C-F Activation of hydrofluorocarbons (HFCs) mediated by aluminum reagents

Article abstract of DOI:10.1016/j.tetlet.2009.04.104

In the presence of various aluminum reagents, the difluoromethylene group (CF₂) in selected hydrofluorocarbons (HFCs) undergoes a Friedel-Crafts type reaction with aromatic compounds in satisfactory yields.

Full text of DOI:10.1016/j.tetlet.2009.04.104

Tetrahedron Letters 50 (2009) 4078–4080
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
C–F Activation of hydrofluorocarbons (HFCs) mediated by aluminum reagents
*
Majeid Ali, Le-Ping Liu, Gerald B. Hammond, Bo Xu
Department of Chemistry, University of Louisville, Louisville, KY 40292, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
In the presence of various aluminum reagents, the difluoromethylene group (CF2) in selected hydroflu-
Received 6 March 2009
Revised 14 April 2009
Accepted 24 April 2009
Available online 3 May 2009
orocarbons (HFCs) undergoes a Friedel–Crafts type reaction with aromatic compounds in satisfactory
yields.
Ó 2009 Elsevier Ltd. All rights reserved.
alkylation
defluori-
nation
The selective substitution of hydrogen by fluorine is a valuable
strategy for the preparation of organic compounds with distinctive
physicochemical and therapeutic properties.1–7 Compared to other
heteroatoms, fluorine is not an easy atom to introduce in an or-
ganic compound. Fluorine incorporation is normally done using
electrophilic or nucleophilic fluorinating agents, or using fluori-
nated building blocks.2–4 The former approach does have draw-
backs, as some reagents are expensive or require stringent
reaction conditions. On the other hand, a significant number of
fluorine-containing building blocks originate from ozone-deplet-
ing substances (ODS), and have been banned by the Montreal Pro-
tocol. In our search to find new non-ODS fluorinated building
blocks, we turned our attention to three- or four-carbon hydroflu-
orocarbons (HFCs) as promising building blocks. Many of these
materials have been used mainly in specific applications (e.g.,
refrigeration), most are cheap industrial feedstock, eco-friendly,
and liquids near 0 °C. HFCs possess multiple fluorine atoms per
molecule, so that even after exchanging one or two fluorines there
remain enough fluorine atoms to produce a valuable building
block.3 But lack of a synthetic handle (functional group) makes
most HFCs difficult to be used in synthesis. Herein we report an
aluminum Lewis acid-promoted C–F bond activation that allows
Friedel–Crafts-type arylations of HFC245fa (CF3–CH2–CHF2), and
that condition can also be used with other non-functionalized flu-
oroaliphatic substrates.
E
F
F
F
F
+
F
X
F
F
easy
F
R
R
R
not easy
F
R = OR', OTs, O-MEM,CONR'2, SR', Cl,
F, NR'2, Ar, COX
ð1Þ
A number of indirect approaches have been sought with the aim
of stabilizing the trifluoroethyl group using electron-withdrawing
groups (R = sulfone, ketone, ester, and phosphine oxide) or ha-
lides,8–12 but these substituents had to be first installed and then
removed. Hartwig and coworkers tackled this challenge by using
trifluoroethyl iodide to form a palladium complex and used it as
a coupling partner with a lithiated tolyl anion in moderate yield.13
But this protocol required stoichiometric amounts of an expensive
transition metal. A method that would deliver directly the trifluo-
roethyl group would extend significantly the range of synthetic
applications.
Chemists have taken a great interest in carbon–fluorine bond
activation to synthesize fluorinated active pharmaceutical ingredi-
ents.14–25 In general, activation of mono-substituted C–F bond is
relative easy, examples include Ni- or Cu-catalyzed cross-coupling
reaction of alkyl fluorides with Grignard reagents,26–28 and a low-
valent niobium-mediated C–F bond activation.29,30 However, un-
like other halogens, each additional fluorine atom strengthens
the C–F bond, so actually the carbon–fluorine bond in CF2 contain-
ing compounds is stronger than the carbon–fluorine bond in
mono-fluorine substituted compounds.4 Thus, the activation of a
C–F bond in non-activated CF2-containing compounds is a greater
challenge. Cleavage of the very strong C–F bonds in HFC245fa
may require coordination with an strong activating reagent such
as aluminum and boron, both of which bind strongly with fluorine
(159 and 181 kcal/mol, respectively)2 and both aluminum and bor-
on reagents have been used successfully to activate mono-substi-
tuted alkyl fluorides.31–35
Our first aim was the conversion of HFC245fa into the syn-
thetic equivalent of the trifluoroethyl group. Despite its potential
application in chemistry and biology, the CF3–CH2– group is a
challenging target. Its synthesis has eluded traditional approaches
because of its inherent tendency to defluorinate upon deprotona-
tion (Eq. 1).
We decided to screen commercially available boron and
aluminum reagents that could activate HFC245fa, and allow its
* Corresponding author. Tel.: +1 502 852 5978; fax: +1 502 852 5998.
E-mail address: bo.xu@louisville.edu (B. Xu).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.104

M. Ali et al. / Tetrahedron Letters 50 (2009) 4078–4080
4079
Table 1
ity of the aluminum reagent by replacing all chlorines with alkyl
groups led to no reaction at all (Table 1, entry 13).
Optimization of reaction conditionsa
From these results we can see that CFH2, CF2H, and CF3 groups
have different reactivities (CFH2 > CF2H > CF3). This fact allowed us
to substitute both fluorines in CF2H without affecting the CF3
group, but we were not able to selectively replace one of the two
C–F bonds. This result can be explained by the fact that additional
fluorine atoms will strengthen the neighboring C–F bonds.
Having found conditions to activate HFC245fa, we decided to
examine the scope of this reaction using other simple aromatic
substrates (Table 2). Using benzene, toluene, or p-xylene, we ob-
tained the corresponding bisarylated trifluoroethyl derivatives in
good yields (Table 2, entries 1–3).36 Other CF2-containing com-
pounds also work under similar conditions (Table 2, entry 4).
We also screened some other CF2-containing compounds (1c–h,
Scheme 1), but selective activation of those CF2 groups proved to
be difficult. Under similar condition to those used in Table 2, there
was no reaction between 1c and benzene. This may be due to the
strong deactivation effect of neighboring fluorine atoms. Reaction
of 1d with benzene gave a complex mixture due to possible poly-
merization of 1d in the presence of the strong Lewis acid. Also,
there were no reactions between 1e–g and benzene; this may be
due to the deactivation of aluminum Lewis acid by oxygen and
nitrogen functionalities present in 1e–g. The reaction of 1h with
benzene gave only a hydrolyzed product after work-up.
reagent
F3C
CF3CH2CHF2
+
Hexanes,
r.t.,10 h
HFC 245fa
2a
Entry
Reagent
Yield (%)/[2a]b
1
2
3
4
5
6
7
8
9
10
11
12
13
BF3ꢀOEt2
No reaction
No reaction
No reaction
No reaction
No reaction
No reaction
Trace
52
83
35
46
BCl3
c
BCl3
Et3B
Cy2BCl
NbCl4
AlCl3
d
AlCl3
EtAlCl2
Me2AlCl
Et2AlCl
Et2AlCld
Me3Al
Trace
No reaction
a
General conditions: HFC 245fa 2.0 mmol, benzene 1.0 mL, Lewis acid 1.0 mmol,
Hexanes 1.0 mL.
b
Isolated yield based on the Lewis acid loading.
c
At 80 °C.
At 0 °C.
d
Mono-substituted alkyl fluorides can also undergo a Friedel–
Crafts-type reaction under similar conditions, but due to the prone
rearrangements of carbocation intermediates, the yields were only
moderate (Eqs. 2–4).
subsequent electrophilic trapping with a nucleophile (benzene, see
Table 1). No reaction took place using boron halides or alkyl boron
at room temperature, or even at 80 °C (Table 1, entries 1–5). Low-
valent niobium catalyst is also ineffective (Table 1, entry 6). To our
delight, using AlCl3 at 0 °C, we observed traces of diarylated prod-
uct 2a (Table 1, entry 7); by increasing the temperature of the reac-
tion we increased the yield to 52% (Table 1, entry 8). However, fine
tuning the Lewis acidity of AlCl3 by replacing one chlorine atom
with an ethyl group improved the yield (83%) substantially (Table
1, entry 9). Replacing two chlorines with alkyl groups lowered the
yield of 2a (Table 1, entries 10–12) and diminishing the Lewis acid-
Benzene
F
ð2Þ
ð3Þ
AlCl3
67%a
26%b
16%b
F
F
Pentamethylbenzene
AlCl3
Mesitylene
AlCl3
Table 2
ð4Þ
Reactions of difluoro compounds (R-F2) with aromatic substrates (Ar-H)
A lreagent
aIsolated yield. b1H NMR yield.
Ar-H
Ar-H
R-F2
R-F2
R-Ar2
R-Ar2 (%)
+
r.t., 10 h
Entry
1
Al reagent
In summary, we have discovered an aluminum Lewis acid-med-
iated reaction of the difluoromethylene group (CF2) in HFC245fa
with simple aromatic nucleophiles, in satisfactory yields. Poten-
tially, the scope of this reaction could be expanded to other HFCs
containing CF2 or CF groups.
Ph
F3C
HFC245fa 1a
Benzenea
Toluenea
p-Xylenea
EtAlCl2
EtAlCl2
EtAlCl2
Ph
2a, 83b
tol
F3C
F3C
2
3
1a
1a
tol
, 71
F
F
F
F
F
F
b
2b
F
F
CF2H
HO
F
p-xyl
p-xyl
F
1e
F
F
1d
1c
b
2c
, 76
F
F
F
F
F
F
F
O
H2N
F
F
F
F
CHF2
F
4
Benzenec
AlCl3
1g
1f
Br
1b
Br
2d, 39d
F
F
EtAlCl2 or AlCl3
Benzene
F
F
N
F
F
N
a
F
F
HFC245fa (2.0 mmol), Hexanes (1.0 mL), ArH (1.0 mL), EtAlCl2 (1.0 mmol).
Isolated yield based on EtAlCl2.
R-F2 (0.5 mmol), ArH (1.0 mL), AlCl3 (0.5 mmol), Hexanes (1.0 mL).
Isolated yield.
F
F
O
b
c
1h
d
Scheme 1. Other CF2 containing substrates screened.

4080
M. Ali et al. / Tetrahedron Letters 50 (2009) 4078–4080
20. Nova, A.; Mas-Balleste, R.; Ujaque, G.; Gonzalez-Duarte, P.; Lledos, A. Chem.
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We are grateful to the National Science Foundation for financial
support (CHE-0809683), and to Professor Kenji Uneyama (Oka-
yama University, Japan) for helpful suggestions and for providing
us with background information.
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36. Typical procedure for preparation of 2a: To a solution of HFC245fa (268 mg,
2.0 mmol) in benzene (1.0 mL) and hexanes (1.0 mL) was added
a 1.0 M
solution of EtAlCl2 in hexanes (1.0 mL, 1 mmol) at room temperature. The
mixture was stirred for 10 h at room temperature; afterwards the solvent was
removed under reduced pressure and the residue was subjected to flash
column chromatography (eluent: ethyl acetate/petroleum ether = 1/100) to
give product 2a (208 mg, 83%) as a colorless oil. IR (neat)
m
3030, 1600, 1495,
1381, 1256, 1132, 700, 610 cmꢁ1
;
1H NMR (CDCl3, 500 MHz) d 2.89–2.97 (2H,
m), 4.35 (1H, t, J = 7.5 Hz), 7.17–7.34 (10H, m); 13C NMR (CDCl3, 126 MHz) d
39.8 (q, JC–F = 27.5 Hz), 45.3, 126.7 (q, JC–F = 277.2 Hz), 127.1, 127.7, 129.0,
143.0; 19F NMR (CDCl3, 470 MHz) d 64.1 (t, JH–F = 19.7 Hz); MS (EI) m/z 250
(M+), 164 (100); Anal. Calcd for C15H13F3: C, 71.99; H, 5.24. Found: C, 71.73; H,
5.32.
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