Efficient trifluoromethylation of activated and non-activated alkenyl halides by using (trifluoromethyl)trimethylsilane

Article abstract of DOI:10.1002/adsc.201100528

An efficient method for the trifluoromethylation of halogenated double bonds by using in situ generated "trifluoromethyl copper" is described. Herein, the most common trifluoromethyl source, (trifluoromethyl) trimethylsilane, was converted selectively int

Full text of DOI:10.1002/adsc.201100528

UPDATES
DOI: 10.1002/adsc.201100528
Efficient Trifluoromethylation of Activated and Non-Activated
Alkenyl Halides by Using (Trifluoromethyl)trimethylsilane
Andreas Hafnera and Stefan Brꢀsea,*
a
Institute for Organic Chemistry, Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax : (+49)-721-6084-8581; phone: (+49)-721-6084-2903; e-mail: braese@kit.edu
Received: July 8, 2011; Revised: August 15, 2011; Published online: October 20, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100528.
Abstract: An efficient method for the trifluorome-
thylation of halogenated double bonds by using in
situ generated “trifluoromethyl copper” is de-
scribed. Herein, the most common trifluoromethyl
source, (trifluoromethyl)trimethylsilane, was con-
verted selectively into “trifluoromethyl copper” by
using copper iodide as copper source and potassium
fluoride as promoter. In 1,3-dimethyl-3,4,5,6-tetra-
hydro-2(1H)-pyrimidinone (DMPU) as chelating
solvent the trifluoromethylation of activated and
non-activated alkenyl halides occurred mostly in
good to excellent yields in up to a gram scale.
exhibit special chemical and physical properties. For
example, their presence can increase the lipophilicity
or metabolic stability and therefore enhance the bio-
logical activity of drugs or crop protection agents.[1]
Over the last decades a lot of effort has been made
to introduce the CF3 group into aromatic compounds.
The most common routes use stoichiometric amounts
of in situ generated “CuCF3” and aryl halides, mostly
iodides.[2] A few catalytic examples[3] as well as a few
Pd-catalyzed cross-coupling reactions are also
known.[4]
Recently, it was reported that fluorine- and
trifluoroACTHNUGRTNEUNGmethyl-substituted double bonds can work as
peptidomimetics due to their similar steric and elec-
tronic properties.[5] Because of the broad range of bio-
logically active compounds containing a peptide bond
as central structural unit, mimics of this bond repre-
sent a potential way to improve biological activity.
The trifluoromethylation of halogenated olefins
Keywords: alkenyl halides; copper; trifluoromethy-
lation; (trifluoromethyl)trimethylsilane
A large number of pharmaceutical and agrochemical would be a straightforward route to synthesize these
agents contain fluorine or fluoroalkyl groups like the structural moieties, because alkenyl halides are easily
CF3 group (Figure 1). Fluorine-substituted moieties accessible from several starting materials.
For example, bromoolefins can be generated by a
simple bromination/elimination procedure[6] of double
bonds or by Wittig reaction of aldehydes with bromo
ylides.[7] Iodides can be synthesized by metalation (for
example, hydrozirconation) and then iodination.[8] a-
Iodo esters are accessible from alkynyl esters with
lithium iodide and acetic acid.[9]
To date, only a few one-pot procedures are known
where halogenated olefins are converted into the tri-
fluoromethylated species.[7,10] Due to the great impor-
tance of (trifluoromethyl)trimethylsilane, known as
“Ruppert–Prakash agent,”[11] copper-mediated cou-
pling reactions with olefins using this agent as CF3
source would be of interest.
In 1991, Urata and Fuchikami showed that trifluor-
omethylation of simple terminal bromo- and iodoole-
fins is possible with a system of KF/CuI in a 1:1 mix-
Figure 1. Drugs and crop protection agents containing a CF3
group.
ture of DMF/NMP and Et3SiCF3 as CF3 source.[12]
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Adv. Synth. Catal. 2011, 353, 3044 – 3048

Efficient Trifluoromethylation of Activated and Non-Activated Alkenyl Halides
Table 1. Optimization of reaction conditions for the tri-
AHCTUNGTRENNUNG
fluoromethylation of alkenyl bromides.[a,b]
The major problem of these reactions was the fact
that apart from the transferred CF3 group, a CF2CF3
group was introduced, too. Responsible for this side
reaction is the a-F-elimination of the in situ generated
CuCF3 in DMF. The generated difluorocarbene can
À
then insert into the Cu CF3 bond of another CuCF3
unit to produce CuCF2CF3, which reacts like the origi-
Entry Solvent
Conversion
[%][c]
2a
3a
4a
nal copper species (Scheme 1).[13]
[%][c] [%][c] [%][c]
1
DMF/NMP 98
82
18
0
(1:1)
2
3
DMF
DMF/DMI
(1:1)
98
77
74
83
24
16
2
1
4
5
6
7
DMI
DMA
traces
>99
>99
>99
–
58
92
>99
–
37
8
–
5
0
0
Scheme 1. Formation of CuCF2CF3 by in situ generated
CuCF3 in DMF.
DMPU
DMPU[d]
0
[a]
Reaction conditions: 1a (0.40 mmol), Me3SiCF3
(0.48 mmol), CuI (0.68 mmol), KF (0.80 mmol), solvent
(1.5 mL), 808C, 16 h.
1a was used as a commercial available mixture of E/Z=
5.8:1.
Yields and composition were determined by GC-MS
analysis, using n-dodecane as internal standard.
Me3SiCF3 was slowly added via syringe pump over two
hours.
In the work of Urata and Fuchikami,[12] 14% by-
product was obtained in the case of b-bromostyrene
with a total yield of 51%. Due to their high physical
similarities, separation of the pure product is a chal-
lenge. Thus, the synthetic application of this reaction
is limited. Surprisingly, no further experiments have
been performed to improve selectivity and yields of
this reaction until today. Therefore, it was important
for us to find new reaction conditions under which
[b]
[c]
[d]
the trifluoromethylation of alkenyl halides, such as to decrease the formation of by-product by simply
bromides and iodides, is possible in good yields with- changing the solvent to DMPU [1,3-dimethyl-3,4,5,6-
out the occurrence of any perfluorated by-products.
tetrahydro-2(1H)-pyrimidinone]. DMPU possesses
In first experiments we tried similar conditions as nearly the same chelating properties as HMPA, but is
described by Urata and Fuchikami, but used the less toxic.[14] The influence on conversion and selectiv-
cheaper Me3SiCF3 instead of Et3SiCF3. The bromoole- ity by changing DMI to DMPU is remarkable. In the
fin, copper iodide, potassium fluoride and Me3SiCF3 case of entry 7 the CuCF3 agent was generated in situ
were heated in DMF/NMP (1:1) at 808C for 16 h. by heating a mixture of bromo olefin 1a, copper
Thus, the observation of over 10% by-product and iodide and potassium fluoride in DMPU to 808C with
the moderate yields could be confirmed. To get com- slow addition of Me3SiCF3 over two hours.
plete conversion, we increased the CuI equivalents,
Attempts to generate the CuCF3 species before
but the selectivity decreased (Table 1, entry 1). When adding the bromoolefin failed due to the rapid forma-
changing the fluoride source to TBAF, CsF or NaF tion of CF3CF2Cu.
lower yields were obtained, too.
With the new conditions in hand it was possible to
Changing the solvent from DMF/NMP to pure generate a number of trifluoromethylolefins starting
DMF led to more by-product. Actually, not only the from alkenyl bromides and iodides. This proceeded
perfluoroethyl-substituted side product was obtained, mostly without the appearance of any perfluoroethy-
but also the perfluoropropyl-substituted by-product lated by-product. Terminal bromides, such as 1a and
could be monitored via GC-MS analysis. Thus, we 1b (Table 2), could be converted selectively in good
started looking for better, more selective reaction to excellent yields to the corresponding trifluorome-
conditions. For stabilizing the “CuCF3” agent, a che- thylated olefins. When more complex substrates were
lating solvent seemed promising. Because NMP is used (1c, 1d and 1e) the yields decreased. In the case
known as a good stabilizer, we tested similar systems. of non-activated bromides 1d and 1e traces of per-
In pure DMI (1,3-dimethyl-2-imidazolidinone) no re- fluoroethylated by-product could be detected by GC-
action occurred, while in a 1:1 mixture of DMF/DMI MS analysis (<3%).
less conversion was observed. Dimethylacetamide
In the case of 1d 1,2-diphenylethyne could be also
(DMA), which was used as solvent in the generation found as by-product (5%), generated by elimination
of CuCF3 from (CF3)2Hg and Cu[10a] also did not sta- of HBr. Nevertheless, the yields of non-activated,
bilize in situ generated CuCF3. Finally, we were able complex olefins were still satisfying.
Adv. Synth. Catal. 2011, 353, 3044 – 3048
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3045

Andreas Hafner and Stefan Brꢀse
UPDATES
Table 2. Scope of the trifluoromethylation reaction with
Table 3. Scope of the trifluoromethylation reaction with
alkenyl bromides.[a]
alkenyl iodides.[a]
Product[b]
Yield [%][c]
Entry
1
Alkenyl bromide
Product[b]
Yield [%][c]
Entry
1
Alkenyl iodide
>99
>99
2
>99
2
3
4
78
66
58
3
4
86
88
5[d]
78[e]
5
23
6
>99[f]
[a]
Reaction
conditions:
1
(0.40 mmol),
Me3SiCF3
(0.80 mmol), CuI (0.68 mmol), KF (0.60 mmol), DMPU
(1.5 mL), 808C, 16 h.
[a]
Reaction
conditions:
5
(0.40 mmol),
Me3SiCF3
[b]
[c]
E/Z ratios were determined by 19F NMR.
Isolated yields.
(0.48 mmol), CuI (0.68 mmol), KF (0.60 mmol), DMPU
(1.5 mL), 808C, 16 h.
[b]
[c]
[d]
[e]
E/Z ratios were determined by 19F NMR.
Isolated yield.
In contrast to bromides, iodides 5 reacted much
0.80 mmol Me3SiCF3 were used.
more smoothly (Table 3). However, when we tried to
transfer our conditions to the trifluoromethylation of
alkenyl iodides, first experiments showed that not
only our desired product but also the corresponding
alkyne (<5%) was formed, due to elimination. There-
fore, we changed our reaction conditions and added
Me3SiCF3 directly before heating. Now, all tested al-
kenyl iodides could be trifluoromethylated in excel-
Conversion was quantitative but ethyl 3-phenyl-2-(tri-
fluoromethyl)but-3-enoate was also obtained in 22%
yield.
Yield was determined by using GC-MS analysis, due to
the high volatility.
[f]
In summary, it was shown that alkenyl iodides and
lent yields without any appearance of perfluoroethy- bromides can be easily trifluoromethylated using a
lated by-products. Even when the quaternary olefin system of Me3SiCF3/CuI/KF in DMPU without ap-
5e was used, no traces of perfluoroethylated by-prod- pearance of perfluoroethylated compounds. In most
uct were detected by GC-MS analysis. However, in cases this proceeded under retention of the configura-
the case of 6e ethyl 3-phenyl-2-(trifluoromethyl)but-3- tion and the desired products could be obtained in
enoate was surprisingly found in 22% yield, which good to excellent yields. Gram-scale reactions are
could not be separated from the product.
possible without reduced yields.
When only the E or Z isomer (dr>20:1) was used,
each olefin could be converted selectively under re-
tention of the configuration into the corresponding
CF3-substituted product. When a mixture of both iso-
mers was used, the turnover of the Z-isomer was
lower, presumably because of higher steric require-
ments. However, in cases of a-bromo-a,b-unsaturated
esters partial E/Z isomerization during trifluorome-
thylation is also known.[7,10a]
Experimental Section
General Remarks
NMR spectra were recorded on a Bruker AM 400, a Bruker
Avance 300 or a Bruker DRX 500 spectrometer as solutions.
Chemical shifts are expressed in parts per million (ppm, d)
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Adv. Synth. Catal. 2011, 353, 3044 – 3048

Efficient Trifluoromethylation of Activated and Non-Activated Alkenyl Halides
downfield from tetramethylsilane (TMS) and are referenced
Acknowledgements
to residual solvent peaks. All coupling constants (J) are ab-
solute values and J values are expressed in Hertz (Hz). The
descriptions of signals include: s=singlet, d=doublet, t=
triplet, q=quartet, m=multiplet. The spectra were analyzed
according to first order. The signal structure in 13C NMR
was analyzed by DEPT and is described as follows: +=pri-
mary or tertiary C-atom (positive signal), À=secondary C-
atom (negative signal) and Cquart =quaternary C-atom (no
signal). MS (EI) (electron impact mass spectrometry) was
performed by using a Finnigan MAT 90 (70 eV). In cases
where no MS (EI) could be measured due to high volatility
of the compound, the GC-MS were used for characteriza-
tion. IR (infrared spectroscopy) was recorded on a FT-IR
Bruker alpha. Solvents, reagents and chemicals were pur-
chased from Aldrich, ABCR and Acros. All solvents, re-
agents and chemicals were used as purchased unless stated
otherwise.
We thank the Landesgraduiertenfçrderung Baden-Wꢀrttem-
berg for financial support.
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General Procedure for the Trifluoromethylation of
Alkenyl Bromides
A vial equipped with a septum and a stirring bar was
charged with 130 mg (0.68 mmol) CuI, 35.0 mg (0.60 mmol)
KF and 1 (0.40 mmol). The reaction vessel was closed and
anhydrous DMPU (1.5 mL) was added via syringe under
argon. Then 0.015 mL (14.2 mg, 0.10 mmol) Me3SiCF3 was
added and the suspension was heated to 808C. Then another
0.10 mL (99.5 mg, 0.70 mmol) Me3SiCF3 were added by
using a syringe pump over a period of 2 h. After complete
addition the suspension was stirred for 14 h. Then, the solu-
tion was cooled to room temperature and diluted with Et2O
(5 mL). The organic layer was washed with 1N HCl (10 mL)
and the aqueous phase was reextracted with Et2O (5 mL).
The combined organic phases were washed with concentrat-
ed ammonia (10 mL), water (10 mL) and again with 1N
HCl (10 mL), dried over Na2SO4 and concentrated in
vacuum. The crude product was purified by bulb-to-bulb dis-
tillation or preparative HPLC.
General Procedure for the Trifluoromethylation of
Alkenyl Iodides
A vial equipped with a septum and a stirring bar was
charged with 130 mg (0.68 mmol) CuI, 35.0 mg (0.60 mmol)
KF and 5 (0.40 mmol). The reaction vessel was closed and
anhydrous DMPU (1.5 mL) was added via syringe. 0.070 mL
(68.3 mg, 0.48 mmol) Me3SiCF3 were added and the suspen-
sion was heated to 808C for 16 h. Then the solution was
cooled to room temperature and diluted with Et2O (5 mL).
The organic layer was washed with 1N HCl (10 mL) and the
aqueous phase was reextracted with Et2O (5 mL). The com-
bined organic layers were washed with concentrated ammo-
nia (10 mL), water (10 mL) and again with 1N HCl
(10 mL), dried over Na2SO4 and concentrated in vacuum.
The crude product was purified by flash column chromatog-
raphy or bulb-to-bulb distillation.
Supporting Information with full characterization and
spectroscopic data is available.
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Adv. Synth. Catal. 2011, 353, 3044 – 3048