Cyanation of aromatic halides
View Patent ↗A practical, ligand-free cyanation of aryl bromides employs Pd catalyst in combination with a non-toxic cyanide source, M n [Fe(CN) 6 ] (M=K or Na; n is 3 or 4), or a hydrate thereof, and a base. The reactions are performed in a polar aprotic solvents and provide the corresponding aryl nitrile in 83-96% yield, typically in less than 5 h.
1. A process for the synthesis of II,
wherein:
Ar is phenyl:
R is:
R 2 is selected from: hydrogen, halogen and hydroxyl;
comprising treating a bromo compound of formula I:
with M n [Fe(CN) 6 ], or a hydrate thereof, in the presence of a palladium source, and a base in a polar aprotic solvent, to form a solvent mixture, wherein: M is selected from sodium and potassium, n is selected from 3 and 4;
and heating the reaction mixture to obtain the product compound II.
2. The process according to claim 1 , wherein the product compound II is isolated.
3. The process according to claim 1 , wherein the palladium source is selected from palladium acetate, tris(dibenzylideneacetone)dipalladium, and palladium chloride.
4. The process according to claim 3 , wherein the palladium source is palladium acetate.
5. The process according to claim 1 , wherein the base is sodium carbonate.
6. The process according to claim 5 , wherein the solvent is dimethyl acetate.
7. The process according to claim 1 , wherein M is potassium, and M 4 [Fe(CN) 6 ] is K 4 [Fe(CN) 6 ]·3H 2 O, and is employed at 0.18 to 0.25 mole % relative to bromo compound I.
8. The process according to claim 7 , wherein the palladium acetate is employed at 0.1 to 0.5 mole % relative to bromo compound I, and the sodium carbonate is employed at 0.3 to 2.0 mole % relative to bromo compound I.
9. The process according to claim 8 , additionally comprising treatment with an amine ligand selected from a secondary monoamine and a diamine.
10. The process according to claim 9 , wherein the amine ligand is selected from dicyclohexylamine, DABCO and TMEDA.
11. The process according to claim 10 , wherein the amine ligand is DABCO.
12. The process according to claim 1 , wherein:
R 2 is chloro.
13. The process according to claim 1 , wherein the reaction is carried out under an inert atmosphere.
14. The process according to claim 1 , additionally comprising treating the compound of formula II with NaOtBu and [R 4 —S(O) 2 ] 2 O, wherein:
R 4 is selected from: aryl , heteroaryl and C 1-10 alkyl, wherein the aryl and heteroaryl moieties are unsubstituted or substituted with one to three R c substituents, and the alkyl moiety is unsubstituted or substituted with one or two R d substituents
each R c is independently selected from halogen, hydroxy, C 1-3 alkyl, cyano, methoxy and trifluoromethyl;
each R d is independently selected from: halogen, hydroxy, cyano, methoxy and trifluoromethyl;
to form a compound of structural formula (III):
15. The process according to claim 14 , additionally comprising treating the compound of formula III with amide IV:
in the presence of a base and a palladium catalyst;
wherein:
R 3 is
R a is selected from phenyl, pyridyl, and pyrimidinyl, wherein each of phenyl, pyridyl and pyrimidinyl are independently unsubstituted or substituted with an R b substituent; each R b is independently selected from: chloro, iodo, methyl, cyano and trifluoromethyl to form the enamide V:
16. The process according to claim 15 , additionally comprising treating the enamide V with hydrogen gas in the presence of a chiral catalyst to form amide VI:
17. The process according to claim 16 , wherein:
R 3 is:
R a is
the hydrogen gas is at a pressure of from 30 to 60 atmospheres.