Hydroxylation of beta-dicarbonyls with zirconium catalysts
View Patent ↗The present invention pertains to a process for preparing a compound of Formula I that is achiral, racemic or enantiomerically enriched at the hydroxylation center indicated by * comprising contacting a compound of Formula II with an oxidant selected from oxygen, hydrogen peroxide, peracids or alkyl hydroperoxides in the presence of a zirconium complex, wherein R 1 , R 2 and R 3 are as defined in the disclosure. This invention also pertains to zirconium complexes useful in this procedure comprising zirconium and a ligand of Formula III or its enantiomer wherein J, R 6 and n are as defined in the disclosure. This invention further pertains to a compound of Formula III or its enantiomer.
1. A zirconium complex comprising zirconium and a chiral ligand of Formula III of at least about 50% enantiomeric purity
wherein
J is an optionally substituted linking chain of 2 to 4 members consisting of at least one carbon atom member and optionally one member selected from nitrogen and oxygen, of which no more than two carbon atom members are substituted as C(═O); the linking chain optionally fused through adjacent linking chain members to 1 or 2 rings or ring systems selected from the group consisting of a C 3 -C 8 cycloalkyl ring, a phenyl ring or a 1,2-naphthalenyl ring system, each ring or ring system optionally substituted; such that the attached nitrogen atoms are held in a stereospecific orientation with respect to J and each other as depicted;
each R 6 is independently selected from the group consisting of halogen; NO 2 ; cyano; C 2 -C 5 alkoxycarbonyl; N(C 1 -C 4 alkyl) 2 ; CON(C 1 -C 4 alkyl) 2 ; C 1 -C 4 alkoxy; C 2 -C 5 alkylcarbonyloxy; C 2 -C 5 alkoxycarbonyloxy; optionally substituted phenylcarbonyloxy; (C 1 -C 4 alkyl)silyl; tri(C 1 -C 4 alkyl)siloxy; C 1 -C 4 alkyl optionally substituted with 1-3 phenyl rings; C 3 -C 6 cycloalkyl optionally substituted with C 1 -C 2 alkyl; adamantyl; or a phenyl ring, or a 5- or 6-membered heteroaromatic ring, each ring optionally substituted; and
when two R 6 are attached to adjacent phenyl ring carbon atoms, said two R 6 may be taken together with the phenyl ring to form a naphthalene ring system optionally substituted on either ring of said naphthalene ring system; and
each n is independently an integer from 0 to 4.
2. The zirconium complex of claim 1 wherein each phenyl ring in Formula III has an R 6 substituent ortho to the —OH function.
3. The zirconium complex of claim 2 wherein the chiral ligand of Formula III is a ligand of Formula IIIa
wherein each R 6 is the same and is selected from H and C(CH 3 ) 3 .
4. The zirconium complex of claim 2 wherein the chiral ligand of Formula III is a ligand of Formula IIIb
wherein each R 6 is the same and is selected from H and C(CH 3 ) 3 .
5. A zirconium complex comprising zirconium and a chiral ligand of Formula ent-III of at least about 50% enantiomeric purity
wherein
J is an optionally substituted linking chain of 2 to 4 members consisting of at least one carbon atom member and optionally one member selected from nitrogen and oxygen, of which no more than two carbon atom members are substituted as C(═O); the linking chain optionally fused through adjacent linking chain members to 1 or 2 rings or ring systems selected from the group consisting of a C 3 -C 8 cycloalkyl ring, a phenyl ring or a 1,2-naphthalenyl ring system, each ring or ring system optionally substituted; such that the attached nitrogen atoms are held in a stereospecific orientation with respect to J and each other as depicted;
each R 6 is independently selected from the group consisting of halogen; NO 2 ; cyano; C 2 -C 5 alkoxycarbonyl; N(C 1 -C 4 alkyl) 2 ; CON(C 1 -C 4 alkyl) 2 ; C 1 -C 4 alkoxy; C 2 -C 5 alkylcarbonyloxy; C 2 -C 5 alkoxycarbonyloxy; optionally substituted phenylcarbonyloxy; (C 1 -C 4 alkyl)silyl; tri(C 1 -C 4 alkyl)siloxy; C 1 -C 4 alkyl optionally substituted with 1-3 phenyl rings; C 3 -C 6 cycloalkyl optionally substituted with C 1 -C 2 alkyl; adamantyl; or a phenyl ring, or a 5- or 6-membered heteroaromatic ring, each ring optionally substituted; and
when two R 6 are attached to adjacent phenyl ring carbon atoms, said two R 6 may be taken together with the phenyl ring to form a naphthalene ring system optionally substituted on either ring of said naphthalene ring system; and
each n is independently an integer from 0 to 4.
6. The zirconium complex of claim 5 wherein each phenyl ring in Formula ent-III has an R 6 substituent ortho to the —OH function.
7. The zirconium complex of claim 6 wherein the chiral ligand of Formula ent-III is a ligand of Formula ent-IIIa
wherein each R 6 is the same and is selected from H and C(CH 3 ) 3 .
8. The zirconium complex of claim 6 wherein the chiral ligand of Formula ent-III is a ligand of Formula ent-IIIb
wherein each R 6 is the same and is selected from H and C(CH 3 ) 3 .