The invention discloses a method for preparation of fluoro, chloro and fluorochloro alkylated
compounds by homogeneous Pd catalyzed fluoro, chloro and fluorochloro alkylation with
fluoro, chloro and fluorochloro alkyl halides in the presence of di(l-adamantyl)-nbutylphosphine
and in the presence of 2,2,6,6-tetramethylpiperidine 1-oxyl.
BACKGROUND OF THE INVENTION
Organofluorine chemistry plays an important role in medicinal, agricultural, and material
sciences and fields. Fluoroalkyl groups have strong effects such as high stability and
lipophilicity, in addition, longer fluoroalkyl groups have high water and oil resistance and low
fricition.
Loy, R.N., et al, Organic Letters 201 1, 13, 2548-2551, discloses Pd-catalyzed coupling of
CF3-I with benzene in 26% GC yield.
According to Table 1 entry 10 the coupling of C Fi3l provided 81% yield.
But a repetition of this experiment with the bromide instead of the iodide provided less than 1
% yield, see Comparative Example 11 herein.
There was a need for a homogenous catalyzed method for the preparation of fluoro, chloro
and fluorochloro alkylated compounds by direct C-H trifluoromethylation, which provides
high yields but does not need the assistance of a directing group or of electron rich aromatic
compounds. The method should be applicable to a wide variety of substrates and should be
compatible with a wide variety of functional groups. Furthermore the method should not be
restricted to iodides as alkylating agents only, but should also work with other halides. And
the method should work not only with perfluorinated alkyl iodides, but also with fluorinated,
chlorinated and fluorochlorinated alkyl halides, especially for fluorinated alkyl halides.
Unexpectedly the presence of di(l-adamantyl)-n-butylphosphine and 2,2,6,6-
tetramethylpiperidine 1-oxyl together with a soluble Pd based catalyst meets these
requirements. No dialkylated products are observed.
In this text, the following meanings are used, if not otherwise stated:
Ac acetate;
alkyl linear or branched alkyl;
BuPAd2 CAS 321921-71-5, di(l-adamantyl)-n-butylphosphine;
DMSO dimethylsulfoxide;
eq, equiv equivalent;
halide F-, C1-, Br- or I-, preferably C1-, Br-, and I-, more preferably Br- and I-;
halogen F, CI, Br or I; preferably F, CI or Br; more preferably F or CI;
"linear" and "n-" are used synonymously with respect to the respective isomers of alkanes;
MTBE methyl tert-butyl ether;
RT room temperature, it is used synonymously with the expression ambient
temperature;
TEA triethylamine;
TEMPO CAS 2564-83-2, 2,2,6,6-tetramethylpiperidine 1-oxyl;
TFA trifluoroacetate;
"wt%", "% by weight" and "weight-%" are used synonymously and mean percent by weight.
SUMMARY OF THE INVENTION
Subject of the invention is a method for the preparation of a fluoro, chloro or fluorochloro
alkylated compound by a reaction of a compound COMPSUBST with a compound
FCLALKYLHALIDE by homogeneous catalysis using a catalyst CAT
in the presence of BuPAd2 and
in the presence of TEMPO and
in the presence of a compound BAS,
BAS is selected from the group consisting of CS2CO3, CSHCO 3, NEt3, and mixtures thereof;
FCLALKYLHALIDE is a compound of formula (III);
R3-X (III)
X is CI, Br or I;
R3 is Ci_2o alkyl or a Ci_2o alkyl, wherein in the alkyl chain at least one of the hydrogens is
substituted by F or CI;
CAT is selected from the group consisting of Pd(OAc)2, Pd(TFA)2, and mixtures thereof;
COMPSUBST is selected from the group consisting of a compound COMPSUBST-I, ethene,
cyclohexene, ethine, and polystyrene;
the ethene and the cyclohexene being unsubstituted or substituted by 1, 2 or 3
substitutents selected from the group consisting of C1-10 alkyl, C3-8 cycloalkyl, Ci_4
alkoxy, N(R10)R1 1, CN, NO, N0 2, F, CI, Br, I , CF3, (CH 2)m-C(0)Yl, S(O) 2R50,
CH=C(H)R28, z '-R24 benzyl, phenyl, naphthyl and morpholine;
the ethine being unsubstituted or substituted by 1 substitutent selected from the group
consisting of C Oalkyl, C3_ cycloalkyl, Ci_4 alkoxy, N(R10)R1 1, CN, NO, N0 2, F,
CI, Br, I , CF3, (CH 2)m-C(0)Yl, S(O) 2R50, CH=C(H)R28, Cº C-R24 benzyl,
phenyl and naphthyl;
COMPSUBST-I contains a ring RINGA;
RINGA is a 5 or 6 membered carbocyclic or heterocyclic ring,
when RINGA is a heterocyclic ring, then RINGA has 1, 2 or 3 identical or different
endocyclic heteroatoms independently from each other selected from the group
consisting of N , O and S,
when RINGA ia a 5 membered ring, then RINGA is unsubstituted or substituted by 1, 2,
3 or 4 identical or different subsitutents,
when RINGA is a 6 membered ring then RINGA is unsubstituted or substituted by 1, 2,
3, 4 or 5 identical or different subsitutents,
any of said subsitutents of RINGA is independently from any other of said substitutent of
RINGA selected from the group consisting of Ci_io alkyl, C3_ cycloalkyl, Ci_4
alkoxy, OH, N(R10)R1 1, CN, NH-OH, NO, N0 2, F, CI, Br, I , CF3, (CH 2)m-
C(0)Y1, S(O) 2R50, CH=C(H)R28, Cº C-R24 benzyl, phenyl and naphthyl;
RINGA can be condensed with a ring RINGB, RINGB is a 5 or 6 membered carbocyclic
or heterocyclic ring,
when RINGB is a heterocyclic ring, is contains 1, 2 or 3 identical or different endocyclic
heteroatoms independently from each other selected from the group consisting of
N , O and S;
RINGB is unsubstituted or substituted with 1, 2 or 3 in case of RINGB being a 5
membered ring, with 1, 2, 3 or 4 in case of RINGB being a 6 membered ring,
identical or different substitutents independently from each other selected from the
group consisting of Ci_io alkyl, C3_ cycloalkyl, Ci_4 alkoxy, OH, N(R17)R18, CN,
NH-OH, NO, N0 2, F, CI, Br, I, CF3, (CH 2)„-C(0)Y2, S(0) 2R51, CH=C(H)R38,
= - 4 benzyl, phenyl and naphthyl;
any of said C1-10 alkyl substitutent of RINGA or RINGB is unsubstituted or substituted
with 1, 2, 3, 4 or 5 identical or different substituents selected from the group
consisting of halogen, OH, 0-C(0)-Ci_ alkyl, O-C 1-10 alkyl, S-C 1-10 alkyl,
S(0)-Ci_io alkyl, S(O2)-Ci_i 0 alkyl, 0-Ci_ 6 alkylen-0-Ci_ 6 alkyl, C3_ cycloalkyl and
1,2,4-triazolyl;
any of said benzyl, phenyl and naphthyl substitutent of RINGA or RINGB is
independently from each other unsubstituted or substituted with 1, 2, 3, 4 or 5
identical or different substituents selected from the group consisting of halogen,
Ci_4 alkoxy, N0 2 and CN;
m, n and q are identical or different and independently from each other 0, 1, 2, 3, 4, 5, 6, 7,
8, 9 or 10;
Yl, Y2 and R13 are identical or different and independently from each other selected
from the group consisting of H, OH, C(R14)(R15)R16, Ci_6 alkyl, 0-Ci_ 6 alkyl, phenyl,
benzyl, O-phenyl, 0-Ci_ 6 alkylen-0-Ci_ 6 alkyl and N(R19)R20;
R14, R15 and R16 are identical or different and independently from each other selected
from the group consisting of H, F, CI and Br;
R10, R l 1, R17, R18, R19 and R20 are identical or different and are independently from
each other H or Ci_ alkyl, or R10 and R l 1, R17 and R18 or R19 and R20 represent
together a tetramethylene or a pentamethylene chain;
R50 and R5 1 are identical or different and independently from each other selected from the
group consisting of OH, Ci_ alkyl and Ci_ alkoxy;
R24, R34, R28 and R38 are identical or different and independently from each other
selected from the group consisting of H, C1-10 alkyl, C(R25)(R26)-0-R27;
R25, R26 and R27 are identical or different and independently from each other selected
from the group consisting of H and C1-10 alkyl.
DETAILED DESCRIPTION OF THE INVENTION
Preferably, RINGA is an unsaturated or aromatic ring.
More preferably, RINGA is a carbocyclic unsaturated ring, a carbocyclic aromatic
heterocyclic unsaturated ring or a heterocyclic aromatic ring.
Preferably, COMPSUBST is selected from the group consisting of compound
COMPSUBST-I, ethene, cyclohexene, ethine, and polystyrene;
the ethene and the cyclohexene being unsubstituted or substituted by 1 or 2 substitutents
selected from the group consisting of C1-10 alkyl, C3-6 cycloalkyl, Ci_4 alkoxy,
N(R1 0)R1 1, CN, F, CI, Br, I, CF3, (CH2)m-C(0)Yl, S(O)2R50, benzyl, phenyl,
naphthyl and morpholine;
the ethine being unsubstituted or substituted by 1 substitutent selected from the group
consisting of C Oalkyl, C3_6 cycloalkyl, Ci_4 alkoxy, N(R1 0)R1 1, CN, F, CI, Br, I,
CF3, (CH2)m-C(0)Yl, S(O)2R50, benzyl, phenyl and naphthyl;
with COMPSUBST-I bein selected from the group consisting
with COMPSUBST-I being unsubstituted or substituted
by 1, 2, 3 or 4 in case of COMPSUBST-I being a monocyclic compound with 5
endocyclic atoms,
by 1, 2, 3, 4 or 5 in case of COMPSUBST-I being a monocyclic compound with 6
endocyclic atoms,
by 1, 2, 3, 4, 5 or 6 in case of COMPSUBST-I being a bicyclic compound wherein a 5-
membered and a 6-membered ring are ortho-fused,
by 1, 2, 3, 4, 5, 6 or 7 in case of COMPSUBST-I being a bicyclic compound wherein two
6-membered rings are ortho-fused,
identical or different substituents independently from each other selected from the group
consisting of C Oalkyl, C3_ cycloalkyl, Ci_4 alkoxy, OH, C(H)=0, N(R10)R1 1,
CN, NH-OH, NO, N0 2, F, CI, Br, I, CF3, (CH2)m-C(0)Yl, S(O)2R50,
CH=C(H)R28, C =C-R24 , benzyl, phenyl and naphthyl;
said Ci_io alkyl substitutent of COMPSUBST-I is unsubstituted or substituted with 1, 2, 3, 4
or 5 identical or different substituents selected from the group consisting of halogen, OH,
0-C(0)-Ci_5 alkyl, O-CMO alkyl, S-CMO alkyl, S(O)-Ci_i0 alkyl, S(O2)-Ci_i 0 alkyl, 0-Ci_ 6
alkylen-0-Ci_6 alkyl, C3_8 cycloalkyl and 1,2,4-triazolyl;
said benzyl, phenyl and naphthyl substitutent of COMPSUBST-I is independently from each
other unsubstituted or substituted with 1, 2, 3, 4 or 5 identical or different substituents
selected from the group consisting of halogen, Ci_4 alkoxy, N0 2 and CN;
RIO, R l 1, m, n, Yl, Y2, R28, R50 and R24 are defined as above, also with all their
embodiments.
Preferably, m, n and q are identical or different and independently from each other 0, 1, 2, 3
or 4;
more preferably, m, n and q are 0 or 4.
In another embodiment, Yl, Y2 and R13 are identical or different and independently from
each other selected from the group consisting of H, OH, C(R14)(R15)R16, C2_ alkyl,
0-Ci_6 alkyl, phenyl, benzyl, O-phenyl, 0-Ci_ 6 alkylen-0-Ci_ 6 alkyl and N(R19)R20.
Preferably, Yl, Y2 and R13 are identical or different and independently from each other
selected from the group consisting of H, OH, Ci_2 alkyl, and 0-Ci_ 2 alkyl.
More preferably, COMPSUBST-I is unsubstituted or substituted
by 1, 2 or 3 in case of COMPSUBST-I being a monocyclic compound with 5
endocyclic atoms,
by 1, 2, 3, 4 or 5 in case of COMPSUBST-I being a monocyclic compound with 6
endocyclic atoms,
by 1, 2, 3, 4 or 5 in case of COMPSUBST-I being a bicyclic compound wherein a 5-
membered and a 6-membered ring are ortho-fused,
by 1, 2, 3 or 4 in case of COMPSUBST-I being a bicyclic compound wherein two 6-
membered rings are ortho-fused,
identical or different substituents independently from each other selected from the group
consisting of Ci_4 alkyl, Ci_4 alkoxy, OH, C(H)=0, N(R10)R1 1, CN, F, CI, Br,
CF3, (CH2)m-C(0)Yl, and S(O)2R50;
said Ci_4 alkyl substitutent of COMPSUBST-I is unsubstituted or substituted with 1, 2 or 3
identical or different substituents selected from the group consisting of halogen;
with RIO, Rl 1, Yl and R50 as defined above, also with all their embodiments.

formula (VI), ethene, cyclohexene, ethine, and polystyrene;
Y is Ci_ alkyl;
the ethene and the cyclohexene being unsubstituted or substituted by 1 or 2 substitutents
selected from the group consisting of C1-10 alkyl, Ci_4 alkoxy, N(R10)R1 1, CN, F, CI,
Br, I, CF3, (CH2)m-C(0)Yl, benzyl, phenyl and morpholine;
the ethine being unsubstituted or substituted by 1 substitutent selected from the group
consisting of C O alkyl, Ci_4 alkoxy, N(R10)R1 1, CN, F, CI, Br, I, CF3, (CH2)m-
C(0)Y1, benzyl and phenyl;
wherein
R44 is selected from the group consisting of C1-10 alkyl, Ci_4 alkoxy, OH, N(R10)R1 1, CN,
NO, N0 2, F, CI, Br, I, CF3, (CH2)m-C(0)Yl, S(O)2R50;
with RIO, Rl 1, m, Yl and R50 as defined above, also with all their embodiments.
Embodiments of the substituted ethene are propene, ethene- 1,1-diyldibenzene and
3,3-dimethylbut-1-ene.
An embodiment of substituted cyclohexene is 4-(cyclohex-l-en-l-yl)morpholine.
An embodiment of the substituted ethine is 1-octyne.
Preferably, Y is methyl or ethyl.
An embodiment of COMPSUBST is ;
Y is methyl or ethyl, preferably ethyl.
The fluoro, chloro or fluorochloro alkylated compound is called compound
ALKYLCOMPSUBST.
The fluoro, chloro and fluorochloro alkyl halide is compound FCLALKYLHALIDE.
Preferably, FCLALKYLHALIDE is a compound of formula (III);
R3-X (III)
X is CI, Br or I;
R3 is Ci_2o alkyl or a Ci_2o alkyl, wherein in the alkyl chain at least one of the hydrogens
is substituted by F or CI;
more preferably,
R3 is Ci_i alkyl or C1-15 alkyl, wherein in the alkyl chain at least one of the hydrogens is
substituted by F or CI;
even more preferably,
R3 is Ci-io alkyl or C1-10 alkyl, wherein in the alkyl chain at least one of the hydrogens is
substituted by F or CI.
Preferably,
X is Br or I;
more preferably,
X is I;
in another more preferably embodiment,
X is Br;
also with R3 in all its embodiments.
In an especial ambodiment, compound FCLALKYLHADLIDE is a perfluoroalkyl halide,
F2HC-C1 or F2HC-Br, preferably FCLALKYLHADLIDE is a perfluoroalkylated bromide
or iodide, F2HC-C1 or F2HC-Br;
preferably
X is CI, Br or I, and
R3 is perfluoro Ci_2o alkyl; or
FCLALKYLHADLIDE is F2HC-C1 or F2HC-Br;
more preferably,
X is Br or I, and
R3 is perfluoro Ci_20 alkyl; or
FCLALKYLHADLIDE is F2HC-C1 or F2HC-Br;
even more preferably,
X is Br or I, and
R3 is perfluoro Ci_i alkyl; or
FCLALKYLHADLIDE is F2HC-C1 or F2HC-Br.
In particular, FCLALKYLHALIDE is selected from the group consisting of F2iCio-I, F C -I,
F C -I, F9C4-I, F3C-I, F3C-Br, F3C-C1, F2HC-C1, and F2HC-Br;
more in particular, FCLALKYLHALIDE is selected from the group consisting of n-F 2iCio-I,
n-FiyCs-I, n-Fi 3C6-I, n-F C4-I, F3C-I, F3C-Br, F3C-C1, F2HC-C1, and F2HC-Br.
In one embodiment, the reaction is done in the presence of a compound COMPSALT;
COMPSALT is selected from the group consisting of Nal, KI, Csl and
N(R30)(R31)(R32)R33I;
R30, R31, R32 and R33 are identical or different and independently from each other selected
from the group consisting of H and C1-10 alkyl;
preferably, R30, R31, R32 and R33 are identical or different and independently from each
other selected from the group consisting of H and C2_ alkyl;
more preferably, COMPSALT is selected from the group consisting of Nal and (n-Bu)4NI.
The reaction is preferably done in the presence of a compound COMPSALT and X is CI or
Br, preferably X is CI.
Preferably, CAT is Pd(OAc) 2.
Preferably, from 0.1 to 20 mol%, more preferably from 1 to 15 mol %, even more preferably
from 2.5 to 12.5 mol %, of CAT are used in the reaction, the mol % are based on the molar
amount of COMPSUBST.
Preferably, from 1 to 20 mol equivalents, more preferably 1 to 15 mol equivalents, even more
preferably from 1 to 10 mol equivalents, of FCLALKYLHALIDE are used in the reaction, the
mol equivalents are based on the molar amount of COMPSUBST.
In case of FCLALKYLHALIDE being in gaseous form, preferably FCLALKYLHALIDE
was used in the reaction in an amount which corresponds to a pressure of from 1 to 10 bar,
more preferably from 1 to 5 bar, at ambient temperature.
Preferably, from 1 to 40 mol%, more preferably 5 to 30 mol%, even more preferably from 5
to 25%, of BuPAd2 are used in the reaction, the mol% are based on the molar amount of
COMPSUBST.
Preferably, from 0.1 to 10 mol equivalents, more preferably 0.5 to 5 mol equivalents, even
more preferably from 0.75 to 2.5 mol equivalents, of TEMPO are used in the reaction, the mol
equivalents are based on the molar amount of COMPSUBST.
Preferably, BAS is Cs2C0 3.
Preferably, from 0.1 to 10 mol equivalents, more preferably 0.5 to 5 mol equivalents, even
more preferably from 0.75 to 2.5 mol equivalents, of BAS are used in the reaction, the mol
equivalents are based on the molar amount of COMPSUBST.
The reaction temperature of the reaction is preferably from 20 to 200°C, more preferably from
50 to 200°C, even more preferably from 50 to 150°C, especially from 100 to 150°C, more
especially from 110 to 145°C.
The reaction time of the reaction is preferably from 1 h to 60 h, more preferably from 10 h to
50 h, even more preferably from 15 h to 50 h.
Preferably, the reaction is done under inert atmosphere. Preferably, the inert atmosphere is
achieved by the use if an inert gas preferably selected from the group consisting of argon,
another noble gas, lower boiling alkane, nitrogen and mixtures thereof.
The lower boiling alkane is preferably a Ci_3 alkane, i.e. methane, ethane or propane.
The reaction can be done in a closed system, it can be done at a pressure caused by the chosen
temperature in a closed system, and/or caused by the pressure applied by COMPSUBST, in
case that COMPSUBST is in gaseous form. It is also possible to apply pressure with said inert
gas. It is also possible to carry out the reaction at ambient pressure.
The reaction can be done in a solvent SOL, SOL is preferably selected from the group
consisting of alkanes, chlorinated alkanes, ketones, ethers, esters, aliphatic nitrils, aliphatic
amides, sulfoxides, and mixtures thereof;
preferably SOL is selected from the group consisting of C - alkane, chlorinated C5-8 alkane,
acetone, methylethylketone, diethylketone, MTBE, tetrahydrofuran,
methyltetrahydrofuran, ethylacetate, butylacetate, valeronitril, acetonitrile,
dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, and
mixtures thereof;
more preferably SOL is selected from the group consisting of acetone, methylethylketone,
diethylketone, valeronitril, acetonitrile, dimethylsulfoxide, and mixtures thereof;
even more preferably SOL is selected from the group consisting of acetone,
methylethylketone, diethylketone, dimethylsulfoxide, and mixtures thereof.
It is also possible to use COMPSUBST simultaneously as substrate and as solvent.
As an alternative, the reaction can also be carried out in the absence of a solvent. In another
embodiment, COMPSUBST is used as SOL.
The amount of SOL is preferably from 0.1 to 100 fold, more preferably from 1 to 50 fold,
even more preferably from 1 to 25 fold, of the weight of COMPSUBST.
After the reaction, ALKYLCOMPSUBST can be isolated by standard methods such as
evaporation of volatile components, extraction, washing, drying, concentration,
crystallization, chromatography and any combination thereof, which are known per se to the
person skilled in the art.
COMPSUBST, BAS, CAT, BuPAd2, TEMPO and FCLALKYLHALIDE, the fluoro, chloro
and fluorochloro alkyl halide, are commercially available and can be prepared according
to known precedures.
EXAMPLES
Yield:
The yield is given in % as a molar yield of the expected ALKYLCOMPSUBST in the
reaction mixture after the reaction, and is based on molar amount of COMPSUBST and was
determined by 1 F NMR with 1, 4 difluorobenzene as internal standard, if not otherwise
stated.
Isolated yield was derived from the weight of the isolated product and is based on the weight
of COMPSUBST, isolated yield is given in parenthesis in Table 1.
Ratio of Isomers and position of alkylation
were determined by NMR spectroscopy
Example 1
An oven-dried 4 mL vial with stir bar was charged with Pd(OAc)2 (10 mol%), BuPAd2 (20
mol%), TEMPO (1.0 eq), Cs2C0 3 (2.0 eq), 1, 4 dimethoxybenzene (0.2 mmol, 1 eq). Then,
acetone (0.5 mL) were injected into the vial under argon flow. The vial was placed in an alloy
plate, which was transferred into a 300 mL autoclave of the 4560 series from Parr Instruments
under an argon atmosphere. A pressure of 3 to 5 bar CF3Br followed by 15 bar of N2 was
adjusted at ambient temperature. The reaction mixture was stirred at 130°C for 40 h. After the
reaction was finished, the autoclave was cooled down to room temperature and the pressure
was released.
The reaction mixture was extracted with water and ethyl acetate (5 times, each time with 3
mL). The organic layers were washed with brine, dried over Na2S0 4, and evaporated to yield
the crude product. The yield was 8 1 %.
The purification was done by flash chromatography on silica gel (eluent: heptanes :EtOAc =
60:40 (v/v)). Isolated yield was 69%.
Details are also given in Table 1
Example 2
Example 1 repeated with the sole difference that Pd(TFA)2 was used as CAT instead of
Pd(OAc)2. The yield was 78%.
Example 3
Example 1 repeated with the diffenerence that only 5 mol% of of Pd(OAc)2 were used instead
of 10 mol%, and that only 10 mol% BuPAd2 were used instead of 20 mol%. The yield was
42%.
Example 4
Example 1 repeated with the sole diffenerence that the reaction mixture was stirred at 130°C
for 30 h instead of 40 h. The yield was 70%.
Examples 5 to 21
Example 1 was repeated with the difference that as COMPSUBST the compound listed in
Table 1 was used.

Example 22
An oven-dried 4 mL vial with stir bar was charged with Pd(OAc)2 (10 mol%), BuPAd2 (20
mol%), TEMPO (1.0 eq), Cs2C0 3 (2.0 eq), benzene (0.6 mmol, 1 eq) and perfluorohexyl
bromide (3.2 eq). Then, acetone (2.5 mL) were injected into the vial under argon flow. The
vial was placed in an alloy plate, which was transferred into a 300 mL autoclave of the 4560
series from Parr Instruments under an argon atmosphere. A pressure of 15 bar of N2 was
adjusted at ambient temperature. The reaction mixture was stirred at 130°C for 40 h. After the
reaction was finished, the autoclave was cooled down to room temperature and the pressure
was released.
The reaction mixture was extracted with water and ethyl acetate (5 times, each time with 3
mL). The organic layers were washed with brine, dried over Na2S0 4, and evaporated to yield
the crude product. The reaction mixture was analyzed by 1 F-NMR by which an yield of 2 1 %
(perfluorohexyl)benzene was found. The identity of the (perfluorohexyl)benzene was
confirmed by GC-MS.
A repetition of the experiment provided 28 % yield with a conversion of 35%.
Example 23
An oven-dried 4 mL vial with stir bar was charged with Pd(OAc)2 (10 mol%), BuPAd2 (20
mol%), TEMPO (1.0 eq), Cs2C0 3 (2.0 eq), 1,4-dimethoxybenzene (0.2 mmol, 1 eq) and
perfluorohexyl bromide (3.2 eq). Then, acetone ( 1 mL) were injected into the vial under argon
flow. The vial was placed in an alloy plate, which was transferred into a 300 mL autoclave of
the 4560 series from Parr Instruments under an argon atmosphere. A pressure of 15 bar of N2
was adjusted at ambient temperature. The reaction mixture was stirred at 130°C for 40 h.
After the reaction was finished, the autoclave was cooled down to room temperature and the
pressure was released.
The reaction mixture was extracted with water and ethyl acetate (5 times, each time with 3
mL). The organic layers were washed with brine, dried over Na2S0 4, and evaporated to yield
the crude product. The reaction mixture was analyzed by GC-MS by which an yield of 42 %
1,4-dimethoxy-2-(perfluorohexyl)benzene was found.
Example 24
An oven-dried 4 mL vial with stir bar was charged with Pd(OAc)2 (10 mol%), BuPAd2 (20
mol%), TEMPO (1.0 eq), Cs2C0 3 (2.0 eq), ethene-l,l-diyldibenzene (0.5 mmol, 1 eq). Then,
acetone (2 mL) were injected into the vial under argon flow. The vial was placed in an alloy
plate, which was transferred into a 300 mL autoclave of the 4560 series from Parr Instruments
under an argon atmosphere. A pressure of 3 to 5 bar CF3Br followed by 15 bar of N2 was
adjusted at ambient temperature. The reaction mixture was stirred at 130°C for 40 h. After the
reaction was finished, the autoclave was cooled down to room temperature and the pressure
was released.
The reaction mixture was filtered and the filter residue was washed with ethylacetate and
acetone. The combined filtrates were concentrated on a rotary evaporator. The residue was
purified by colomn chromatography on silica gel (eluent: heptanes:EtOAc = 90:10 (v/v)).
Isolated yield was 58%.
' NMR Analysis of the obtained product showed a 2:1 mixture of (3,3,3-trifluoroprop-lene-
l,l-diyl)dibenzene and (3,3,3-trifluoropropane-l,l-diyl)dibenzene. The identities of
(3,3 ,3-trifluoroprop- 1-ene- 1,1-diyl)dibenzene and (3,3 ,3-trifluoropropane- 1,1-diyl)dibenzene
were confirmed by GC-MS.
Examples (Ex) 25 and 26 and Comparative Examples (CompEx) 1 to 10
Standard Procedure:
An oven-dried 4 mL vial with stir bar was charged with Pd(OAc)2 (10 mol%), BuPAd2 (20
mol%), ADDITIVE (1.0 eq), BASE (2.0 eq) and 1, 4 dimethoxybenzene (0.2 mmol, 1 eq).
Then, SOLVENT (0.5 mL) was injected into the vial under argon flow. The vial was placed
in an alloy plate, which was transferred into a 300 mL autoclave of the 4560 series from Parr
Instruments under an argon atmosphere. A pressure of 3 to 5 bar CF3Br followed by 15 bar of
N2 was adjusted at ambient temperature. The reaction mixture was stirred at 130°C for 40 h.
After the reaction was finished, the autoclave was cooled down to room temperature and the
pressure was released.
The reaction mixture was extracted with water and ethyl acetate (5 times, each time with 3
mL). The organic layers were washed with brine, dried over Na2S0 4, and evaporated to yield
the crude product. The yield of the product was determined by 1 F-NMR spectroscopy.
In CompEx 4 Pd(TFA) 2 was used as CAT instead of Pd(OAc) 2.
Table 2 shows the parameters that were tested.
Example 27
An oven-dried 4 mL vial with stir bar was charged with Pd(OAc) 2 (10 mol%>), BuPAd 2 (20
mol%>), TEMPO ( 1 eq), Cs2C0 3 (2.0 eq) and ethyl acrylate (0.5 mmol, 1 eq). Then, acetone
(0.5 mL) were injected into the vial under argon flow sequentially. The vial was placed in an
alloy plate, which was transferred into a 300 mL autoclave of the 4560 series from Parr
Instruments under an argon atmosphere. A pressure of 3 to 5 bar CF3Br followed by 15 bar of
N2 was adjusted at ambient temperature. The reaction mixture was stirred at 130 °C for 40 h.
After the reaction was finished, the autoclave was cooled down to room temperature and the
pressure was released.
The resulting reaction mixture was cooled, the pressure released from the autoclave, and the
solids filtered. The filtered reaction mixture was analyzed by 1 F-NMR using the internal
standard 1,4-difluorobenzene showing an yield of 26 % of ethyl-4,4,4-trifluorobut-2-enoat
(delta 1 F-NMR: -65.68 ppm (d, J= 9.5 Hz)). GC-MS Analysis showed a molecular weight
peak at 168 g/mol confirming monotrifluormethylation.
Comparative Example 11
5 mol% Pd2dba
20 mol% BINAP
2 equiv base
80 °C, 15 h
The entry 10 in Table 1 of Loy, R.N., et al, Organic Letters 201 1, 13, 2548-2551, was
repeated according to the detailed procedure given in the Supporting Information for said
article, which is described under "Optimization procedure" on page S3 in connection with
entry 9 in Table S4 on page S5.
The phosphine was BINAP.
[Pd] was Pd2dba3.
The base was Cs2C0 3.
The alkylhalogenid was perfluorohexyl bromide instead of perfluorohexyl iodide.
To a screw cap 1 dram vial was added base (0.4 mmol, 2 equiv), [Pd] (0.02 mmol, 10 mol %)
and phosphine (0.04-0.08 mmol, 20-40 mol %). Benzene ( 1 mL) and perfluorohexyl bromide
(43 microL, 0.2 mmol, 1 equiv) were added, and the resulting mixture was sealed with a
Teflon-lined cap and heated in an aluminum reaction block with vigorous stirring for 15 h at
80°C. The reaction mixture was cooled to 23°C and chlorobenzene (20 microL) was added as
a GC internal standard. An aliquot (-100 microL) was removed from the crude reaction
mixture and passed through a plug of Celite, eluting with EtOAc (2 mL). This sample was
then analyzed by GC, and the yield was determined by comparison to a calibration against the
chlorobenzene internal standard.
Result:
A yield of less than 1% was measured.
Example 28
130°C, 40 h
N2 ( 5 bar) Conversion 42%
Yield 29.85%
F NMR delta -69ppm
A dried 50 mL autoclave was charged with 4-(cyclohex-l-en-l-yl)morpholine (0.2 mmol),
Pd(OAc)2 (10 mol%), BuPAd2 (20 mol%), TEMPO (1.0), Cs2C0 3 (2.0 equivalents). Then,
acetone (2 mL) was injected into the autoclave and the autoclave was flushed with argon for 3
times. A pressure of 6 bar CF3Br followed by 15 bar of N2 was adjusted at ambient
temperature. The reaction mixture was heated at 130°C for 40 h. The autoclave was placed in
a heating system and heated at 130 °C for 40 h. After the completion of the reaction, the
autoclave was cooled down to room temperature and the pressure was released. 20 micdoL of
1,2 difluorobenzene (internal standard) was added to the reaction mixture and a sample was
submitted for 1 F NMR. The yield was measured by 1 F NMR. The NMR data is in
accordance with the literature N.V. Kirij et al., Journal of Fluorine Chemistry, 2000, 106, 217
to 221.

CLAIMS
1. Method for the preparation of a fluoro, chloro or fluorochloro alkylated compound by a
reaction of a compound COMPSUBST with a compound FCLALKYLHALIDE by
homogeneous catalysis using a catalyst CAT
in the presence of BuPAd2 and
in the presence of TEMPO and
in the presence of a compound BAS,
BAS is selected from the group consisting of CS2CO3, CSHCO3, NEt3, and mixtures thereof;
FCLALKYLHALIDE is a compound of formula (III);
R3-X (III)
X is CI, Br or I;
R3 is Ci_2o alkyl or a Ci_2o alkyl, wherein in the alkyl chain at least one of the hydrogens is
substituted by F or CI;
CAT is selected from the group consisting of Pd(OAc)2, Pd(TFA)2, and mixtures thereof;
COMPSUBST is selected from the group consisting of a compound COMPSUBST-I, ethene,
cyclohexene, ethine, and polystyrene;
the ethene and the cyclohexene being unsubstituted or substituted by 1, 2 or 3
substitutents selected from the group consisting of C1-10 alkyl, C3-8 cycloalkyl, Ci_4
alkoxy, N(R10)R1 1, CN, NO, N0 2, F, CI, Br, I, CF3, (CH2)m-C(0)Yl, S(O)2R50,
CH=C(H)R28, C^^C-R24 benzyl, phenyl, naphthyl and morpholine;
the ethine being unsubstituted or substituted by 1 substitutent selected from the group
consisting of C Oalkyl, C3_ cycloalkyl, Ci_4 alkoxy, N(R10)R1 1, CN, NO, N0 2, F,
CI, Br, I, CF3, (CH2)m-C(0)Yl, S(O)2R50, CH=C(H)R28, C=C-R24 benzyl,
phenyl and naphthyl;
COMPSUBST-I contains a ring RINGA;
RINGA is a 5 or 6 membered carbocyclic or heterocyclic ring,
when RINGA is a heterocyclic ring, then RINGA has 1, 2 or 3 identical or different
endocyclic heteroatoms independently from each other selected from the group
consisting of N, O and S,
when RINGA ia a 5 membered ring, then RINGA is unsubstituted or substituted by 1, 2,
3 or 4 identical or different subsitutents,
when RINGA is a 6 membered ring then RINGA is unsubstituted or substituted by 1, 2,
3, 4 or 5 identical or different subsitutents,
any of said subsitutents of RINGA is independently from any other of said substitutent of
RINGA selected from the group consisting of C1-10 alkyl, C3-8 cycloalkyl, Ci_4
alkoxy, OH, N(R10)R1 1, CN, NH-OH, NO, N0 2, F, CI, Br, I, CF3, (CH2)m-
C(0)Y1, S(O)2R50, CH=C(H)R28, Cº C-R24 benzyl, phenyl and naphthyl;
RINGA can be condensed with a ring RINGB, RINGB is a 5 or 6 membered carbocyclic
or heterocyclic ring,
when RINGB is a heterocyclic ring, is contains 1, 2 or 3 identical or different endocyclic
heteroatoms independently from each other selected from the group consisting of
N, O and S;
RINGB is unsubstituted or substituted with 1, 2 or 3 in case of RINGB being a 5
membered ring, with 1, 2, 3 or 4 in case of RINGB being a 6 membered ring,
identical or different substitutents independently from each other selected from the
group consisting of Ci_io alkyl, C3-8 cycloalkyl, Ci_4 alkoxy, OH, N(R17)R18, CN,
NH-OH, NO, N0 2, F, CI, Br, I, CF3, (CH2) -C(0)Y2, S(0) 2R51, CH=C(H)R38,
- 4 benzyl, phenyl and naphthyl;
any of said C1-10 alkyl substitutent of RINGA or RINGB is unsubstituted or substituted
with 1, 2, 3, 4 or 5 identical or different substituents selected from the group
consisting of halogen, OH, 0-C(0)-Ci_ alkyl, O-C 1-10 alkyl, S-C 1-10 alkyl,
S(0)-Ci_io alkyl, S(O2)-Ci_i 0 alkyl, 0-Ci_ 6 alkylen-0-Ci_ 6 alkyl, C3_ cycloalkyl and
1,2,4-triazolyl;
any of said benzyl, phenyl and naphthyl substitutent of RINGA or RINGB is
independently from each other unsubstituted or substituted with 1, 2, 3, 4 or 5
identical or different substituents selected from the group consisting of halogen,
Ci_4 alkoxy, N0 2 and CN;
, n and q are identical or different and independently from each other 0, 1, 2, 3, 4, 5, 6, 7,
8, 9 or 10;
Yl, Y2 and R13 are identical or different and independently from each other selected
from the group consisting of H, OH, C(R14)(R15)R16, Ci_6 alkyl, 0-Ci_ 6 alkyl, phenyl,
benzyl, O-phenyl, 0-Ci_ 6 alkylen-0-Ci_ 6 alkyl and N(R19)R20;
R14, R15 and R16 are identical or different and independently from each other selected
from the group consisting of H, F, CI and Br;
RIO, R l 1, R17, R18, R19 and R20 are identical or different and are independently from
each other H or Ci_6 alkyl, or RIO and Rl 1, R17 and R18 or R19 and R20 represent
together a tetramethylene or a pentamethylene chain;
R50 and R5 1 are identical or different and independently from each other selected from the
group consisting of OH, Ci_ alkyl and Ci_ alkoxy;
R24, R34, R28 and R38 are identical or different and independently from each other
selected from the group consisting of H, Ci_io alkyl, C(R25)(R26)-0-R27;
R25, R26 and R27 are identical or different and independently from each other selected
from the group consisting of H and Ci_io alkyl.
2. Method according to claim 1, wherein
COMPSUBST is selected from the group consisting of compound COMPSUBST-I, ethene,
cyclohexene, ethine, and polystyrene;
the ethene and the cyclohexene being unsubstituted or substituted by 1 or 2 substitutents
selected from the group consisting of Ci_io alkyl, C3-6 cycloalkyl, Ci_4 alkoxy,
N(R10)R1 1, CN, F, CI, Br, I, CF3, (CH2)m-C(0)Yl, S(O) 2R50, benzyl, phenyl,
naphthyl and morpholine;
the ethine being unsubstituted or substituted by 1 substitutent selected from the group
consisting of C Oalkyl, C3_6 cycloalkyl, Ci_4 alkoxy, N(R10)R1 1, CN, F, CI, Br, I,
CF3, (CH2)m-C(0)Yl, S(O)2R50, benzyl, phenyl and naphthyl;
with COMPSUBST-I bein selected from the group consisting
with COMPSUBST-I being unsubstituted or substituted
by 1, 2, 3 or 4 in case of COMPSUBST-I being a monocyclic compound with 5
endocyclic atoms,
by 1, 2, 3, 4 or 5 in case of COMPSUBST-I being a monocyclic compound with 6
endocyclic atoms,
by 1, 2, 3, 4, 5 or 6 in case of COMPSUBST-I being a bicyclic compound wherein a 5-
membered and a 6-membered ring are ortho-fused,
by 1, 2, 3, 4, 5, 6 or 7 in case of COMPSUBST-I being a bicyclic compound wherein two
6-membered rings are ortho-fused,
identical or different substituents independently from each other selected from the group
consisting of C O alkyl, C3_ cycloalkyl, Ci_4 alkoxy, OH, C(H)=0, N(R10)R1 1,
CN, NH-OH, NO, N0 2, F, CI, Br, I, CF3, (CH2)m-C(0)Yl, S(O)2R50,
CH=C(H)R28, C= C-R24 benzyl, phenyl and naphthyl;
said Ci_io alkyl substitutent of COMPSUBST-I is unsubstituted or substituted with 1, 2, 3, 4
or 5 identical or different substituents selected from the group consisting of halogen, OH,
0-C(0)-Ci_ 5 alkyl, O-C O alkyl, S-C O alkyl, S(O)-Ci_i0 alkyl, S(O2)-Ci_i 0 alkyl, 0-Ci_ 6
alkylen-0-Ci_ 6 alkyl, C3_8 cycloalkyl and 1,2,4-triazolyl;
said benzyl, phenyl and naphthyl substitutent of COMPSUBST-I is independently from each
other unsubstituted or substituted with 1, 2, 3, 4 or 5 identical or different substituents
selected from the group consisting of halogen, C1-4 alkoxy, N0 2 and CN.
3. Method according to claim 1 or 2, wherein
, n and q are identical or different and independently from each other 0, 1, 2, 3 or 4.
Method according to one or more of claims 1to 3, wherein
COMPSUBST is selected from the group consisting of benzene, pyrazole,

, compound of formula (VI), ethene,
cyclohexene, ethine, and polystyrene;
Y is Ci_ alkyl;
the ethene and the cyclohexene being unsubstituted or substituted by 1 or 2 substitutents
selected from the group consisting of C1-10 alkyl, Ci_4 alkoxy, N(R10)R1 1, CN, F, CI,
Br, I, CF3, (CH2)m-C(0)Yl, benzyl, phenyl and morpholine;
the ethine being unsubstituted or substituted by 1 substitutent selected from the group
consisting of C O alkyl, Ci_4 alkoxy, N(R10)R1 1, CN, F, CI, Br, I, CF3, (CH2)m-
C(0)Y1, benzyl and phenyl;
wherein
R44 is selected from the group consisting of Ci_io alkyl, Ci_4 alkoxy, OH, N(R10)R1 1, CN,
NO, N0 2, F, CI, Br, I, CF3, (CH2)m-C(0)Yl, S(O)2R50.
5. Method according to one or more of claims 1 to 4, wherein
X is Br or I .
6. Method according to one or more of claims 1 to 5, wherein
X is Br.
7. Method according to one or more of claims 1 to 4, wherein
compound FCLALKYLHADLIDE is a perfluoroalkyl halide, F2HC-C1 or F2HC-Br.
8. Method according to one or more of claims 1 to 4, wherein
X is CI, Br or I, and
R3 is perfluoro Ci_2o alkyl, or
FCLALKYLHADLIDE is F2HC-C1 or F2HC-Br.
9. Method according to one or more of claims 1 to 4, wherein
FCLALKYLHALIDE is selected from the group consisting of F2 1C10-I, F1 C8-I, F13C6-I,
F9C4-I, F3C-I, F3C-Br, F3C-C1, F2HC-C1, and F2HC-Br.
10. Method according to one or more of claims 1 to 9, wherein
the reaction is done in the presence of a compound COMPSALT;
COMPSALT is selected from the group consisting of Nal, KI, Csl and
N(R30)(R31)(R32)R33I;
R30, R31, R32 and R33 are identical or different and independently from each other selected
from the group consisting of H and C1-10 alkyl.
11. Method according to claim 10, wherein
R30, R31, R32 and R33 are identical or different and independently from each other selected
from the group consisting of H and C2_ alkyl.
12. Method according to claim 10 or 11, wherein
COMPSALT is selected from the group consisting of Nal and (n-Bu)4NI.
13. Method according to one or more of claims 1 to 12, wherein
CAT is Pd(OAc) 2.