Hydrogenation of prochiral ketones

Details Hydrogenation of prochiral ketones Hydrogenation of prochiral ketones

2003-04-11

2004-09-21

Richter, Johann (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S179000

Reexamination Certificate

active

06794532

ABSTRACT:

The present invention relates to a process for enantioselectively hydrogenating prochiral ketones to (S)-alcohols using platinum catalysts in the presence of cinchonines or quinidines as modifiers and of hydrogen, which is characterized in that the modifiers used are cinchonines unsubstituted in the 3-position, 3-ethylidenyl- or 9-methoxycinchonines or derivatives thereof in which the quinoline ring is replaced by other rings.
The enantioselective hydrogenation of &agr;-ketoesters using platinum catalysts in the presence of cinchonidine or cinchonine and derivatives of these quinuclidines has been described by H.-U. Blaser et al. in Catalysis Today 37 (1997), pages 441 to 463. This publication also discloses that the enantioselectivity in the presence of cinchonidine for preparing (R)-alcohols is considerably higher than in the presence of cinchonine for preparing (S)-alcohols. The same observation is made by B. Török et al. in Chem. Comm. (1999), pages 1725 to 1726 in the enantioselective hydrogenation of an &agr;-ketodiacetal. The hydrogenation of &agr;-ketoacetals is also described by M. Studer et al. in Chem. Comm. (1999), pages 1727 to 1728. In J. Am. Chem. Soc. (2000) 122, pages 12675 to 12682, H. U. Blaser describes the influence of modification of cinchona alkaloids on the hydrogenation of ethyl pyruvate using cinchona-modified platinum catalysts. It is established that the substitution in the 3-position of the quinuclidine radical has virtually no or only a small influence. In connection with the determination of the pK
a
values of cinchona alkaloids, C. Drzewiczak et al. in Polish J. Che., 67, 48ff (1993) mention 3-ethylidenecinchonine without specifying a synthesis or use.
It has now been found that, surprisingly, it is possible to achieve a distinctly higher catalyst activity and increased enantioselectivity in the hydrogenation of prochiral ketones to (S)-alcohols using hydrogen when platinum catalysts are modified with 3-ethylidene- or 9-methoxycinchonines or derivatives thereof in which the quinoline ring is replaced by other rings. The optical yields of (S)-alcohols may be over 90% ee and such high yields could hitherto be achieved in the preparation of (S)-alcohols by this hydrogenation route only by the use of ultrasound (B. Török et al., Ultrasonics Sonochemistry 7 (2000) 151) or by continuously adding modifier (C. LeBlond et al., JACS 121 (1999) 4920).
The invention provides a process for enantioselectively hydrogenating prochiral ketones to (S)-alcohols using platinum catalysts in the presence of cinchonines or quinidines as modifiers and in the presence of hydrogen, which is characterized in that the modifiers used are cinchonines from the group of cinchonines unsubstituted in the 3-position, 3-ethylidenyl- or 9-methoxycinchonines or derivatives thereof in which the quinoline ring is replaced by other rings.
Prochiral ketones are well known. The prochiral &agr;-ketones may be saturated or unsaturated, open-chain or cyclic compounds which preferably have 5 to 30, more preferably 5 to 20, carbon atoms which are unsubstituted or substituted with radicals which are stable under the hydrogenation conditions. The carbon chain may be interrupted by heteroatoms, preferably from the group of —O—, ═N— and —NR′—, where R′ is H, C
1
-C
8
-alkyl, preferably C
1
-C
4
-alkyl, C
5
-C
8
-cycloalkyl, for example cyclopentyl, cyclohexyl or cyclooctyl, C
6
-C
10
-aryl, for example phenyl or naphthyl, or C
7
-C
12
-aralkyl, for example phenylmethyl or phenylethyl. The prochiral ketones preferably have an activating group in the &agr;-position, for example a carboxyl, carboxylic ester, acetal, keto or ether group.
The prochiral ketones may be &agr;-ketocarboxylic acids, &agr;-ketocarboxylic esters, &agr;-ketoethers, &agr;-ketoacetals and &agr;,&bgr;-diketones. These prochiral ketones may correspond to the formulae I, II, III, IV and V
where
R
1
, R
2
, R
3
and R
6
are each independently a monovalent, saturated or unsaturated aliphatic radical having 1 to 12 carbon atoms, a saturated or unsaturated cycloaliphatic radical having 3 to 8 carbon atoms, a saturated or unsaturated heterocycloaliphatic radical having 3 to 8 ring members and one or two heteroatoms from the group of O, N and NR′, a saturated or unsaturated cycloaliphatic-aliphatic radical having 4 to 12 carbon atoms, a saturated or unsaturated heterocycloaliphatic-aliphatic radical having 3 to 12 carbon atoms and one or two heteroatoms from the group of O, N and NR′, an aromatic radical having 6 to 10 carbon atoms, a heteroaromatic radical having 4 to 9 carbon atoms and one or two heteroatoms from the group of O and N, an aromatic-aliphatic radical having 7 to 12 carbon atoms or a heteroaromatic-aliphatic radical having 5 to 11 carbon atoms and one or two heteroatoms from the group of O and N where R′ is H, C
1
-C
8
-alkyl, preferably C
1
-C
4
-alkyl, C
5
- or C
6
-cycloalkyl, C
6
-C
10
-aryl, for example phenyl or naphthyl, C
7
-C
12
-aryl, for example phenylmethyl or phenylethyl,
R
1
and R
2
or R
1
and R
6
together are C
1
-C
6
-alkylene or C
3
-C
8
-1,2-cycloalkylene, or C
2
-C
4
-alkylene or C
3
-C
8
-cycloalkylene fused to 1,2-phenylene, and R
3
is as defined above,
R
2
and R
3
together are C
1
-C
6
-alkylene, C
1
-C
8
-alkylidene, C
3
-C
8
-1,2-cycloalkylene, C
3
-C
8
-cycloalkylidene, benzylidene, 1,2-phenylene, 1,2-pyridinylene, 1,2-naphthylene, or C
3
-C
4
-alkylene or C
3
-C
8
-1,2-cycloalkylene fused to 1,2-cycloalkylene or 1,2-phenylene, and R
1
is as defined above,
and R
1
, R
2
, R
3
and R
6
are each unsubstituted or substituted by one or more, identical or different radicals selected from the group of C
1
-C
4
-alkyl, C
2
-C
4
-alkenyl, C
1
-C
4
-alkoxy, C
1
-C
4
-haloalkyl, C
1
-C
4
-hydroxyalkyl, C
1
-C
4
-alkoxymethyl or -ethyl, C
1
-C
4
-haloalkoxy, cyclohexyl, cyclohexyloxy, cyclohexylmethyl, cyclohexylmethyloxy, phenyl, phenyloxy, benzyl, benzyloxy, phenylethyl, phenylethyloxy, halogen, —OH, —OR
4
, —OC(O)R
4
, —NH
2
, —NHR
4
, —NR
4
R
5
, —NH—C(O)—R
4
, —NR
4
—C(O)—R
4
, —CO
2
R
4
, —CO
2
—NH
2
, —CO
2
—NHR
4
, —CO
2
—NR
4
R
5
where R
4
and R
5
are each independently C
1
-C
4
-alkyl, cyclohexyl, cyclohexylmethyl, phenyl or benzyl.
The heterocyclic radicals are bonded via a ring carbon atom to the oxygen atoms or the carbon atom of the carbonyl groups in the compounds of the formulae I, II, III, IV and V.
Preferred substituents are methyl, ethyl, n- and i-propyl, n- and t-butyl, vinyl, allyl, methyloxy, ethyloxy, n- and i-propyloxy, n- and t-butyloxy, trifluoromethyl, trichloromethyl, &bgr;-hydroxyethyl, methoxy- or ethoxymethyl or -ethyl, trifluoromethoxy, cyclohexyl, cyclohexyloxy, cyclohexylmethyl, cyclohexylmethyloxy, phenyl, phenyloxy, benzyl, benzyloxy, phenylethyloxy, phenylethyl, halogen, —OH, —OR
4
, —OC(O)R
4
, —NH
2
, —NHR
4
, —NR
4
R
5
, —NH—C(O)—R
4
, —NR
4
—C(O)—R
4
, —CO
2
R
4
, —CO
2
—NH
2
, —CO
2
—NHR
4
, —CO
2
—NR
4
R
5
where R
4
and R
5
are each independently C
1
-C
4
-alkyl, cyclohexyl, cyclohexylmethyl, phenyl or benzyl.
The aliphatic radical is preferably alkyl which may be linear or branched and preferably has 1 to 8, more preferably 1 to 4, carbon atoms, or preferably alkenyl or alkynyl, each of which may be linear or branched and preferably have 2 to 8, more preferably 2 to 4, carbon atoms. When R
2
and R
3
are alkenyl or alkynyl, the unsaturated bond is preferably in the &bgr;-position to the oxygen atom. Examples include methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, pentyl, i-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl, vinyl, allyl, ethynyl and propargyl. A preferred group of aliphatic radicals is methyl, ethyl, n- and i-propyl, n-, i- and t-butyl.
The cycloaliphatic radical is preferably cycloalkyl or cycloalkenyl having preferably 3 to 8, more preferably 5 or 6, ring carbon atoms. Some examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and also cyclopentenyl, cyclohexenyl and cyclohexadienyl. Particular preference is given to cyclopentyl and cycloh

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