Method for preparation of fluoro alkylated compounds by homogeneous Ni catalysis

1. A method for preparation of a mono-fluoro alkylated compound FACOMPSUBST that is mono-fluoroalkylated at a sp2 carbon, by a reaction of a compound COMPSUBST with a fluoro alkyl halide FAHALIDE by homogeneous catalysis using a Ni catalyst NICAT in the presence of a base BAS;

wherein

NICAT is Ni-cat1 or Ni-cat2;

Ni-cat1 is a combination of a nickel salt NISALT with a ligand LIG

NISALT is NiCl 2 or Ni(NO 3 ) 2 ;

LIG is selected from the group consisting of compound of formula (DPEPhos), compound of formula (dppb) and Ph 3 P;

Ni-cat2 is compound of formula (Ni-cat2);

BAS is selected from the group consisting of Cs 2 CO 3 , CsHCO 3 , K 3 PO 4 , NaH and NaOtBu;

FAHALIDE is selected from the group consisting of perfluoro C 1-20 alkyl-X1, and Br—(CF 2 ) n3 —Br;

wherein X1 is Br or I;

with n3 being an integer of 2 to 10;

COMPSUBST is selected from the group consisting of a compound COMPSUBST-I, ethene, and polystyrene;

the ethene being substituted by 1 substituent selected from the group consisting of C 1-10 alkyl;

COMPSUBST-I is a compound of formula (COMPSUBST-I);

RINGA(COMPSUBST-I)

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 is a 5 membered ring, then RINGA is unsubstituted or substituted by 1, 2, 3 or 4 identical or different substituents,

when RINGA is a 6 membered ring then RINGA is unsubstituted or substituted by 1, 2, 3, 4 or 5 identical or different substituents,

any of the substituents of RINGA is independently from any other of the substituents of RINGA selected from the group consisting of 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, C 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;

when RINGB is a 5 membered ring, then RINGB is unsubstituted or substituted by 1, 2 or 3 identical or different substituents,

when RINGB is a 6 membered ring then RINGB is unsubstituted or substituted by 1, 2, 3 or 4 identical or different substituents,

any of the substituents of RINGB is independently from any other of the substituents of RINGB 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)Y2, S(O) 2 R51, CH═C(H)R38, C C—R34, benzyl, phenyl and naphthyl;

any of the C 1-10 alkyl substituent 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, O—C(O)—C 1-5 alkyl, O—C 1-10 alkyl, S—C 1-10 alkyl, S(O)—C 1-10 alkyl, S(O 2 )—C 1-10 alkyl, O—C 1-6 alkylen-O—C 1-6 alkyl, C 3-8 cycloalkyl and 1,2,4-triazolyl;

any of said benzyl, phenyl and naphthyl substituent 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, C 1-4 alkoxy, NO 2 and CN;

m and n are identical or different and independently from each other 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

Y1 and Y2 are identical or different and independently from each other selected from the group consisting of H, OH, C(R14)(R15)R16, C 1-6 alkyl, O—C 1-6 alkyl, phenyl, benzyl, O-phenyl, O—C 1-6 alkylen-O—C 1-6 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, Cl and Br;

R10, R11, R17, R18, R19 and R20 are identical or different and are independently from each other H or C 1-6 alkyl, or R10 and R11, R17 and R18 or R19 and R20 represent together a tetramethylene or a pentamethylene chain;

R50 and R51 are identical or different and independently from each other selected from the group consisting of OH, C 1-6 alkyl and C 1-6 alkoxy;

R24, R34, R28 and R38 are identical or different and independently from each other selected from the group consisting of H, C 1-10 alkyl, C(R25)(R26)-O—R27;

R25, R26 and R27 are identical or different and independently from each other selected from the group consisting of H and C 1-10 alkyl; and

wherein if COMPSUBST is ethene as defined above, FACOMPSUBST is a 1,2-disubstituted ethene.

2. The method according to claim 1 , wherein

LIG is compound of formula (DPEPhos) or Ph 3 P.

3. The method according to claim 1 , wherein

BAS is selected from the group consisting of Cs 2 CO 3 , K 3 PO 4 , NaH and NaOtBu.

4. The method according to claim 1 , wherein

COMPSUBST is selected from the group consisting of compound COMPSUBST-I, ethene, and polystyrene;

the ethene being substituted by 1 substituent selected from the group consisting of C 1-10 alkyl;

with COMPSUBST-I being selected from the group consisting of

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 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 R50, CH═C(H)R28, C C—R24, benzyl, phenyl and naphthyl;

said 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 the group consisting of halogen, OH, O—C(O)—C 1-5 alkyl, O—C 1-10 alkyl, S—C 1-10 alkyl, S(O)—C 1-10 alkyl, S(O 2 )—C 1-10 alkyl, O—C 1-6 alkylen-O—C 1-6 alkyl, C 3-8 cycloalkyl and 1,2,4-triazolyl;

said benzyl, phenyl and naphthyl substituents of COMPSUBST-I are 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, C 1-4 alkoxy, NO 2 and CN.

5. The method according to claim 1 , wherein

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 or 4 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 or 5 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 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;

said C 1-4 alkyl substituent of COMPSUBST-I is unsubstituted or substituted with 1, 2 or 3 identical or different substituents selected from the group consisting of halogen.

6. The method according to claim 1 , wherein

COMPSUBST is selected from the group consisting of

 ethene, and polystyrene;

Y is C 1-6 alkyl;

the ethene being substituted by 1 substituent selected from the group consisting of C 1-10 alkyl.

7. The method according to claim 1 , wherein

n3 is 2, 3, 4, 5, 6.

8. The method according to claim 1 , wherein

FAHALIDE is selected from the group consisting of F 21 C 10 —I, F 21 C 10 —Br, F 17 C 8 —Br, F 13 C 6 —Br, F 9 C 4 —Br, F 7 C 3 —Br, F 3 C—Br, Br—(CF 2 ) 4 —Br, F 2 HC—I, and F 2 HC—Br.

9. The method according to claim 1 , wherein

the reaction is done in the presence of a drying agent DRYAG;

wherein DRYAG is selected from the group consisting of molecular sieve and Na 2 SO 4 .

10. The method according to claim 1 , wherein

the reaction is done neat or in a solvent SOL.

11. The method according to claim 10 , wherein SOL is selected from the group consisting of alkanes, chlorinated alkanes, ketones, ethers, esters, aliphatic nitrils, aliphatic amides, sulfoxides, C 6 F 6 , and mixtures thereof.