HK1237759B - Method for preparation of fluoro, chloro and fluorochloro alkylated compounds by homogeneous catalysis - Google Patents

Description

Method for preparing fluoroalkylated compounds, chloroalkylated compounds and fluorochloroalkylated compounds by homogeneous catalysis

Technical Field

The present invention provides a method for preparing fluoroalkylated compounds, chloroalkylated compounds and fluorochloroalkylated compounds by using fluoroalkyl halides, chloroalkyl halides and fluorochloroalkyl halides through homogeneous Pd-catalyzed fluoroalkylation, chloroalkylation and fluorochloroalkylation in the presence of di(1-adamantyl)-n-butylphosphine and 2,2,6,6-tetramethylpiperidine 1-oxyl.

Background Art

Organofluorine chemistry plays an important role in medicine, agriculture, and materials science. Fluoroalkyl groups have strong effects such as high stability and lipophilicity. In addition, longer fluoroalkyl groups have high water and oil resistance and low friction.

Loy, RN et al., Organic Letters 2011, 13, 2548-2551 disclose the Pd-catalyzed coupling of CF3- _I with benzene in 26% GC yield.

According to Table 1, entry 10, the coupling yield of C ₆ F ₁₃ I was 81%.

However, repeating the experiment using bromide instead of iodide provided a yield of less than 1%, see Comparative Example 11 herein.

Homogeneous catalytic methods for the preparation of fluoroalkylated, chloroalkylated, and fluorochloroalkylated compounds by direct C-H trifluoromethylation are needed that provide high yields without the aid of directing groups or electron-rich aromatic compounds. Such methods should be applicable to a variety of substrates and compatible with a variety of functional groups. Furthermore, such methods should not be limited to iodides as alkylating agents but should be used with other halides. Such methods should be applicable not only to perfluorinated alkyl iodides but also to fluorinated, chlorinated, and fluorochloroalkyl halides, particularly to fluorinated alkyl halides.

Surprisingly, the presence of bis(1-adamantyl)-n-butylphosphine and 2,2,6,6-tetramethylpiperidinyl 1-oxyl together with a soluble Pd-based catalyst meets these requirements. No dialkylated products were observed.

In this document, unless otherwise stated, the following meanings apply:

Ac acetate;

Alkyl straight chain or branched chain alkyl;

BuPAd ₂ CAS 321921-71-5, bis(1-adamantyl)-n-butylphosphine;

DMSO dimethyl sulfoxide;

eq,equiv equivalent;

Halides F-, Cl-, Br- or I-, preferably Cl-, Br- and I-, more preferably Br- and I-;

Halogen F, Cl, Br or I; preferably F, Cl or Br; more preferably F or Cl;

For the corresponding isomers of alkanes, "straight-chain" and "n-" are used synonymously;

MTBE methyl tert-butyl ether;

RT Room temperature, which is synonymous with ambient temperature;

TEA triethylamine;

TEMPO CAS 2564-83-2, 2,2,6,6-tetramethylpiperidinyl 1-oxyl;

TFA trifluoroacetate;

"Wet%", "weight %" and "weight-%" are used synonymously and mean percentage by weight.

Summary of the Invention

The subject of the present invention is a process for preparing fluoroalkylated compounds, chloroalkylated compounds or fluorochloroalkylated compounds by reacting the compound COMPSUBST with the compound FCLALKYLHALIDE in the presence of BuPAd ₂ and in the presence of TEMPO and in the presence of the compound BAS, by homogeneous catalysis using the catalyst CAT.

BAS is selected from Cs ₂ CO ₃ , CsHCO ₃ , NEt ₃ and mixtures thereof;

FCLALKYLHALIDE is a compound of formula (III);

R3-X (III)

X is Cl, Br or I;

R3 is C _1-20 alkyl or C _1-20 alkyl, wherein at least one hydrogen in the alkyl chain is replaced by F or Cl;

CAT is selected from Pd(OAc) ₂ , Pd(TFA) ₂ and mixtures thereof;

COMPSUBST is selected from the group consisting of compound COMPSUBST-I, ethylene, cyclohexene, acetylene, and polystyrene;

The ethylene and the cyclohexene are unsubstituted or substituted with 1, 2 or 3 substituents selected from C _1-10 alkyl, C _3-8 cycloalkyl, C _1-4 alkoxy, N(R10)R11, CN, NO, NO ₂ , F, Cl, Br, I, CF ₃ , (CH ₂ ) _m -C(O)Y1, S(O) ₂ R50, CH═C(H)R28, benzyl, phenyl, naphthyl and morpholine;

The acetylene is unsubstituted or substituted with one substituent selected from C _1-10 alkyl, C _3-8 cycloalkyl, C _1-4 alkoxy, N(R10)R11, CN, NO, NO ₂ , F, Cl, Br, I, CF ₃ , (CH ₂ ) _m -C(O)Y1, S(O) ₂ R50, CH═C(H)R28, benzyl, phenyl and naphthyl;

COMPSUBST-I contains the ring RINGA;

RINGA is an unsaturated or aromatic, 5-membered or 6-membered carbocyclic or heterocyclic ring.

When RINGA is a heterocycle, RINGA has 1, 2 or 3 identical or different endocyclic heteroatoms independently selected from N, O and S,

When RINGA is a 5-membered ring, RINGA is unsubstituted or substituted with 1, 2, 3 or 4 substituents which are the same or different,

When RINGA is a 6-membered ring, RINGA is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents which are the same or different,

Any one of the substituents of RINGA is independent of any other substituent among the substituents of RINGA selected from C _1-10 alkyl, C _3-8 cycloalkyl, C _1-4 alkoxy, OH, N(R10)R11, CN, NH-OH, NO, NO ₂ , F, Cl, Br, I, CF ₃ , (CH ₂ ) _m -C(O)Y1, S(O) ₂ R50, CH═C(H)R28, benzyl, phenyl, and naphthyl;

RINGA can condense with the ring RINGB, RINGB is a 5-membered or 6-membered carbocyclic or heterocyclic ring,

When RINGB is a heterocycle, it contains 1, 2 or 3 identical or different endocyclic heteroatoms independently selected from N, O and S;

RINGB is unsubstituted or substituted with 1, 2 or 3 identical or different substituents when RINGB is a 5-membered ring, or with 1, 2, 3 or 4 identical or different substituents when RINGB is a 6-membered ring, wherein the substituents are independently selected from the group consisting of C _1-10 alkyl, C _3-8 cycloalkyl, C _1-4 alkoxy, OH, N(R17)R18, CN, NH—OH, NO, NO ₂ , F, Cl, Br, I, CF ₃ , (CH ₂ ) _n —C(O)Y ₂ , S(O) ₂ R51, CH═C(H)R38, benzyl, phenyl and naphthyl;

Any of the C _1-10 alkyl substituents of RINGA or RINGB is unsubstituted or substituted with 1, 2, 3, 4 or 5 identical or different substituents selected from halogen, OH, OC(O)-C _1-5 alkyl, OC _1-10 alkyl, SC _1-10 alkyl, S(O)-C _1-10 alkyl, S(O ₂ )-C _1-10 alkyl, OC _1-6 alkylene-OC 1-6 alkyl, C _3-8 cycloalkyl and 1,2,4-triazolyl _;

Any of the benzyl, phenyl and naphthyl substituents of RINGA or RINGB are independently unsubstituted or substituted with 1, 2, 3, 4 or 5 identical or different substituents selected from halogen, C _1-4 alkoxy, NO ₂ and CN;

m, n and q are the same or different and are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

Y1, Y2 and R13 are the same or different and are independently selected from H, OH, C(R14)(R15)R16, C _1-6 alkyl, OC _1-6 alkyl, phenyl, benzyl, O-phenyl, OC _1-6 alkylene-OC _1-6 alkyl and N(R19)R20;

R14, R15 and R16 are the same or different and are independently selected from H, F, Cl and Br;

R10, R11, R17, R18, R19 and R20 are the same or different and are independently H or C _1-6 alkyl, or R10 and R11, R17 and R18 or R19 and R20 together represent a tetramethylene chain or a pentamethylene chain;

R50 and R51 are the same or different and are independently selected from OH, C _1-6 alkyl and C _1-6 alkoxy;

R24, R34, R28 and R38 are the same or different and are independently selected from H, C _1-10 alkyl, C (R25) (R26) -O-R27;

R25, R26 and R27 are the same or different and are independently selected from H and C _1-10 alkyl.

DETAILED DESCRIPTION

Preferably, RINGA is a carbocyclic unsaturated ring, a carbocyclic aromatic ring, a heterocyclic unsaturated ring or a heterocyclic aromatic ring.

Preferably, COMPSUBST is selected from the group consisting of compound COMPSUBST-I, ethylene, cyclohexene, acetylene and polystyrene;

The ethylene and the cyclohexene are unsubstituted or substituted with one or two substituents selected from C _1-10 alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, N(R10)R11, CN, F, Cl, Br, I, CF ₃ , (CH ₂ ) _m -C(O)Y1, S(O) ₂ R50, benzyl, phenyl, naphthyl and morpholine;

The acetylene is unsubstituted or substituted with one substituent selected from C _1-10 alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, N(R10)R11, CN, F, Cl, Br, I, CF ₃ , (CH ₂ ) _m -C(O)Y1, S(O) ₂ R50, benzyl, phenyl and naphthyl;

Where COMPSUBSIT-I is selected from:

wherein COMPSUBST-I is unsubstituted or

In the case where COMPSUBST-I is a monocyclic compound having 5 internal ring atoms, it is substituted by 1, 2, 3 or 4 identical or different substituents,

In the case where COMPSUBST-I is a monocyclic compound having 6 internal ring atoms, it is substituted by 1, 2, 3, 4 or 5 identical or different substituents,

In the case where COMPSUBST-1 is a bicyclic compound in which the 5-membered and 6-membered rings are ortho-fused, substituted with 1, 2, 3, 4, 5 or 6 substituents which may be the same or different,

In the case where COMPSUBST-1 is a bicyclic compound in which the two 6-membered rings are ortho-fused, substituted with 1, 2, 3, 4, 5, 6 or 7 identical or different substituents,

The substituents are independently selected from C _1-10 alkyl, C _3-8 cycloalkyl, C _1-4 alkoxy, OH, C(H)=O, N(R10)R11, CN, NH-OH, NO, NO ₂ , F, Cl, Br, I, CF ₃ , (CH ₂ ) _m -C(O)Y1, S(O) ₂ R ₅₀ , CH=C(H)R28, benzyl, phenyl and naphthyl;

The C _1-10 alkyl substituent of COMPSUBST-I is unsubstituted or substituted with 1, _{2, 3, 4 or 5 identical or different substituents selected from halogen, OH, OC(O)-C 1-5 alkyl, OC 1-10 alkyl, SC 1-10 alkyl , S} ( _O )-C _1-10 alkyl, S(O 2 )-C _{1-10 alkyl, OC 1-6 alkylene-OC 1-6 alkyl} , C _3-8 cycloalkyl and 1,2,4-triazolyl;

The benzyl, phenyl and naphthyl substituents of COMPSUBST-I are independently unsubstituted or substituted with 1, 2, 3, 4 or 5 identical or different substituents selected from halogen, C _1-4 alkoxy, NO ₂ and CN;

R10, R11, m, n, Y1, Y2, R28, R50 and R24 are as defined above, including all embodiments thereof.

Preferably, m, n and q are the same or different and are independently 0, 1, 2, 3 or 4;

More preferably, m, n and q are 0 or 4.

In another embodiment, Y1, Y2 and R13 are the same or different and are independently selected from H, OH, C(R14)(R15)R16, C _2-6 alkyl, OC _1-6 alkyl, phenyl, benzyl, O-phenyl, OC _1-6 alkylene-OC _1-6 alkyl and N(R19)R20.

Preferably, Y1, Y2 and R13 are the same or different and are independently selected from H, OH, C _1-2 alkyl and OC _1-2 alkyl.

More preferably, COMPSUBST-1 is unsubstituted or

substituted with 1, 2 or 3 identical or different substituents in the case where COMPSUBST-I is a monocyclic compound having 5 internal ring atoms;

In the case where COMPSUBST-1 is a monocyclic compound having 6 internal ring atoms, it is substituted by 1, 2, 3, 4 or 5 identical or different substituents,

In the case where COMPSUBST-1 is a bicyclic compound in which the 5-membered and 6-membered rings are ortho-fused, it is substituted with 1, 2, 3, 4 or 5 substituents which are the same or different,

In the case where COMPSUBST-1 is a bicyclic compound in which the two 6-membered rings are ortho-fused, it is substituted with 1, 2, 3 or 4 identical or different substituents,

The substituents are independently selected from C _1-4 alkyl, C _1-4 alkoxy, OH, C(H)=O, N(R10)R11, CN, F, Cl, Br, CF ₃ , (CH ₂ ) _m -C(O)Y1 and S(O) ₂ R50;

The C _1-4 alkyl substituent of COMPSUBST-I is unsubstituted or substituted with 1, 2 or 3 identical or different substituents selected from halogen;

wherein R10, R11, Y1 and R50 are as defined above, including all embodiments thereof.

In particular, COMPSUBST is selected from benzene, pyrazole,

A compound of formula (VI), ethylene, cyclohexene, acetylene and polystyrene;

Y is C _1-6 alkyl;

The ethylene and the cyclohexene are unsubstituted or substituted with one or two substituents selected from C _1-10 alkyl, C _1-4 alkoxy, N(R10)R11, CN, F, Cl, Br, I, CF ₃ , (CH ₂ ) _m -C(O)Y1, benzyl, phenyl and morpholine;

The acetylene is unsubstituted or substituted with one substituent selected from C _1-10 alkyl, C _1-4 alkoxy, N(R10)R11, CN, F, Cl, Br, I, CF ₃ , (CH ₂ ) _m -C(O)Y1, benzyl and phenyl;

in,

R44 is selected from C _1-10 alkyl, C _1-4 alkoxy, OH, N(R10)R11, CN, NO, NO ₂ , F, Cl, Br, I, CF ₃ , (CH ₂ ) _m -C(O)Y1, S(O) ₂ R50;

wherein R10, R11, m, Y1 and R50 are as defined above, including all embodiments thereof.

Embodiments of substituted ethylenes are propylene, ethylene-1,1-diyldiphenyl, and 3,3-dimethylbut-1-ene.

An embodiment of a substituted cyclohexene is 4-(cyclohex-1-en-1-yl)morpholine.

An embodiment of a substituted acetylene is 1-octyne.

Preferably, Y is methyl or ethyl.

One implementation of COMPSUBST is

Y is methyl or ethyl, preferably ethyl.

Fluoroalkylated compounds, chloroalkylated compounds or fluorochloroalkylated compounds are referred to as compounds ALKYLCOMPSUBST.

Fluoroalkyl halides, chloroalkyl halides and fluorochloroalkyl halides are compounds FCLALKYLHALIDE.

Preferably, FCLALKYLHALIDE is a compound of formula (III);

R3-X (III)

X is Cl, Br or I;

R3 is C _1-20 alkyl or C _1-20 alkyl in which at least one hydrogen in the alkyl chain is replaced by F or Cl;

More preferably, R3 is _C1-15 alkyl or _C1-15 alkyl in which at least one hydrogen in the alkyl chain is replaced by F or Cl;

Even more preferably, R3 is _C1-10 alkyl or _C1-10 alkyl wherein at least one hydrogen in the alkyl chain is replaced by F or Cl.

Preferably, X is Br or I;

More preferably, X is 1;

In another more preferred embodiment, X is Br;

R3 also has the definition in all its embodiments.

In a particular embodiment, the compound FCLALKYLHADLIDE is a perfluoroalkyl halide, F ₂ HC-Cl or F ₂ HC-Br, preferably FCLALKYLHADLIDE is a perfluoroalkyl bromide or iodide, F ₂ HC-Cl or F ₂ HC-Br;

Preferably,

X is Cl, Br or I, and

R3 is a perfluoroC _1-20 alkyl group; or

FCLALKYLHADLIDE is F ₂ HC-Cl or F ₂ HC-Br;

More preferably,

X is Br or I, and

R3 is a perfluoroC _1-20 alkyl group; or

FCLALKYLHADLIDE is F ₂ HC-Cl or F ₂ HC-Br;

Even more preferably,

X is Br or I, and

R3 is a perfluoroC _1-15 alkyl group; or

FCLALKYLHADLIDE is F ₂ HC-Cl or F ₂ HC-Br.

In particular, the FCLALKYLHALIDE is selected from F ₂₁ C ₁₀ -I, F ₁₇ C ₈ -I, F ₁₃ C ₆ -I, F ₉ C ₄ -I, F ₃ CI, F ₃ C-Br, F ₃ C-Cl, F ₂ HC-Cl and F ₂ HC-Br;

More particularly, the FCLALKYLHALIDE is chosen from nF ₂₁ C ₁₀ -I, nF ₁₇ C ₈ -I, nF ₁₃ C ₆ -I, nF ₉ C ₄ -I, F ₃ CI, F ₃ C-Br, F ₃ C-Cl, F ₂ HC-Cl and F ₂ HC-Br.

In one embodiment, the reaction is carried out in the presence of the compound COMPSALT;

COMPSALT is selected from NaI, KI, CsI and N(R30)(R31)(R32)R33I;

R30, R31, R32 and R33 are the same or different and are independently selected from H and C _1-10 alkyl;

Preferably, R30, R31, R32 and R33 are the same or different and are independently selected from H and C _2-6 alkyl;

More preferably, COMPSALT is selected from NaI and (n-Bu) ₄ NI.

The reaction is preferably carried out in the presence of the compound COMPSALT, and X is Cl or Br, preferably X is Cl.

Preferably, CAT is Pd(OAc) ₂ .

It is preferred to use 0.1 mol% to 20 mol%, more preferably 1 mol% to 15 mol%, even more preferably 2.5 mol% to 12.5 mol% of CAT in the reaction, the mol% being based on the molar amount of COMPSUBST.

Preferably, 1 to 20 molar equivalents, more preferably 1 to 15 molar equivalents, even more preferably 1 to 10 molar equivalents of FCLALKYLHALIDE are used in the reaction, the molar equivalents being based on the molar amount of COMPSUBST.

In case the FCLALKYLHALIDE is gaseous, it is preferred to use FCLALKYLHALIDE in the reaction in an amount corresponding to a pressure of 1 to 10 bar, more preferably 1 to 5 bar, at ambient temperature.

Preferably 1 mol % to 40 mol %, more preferably 5 mol % to 30 mol %, even more preferably 5 mol % to 25 mol % of BuPAd ₂ is used in the reaction, the mol % being based on the molar amount of COMPSUBST.

Preferably, 0.1 to 10 molar equivalents, more preferably 0.5 to 5 molar equivalents, even more preferably 0.75 to 2.5 molar equivalents of TEMPO are used in the reaction, the molar equivalents being based on the molar amount of COMPSUBST.

Preferably, BAS is Cs ₂ CO ₃ .

Preferably, 0.1 to 10 molar equivalents, more preferably 0.5 to 5 molar equivalents, even more preferably 0.75 to 2.5 molar equivalents of BAS are used in the reaction, the molar equivalents being based on the molar amount of COMPSUBST.

The reaction temperature of the reaction is preferably 20 to 200°C, more preferably 50 to 200°C, even more preferably 50 to 150°C, particularly 100 to 150°C, more particularly 110 to 145°C.

The reaction time of the reaction is preferably 1 h to 60 h, more preferably 10 h to 50 h, even more preferably 15 h to 50 h.

Preferably, the reaction is carried out under an inert atmosphere. Preferably, the inert atmosphere is achieved by using an inert gas preferably selected from argon, another noble gas, a low boiling alkane, nitrogen and mixtures thereof.

The low boiling point alkane is preferably a C _1-3 alkane, ie methane, ethane or propane.

The reaction can be carried out in a closed system, under a pressure caused by a selected temperature in the closed system, and/or under a pressure caused by the pressure exerted by the COMPSUBST if the COMPSUBST is in gaseous form. The pressure can also be exerted by the inert gas. The reaction can also be carried out at ambient pressure.

The reaction can be carried out in a solvent SOL, which is preferably selected from alkanes, chloroalkanes, ketones, ethers, esters, aliphatic nitriles, aliphatic amides, sulfoxides, and mixtures thereof;

Preferably, SOL is selected from _C5-8 alkanes, chlorinated _C5-8 alkanes, acetone, methyl ethyl ketone, diethyl ketone, MTBE, tetrahydrofuran, methyltetrahydrofuran, ethyl acetate, butyl acetate, valeronitrile, acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and mixtures thereof;

More preferably, SOL is selected from acetone, methyl ethyl ketone, diethyl ketone, valeronitrile, acetonitrile, dimethyl sulfoxide and mixtures thereof;

Even more preferably, the SOL is selected from acetone, methyl ethyl ketone, diethyl ketone, dimethyl sulfoxide and mixtures thereof.

It is also possible to use COMPSUBST as both substrate and solvent.

Alternatively, 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 0.1 to 100 times, more preferably 1 to 50 times, even more preferably 1 to 25 times the weight of COMPSUBST.

After the reaction, ALKYLCOMPSUBST can be isolated by standard methods known to those skilled in the art, such as evaporation of volatile components, extraction, washing, drying, concentration, crystallization, chromatography, and any combination thereof.

COMPSUBST, BAS, CAT, _BuPAd2 , TEMPO and FCLALKYLHALIDE, fluoroalkyl halides, chloroalkyl halides and fluorochloroalkyl halides are commercially available and can be prepared according to known procedures.

Example

Yield:

Yields are given as a percentage of the expected molar yield of ALKYLCOMPSUBST in the reaction mixture after the reaction and are based on the molar amount of COMPSUBST and, if not stated otherwise, determined by ¹⁹ F NMR with 1,4-difluorobenzene as internal standard.

The isolated yields are derived from the weight of the isolated product and are given in parentheses in Table 1 based on the weight of COMPSUBST.

Isomer ratio and position of alkylation

Determined by NMR spectroscopy.

Example 1

To an oven-dried 4 mL vial with a stir bar were added Pd(OAc) _₂ (10 mol%), _BuPAd₂ (20 mol%), TEMPO (1.0 eq), _Cs₂CO₃ (2.0 _eq ), and 1,4-dimethoxybenzene (0.2 mmol, 1 equivalent). Acetone (0.5 mL) was then injected into the vial under an argon stream. The vial was placed on an alloy plate and transferred to a 300 mL Parr Instruments 4560 series autoclave under an argon atmosphere. A pressure of 3 to 5 bar of _CF₃Br followed by 15 bar of _N₂ was maintained at ambient temperature. The reaction mixture was stirred at 130°C for 40 hours. After the reaction was complete, the autoclave was cooled to room temperature and the pressure released.

The reaction mixture was extracted with water and ethyl acetate (5 times, 3 mL each time). The organic layer was washed with brine, dried over Na ₂ SO ₄ , and evaporated to give the crude product. The yield was 81%.

Purification was performed by flash chromatography on silica gel (eluent: heptane: EtOAc = 60:40 (v/v)). The isolated yield was 69%.

Details are also given in Table 1.

Example 2

Example 1 was repeated, with the only difference being that Pd(TFA) ₂ was used instead of Pd(OAc) ₂ as CAT. The yield was 78%.

Example 3

Example 1 was repeated except that only 5 mol% of Pd(OAc) ₂ was used instead of 10 mol%, and only 10 mol% of BuPAd ₂ was used instead of 20 mol%. The yield was 42%.

Example 4

Example 1 was repeated with the only difference that the reaction mixture was stirred at 130° C. for 30 hours instead of 40 hours. The yield was 70%.

Examples 5 to 21

Example 1 was repeated except that the compound listed in Table 1 was used as COMPSUBSST.

Example 22

To an oven-dried 4 mL vial with a stir bar were added Pd(OAc) ₂ (10 mol%), _BuPAd2 (20 mol%), TEMPO (1.0 eq), _Cs2CO3 (2.0 _eq ), benzene (0.6 mmol, 1 eq), and perfluorohexyl bromide (3.2 eq). Acetone (2.5 mL) was then injected into the vial under an argon stream. The vial was placed in an alloy plate and transferred to a 300 mL Parr Instruments 4560 series autoclave under an argon atmosphere. A pressure of 15 bar _N2 was maintained at ambient temperature. The reaction mixture was stirred at 130°C for 40 hours. After the reaction was complete, the autoclave was cooled to room temperature and the pressure was released.

The reaction mixture was extracted with water and ethyl acetate (5 times, 3 mL each). The organic layer was washed with brine, dried _{over Na2SO4} , and evaporated to yield a crude product. Analysis of the reaction mixture by ^19F -NMR revealed a 21% yield of (perfluorohexyl)benzene. The identity of (perfluorohexyl)benzene was confirmed by GC-MS.

Repeats of the experiment provided a 28% yield with a conversion of 35%.

Example 23

Pd(OAc) ₂ (10 mol%), BuPAd ₂ (20 mol%), TEMPO (1.0 eq), Cs ₂ CO ₃ (2.0 eq), 1,4-dimethoxybenzene (0.2 mmol, 1 eq), and perfluorohexyl bromide (3.2 eq) were placed in an oven-dried 4 mL vial with a stir bar. Acetone (1 mL) was then injected into the vial under an argon stream. The vial was placed in an alloy plate and transferred to a 300 mL Parr Instruments 4560 series autoclave under an argon atmosphere. A pressure of 15 bar N ₂ was maintained at ambient temperature. The reaction mixture was stirred at 130° C. for 40 hours. After the reaction was complete, the autoclave was cooled to room temperature and the pressure was released.

The reaction mixture was extracted with water and ethyl acetate (5 times, 3 mL each). The organic layer was washed with brine, dried _{over Na2SO4} , and evaporated to give a crude product. The reaction mixture was analyzed by GC-MS, giving a 42% yield of 1,4-dimethoxy-2-(perfluorohexyl)benzene.

Example 24

An oven-dried 4 mL vial with a stir bar was charged with Pd(OAc) _₂ (10 mol%), _BuPAd₂ (20 mol%), TEMPO (1.0 eq), _Cs₂CO₃ (2.0 eq), _and ethylene-1,1-diyldiphenyl (0.5 mmol, 1 eq). Acetone (2 mL) was then injected into the vial under an argon stream. The vial was placed on an alloy plate and transferred to a 300 mL Parr Instruments 4560 series autoclave under an argon atmosphere. A pressure of 3 to 5 bar of _CF₃Br followed by 15 bar of _N₂ was maintained at ambient temperature. The reaction mixture was stirred at 130°C for 40 hours. After the reaction was complete, the autoclave was cooled to room temperature and the pressure was released.

The reaction mixture was filtered, and the filter residue was washed with ethyl acetate and acetone. The combined filtrates were concentrated on a rotary evaporator. The residue was purified by silica gel chromatography (eluent: heptane: EtOAc = 90:10 (v/v)). The isolated yield was 58%.

^1H NMR analysis of the resulting product indicated a 2:1 mixture of (3,3,3-trifluoroprop-1-ene-1,1-diyl)dibenzene and (3,3,3-trifluoropropane-1,1-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 a 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 equivalent). The solvent (0.5 mL) was then injected into the vial under an argon stream. The vial was placed on an alloy plate and transferred to a 300 mL Parr Instruments 4560 series autoclave under an argon atmosphere. A pressure of 3 to 5 bar of _CF₃Br followed by 15 bar of _N₂ was maintained at ambient temperature. The reaction mixture was stirred at 130°C for 40 hours. After the reaction was complete, the autoclave was cooled to room temperature and the pressure released.

The reaction mixture was extracted with water and ethyl acetate (5 times, 3 mL each time). The organic layer was washed with brine, dried over Na ₂ SO ₄ , and evaporated to give a crude product. The yield of the product was determined by ¹⁹ F-NMR spectroscopy.

In CompEx 4, Pd(TFA) ₂ was used instead of Pd(OAc) ₂ as the CAT.

Table 2 shows the parameters of the test.

Example 27

To an oven-dried 4 mL vial with a stir bar were added Pd(OAc) _₂ (10 mol%), _BuPAd₂ (20 mol%), TEMPO (1 eq), _Cs₂CO₃ (2.0 eq), and ethyl _acrylate (0.5 mmol, 1 eq). Acetone (0.5 mL) was then injected sequentially into the vial under an argon stream. The vial was placed on an alloy plate and transferred to a 300 mL Parr Instruments 4560 series autoclave under an argon atmosphere. A pressure of 3 to 5 bar of _CF₃Br followed by 15 bar of _N₂ was maintained at ambient temperature. The reaction mixture was stirred at 130°C for 40 hours. Upon completion of the reaction, the autoclave was cooled to room temperature and the pressure released.

The resulting reaction mixture was cooled, the pressure was released from the autoclave, and the solid was filtered. The filtered reaction mixture was analyzed by ¹⁹ F-NMR using the internal standard 1,4-difluorobenzene, which showed a yield of 26% of ethyl-4,4,4-trifluorobut-2-enoate (δ ¹⁹ F-NMR: -65.68 ppm (d, J=9.5 Hz)). GC-MS analysis showed a molecular weight peak of 168 g/mol, confirming monotrifluoromethylation.

Comparative Example 11

Entry 10 in Table 1 of Loy, R.N et al., Organic Letters 2011, 13, 2548-2551 was repeated according to the detailed procedure given in the Supporting Information of said article, which is described under “Optimization procedure” on page S5 in conjunction with entry 9 in Table S4 on page S3.

Phosphine is BINAP.

[Pd] is Pd ₂ dba3.

The base is Cs ₂ CO ₃ .

The alkyl halide is perfluorohexyl bromide rather than perfluorohexyl iodide.

Base (0.4mmol, 2 equivalents), [Pd] (0.02mmol, 10mol%) and phosphine (0.04-0.08mmol, 20-40mol%) were added to a screw cap 1 dram vial. Benzene (1mL) and perfluorohexyl bromide (43 μL, 0.2mmol, 1 equivalent) were added, and the resulting mixture was sealed with a Teflon-lined lid and heated in an aluminum reaction block with vigorous stirring at 80°C for 15 hours. The reaction mixture was cooled to 23°C and chlorobenzene (20 microliters) was added as a GC internal standard. An aliquot (approximately 100 μL) was taken from the crude reaction mixture and eluted with EtOAc (2mL) through a plug of Celite. The sample was then analyzed by GC and the yield was determined by comparison with the calibration of the p-chlorobenzene internal standard.

result:

A yield of less than 1% was measured.

Example 28

To a dry 50 mL autoclave were added 4-(cyclohex-1-en-1-yl)morpholine (0.2 mmol), Pd(OAc) ₂ (10 mol%), BuPAd ₂ (20 mol%), and TEMPO(1.0)Cs ₂ CO ₃ (2.0 equivalents). Acetone (2 mL) was then injected into the autoclave, which was flushed three times with argon. A pressure of 6 bar of CF ₃ Br followed by 15 bar of N ₂ was maintained at ambient temperature. The reaction mixture was heated at 130° C. for 40 hours. The autoclave was placed in a heating system and heated at 130° C. for 40 hours. After the reaction was complete, the autoclave was cooled to room temperature and the pressure released. 20 microliters of 1,2-difluorobenzene (internal standard) was added to the reaction mixture, and a sample was subjected to ¹⁹ F NMR. The yield was measured by ¹⁹ F NMR. The NMR data were consistent with those reported in NV Kirij et al., Journal of Fluorine Chemistry, 2000, 106, 21-221.

Claims (12)

1. A method for preparing fluoroalkylated compounds, chloroalkylated compounds, or fluorochloroalkylated compounds by homogeneous catalysis using catalyst CAT in the presence of BuPAd ₂ , TEMPO, and BAS, via the reaction of compound COMPSUBST with compound FCLALKYLHALIDE. BAS is selected _{from Cs₂CO₃} , _CsHCO₃ , _NEt₃ and their mixtures; FCLALKYLHALIDE is a compound of formula (III); R3-X (III) X is Cl, Br, or I; R3 is a _C1-20 alkyl or _C1-20 alkyl chain in which at least one hydrogen atom is substituted by F or Cl; CAT is selected from Pd(OAc) ₂ , Pd(TFA) ₂ and their mixtures; COMPSUBST is selected from the compounds COMPSUBST-I, ethylene, cyclohexene, acetylene, and polystyrene; The ethylene and the cyclohexene are unsubstituted or substituted with one or two substituents selected from _C1-10 alkyl, _C3-6 cycloalkyl, _C1-4 alkoxy, N(R10)R11, CN, F, Cl, Br, I, _CF3 , ( _CH2 ) _m -C(O)Y1, S(O) _2R50 , benzyl, phenyl, naphthyl and morpholine; The acetylene is unsubstituted or substituted with one substituent selected from _C1-10 alkyl, _C3-6 cycloalkyl, _C1-4 alkoxy, N(R10)R11, CN, F, Cl, Br, I, _CF3 , ( _CH2 ) _m -C(O)Y1, S(O) _2R50 , benzyl, phenyl and naphthyl; COMPSUBST-I is selected from: COMPSUBST-I is unsubstituted or In the case of COMPSUBST-I being a monocyclic compound with 5 inner ring atoms, substitution can be achieved by 1, 2, 3, or 4 identical or different substituents. In the case of COMPSUBST-I being a monocyclic compound with 6 inner ring atoms, substitution can be achieved by 1, 2, 3, 4, or 5 identical or different substituents. In COMPSUBST-I, a bicyclic compound in which the 5-membered and 6-membered rings are ortho-fused, substitution can be achieved by 1, 2, 3, 4, 5, or 6 identical or different substituents. In COMPSUBST-I, a bicyclic compound in which two 6-membered rings are ortho-fused, substitution can be achieved by 1, 2, 3, 4, 5, 6, or 7 identical or different substituents. The substituents are independently selected from _C1-10 alkyl, _C3-8 cycloalkyl, _C1-4 alkoxy, OH, C(H)=O, N(R10)R11, CN, NH-OH, NO, _NO2 , F, Cl, Br, I, _CF3 , ( _CH2 ) _m -C(O)Y1, S(O) _2R50 , _CH =C(H)R28, C≡C-R24, benzyl, phenyl, and naphthyl; The _C1-10 alkyl substituents of COMPSUBST-I are unsubstituted or substituted by one, two, three, four or five identical or different substituents selected from halogens, OH, OC(O) _-C1-5 alkyl, _OC1-10 alkyl, _SC1-10 alkyl, S(O) _-C1-10 alkyl, S( _O2 ) _-C1-10 alkyl, _OC1-6 alkylene- _OC1-6 alkyl, _C3-8 cycloalkyl and 1,2,4-triazolyl; The benzyl, phenyl, and naphthyl substituents of COMPSUBST-I are independently unsubstituted or substituted by one, two, three, four, or five identical or different substituents selected from halogens, _C1-4 alkoxy groups, _NO2 , and CN. m and q may be the same or different, and are independent of each other as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Y1 and R13 may be the same or different, and are independently selected from H, OH, C(R14)(R15)R16, _C1-6 alkyl, _OC1-6 alkyl, phenyl, benzyl, O-phenyl, _OC1-6 alkylene- _OC1-6 alkyl and N(R19)R20; R14, R15, and R16 may be the same or different, and are selected independently from H, F, Cl, and Br; R10, R11, R19 and R20 may be the same or different and are H or _C1-6 alkyl independently of each other, or R10 and R11, or R19 and R20 together represent a tetramethylene chain or a pentamethylene chain; R50 is selected from OH, _C1-6 alkyl, and _C1-6 alkoxy groups; R24 and R28 may be the same or different, and are independently selected from H, _C1-10 alkyl groups and C(R25)(R26)-O-R27; R25, R26, and R27 may be the same or different, and are independently selected from H and _C1-10 alkyl groups. 2. The method according to claim 1, wherein, m and q may be the same or different, and are independent of each other as 0, 1, 2, 3 or 4. 3. The method according to claim 1 or 2, wherein COMPSUBST is selected from benzene, pyrazole, Compounds of formula (VI), ethylene, cyclohexene, acetylene, and polystyrene; Y is a _C1-6 alkyl group; The ethylene and the cyclohexene are unsubstituted or substituted with one or two substituents selected from _C1-10 alkyl, _C1-4 alkoxy, N(R10)R11, CN, F, Cl, Br, I, _CF3 , ( _CH2 ) _m -C(O)Y1, benzyl, phenyl and morpholine; The acetylene is unsubstituted or substituted with one substituent selected from _C1-10 alkyl, _C1-4 alkoxy, N(R10)R11, CN, F, Cl, Br, I, _CF3 , ( _CH2 ) _m -C(O)Y1, benzyl and phenyl; in, R44 is selected from _C1-10 alkyl, _C1-4 alkoxy, OH, N(R10)R11, CN, NO, _NO2 , F, Cl, Br, I, _CF3 , ( _CH2 ) _m -C(O)Y1, and S(O) _2R50 . 4. The method according to claim 1 or 2, wherein, X is Br or I. 5. The method according to claim 1 or 2, wherein, X is Br. 6. The method according to claim 1 or 2, wherein, The compound FCLALKYLHADLIDE is a perfluoroalkyl halide, _F₂HC -Cl or _F₂HC -Br. 7. The method according to claim 1 or 2, wherein, X is Cl, Br, or I, and R3 is a perfluorinated _C1-20 alkyl group, or FCLALKYLHADLIDE is _F₂HC -Cl or _F₂HC -Br. 8. The method according to claim 1 or 2, wherein, FCLALKYLHALIDE is selected from F ₂₁ C ₁₀ -I, F ₁₇ C ₈ -I, F ₁₃ C ₆ -I, F ₉ C ₄ -I, F ₃ CI, F ₃ C-Br, F ₃ C-Cl, F ₂ HC-Cl and F ₂ HC-Br. 9. The method according to claim 1 or 2, wherein, The reaction was carried out in the presence of the compound COMPSALT; COMPSALT is selected from NaI, KI, CsI and N(R30)(R31)(R32)R33I; R30, R31, R32, and R33 may be the same or different, and are independently selected from H and _C1-10 alkyl groups. 10. The method according to claim 9, wherein, R30, R31, R32, and R33 may be the same or different, and are independently selected from H and _C2-6 alkyl groups. 11. The method according to claim 9, wherein, COMPSALT is selected from NaI and (n-Bu) _4NI . 12. The method according to claim 1 or 2, wherein, CAT is Pd(OAc) ₂ .