Method for fluoroalkylation of enamines

1. A method for a fluoroalkylation of an enamine ENAM by a reaction REAC2, wherein

ENAM is reacted with a fluoro alkyl halide FAHALIDE in the presence of a base BAS;

wherein

FAHALIDE is a compound of formula (FAHALIDE);

X2-R3-X1  (FAHALIDE)

R3 is C 1-20 alkylene, wherein in the alkylene chain at least one of the hydrogens is substituted by F;

X1 is Cl, Br or I;

X2 is C(O)—OC 1-4 alkyl, F, Br or H;

BAS is selected from the group consisting of Na 3 PO 4 , Na 2 HPO 4 , K 3 PO 4 , K 2 HPO 4 , Na 2 CO 3 , NaHCO 3 , K 2 CO 3 , KHCO 3 , Cs 2 CO 3 , CsHCO 3 , NaOH, KOH, NaOtBu, KOtBu, and DBU;

wherein the reaction REAC2 is performed in the absence of a metal catalyst, in the absence of a Pd catalyst;

wherein the fluoroalkylation of said enamine ENAM by a reaction REAC2 occurs at a carbon atom of said ENAM; and

wherein

ENAM is a compound of formula (ENAM);

wherein

the N atom depicted with (i) is a tertiary, non-aromatic N atom;

the C atoms depicted with (ii) and (iii) are non-aromatic C atoms;

wherein the reaction is between about 16 hours and about 96 hours and the reaction temperature is between about 25° C. and about 80° C.; and

wherein the reaction REAC2 excludes perfluoroalkyl iodide.

2. The method according to claim 1 , wherein

BAS is selected from the group consisting of K 3 PO 4 , K 2 CO 3 , Cs 2 CO 3 , KOH, KOtBu, and DBU.

3. The method according to claim 1 , wherein

R3 is C 1-15 alkylene, wherein in the alkylene chain at least one of the hydrogens is substituted by F.

4. The method according to claim 1 , wherein

X1 is Br or I.

5. The method according to claim 1 , wherein

X2 is C(O)—OC 1-4 alkyl, F or Br.

6. The method according to claim 1 , wherein

the alkylene, that is represented by R3, wherein in the alkylene chain at least one of the hydrogens is substituted by F, is a perfluoroalkylene.

7. The method according to claim 1 , wherein

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

wherein

the N atom depicted with (i) is a tertiary, non-aromatic N atom;

the C atoms depicted with (ii) and (iii) are non-aromatic C atoms;

R20 and R21 are identical or different and selected from the group consisting of H, C 1-10 alkyl, C(O)—C 1-4 alkyl, COOH, C(O)—O—C 1-4 alkyl;

or

R20 and R21 form together with the 3 C atoms in-C (iii) H═C (ii) (N (i) (R10)R11)-CH 2 —, which connect R20 and R21 and with (i), (ii) and (iii) as defined herein, a 5, 6 or 7 membered carbocyclic or heterocyclic, non-aromatic ring RINGA;

the 5 membered RINGA being a ring RINGA-V as depicted in formula (RINGA-V),

the 6 membered RINGA being a ring RINGA-VI as depicted in formula (RINGA-VI), and

the 7 membered RINGA being a ring RINGA-VII as depicted in formula (RINGA-VII);

wherein

each of the two endocyclic C atoms depicted with (1) and (2) in case of RINGA-V,

each of the three endocyclic C atoms depicted with (1), (2) and (3) in case of RINGA-VI, and

each of the four endocyclic C atoms depicted with (1), (2), (3) and (4) in case of RINGA-VII

may be exchanged for a heteroatom O, N or S, said N may be unsubstituted or substituted by

a substituent selected from the group consisting of C 1-10 alkyl, C(O)—C 1-4 alkyl, and phenyl;

any of the bonds connecting the endocyclic atoms depicted with (1), (2), (3) or (4) in RINGA-V, RINGA-VI and RINGA-VII respectively may be a single or a double bond;

any of the endocyclic C atoms depicted with (1), (2), (3) or (4) in RINGA-V, RINGA-VI and RINGA-VII respectively may be unsubstituted or substituted by one or two identical or different substituents selected from the group consisting of C 1-10 alkyl, C(O)—C 1-4 alkyl, COOH, C(O)—O—C 1-4 alkyl, CN, phenyl, N(R12)R13, and oxo, or may be a carbonyl protected with ethylene glycol;

the two endocyclic C atoms depicted with (1) and (4) in RINGA-VII may be connected by —CH 2 — or by —N(R30)-;

R30 is C 1-4 alkyl, phenyl or benzyl;

R12 and R13 are identical or different and selected from the group consisting of H, C 1-10 alkyl, phenyl, and C(O)—C 1-4 alkyl;

or

R20 and R21 together with the 3 C atoms in the —C (iii) H═C (ii) (N (i) (R10)R11)-CH 2 — of formula (ENAM-I), which connect R20 and R21 and with (i), (ii) and (iii) as defined herein, are part of a steroid ring system;

R10 and R11 are identical or different and selected from the group consisting of C 1-10 alkyl and phenyl;

or

R10 and R11 form together with the N atom, which connects R10 and R11, a 5, 6 or 7 membered heterocyclic, non-aromatic ring RINGB;

the 5 membered RINGB being a ring RINGB-V as depicted in formula (RINGB-V),

the 6 membered RINGB being a ring RINGB-VI as depicted in formula (RINGB-VI), and

the 7 membered RINGB being a ring RINGB-VII as depicted in formula (RINGB-VII);

wherein

each of the two endocyclic C atoms depicted with (1) and (2) in case of RINGB-V,

each of the three endocyclic C atoms depicted with (1), (2) and (3) in case of RINGB-VI, and

each of the four endocyclic C atoms depicted with (1), (2), (3) and (4) in case of RINGB-VII

may be exchanged for a heteroatom O, N or S said N may be unsubstituted or substituted by a substituent selected from the group consisting of C 1-10 alkyl, C(O)—C 1-4 alkyl, and phenyl;

any of the bonds connecting the endocyclic atoms depicted with (1), (2), (3) or (4) in RINGB-V, RINGB-VI and RINGB-VII respectively may be a single or a double bond;

any of the endocyclic C atoms depicted with (1), (2), (3) or (4) in RINGB-V, RINGB-VI and RINGB-VII respectively may be unsubstituted or substituted by one or two identical or different substituents selected from the group consisting of C 1-10 alkyl, C(O)—C 1-4 alkyl, COOH, C(O)—O—C 1-4 alkyl, CN, phenyl, N(R14)R15, and oxo, or may be a carbonyl protected with ethylene glycol;

R14 and R15 are identical or different and selected from the group consisting of H, C 1-10 alkyl, phenyl, and C(O)—C 1-4 alkyl.

8. The method according to claim 7 , wherein

when R20 and R21 together with the 3 C atoms in the —C (iii) H═C (ii) (N (i) (R10)R11)-CH 2 — of formula (ENAM-I), which connect R20 and R21, are part of a steroid ring system, the steroid ring system has gonane as steroid nucleus with a carbonyl (oxo substituent) at C-3.

9. The method according to claim 1 , wherein

ENAM is prepared with a reaction REAC1 of a secondary amine SEKAM with a ketone KET.

10. The method according to claim 9 , wherein

SEKAM is a compound of formula (SEKAM);

wherein

the N atom depicted with (i) is a secondary, non-aromatic N atom.

11. The method according to claim 9 , wherein

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

wherein

the N atom depicted with (i) is a secondary, non-aromatic N atom;

R10 and R11 are identical or different and selected from the group consisting of C 1-10 alkyl and phenyl;

or

R10 and R11 form together with the N atom, which connects R10 and R11, a 5, 6 or 7 membered heterocyclic, non-aromatic ring RINGB;

the 5 membered RINGB being a ring RINGB-V as depicted in formula (RINGB-V),

the 6 membered RINGB being a ring RINGB-VI as depicted in formula (RINGB-VI), and

the 7 membered RINGB being a ring RINGB-VII as depicted in formula (RINGB-VII);

wherein

each of the two endocyclic C atoms depicted with (1) and (2) in case of RINGB-V,

each of the three endocyclic C atoms depicted with (1), (2) and (3) in case of RINGB-VI, and

each of the four endocyclic C atoms depicted with (1), (2), (3) and (4) in case of RINGB-VII may be exchanged for a heteroatom O, N or S said N may be unsubstituted or substituted by a substituent selected from the group consisting of C 1-10 alkyl, C(O)—C 1-4 alkyl, and phenyl;

any of the bonds connecting the endocyclic atoms depicted with (1), (2), (3) or (4) in RINGB-V, RINGB-VI and RINGB-VII respectively may be a single or a double bond;

any of the endocyclic C atoms depicted with (1), (2), (3) or (4) in RINGB-V, RINGB-VI and RINGB-VII respectively may be unsubstituted or substituted by one or two identical or different substituents selected from the group consisting of C 1-10 alkyl, C(O)—C 1-4 alkyl, COOH, C(O)—O—C 1-4 alkyl, CN, phenyl, N(R14)R15, and oxo, or may be a carbonyl protected with ethylene glycol.

12. The method according to claim 9 , wherein

KET is a compound of formula (KET);

wherein

the C atoms depicted with (ii) and (iii) are non-aromatic C atoms.

13. The method according to claim 9 , wherein

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

wherein

the C atoms depicted with (ii) and (iii) are non-aromatic C atoms;

R20 and R21 are identical or different and selected from the group consisting of H, C 1-10 alkyl, C(O)—C 1-4 alkyl, COOH, C(O)—O—C 1-4 alkyl;

or

R20 and R21 form together with the 3 C atoms in-C (iii) H═C (ii) (N (i) (R10)R11)-CH 2 —, which connect R20 and R21 and with (i), (ii) and (iii) as defined herein, a 5, 6 or 7 membered carbocyclic or heterocyclic, non-aromatic ring RINGA;

the 5 membered RINGA being a ring RINGA-V as depicted in formula (RINGA-V),

the 6 membered RINGA being a ring RINGA-VI as depicted in formula (RINGA-VI), and

the 7 membered RINGA being a ring RINGA-VII as depicted in formula (RINGA-VII);

wherein

each of the two endocyclic C atoms depicted with (1) and (2) in case of RINGA-V,

each of the three endocyclic C atoms depicted with (1), (2) and (3) in case of RINGA-VI, and

each of the four endocyclic C atoms depicted with (1), (2), (3) and (4) in case of RINGA-VII may be exchanged for a heteroatom O, N or S, said N may be unsubstituted or substituted by a substituent selected from the group consisting of C 1-10 alkyl, C(O)—C 1-4 alkyl, and phenyl;

any of the bonds connecting the endocyclic atoms depicted with (1), (2), (3) or (4) in RINGA-V, RINGA-VI and RINGA-VII respectively may be a single or a double bond;

any of the endocyclic C atoms depicted with (1), (2), (3) or (4) in RINGA-V, RINGA-VI and RINGA-VII respectively may be unsubstituted or substituted by one or two identical or different substituents selected from the group consisting of C 1-10 alkyl, C(O)—C 1-4 alkyl, COOH, C(O)—O—C 1-4 alkyl, CN, phenyl, N(R12)R13, and oxo, or may be a carbonyl protected with ethylene glycol;

the two endocyclic C atoms depicted with (1) and (4) in RINGA-VII may be connected by —CH 2 — or by —N(R30)-;

R30 may be C 1-4 alkyl, phenyl or benzyl;

R12 and R13 are identical or different and selected from the group consisting of H, C 1-10 alkyl, phenyl, and C(O)—C 1-4 alkyl;

or

R20 and R21 together with the 3 C atoms in the —C (iii) H═C (ii) (N (i) (R10)R11)-CH 2 — of formula (ENAM-I), which connect R20 and R21 and with (i), (ii) and (iii) as defined herein, are part of a steroid ring system.

14. The method according to claim 9 , wherein

REAC1 and REAC2 are done without intermediate isolation of ENAM.

15. The method according to claim 1 , wherein

after REAC2, the fluoralkylated ENAM is hydrolyzed with water in a reaction REAC3 to provide a secondary amine SEKAM and a flouralkylated ketone KET.

16. The method according to claim 15 , wherein

REAC3 is done under acidic conditions.

17. The method according to claim 15 , wherein

REAC2 and REAC3 are done without intermediate isolation of the fluoroalkylated ENAM after REAC2.

18. The method according to claim 15 , wherein

REAC1, REAC2 and REAC3 are done without intermediate isolation of ENAM or of the fluoroalkylated ENAM.