Process for hydrogenating ketones in the presence of Ru(II) catalysts
View Patent ↗The present invention relates to a process for hydrogenating a substrate comprising a carbon-heteroatom double bond, the process comprising the step of reacting the substrate with hydrogen gas in the presence of a hydrogenation catalyst, wherein the hydrogenation catalyst is a complex of formula (I): R 1-10 , A and Hal are as defined in the specification. The present invention also provides processes for the preparation of the complex of formula (I) and intermediates thereof.
1. A process for the preparation of a compound of formula (VIII):
comprising the steps of:
a) converting a compound of formula (IX) into a compound of formula (X):
b) reacting the compound of formula (X) with a compound of formula (XI) in a solvent to form the compound of formula (VIII):
wherein,
R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, optionally substituted straight, branched or cyclic C 1-20 alkyl, optionally substituted straight, branched or cyclic C 1-20 alkoxy, optionally substituted C 6-20 aryl, optionally substituted C 6-20 aryloxy, —OH, —CN, —NR 20 R 21 , —COOH, COOR 20 , —CONH 2 , —CONR 20 R 21 and —CF 3 , wherein the substituents are selected from the group consisting of one or more straight, branched or cyclic C 1-20 alkyl, straight, branched or cyclic C 1-20 alkoxy, C 6-20 aryl, C 6-20 aryloxy, —OH, —CN, —NR 30 R 31 , —COOR 30 , —CONR 30 R 31 and —CF 3 ; or
R 3 and R 4 together form an aromatic ring composed of 6 to 10 carbon atoms which is optionally substituted with one or more straight, branched or cyclic C 1-20 alkyl, straight, branched or cyclic C 1-20 alkoxy, C 6-20 aryl, C 6-20 aryloxy, —OH, —CN, —NR 20 R 21 , —COOR 20 , —CONR 20 R 21 and —CF 3 ;
R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of hydrogen, optionally substituted straight, branched or cyclic C 1-20 alkyl, optionally substituted straight, branched or cyclic C 1-20 alkoxy, optionally substituted C 6-20 aryl and optionally substituted C 6-20 aryloxy wherein the substituents are selected from the group consisting of one or more straight, branched or cyclic C 1-20 alkyl, straight, branched or cyclic C 1-20 alkoxy, C 6-20 aryl, C 6-20 aryloxy, —OH, —CN, —NR 20 R 21 —COOR 20 , —CONR 20 R 21 and —CF 3 , or
R 6 and R 7 together with the carbon atom to which they are bound and/or R 8 and R 9 together with the carbon atom to which they are bound form an optionally substituted C 3-20 cycloalkyl or an optionally substituted C 2-20 cycloalkoxy, wherein the substituents are selected from the group consisting of one or more straight, branched or cyclic C 1-20 alkyl, straight, branched or cyclic C 1-20 alkoxy, C 6-20 aryl, C 6-20 aryloxy, —OH, —CN, —NR 20 R 21 , —COOR 20 , —CONR 20 R 21 , and —CF 3 , or one of R 6 and R 7 and one of R 8 and R 9 together form an optionally substituted C 5-10 cycloalkyl or an optionally substituted C 5-10 cycloalkoxy, wherein the substituents are independently selected from the group consisting of one or more straight, branched or cyclic C 1-20 alkyl, straight, branched or cyclic C 1-20 alkoxy, C 6-20 aryl, C 6-20 aryloxy, —OH, —CN, —NR 20 R 21 , —COOR 20 , —CONR 20 R 21 and —CF 3 ;
R 10 is an optionally substituted straight, branched or cyclic C 1-10 alkyl, an optionally substituted C 6-10 aryl or —NR 11 R 12 wherein the substituents are selected from the group consisting of one or more straight, branched or cyclic C 1-10 alkyl, straight, branched or cyclic C 1-10 alkoxy, C 6-10 aryl, C 6-10 aryloxy, —Hal, —OH, —CN, —NR 20 R 21 , —COOR 20 , —CONR 20 R 21 and CF 3 ;
further wherein
R 11 and R 12 are independently selected from the group consisting of hydrogen, optionally substituted straight, branched or cyclic C 1-10 alkyl and optionally substituted C 6-10 aryl, wherein the substituents are selected from the group consisting of one or more straight, branched or cyclic C 1-10 alkyl groups, straight, branched or cyclic C 1-10 alkoxy, C 6-10 aryl, C 6-10 aryloxy, —OH, —CN, —NR 20 R 21 , —COOR 20 , —CONR 20 R 21 and —CF 3 , or
R 11 and R 12 together with the nitrogen atom to which they are bound form an optionally substituted C 2-10 cycloalkyl-amino group wherein the substituents are selected from the group consisting of one or more straight, branched or cyclic C 1-10 alkyl, straight, branched or cyclic C 1-10 alkoxy, C 6-10 aryl, C 6-10 aryloxy, —OH, —CN, —NR 20 R 21 , —COOR 20 , —CONR 20 R 21 and —CF 3 ; R 20 and R 21 are independently selected from the group consisting of hydrogen, optionally substituted straight, branched or cyclic C 1-20 alkyl, optionally substituted straight, branched or cyclic C 1-20 alkoxy, optionally substituted C 6-20 aryl, optionally substituted C 6-20 aryloxy, OH, —CN, —NR 30 R 31 , —COOR 30 , —CONR 30 R 31 and —CF 3 , wherein the substituents are selected from the group consisting of one or more straight, branched or cyclic C 1-20 alkyl, straight, branched or cyclic C 1-20 alkoxy, C 6-20 aryl, C 6-20 aryloxy, —OH, —CN and —CF 3 ;
R 30 and R 31 are independently selected from the group consisting of hydrogen, optionally substituted straight, branched or cyclic C 1-20 alkyl, optionally substituted straight, branched or cyclic C 1-20 alkoxy, optionally substituted C 6-20 aryl, optionally substituted C 6-20 aryloxy, OH, —CN and —CF 3 , wherein the substituents are selected from the group consisting of one or more straight, branched or cyclic C 1-20 alkyl, straight, branched or cyclic C 1-20 alkoxy, C 6-20 aryl, C 6-20 aryloxy, —OH, —CN and —CF 3 ;
and
A is an optionally substituted straight- or branched-chain C 3-5 alkyl wherein the substituents are selected from the group consisting of one or more straight, branched or cyclic C 1-10 alkyl, straight, branched or cyclic C 1-10 alkoxy, C 6-10 aryl and C 6-10 aryloxy, or
A is a group of formula (II):
wherein p is an integer selected from 1, 2, 3 or 4;
each R 40 is independently selected from the group consisting of straight, branched or cyclic C 1-20 alkyl, straight, branched or cyclic C 1-20 alkoxy, C 6-20 aryl, C 6-20 aryloxy, —OH, —CN and —CF 3 ;
q and r are independently integers selected from 0, 1, 2 or 3 wherein q+r =1, 2 or 3;
each R 41 is independently selected from the group consisting of hydrogen, straight, branched or cyclic C 1-20 alkyl, straight, branched or cyclic C 1-20 alkoxy, C 6-20 aryl, C 6-20 aryloxy, —OH, —CN and —CF 3 ; and
Hal is a halogen, and
X is an electrophilic group
c) reacting the compound of formula (VIII) with an acid HZ, where Z is an anion; and
d) reacting the acid addition salt of the compound of formula (VIII) with a Ru(Hal), complex, where Hal is a halogen and n is a number equal to or less than the coordination number of Ru, to form a complex of formula (XIII):
wherein the acid addition salt of the compound of formula (VIII) is prepared without isolation before reaction with the Ru(Hal) n complex.
2. A process according to claim 1 , wherein step (a) comprises reacting the compound of formula (IX) with a base and a compound of formula (XII):
X-LG (XII)
wherein LG is a leaving group.
3. The process according to claim 2 , wherein the base is an amine.
4. The process according to claim 3 , wherein the base is selected from the group consisting of lutidine and triethylamine.
5. The process according to claim 2 , wherein the compound of formula (XII) is selected from the group consisting of trifluoromethane sulfonic anhydride, trifluoromethane sulfonic acid, methanesulfonyl chloride and p-toluenesulfonyl chloride.
6. The process according to claim 1 , wherein step (b) further comprises a base.
7. The process according to claim 6 , wherein the base is an amine.
8. The process according to claim 7 , wherein the base is triethylamine.
9. The process according to claim 1 , further comprising the step of treating the complex of formula (XIII) with a base to form the complex of formula (I):
10. The process according to claim 1 , wherein the complex of formula (XIII) is isolated.