Transition metal-catalyzed protocarboxylation of α-halo-acrylic acid derivatives

1. A method for the synthesis of a halo olefin of formula (I)

the method comprising the step (S1) of protodecarboxylation of an α-halo-acrylic acid derivative of formula (II)

to provide the halo olefin of formula (I),

wherein

Hal is selected from the group consisting of F, Cl, Br and I, and

R 1 , R 2 , R 3 and R 4 are independently selected from the group R i consisting of

H, halogen, CN, substituted or unsubstituted C 1-10 -alkyl, substituted or unsubstituted C 3-10 -cycloalkyl, substituted or unsubstituted C 2-10 -alkenyl, substituted or unsubstituted C 2-10 -alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C 1-6 -alkylene-, substituted or unsubstituted heteroaryl and substituted or unsubstituted heteroaryl-C 1-6 -alkylene-, and

X and Y are independently selected from the groups consisting of

R i , OR X , SR X , S(O)R X , SO 2 R X , NR Y1 R Y2 , N(O)R Y1 R Y2 , PR Y1 R Y2 and P(O)R Y1 R Y2 ,

wherein R X is selected from the group of R i , and

wherein R Y1 and R Y2 are independently selected from the group consisting of

R i , C(O)R i and C(O)OR i or

R Y1 and R Y2 are selected from the group R Y in which

R Y1 and R Y2 are linked to form, together with N or P to which they are attached, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl, and

R i is selected from the group R as defined hereinbefore;

or a salt thereof

wherein (S1) is carried out in the presence of a catalytic amount of copper and/or silver.

2. The method according to claim 1 , wherein copper and/or silver are employed in the form of oxides and/or salts selected from the group consisting of copper(I) oxide, copper(I) salts, silver(I) oxide and silver(I) salts.

3. The method according to claim 1 , wherein Hal is F.

4. The method according to claim 1 , wherein R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of H, halogen, CN and optionally partially or fully halogenated methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl and cyclopropyl.

5. The method according to claim 1 , wherein R i is selected from the group consisting of H, halogen, CN and optionally partially or fully halogenated methyl.

6. The method according to claim 1 , wherein X is selected from the group consisting of OR X , SR X , S(O)R X and SO 2 R X ,

wherein R X is selected from the group consisting of H, substituted or unsubstituted C 1-10 -alkyl, substituted or unsubstituted C 3-10 -cycloalkyl, substituted or unsubstituted C 2-10 -alkenyl, substituted or unsubstituted C 2-10 -alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C 1-6 -alkylene-, substituted or unsubstituted heteroaryl and substituted or unsubstituted heteroaryl-C 1-6 -alkylene-.

7. The method according to claim 1 , wherein Y is selected from the group consisting of NR Y1 R Y2 , PR Y1 R Y2 and P(O)R Y1 R Y2 ,

wherein R Y1 and R Y2 are independently selected from the group consisting of

H, substituted or unsubstituted C 1-10 -alkyl, substituted or unsubstituted C 3-10 -cycloalkyl, substituted or unsubstituted C 2-10 -alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C 1-6 -alkylene-, substituted or unsubstituted C 1-10 -alkyl-C(O)—, substituted or unsubstituted aryl-C(O)—, substituted or unsubstituted aryl-C 1-6 -alkylene-C(O)—, substituted or unsubstituted C 1-10 -alkyl-OC(O)—, substituted or unsubstituted aryl-OC(O)— and substituted or unsubstituted aryl-C 1-6 -alkylene-OC(O)— or

R Y1 and R Y2 are selected from the group R Y in which R Y1 and R Y2 are linked to form, together with N or P to which they are attached, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl.

8. The method according to claim 1 , wherein the compound of formula (II) is compound (II-g)

wherein R ar is selected from the group consisting of C(O)NR N1 R N2 or SO 2 NR N1 R N2 ,

wherein R N1 and R N2 are independently selected from the group consisting of H, substituted or unsubstituted C 1-6 -alkyl and substituted or unsubstituted C 3-7 -cycloalkyl, and

wherein R Y1 and R Y2 are independently selected from the group consisting of H, substituted or unsubstituted acetyl, substituted or unsubstituted tert-butyloxycarbonyl, substituted or unsubstituted carboxybenzyl, substituted or unsubstituted fluorenylmethyloxycarbonyl, substituted or unsubstituted allyloxycarbonyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted benzyl and substituted or unsubstituted phthaloyl or

R Y1 and R Y2 are selected from the group R Y in which

R Y1 and R Y2 are linked to form, together with N to which they are attached, substituted or unsubstituted phthalimide or substituted or unsubstituted pyrrole; and

the compound of formula (I) is compound (I-g)

9. The method according to claim 8 , wherein step (S1) comprises the deprotection of the compound of formula (I-g)

wherein R ar is selected from the group consisting of C(O)NR N1 R N2 or SO 2 NR N1 R N2 ,

wherein R N1 and R N2 are independently selected from the group consisting of H, substituted or unsubstituted C 1-6 -alkyl and substituted or unsubstituted C 3-7 -cycloalkyl, and

wherein R Y1 and R Y2 are independently selected from the group consisting of H, substituted or unsubstituted acetyl, substituted or unsubstituted tert-butyloxycarbonyl, substituted or unsubstituted carboxybenzyl, substituted or unsubstituted fluorenylmethyloxycarbonyl, substituted or unsubstituted allyloxycarbonyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted benzyl and substituted or unsubstituted phthaloyl or

R Y1 and R Y2 are selected from the group R Y in which

R Y1 and R Y2 are linked to form, together with N to which they are attached, substituted or unsubstituted phthalimide or substituted or unsubstituted pyrrole;

to compound (I-g′)

10. The method according to claim 1 , wherein the compound of formula (II) is compound (II-j)

and

the compound of formula (I) is compound (I-j)

11. The method according to claim 1 , further comprising the step (S2) for the formation of the α-halo-acrylic acid derivative of formula (II):

the step (S2) comprising reacting a ketone of formula (III)

with a phosphonate of formula (IV)

wherein

Hal is selected from the group consisting of F, Cl, Br and I,

R 0 is selected from the group consisting of H and C 1-6 -alkyl, and

R is selected from the group consisting of optionally partially or fully halogenated methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl and tert-butyl, phenyl, and

in the presence of at least one basic additive; and

in case R 0 is not H, saponification of the formed ester of formula (II′)

and

optional separation of the E and Z isomers of the compound of formula (II).

12. The method according to claim 11 , wherein in step (S2) the compound of formula (III) is compound (III-g)

wherein R ar is selected from the group consisting of C(O)NR N1 R N2 or SO 2 NR N1 R N2 ,

wherein R N1 and R N2 are independently selected from the group consisting of H, substituted or unsubstituted C 1-6 -alkyl and substituted or unsubstituted C 3-7 -cycloalkyl, and

wherein R Y1 and R Y2 are independently selected from the group consisting of H, substituted or unsubstituted acetyl, substituted or unsubstituted tert-butyloxycarbonyl, substituted or unsubstituted carboxybenzyl, substituted or unsubstituted fluorenylmethyloxycarbonyl, substituted or unsubstituted allyloxycarbonyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted benzyl and substituted or unsubstituted phthaloyl or

R Y1 and R Y2 are selected from the group R Y in which

R Y1 and R Y2 are linked to form, together with N to which they are attached, substituted or unsubstituted phthalimide or substituted or unsubstituted pyrrole,

and Hal in the phosphonate of formula (IV) is F,

and the compound of formula (II) is compound (II-g)

13. The method according to claim 11 , wherein in step (S2) the compound of formula (III) is compound (III-j)

and the compound of formula (II) is compound (II-j)