Hydroxylation of β-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 chiral compound of Formula III of at least about 50% enantiomeric purity
wherein
J is a linking chain of 2 members consisting of carbon atom members; the linking chain fused through adjacent linking chain members to a cyclohexyl ring optionally substituted with substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, halogen and nitro; 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; phenylcarbonyloxy optionally substituted with substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, halogen and nitro; tri(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; a phenyl ring, or a 5- or 6-membered heteroaromatic ring, each ring optionally substituted with substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, halogen and nitro; 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 with substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, halogen and nitro; and
each n is independently an integer from 0 to 4;
provided that (a) when J is a C 6 cycloalkyl ring connected via adjacent carbon atoms to the remainder of Formula III, then at least one n is an integer from 1 to 4; and (b) when J is a C 6 cycloalkyl ring connected via adjacent carbon atoms to the remainder of Formula III, on one phenyl ring n is 2 and (R 6 ) n is 3-t-butyl-5-methyl, then (R 6 ) n on the other phenyl ring is other than 3-t-butyl-5-methyl.
2. The chiral compound of claim 1 that is Formula IIIa
wherein each R 6 is the same and is selected from H and C(CH 3 ) 3 .
3. A chiral compound of Formula ent-III of at least about 50% enantiomeric purity
wherein
J is a linking chain of 2 members consisting of carbon atom members; the linking chain fused through adjacent linking chain members to a cyclohexyl ring optionally substituted with substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, halogen and nitro; 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; phenylcarbonyloxy optionally substituted with substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, halogen and nitro; tri(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; a phenyl ring, or a 5- or 6-membered heteroaromatic ring, each ring optionally substituted with substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, halogen and nitro; 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 with substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, halogen and nitro; and
each n is independently an integer from 0 to 4;
provided that (a) when J is a C 6 cycloalkyl ring connected via adjacent carbon atoms to the remainder of Formula ent-III, then at least one n is an integer from 1 to 4; (b) when J is a C 6 cycloalkyl ring connected via adjacent carbon atoms to the remainder of Formula ent-III, on one phenyl ring n is 2 and (R 6 ) n is 3-t-butyl-5-methyl, then (R 6 ) n on the other phenyl ring is other than 3-t-butyl-5-methyl; and (c) when J is a C 6 cycloalkyl ring connected via adjacent carbon atoms to the remainder of Formula ent-III, on one phenyl ring n is 2 and (R 6 ) n is 3-t-butyl-5-t-butyl, then (R 6 ) n on the other phenyl ring is other than 3-t-butyl-5-t-butyl.
4. The chiral compound of claim 3 that is Formula ent-IIIa
wherein R 6 is H.
5. The chiral compound of claim 2 that is 2,2′-[(1S,2S)-1,2-cyclohexanediylbis(iminomethylene)]bis[4,6-bis(1,1-dimethylethyl)phenol].
6. The chiral compound of claim 2 that is 2,2′-[(1S,2S)-1,2-cyclohexanediylbis(iminomethylene)]bis[6-(1,1-dimethylethyl)phenol].
7. A chiral compound of claim 1 wherein
J is
each R 7 is independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy and halogen; and
p is an integer from 0 to 4.
8. A chiral compound of claim 3 wherein
J is
each R 7 is independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy and halogen; and
p is an integer from 0 to 4.