Homogeneous process for hydrodehalogenating halogenated heteroaryl compounds
The present invention provides a homogeneous process for hydrodehalogenating a halo-substituted C 3 -C 20 heteroaryl starting material to form a non-halogenated C 3 -C 20 heteroaryl product and/or a halo-substituted C 3 -C 20 heteroaryl product, wherein the halo-substituted C 3 -C 20 heteroaryl product has at least one less halogen substituents than the halo-substituted C 3 -C 20 heteroaryl starting material, the process comprising the step of hydrogenating the halo-substituted C 3 -C 20 heteroaryl starting material in the presence of a rhodium or ruthenium complex, molecular hydrogen, a base and a solvent, wherein the process is carried out in a monophasic solvent system and the molar ratio of base to each halogen substituent to be removed is at least 1:1.
1. A homogeneous process for hydrodehalogenating a halo-substituted C 3 -C 20 heteroaryl starting material to form a non-halogenated C 3 -C 20 heteroaryl product and/or a halo-substituted C 3 -C 20 heteroaryl product, wherein the halo-substituted C 3 -C 20 heteroaryl product has at least one less halogen substituent than the halo-substituted C 3 -C 20 heteroaryl starting material, the process comprising the step of:
hydrogenating the halo-substituted C 3 -C 20 heteroaryl starting material in the presence of a rhodium or ruthenium complex, molecular hydrogen, a base and a solvent, wherein the process is carried out in a monophasic solvent system and the base is present in a molar excess of between 0.1 to 1.0 molar equivalents over an amount required for the stoichiometric reaction to remove each halogen substituent.
2. The process of claim 1 , wherein the halo-substituted C 3 -C 20 heteroaryl starting material has a number of halogen substituents which is ≥2 and up to the limitations imposed by the rules of valence.
3. The process of claim 1 , wherein the halo-substituted C 3 -C 20 heteroaryl starting material is a halo-substituted C 3 -C 15 heteroaryl starting material.
4. The process of claim 1 , wherein the halo-substituted C 3 -C 20 heteroaryl starting material is a halo-substituted C 3 -C 20 nitrogen-containing heteroaryl starting material.
5. The process of claim 1 , wherein the halo-substituted C 3 -C 20 heteroaryl starting material is a chloro-substituted C 3 -C 20 heteroaryl starting material.
6. The process of claim 1 , wherein the halo-substituted C 3 -C 20 heteroaryl starting material is trichloro-pyridine.
7. The process of claim 1 , wherein the halo-substituted C 3 -C 20 heteroaryl product is a halo-substituted C 3 -C 20 nitrogen-containing heteroaryl product.
8. The process of claim 1 , wherein the halo-substituted C 3 -C 20 heteroaryl product is a chloro-substituted C 3 -C 20 heteroaryl product.
9. The process of claim 1 , wherein the halo-substituted C 3 -C 20 heteroaryl product is a halo-substituted C 3 -C 20 nitrogen-containing heteroaryl product.
10. The process of claim 1 , wherein the halo-substituted C 3 -C 20 heteroaryl product is dichloro-pyridine.
11. The process of claim 1 , wherein the base is an inorganic base or an organic base.
12. The process of claim 1 , wherein the base is present in a molar ratio of about 1.1:1 to about 2:1 to each halogen substituent to be removed.
13. The process of claim 12 , wherein the base is present in a molar ratio of about 1.5:1 to about 1.75:1 to each halogen substituent to be removed.
14. The process of claim 1 , wherein the solvent is an alcohol or aromatic solvent.
15. The process of claim 14 , wherein the alcohol has a boiling point at atmospheric pressure below 160° C.
16. The process of claim 14 , wherein the aromatic solvent is benzene, toluene or xylene.
17. The process of claim 1 , wherein the molecular hydrogen is molecular deuterium or molecular tritium.
18. The process of claim 1 , wherein the rhodium complex is a rhodium(I) complex or a rhodium(III) complex.
19. The process of claim 18 , wherein the rhodium(I) complex is Rh(monophosphine) 3 X, Rh(monophosphine) 2 (CO)X, Rh(monophosphine) 3 (CO)H, Rh(monophosphine) 4 H, [Rh(CO) 2 X] 2 , [Rh(olefin) m X] 2 , Rh(olefin) m Cp*, [Rh(olefin) m (phosphine) n ]Y, or a complex generated in situ from [Rh(olefin) m X] 2 and phosphine, wherein:
Cp* is 1,2,3,4,5-pentamethyl-cyclopentadienyl;
X is a halogen,
Y is a non-coordinated anionic ligand,
the phosphine is a monophosphine or a diphosphine,
m is 1 or 2,
n is 1 or 2, and wherein:
when m=1, the olefin is a diolefin,
when m=2, the olefin is a mono-olefin,
when n=1, the phosphine is a bidentate phosphine, and
when n=2, the phosphine is a monophosphine.
20. The process of claim 18 , wherein the rhodium(III) complex is Rh(monophosphine) 2 X p H q or [Rh(Cp*)X 2 ] 2 , wherein:
X is a halogen,
p is 1 or 2,
q is 2 or 1, and
p+q is 3.
21. The process of claim 1 , wherein the ruthenium complex is Ru(monophosphine) 3 X 2 , Ru(monophosphine) 3 HX, Ru(monophosphine) 2 (CO) 2 X 2 , Ru(monophosphine) 3 (CO)X r H s , [Ru(Cp*)X 2 ] polymer, Ru(Cp*)(monophosphine) 2 X, [Ru(arene)X 2 ] 2 , Ru(monophosphine)(arene)X 2 , [Ru(olefin) t X 2 ] polymer, Ru(olefin)t(Cp*)X, or a complex generated in situ from [Ru(olefin) t X 2 ] polymer and phosphine, wherein:
X is a halogen,
the phosphine is a monophosphine or a diphosphine,
t is 1 or 2,
r is 0 or 1,
s is 2 or 1, and
r+s is 2, and
wherein:
when t=1, the olefin is a diolefin,
when t=2, the olefin is a mono-olefin.
22. The process of claim 19 , wherein the mono-olefin is ethylene or cyclooctene.
23. The process of claim 21 , wherein the diolefin is 1,5-hexadiene, cyclooctadiene or norbornadiene.
24. The process of claim 19 , wherein the diolefin is 1,5-hexadiene, cyclooctadiene or norbornadiene.
25. The process of claim 21 , wherein the diolefin is 1,5-hexadiene, cyclooctadiene or norbornadiene.
26. The process of claim 16 , wherein Y is [BF 4 ] − , [CF 3 SO 3 ] − , [PF 6 ] − or [SbF 6 ] − .