2 with Me3SiCl, the formation
of significant amounts of Me3SiF drastically lowered the yield.
Electrocoupling did occur, but the conversion and selectivity
were low (15% of the 1:1.5 mixture of 2 and 3 was isolated).
Structurally, the disilylated derivatives 2 and 3 are the first two
homologs in the series Me3Si(CF2)nSiMe3 (n ) 1-10). Higher
members were used by Farnham in copolymerization with
perfluoroalkenes, initiated by trialkylsilyl carboxylates.25 These
higher homologs are readily accessible via Barbier-type reactions
between the corresponding perfluorinated dihalides and trim-
ethylsilyl chloride. Analogous organometallic routes to 2 and
3 from CF2Br2 and CF2BrCF2Br suffer from the competition
(21) Beckers, H.; Burger, H.; Eujen, R.; Rempfer, B.; Oberhammer, H.
J. Mol. Struct. 1986, 140, 281.
(22) Pawlenko, S. Organosilicon Chemistry; W. de Gruyter: Berlin, New
York, 1986.
(23) (a) Fry, A. J.; Porter, J. M.; Fry, P. F. J. Org. Chem. 1996, 61,
3191. (b) Peters, D. G.; Willett, B. C. J. Electroanal. Chem. 1981, 123,
291.
(24) Chen, Q.-Y.; Yang, Z.-Y.; He, Y.-B. J. Fluorine Chem. 1987, 22,
171.
(25) Farnham, W. B. Synthetic Fluorine Chemistry; In Olah, G. A.,
Chambers, R. D., Prakash, G. K. S., Eds.; Wiley: New York, 1992; Chapter
11.

1578 J. Am. Chem. Soc., Vol. 119, No. 7, 1997
Yudin et al.
of R- and â-elimination of the halide ions.26 Even generally
milder and more selective electrochemical routes would be
problematic. For example, an attempt to prepare the parent Me3-
SiCH2CH2SiMe3 by electroreduction of CH2BrCH2Br in the
presence of Me3SiCl leads to the preferential formation of
ethylene by elimination of bromide anion. Ruppert’s procedure
was also found to be unsuitable for the preparation of 2.8 Our
electrochemical methodology thus seems to be a method of
choice for the straightforward preparation of the reagents 2 and
3 from readily available starting materials on a preparative scale.
Synthetic Applications of Bis(trimethylsilyl)difluoromethane
(2) and 1,2-Bis(trimethylsilyl)-1,1,2,2-tetrafluoroethane 3.
Similar to 1a, bis(trimethylsilyl)difluoromethane (2) displayed
rather sluggish reactivity toward carbonyl compounds in THF.
This was observed despite the fact that the formation of the
“Me3SiCF2-” species (the de facto difluoromethylating agent)
upon nucleophilic activation of 2 should be somewhat facilitated
by partial stabilization of the resulting anionic center by the
R-trimethylsilyl group (even if the anion has significant
pyramidal character). For efficient conversion, the addition of
NMP as a cosolvent was again found to be crucial.14 This
promoted the reaction between 2 and aldehydes to afford the
difluoromethylated alcohols after the usual acidic workup
(according to eq 5). DME was also effective as the reaction
Scheme 5
Compared to Me3SiCF2H (bp 50 °C), which can also be
considered as a “CF2H-” equivalent,10,22 2 is hydrolytically
stable and less volatile (bp 130 °C). Additionally, the silylated
adducts 6 can be envisioned to react with other electrophiles
besides “H+” (acidic workup) which would permit 2 to have
general “CF22-” character. We are further investigating this
aspect. Fuchikami et al. recently reported on the difluorom-
ethylating properties of a related silane, PhMe2SiCF2H,13 which
reacts with aldehydes but only at elevated temperatures in polar
solvents (100 °C, DMF) with KF as an initiator. Also, the
observed relative inertness might be a result of the presence of
the phenyl substituent. The formation of silyl enol ethers in
reactions with enolizable carbonyl compounds was reported by
Hiyama et al. as a side reaction.27 This unwanted reaction path
is also facilitated due to the presence of the phenyl substituent.
Probably, its stabilizing effect on the developing negative charge
during enolization is one of the reasons responsible for it. In
fact, the perfluorophenyl derivative Me3SiC6F5 is used for the
preparation of silyl enol ethers from enolizable carbonyl
compounds.28 In any case, the ease of preparation of 2 from
readily available starting materials (CF2BrCl and Me3SiCl) along
with the displayed mild chemistry makes it a convenient CF2H-
equivalent.
medium. Polar solvents apparently accelerate the reaction by
stabilizing the charged species involved in the catalytic cycle
similar to the reactions of 1a. Benzophenone reacted with 2 at
room temperature, albeit much slower, giving the difluorom-
ethylated adduct after the usual workup.
As in the case of 1a, TBAF turned out to be superior to KF
as an initiator (10-15 mol % was necessary to ensure complete
conversion). The only detectable byproducts were CF2H2 (t,
δF -143 ppm) and TMSCF2H (d, δF -140 ppm) formed by
the protonation of CF2H- and TMSCF2-, respectively, by the
residual water present in TBAF solution. From a mechanistic
point of view, the overall process can be considered as an initial
formation of the silylated adduct 8 which starts the catalytic
cycle (Scheme 5, path a). The aldehyde moiety is then
siladifluoromethylated as indicated. Acidic workup of the
adduct furnishes the desired difluoromethylated carbinol 7
(Table 6). Alternatively, Me3SiCF2H formed in situ from 2,
TBAF, and residual moisture could be regarded as a species
that is at least in part involved in the present transformation
(Scheme 5, path b). However, since no reaction occurred when
2 was exposed to TBAF in THF/H2O (separation of 2 from
traces of 3 was performed by using TBAF, Vide supra), this
possibility is less likely. Nevertheless, the process does occur
to some extent which is evident by the traces of CF2H2 detected
in the crude reaction mixture. Higher amounts of TBAF
compared to trifluoromethylation were necessary for efficient
conversion of an aldehyde into the corresponding difluorom-
ethylated carbinol. This fact is mainly attributed to the inhibition
through the competitive migration of the oxophilic trimethylsilyl
group in 8, generating 9 (Scheme 5, path c), which is not capable
of further maintaining the reaction due to the lack of a
nucleophilic oxygen center but does yield the desired difluo-
romethylated carbinols upon acidification.
In contrast to both 1a and 2, 1,2-bis(trimethylsilyl)-1,1,2,2-
tetrafluoroethane (3) was completely used up within 3 h when
reacted with a variety of aldehydes and ketones in THF under
TBAF initiation at room temperature. The analysis of this
exothermic reaction revealed the net transfer of the perfluo-
roVinyl group to the carbonyl carbon accompanied by Me3SiF
elimination. We have found that only a catalytic amount of
TBAF was needed to convert 3 into (perfluorovinyl)trimethyl-
silane (10) (eq 6 and Table 7). The reaction of 3 regenerates
TBAF, making the process catalytic. Upon addition of an
aldehyde or a ketone to the reaction mixture, addition of a
perfluorovinyl unit readily occurs similar to the previously
(27) Fujita, M.; Obayashi, M.; Hiyama, T. Tetrahedron 1988, 44, 4135.
(28) Gostevskii, B. A.; Vyazankina, O. A.; Kalikhman, I. D.; Bannikova,
O. B.; Vyazankin, N. S. Zh. Obshch. Khim. 1983, 53, 229; J. Gen. Chem.
USSR (Engl. Transl.) 1983, 53, 200.
(26) Fry, A. J. Synthetic Organic Electrochemistry, 2nd ed.; Wiley: New
York, 1989; Chapter 5, p 151.

Preparation of Fluoroalkylating Reagents
J. Am. Chem. Soc., Vol. 119, No. 7, 1997 1579
Table 6. Difluoromethylation of Carbonyl Compounds with Me3SiCF2SiMe3 (2)
entrya
aldehyde
PhC(O)H
PhC(O)H
product
solvent
THF
THF/NMP (1:1)
DME
DME
DME
yieldb (%)
1
2
3
4
5
6
7
PhCH(OH)CF2H (7a)
PhCH(OH)CF2H (7a)
PhCH(OH)CF2H (7a)
PhCH2CH2CH(OH)CF2H (7b)
PhCH2CH(OH)CF2H (7c)
n-C6H13CH(OH)CF2H (7d)
Ph2C(OH)CF2H (7e)
20
70
75
66
78
55
40
PhC(O)H
PhCH2CH2C(O)H
PhCH2C(O)H
n-C6H13C(O)H
PhC(O)H
DME
NMP
a All reactions were carried out at room temperature for 24 h using 10 mol % TBAF as an initiator. b Isolated yield after column chromatography.
Table 7. Perfluorovinylation of Carbonyl Compounds with
Me3SiCF2CF2SiMe3 (3)
Although â-fluoride ion elimination in 14 is highly favored
at room temperature, it was possible to find the conditions where
yieldb
solvent (%)
the elimination was suppressed and 2 equiv of a carbonyl
carbonyl
entrya compound
product
-
compound was able to react with 1 equiv of 3 (“-CF2CF2
”
equivalent, Scheme 6, path c). We have found that when the
reaction was carried out at -48 °C in DME as a solvent in the
presence of 3 equiv of benzaldehyde, the formation of the diol
12 containing the perfluoroethylene unit occurred. At the same
time, competitive protonation resulted in the formation of
tetrafluoroethylated carbinol 13. Recently, Fuchikami has
shown that PhMe2SiCF2CF2SiPhMe2 undergoes reaction with
carbonyl compounds, affording mixtures of perfluorovinyl
alcohol, tetrafluoroethylene-containing diol, and tetrafluoroet-
hylated alcohol.30 However, again elevated temperatures were
required in order to activate the silicon center of this phenylated
derivative. Little selectivity with respect to perfluorovinylation
was observed at the needed higher temperatures. Along with
the more convenient method of preparation of 3 adaptable for
a preparative synthetic scale, 3 also shows high reactivity as
well as selectivity for obtaining perfluorovinyl carbinols at room
temperature while giving alcohols 12 and 13 at low tempera-
tures.
1
2
3
PhC(O)H
PhCH(OH)CFdCF2 (11a)
THF
THF
THF
75
80
64
PhC(O)CH3 PhCCH3(OH)CFdCF2 (11b)
C6H13C(O)H C6H13CH(OH)CFdCF2 (11c)
a All reactions were carried out at room temperature for 2 h using
10 mol % TBAF as an initiator. b Isolated yield after column chroma-
tography.
Scheme 6
Experimental Section
General Procedures. Preparation of compounds 1a and 1b was
carried out in oven-dried sealed tubes. Synthesis of compounds 2 and
3 was performed in an oven-dried one-compartment electrochemical
cell. Reactions of 1a, 2, and 3 with carbonyl compounds were
performed under an argon atmosphere in flame-dried glassware with
magnetic stirring. The boiling points are uncorrected. 1H, 13C, 19F,
and 29Si NMR spectra were recorded at 500, 125, 470, and 99 MHz,
respectively, using CDCl3 as solvent. All chemical shifts are reported
in parts per million (δ) and are relative to residual CHCl3 for 1H, CDCl3
for 13C, CFCl3 for 19F, and (CH3)4Si for 29Si NMR. The fluorinated
alcohols 5a-d,9 7a-d,9 11a-c,27,33 12,30 and 1330 were characterized
by comparison of their spectral properties with the literature data.
THF and DME were distilled from sodium/benzophenone ketyl.
N-Methylpyrrolidinone (anhydrous), aluminum powder, chlorotrimeth-
ylsilane and TBAF (hydrate) were purchased from Aldrich Chemical
Co., Inc. Chlorotrimethylsilane was distilled from calcium hydride to
remove traces of hydrochloric acid. Aldehydes were pretreated with
aqueous sodium hydroxide to remove acid impurities. Bromochlo-
rodifluoromethane and dibromodifluoromethane were purchased from
PCR, Inc.
described processes (Scheme 6, path a). Consequently, 3 acts
as a convenient, in situ source of “CF2dCF-”.29 The corre-
sponding secondary and tertiary perfluorovinylated alcohols
were obtained in high yields according to eq 7a. Scheme 6
Preparation of (Chlorodifluoromethyl)trimethylsilane (1a).
A
100 mL thick-walled, high-pressure glass tube equipped with a magnetic
stirring bar and dried in an oven overnight was charged with 0.9 g (52
mmol) of fresh aluminum powder. The tube was then purged with
dry argon three times followed by addition of 30 mL of dry
N-methylpyrrolidinone via syringe. The resulting slurry was stirred
and degassed under vacuum followed by purging with argon. An 8 g
(74 mmol) sample of freshly distilled chlorotrimethylsilane was then
added, and the resulting mixture was frozen at -196 °C. An 8.1 g (49
mmol) portion of bromochlorodifluoromethane was condensed into the
cooled tube followed by sealing under vacuum. The sealed tube was
depicts some considerations of reactivity. After the initial attack
of fluoride on the silicon atom of 3, the transient species 14
can undergo â-fluoride ion elimination, forming perfluorovi-
nylsilane 10 which further reacts with electrophiles present in
the reaction mixture. At the same time, 14 itself can undergo
addition to an aldehyde followed by â-fluoride ion elimination,
giving the trifluorovinyl products (Scheme 6, path b).
(29) For perflurovinylation using Me3SiCFdCF2, obtained from
CF2dCFCl, BuLi, and Me3SiCl, see ref 27.
(30) Fuchikami, T.; Hagiwara, T. Jpn. Kokai Tokkyo Koho JP06,228,-
030[94,228,030] (CL.C07C33144).

1580 J. Am. Chem. Soc., Vol. 119, No. 7, 1997
Yudin et al.
allowed to reach room temperature after which the mixture was stirred
overnight. The reaction was accompanied by the formation of a yellow-
brown dense cake. During the workup, the tube was precooled to -196
°C and then opened on the vacuum line. After warming to room
temperature, the volatile contents were condensed in another flask using
a standard vacuum line technique. The colorless mixture thus obtained
contained the product 1a, traces of CF2HCl, and fluorotrimethylsilane
along with unreacted chlorotrimethylsilane. Further purification in-
cluded hydrolysis, neutralization, and fractional distillation of the
organic phase using a 15 cm column packed with glass helices. This
procedure afforded 1a as a colorless liquid containing 5-10 mol % of
disiloxane. The traces of disiloxane were removed by partitioning
between 98% sulfuric acid and pentane31 at 0 °C . The pentane was
then removed by distillation, giving pure 1a as a colorless liquid, 6.2
g (80% yield of the theoretical yield, based on bromochloro-
in 50 mL of THF in a single-compartment electrochemical cell equipped
with an aluminum rod anode (99% pure) and nickel grid cathode.
Preelectrolysis at 100 mA was performed until hydrogen evolution was
no longer detectable, which corresponded to the removal of the residual
hydrochloric acid. An amount of 6 g of 1a (28 mmol) was introduced
into the cell, and the electrolysis at 100 mA was carried out until
approximately 2.1 F/mol of electric current was consumed. The
reaction mixture was monitored by GC-MS and NMR. Upon
completion, the reaction was quenched with water and extracted with
pentane (4 × 100 mL). The combined pentane fractions were dried
with sodium sulfate. At this point, NMR analysis showed the mixture
to consist of pentane and disiloxane as well as products 2 and 3 in a
10:1 molar ratio. Tetrabutylammonium fluoride (1 M solution in THF)
was added in order to transform 3 into volatile (perfluorovinyl)-
trimethylsilane (10). Pentane and 10 were removed by distillation. In
order to remove disiloxane, the mixture was treated with 98% sulfuric
acid followed by fractionation using a 15 cm column packed with glass
helices which afforded 4.1 g of 2 (65% yield of the theoretical yield,
1
difluoromethane): bp 80-82 °C (lit.10 bp 87 °C); H NMR δ 0.27;
13C NMR δ -4.71, 135.20 (t, 1J(C-F) 327.0 Hz); 19F NMR δ -63.8;
2
29Si NMR δ 10.21 (t, J(Si-F) 32.0 Hz).
1
based on 1a) as a colorless liquid: bp 120 °C; H NMR δ 0.13; 13C
Preparation of (Bromodifluoromethyl)trimethylsilane (1b). Com-
pound 1b was prepared similarly to 1a by reacting 9.45 g of CF2Br2
(45 mmol), 10 g (65 mmol) of Me3SiBr, and 0.85 g of aluminum
powder in a sealed tube. A 60 mL sample of NMP was used in this
case in order to facilitate stirring of the dense reaction mixture.
Compared to the preparation of 1a, a faster rate of thickening of the
reaction mixture in the case of 1b is observed. This is probably due
to the complexation of NMP with the AlBr3 formed during the oxidation
of aluminum metal (the reaction is accompanied by the formation of a
dense “cake” due to this complexation). To some extent, larger amounts
of solvent alleviate the problem. The workup of the contents of the
tube followed by 98% H2SO4/pentane partition and fractional distillation
of the organic phase using a 15 cm column packed with glass helices
afforded 5.1 g of 1b (55% yield of the theoretical yield, based on
bromochlorodifluoromethane) as a colorless liquid: bp 112 °C (lit.10
bp 105-106 °C); 1H NMR δ 0.27; 13C NMR δ -4.45, 132.11 (t, 1J(C-
F) 339.0 Hz); 19F NMR δ -58.3; 29Si NMR δ 12.45 (t, 2J(Si-F) 29.0
Hz).
Reaction of 1b with Chlorotrimethylsilane. A 300 mg (1.5 mmol)
sample of (bromodifluoromethyl)trimethylsilane (1b) (neat) was heated
with excess chlorotrimethylsilane in a closed round-bottom flask at 100
°C for 2 h. The NMR analysis of the reaction mixture showed a
quantitative conversion of 1b into 1a.
Typical Procedure for the Chlorodifluoromethylation of Alde-
hydes Using 1a. To a mixture of (chlorodifluoromethyl)trimethylsilane
(1a) (200 mg, 1.26 mmol) and benzaldehyde (90 mg, 0.85 mmol) in
dry DME (4 mL) was added 10 drops of 1 M solution of TBAF in
THF (ca. 10 mol %).32 The reaction mixture was stirred for 24 h at
room temperature. Gradually, the orange color evolved. When the
TLC analysis indicated complete conversion of the starting benzalde-
hyde, the solution was quenched with 40% HF in acetonitrile in order
to remove the trimethylsilyl group from the initial adduct 4a. Column
chromatography (hexanes/ethyl acetate, 10:1) yielded 121 mg of the
product 2-chloro-2,2-difluoro-1-phenylethanol9 (5a) in 75% yield based
on benzaldehyde.
NMR δ -4.12 (t, 3J(C-F) 2.9 Hz), 138.73 (t, 1J(C-F) 260.7 Hz); 19
F
2
NMR δ -137.3; 29Si NMR δ 1.65 (t, J(Si-F) 29.0 Hz).
Typical Procedure for the Difluoromethylation of Aldehydes
Using 2. To a mixture of bis(trimethylsilyl)difluoromethane (2) (250
mg, 1.27 mmol) and benzaldehyde (90 mg, 0.85 mmol) in dry DME
(4 mL) was added 10 drops of 1 M solution of TBAF in THF (ca. 10
mol %).32 The reaction mixture was stirred for 24 h at room
temperature. When the TLC analysis indicated complete conversion
of the starting benzaldehyde, the solution was quenched with 4 N HCl
in order to remove the trimethylsilyl group from the initial adduct 6a.
Column chromatography (hexanes/ethyl acetate, 10:1) yielded 140 mg
of the product 2,2-difluoro-1-phenylethanol9 (7a) in 70% yield based
on benzaldehyde.
A similar procedure was used for the preparation of compounds 7b-
d. Their spectral properties are reported in the literature.9
Preparation of 1,2-Bis(trimethylsilyl)-1,1,2,2-tetrafluoroethane
(3). A 10 mL sample of chlorotrimethylsilane, 50 mL of TDA-1, and
0.5 g of tetra-n-butylammonium bromide were added under an argon
atmosphere to 50 mL of THF in a single-compartment electrochemical
cell equipped with an aluminum rod anode (99% pure) and nickel grid
cathode. Preelectrolysis at 100 mA was performed until hydrogen
evolution commenced. An amount of 8 g (50 mmol) of 1a was
introduced into the cell, and the electrolysis at 100 mA was carried
out until approximately 1.1 F/mol of electric current was consumed.
The reaction mixture was monitored by GC-MS and NMR. Upon
completion, the reaction was quenched with water and extracted with
pentane (4 × 100 mL). The combined pentane fractions were dried
with sodium sulfate. The NMR analysis showed the mixture to consist
of pentane and disiloxane as well as products 2 and 3 in a 1:8.5 molar
ratio. Pentane was removed by distillation. In order to remove
disiloxane, the mixture was treated with 98% sulfuric acid and extracted
with pentane or, alternatively, fractionated using a 15 cm column packed
with glass helices. When most of the disiloxane was removed, the
mixture was allowed to cool to room temperature. Crystallization at
-20 °C resulted in the formation of white crystals of 3 that were
separated from the mother liquid by filtration, furnishing 4.3 g of 3
(70% yield of the theoretical yield, based on 1a) as a colorless liquid:
bp 120 °C; 1H NMR δ 0.22; 13C NMR δ -4.00 (m), 126.63 (tt, 1J(C-
F) 264.5 Hz, 2J(C-F) 45.8 Hz); 19F NMR δ -122.2; 29Si NMR δ 5.18
A similar procedure was used for the preparation of compounds 5b-
d. Their spectral properties are reported in the literature.9
Preparation of Bis(trimethylsilyl)difluoromethane (2). A 10 mL
portion of chlorotrimethylsilane, 5 mL of HMPA, and 0.5 g of tetra-
n-butylammonium bromide were dissolved under an argon atmosphere
2
3
(tt, J(Si-F) 34.3 Hz, J(Si-F) 17.2 Hz).
X-ray Analysis of 3. Crystals of 3, suitable for an X-ray structure
determination, were grown via crystallization from the mixture of 2
and 3. The compound crystallizes very well as large, beautiful needles,
with some specimens reaching dimensions as large as 0.5 × 0.5 ×
10.0 mm. X-ray diffraction data were collected on a small crystal using
Cu KR radiation on a Siemens P4/RA automated diffractometer at low
temperature (-120 °C). The structure was solved by direct methods
and refined to final agreement factors of R ) 4.6% and Rw ) 5.2% for
1852 nonzero reflections. Details of the structure analysis are given
in Table 5.
(31) A series of (perfluoroalkyl)trialkylsilanes were purified by partition-
ing between 98% sulfuric acid and hexane: Sekya, A.; Hoshi, N.;
Kobayashi, T. Jpn. Kokai Tokkyo Koho JP06,228,164[94,228,164]
(CL.C07F7/12).
(32) Tetrabutylammonium fluoride (TBAF) is known for its highly
hygroscopic nature caused by the basicity of fluoride ion. However, the
amount of water associated with fluoride ion can be drastically lowered
using the procedure of Cox et al. (see ref 15) by heating the TBAF/H2O
complex at 40 °C under dynamic vacuum until ca. 20% loss of the sample
weight occurs. Alternatively, we have found that anhydrous 2-propanol
(0.005% H2O, Aldrich) is suitable for azeotropic removal of water. Thereby,
the yellow-brown TBAF/H2O complex is mixed in a Schlenk flask with
isopropanol which is removed under vacuum. The cycle is repeated 10-
15 times. As a result of this treatment, an off-yellow powder is obtained
which was found to be suitable for our synthetic purposes.
Typical Procedure for the Perfluorovinylation of Carbonyls
Using 3. To a mixture of 1,2-bis(trimethylsilyl)-1,1,2,2-tetrafluoroet-
hane (3) (300 mg, 1.22 mmol) and benzaldehyde (90 mg, 0.85 mmol)

Preparation of Fluoroalkylating Reagents
J. Am. Chem. Soc., Vol. 119, No. 7, 1997 1581
in dry THF was added 3 drops of 1 M solution of TBAF in THF (ca.
3 mol %).32 The color instantaneously changed to dark-brown. The
reaction mixture was stirred for 4 h at room temperature. When the
TLC analysis indicated complete conversion of the starting benzalde-
hyde, the solution was quenched with 4 N HCl in order to remove the
trimethylsilyl group from the initial adduct 6a. Column chromatography
(hexanes/ethyl acetate, 10:3) yielded 172 mg of the product 1-(trifluo-
roethenyl)-1-phenylmethanol (11a) in 75% yield based on benzalde-
hyde.
A similar procedure was used for the preparation of compounds
11b-c. Their spectral properties are reported in the literature.27
Low-Temperature Reaction of 1,2-Bis(trimethylsilyl)-1,1,2,2-
tetrafluoroethane (3) with Benzaldehyde. To a mixture of 1,2-bis-
(trimethylsilyl)-1,1,2,2-tetrafluoroethane (3) (500 mg, 2 mmol) and
benzaldehyde (646 mg, 6 mmol) in dry DME at -48 °C were added
5 drops of 1 M solution of TBAF in THF (ca. 3 mol %).32 The reaction
mixture was stirred for 4 h at -48 °C and then allowed to warm to
room temperature. Usual workup, followed by column chromatogra-
phy, afforded compounds 11, 12, and 13 in a 1:3:2 molar ratio,
determined by 19F NMR. The overall yield was 75%.
Acknowledgment. Support of our work in part by the Loker
Hydrocarbon Research Institute is gratefully acknowledged. R.B.
acknowledges support from NSF Grant CHE-94-21769. This
paper is dedicated to Professor Horst Prinzbach of the Unversity
of Freiburg on the occassion of his 65th birthday.
JA962990N