Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-04-10
2003-03-18
Lambkin, Deborah C. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S090000
Reexamination Certificate
active
06534653
ABSTRACT:
The present invention relates to 8-azadioxolanebicyclomethanols; metal complexes with metals selected from the eighth sub-group of the Periodic Table of the Elements (subsequently designated as TM8 metals) and 8-azadioxolanebicyclomethanols as ligands; a process for the asymmetric transfer hydrogenation of prochiral carbon double bonds or heteroatom carbon double bonds using hydrogen or hydrogen donors; the use of metal complexes with TM8 metals and azadioxolanebicyclomethanols as ligands for the asymmetric transfer hydrogenation of prochiral carbon and heteroatom carbon double bonds; and a kit formed from (a) a TM8 metal compound as precursor for a metal complex and (b) 8-azadioxolanebicyclomethanols as ligands, the components (a) and (b) being located in separate vessels.
CA-A-2,239,970 describes a process for the asymmetric hydrogenation of C-heteroatom double bonds in, for example, prochiral ketones or imines using inorganic or organic hydrogen donors, for example secondary alcohols, in which transition metal complexes are employed as enanantioselective catalysts which contain compounds comprising chiral nitrogen as ligands. In the description, the ligands having a 1,2-aminoethanol parent structure are mentioned. Good optical yields are achieved. The low catalyst activity causes long reaction times and the use of relatively high amounts of catalyst, which stands in the way of industrial application.
WO 98/42643 describes the same process, identical or similar ligands being used, and Ru, Rh and iridium complexes with substituted cyclopentadienyl ligands being employed as catalysts. The disadvantages mentioned beforehand also exist here.
In J. Org. Chem. 1998, 63, pages 2749 to 2751, D. A. Alonso et al. also describe the process mentioned, 2-aza-1-hydroxymethyinorbornane being used as bicyclic asymmetric ligand. Using this ligand, high optical yields are in turn achieved, the catalyst activity, however, being felt to be inadequate.
It has now surprisingly been found that high conversions can be achieved in asymmetric transfer hydrogenation using chiral 8-aza-1-hydroxymethylnorbornanes as ligands in TM8 metal complexes as catalysts in significantly shorter reaction times and high optical yields even with relatively low amounts of catalyst if a dioxolane ring is fused to the bicyclic ring system.
A first subject of the invention is compounds of the formula I, in the form of their racemates, mixtures of stereoisomers or mainly pure stereoisomers,
in which
Y is C
1
-C
4
alkylene or —SiR
1
R
2
—;
X is a carbon atom and A
1
and A
2
independently of one another are hydrogen, C
1
-C
12
alkyl, C
2
-C
12
alkenyl, C
3
-C
8
cycloalkyl, C
3
-C
8
cycloalkenyl, C
3
-C
8
cycloalkyl-C
1
-C
4
alkyl, C
3
-C
8
cycloalkenyl-C
1
-C
4
alkyl, C
6
-C
10
aryl or C
7
-C
14
aralkyl; or
X is a silicon atom and A
1
and A
2
independently of one another are C
1
-C
12
alkyl, C
3
-C
8
cycloalkyl, C
3
-C
8
cycloalkyl-C
1
-C
4
alkyl, C
6
-C
10
aryl or C
7
-C
14
aralkyl;
A
3
and A
4
independently of one another are hydrogen, C
1
-C
12
alkyl, C
3
-C
8
cycloalkyl, C
3
-C
8
cycloalkyl-C
1
-C
4
alkyl, C
6
-C
10
aryl or C
7
-C
14
aralkyl; and
R
1
and R
2
independently of one another are C
1
-C
6
alkyl, cyclohexyl, phenyl or benzyl.
Among the stereoisomers, those having the configuration 1S, 2R, 6S, 7R, 9R are preferred. Among the enantiomers, those having the configuration 1S, 2R, 6S, 7R, 9R, 10R are preferred.
R
1
and R
2
are preferably independently of one another linear C
1
-C
4
alkyl. In formula I, Y is preferably linear or branched alkylene, and particularly preferably methylene or ethylene.
In formula I, X is preferably a carbon atom. A
1
and A
2
are preferably identical radicals.
As alkyl, A
1
and A
2
preferably contain 1 to 6 and particularly preferably 1 to 4 C atoms. Examples of alkyl are methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, and the isomers of pentyl and hexyl.
As alkenyl, A
1
and A
2
preferably contain 2 to 6 and particularly preferably 2 to 4 C atoms. Examples of alkenyl are vinyl, allyl and crotonyl.
As cycloalkyl, A
1
and A
2
preferably contain 4 to 7 and particularly preferably 5 or 6 ring C atoms. Examples of cycolalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Cyclopentyl and cyclohexyl are preferred.
As cycloalkenyl, A
1
and A
2
preferably contain 4 to 7 and particularly preferably 5 or 6 ring C atoms. Examples of cycloalkenyl are cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Cyclopentenyl and cyclohexenyl are preferred.
As cycloalkylalkyl, A
1
and A
2
are preferably C
5
-C
6
cycloalkyl-C
1
-C
2
alkyl. Examples are cyclopentylmethyl, cyclohexylmethyl, cyclopentylethyl and cyclohexylethyl.
As cycloalkenylalkyl, A
1
and A
2
are preferably C
5
-C
6
cycloalkenyl-C
1
-C
2
alkyl. Examples are cyclopentenylmethyl, cyclohexenylmethyl, cyclopentenylethyl and cyclohexenylethyl.
As aryl, A
1
and A
2
can be, for example, phenyl or naphthyl.
As aralkyl, A
1
and A
2
can be, for example, phenyl-C
1
-C
4
alkyl or naphthyl-C
1
-C
4
alkyl. Benzyl and phenylethyl are preferred.
In a preferred embodiment, A
1
and A
2
are hydrogen, C
1
-C
4
alkyl, cyclopentyl, cyclohexyl, phenyl or benzyl. Particularly preferably, A
1
and A
2
are each C
1
-C
4
alkyl and very particularly preferably each methyl.
If X is a silicon atom, A
1
and A
2
are preferably each methyl, ethyl or phenyl.
A
3
and A
4
can be identical or different. Preferably, A
3
and A
4
are identical and are hydrogen. Another preferred group are compounds of the formula I in which A
3
and A
4
are different, particularly those in which A
3
is hydrogen and A
4
is C
1
-C
12
alkyl, C
3
-C
8
cycloalkyl, C
3
-C
8
cycloalkyl-C
1
-C
4
alkyl, C
6
-C
10
aryl or C
7
-C
14
aralkyl, preferably C
1
-C
4
alkyl. It has surprisingly been found that the catalyst activity can be further increased if, in the ligand of the formula I, A
3
is hydrogen and A
4
is a substituent, and the chiral C atom to which A
4
is bonded has the R configuration, the other chiral C atoms having the configuration 1S, 2R, 6S, 7R, 9R.
As alkyl, A
3
and A
4
preferably contain 1 to 6 and particularly preferably 1 to 4 C atoms. Examples of alkyl are methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, and the isomers of pentyl and hexyl. Methyl and ethyl are particularly preferred.
As cycloalkyl, A
3
and A
4
preferably contain 4 to 7 and particularly preferably 5 or 6 ring C atoms. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Cyclopentyl and cyclohexyl are preferred.
As cycloalkylalkyl, A
3
and A
4
are preferably C
5
-C
6
cycloalkyl-C
1
-C
2
alkyl. Examples are cyclopentylmethyl, cyclohexylmethyl, cyclopentylethyl and cyclohexylethyl.
As aryl, A
3
and A
4
can be, for example, phenyl or naphthyl.
As aralkyl, A
3
and A
4
can be, for example, phenyl-C
1
-C
4
alkyl or naphthyl-C
1
-C
4
alkyl. Benzyl and phenylethyl are preferred.
In a preferred embodiment, A
3
and A
4
are hydrogen, methyl or ethyl.
Particularly preferred compounds of the formula I have the formula Ia
in which
A
1
and A
2
independently of one another are hydrogen, C
1
-C
4
alkyl, C
5
-C
6
cycloalkyl, C
5
-C
6
cycloalkylmethyl, phenyl or benzyl; and
A
3
and A
4
independently of one another are hydrogen or C
1
-C
4
alkyl.
Among the stereoisomers of the compounds of the formula Ia those having the configuration 1S, 2R, 6S, 7R, 9R are preferred. Among the enantiomers of the compounds of the formula Ia those having the configuration 1S, 2R, 6S, 7R, 9R, 10R are preferred.
In formula Ia, A
1
and A
2
are preferably hydrogen, C
1
-C
4
alkyl, cyclohexyl or phenyl. A
1
and A
2
are preferably each C
1
-C
4
alkyl, cyclohexyl or phenyl. In another preferred embodiment, A
1
is hydrogen and A
2
is C
1
-C
4
alkyl, cyclohexyl or phenyl.
The compounds of the formula I can be prepared according to process steps known per se from 2-azabicycloalkene-1-carboxylic acids, which for their part are accessible in a known manner by means of Diels-Aider ad
Andersson Pher G.
Nordin Sofia J. M.
Roth Peter
Lambkin Deborah C.
Solvias AG
Wenderoth , Lind & Ponack, L.L.P.
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