Ruthenium complexes and their use in asymmetric hydrogenation

Details Ruthenium complexes and their use in asymmetric hydrogenation Ruthenium complexes and their use in asymmetric hydrogenation

2001-07-23

2003-03-04

Davis, Brian J. (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S413000, C564S448000, C564S487000, C564S489000

Reexamination Certificate

active

06528687

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to ruthenium complexes bearing a chiral diphosphine and a chiral diamine and their use as catalysts for the asymmetric hydrogenation of imines.
In this context and throughout the following text, the term “catalyst(s)” refers to the isolated pre-catalyst that is added to the reaction vessel for hydrogenation and which typically undergoes a change in composition in situ to generate one or more catalytically active species.
BACKGROUND OF THE INVENTION
Although many highly enantioselective chiral catalysts are available for the asymmetric hydrogenation of C═C and C═O bonds, relatively few exist for effective reduction of the analogous C═N function. The production of chiral amines via this methodology still represents a major challenge. In the past ten years, progress in this field has been made with catalysts based on complexes of rhodium, iridium, ruthenium and titanium, with most recent emphasis being devoted to Ir and Ti.
A recent review provides a comprehensive summary of the most important advances in this field (Kobayashi and Ishitani,
Chem. Rev.,
1999, 99, 1069); representative examples include those detailed below. Osborn and co-workers developed chiral Ir complexes of the type [Ir(P—P)HI
2
]
2
(1), in which (P—P) represents a chiral ligand, and analogues thereof, see Chan and Osborn,
J Am. Chem. Soc.,
1990, 112, 9400; Chan et al.,
J Chem. Soc., Chem. Commun.,
1990, 869; Sablong and Osborn,
Tetrahedron Lett.,
1996, 37, 4937. Although these systems showed reasonable activities, the enantioselectivites were in general only moderate, despite employing various chiral diphosphines (e.g. up to 35% ee for the cyclic imine 2). Spindler et al. independently reported an in situ prepared Ir catalyst incorporating JOSIPHOS (3) as the chiral ligand, and subsequently applied it to the industrial production of (S)-Metolachlor (4) (Spindler et al.,
Angew. Chem., Int. Ed Engl.,
1990, 29, 558; Blaser and Spindler,
Topics in Catalysis,
1997, 4, 275).
Buchwald and co-workers have prepared chiral titanocene complexes 5 and 6, and have effectively employed them in reductive amination of a range of imines (Willoughby and Buchwald,
J Am. Chem. Soc.,
1992, 114,7562;
J Am. Chem. Soc.,
1994, 116, 8952;
J Am. Chem. Soc.,
1994, 116, 11703). These catalysts are effective in both asymmetric hydrogenation and asymmetric hydrosilylation processes, although their practical utility is limited by (a) the requirement for high operating pressures (typically >60 bar H
2
) in the former and (b) the requirement to activate the catalyst in the reaction vessel by addition of butyl-lithium and phenyl silane. More recently, Pfaltz and co-workers have employed an Ir phosphine-oxazolidine complex (7) for the asymmetric hydrogenation of various prochiral imines. Although N-(phenylethylidene)aniline was successfully reduced in 99% yield with 89% ee, the use of cyclic imines as substrates resulted in much lower enantioselectivities (Schnider et al,
Chem. Eur. J.,
1997, 3, 887). Lastly, Bianchini et al. have addressed the asymmetric hydrogenation of 2-methylquinoxaline (8), which is challenging due to the aromatic nature of the substrate (Bianchini et al.,
Organometallics,
1998, 17, 3308). Ee's of up to 90% (at 54% substrate conversion) were achieved using the orthometalated dihydride complex (9) as catalyst, although at 96.5% substrate conversion the ee decreased to 73%.
After the date of the present invention, Abdur-Rashid et al, in
Organometallics
2001, 21, 1047, disclosed that RuHCl (diphosphine) (diamine) complexes catalyse the hydrogenation of imines. The disphosphine ligands that were used are BINAP and DPPACH. The imine substrates were all acylic. It is unclear what of this paper was published, at a conference in May 2000.
Despite the successful examples cited above, there remains a need to identify a general class of structurally related catalysts that are chemically robust and give high activity and enantioselectivity in the asymmetric hydrogenation of a broad range of imine substrates, both cyclic (including aromatic imines) and acyclic. For commercial applications, an important requirement of such a class of catalysts is the facility to readily vary individual components of the catalyst, especially the chiral ligand, such that for a given application the best match of substrate and catalyst can be identified by multi-well screening.
In the related field of catalytic asymmetric hydrogenation of ketones, Noyori et al. have pioneered the use of ruthenium complexes bearing a diphosphine ligand and a diamine ligand. At least one and usually both of these ligands are chiral. Initial studies of these complexes, as reported in EP-A-0718265, demonstrated the highly efficient reduction of unfunctionalised aromatic ketones. Examples of chiral diphosphines employed were BINAP, Tol-BINAP, Xylyl-BINAP, H
8
BINAP and CHIRAPHOS. Examples of chiral diamines employed were DPEN, DAIPEN and others.
It was subsequently disclosed by R. Noyori and co-workers (Ohkuma et al.,
J. Am. Chem. Soc.,
1995, 107,2675 and 10417) that a fully characterised diphosphine-ruthenium-diamine complex could be isolated and used as the catalyst. In particular, high productivity and high selectivity were always associated with the use of the chiral biaryl-phosphines Tol-BINAP and Xylyl-BINAP and the chiral diamines DPEN and DAIPEN (Doucet et al.,
Angew. Chem. Int. Ed.
1998, 37, 1703 and Ohkuma et al.,
J Am. Chem. Soc.,
1998, 120, 13529). Analogous catalysts incorporating the DuPHOS family of ligands have recently been prepared (Akotsi et al.,
Chirality,
2000, 12, 514), although their application to the asymmetric hydrogenation of ketones or imines has not been reported.
SUMMARY OF THE INVENTION
According to the present invention, a ruthenium complex, bearing a chiral diphosphine and chiral diamine, is used in the asymmetric hydrogenation of a diverse range of prochiral imines. When in the presence of a base, such catalysts can be used to produce chiral amines with high to excellent enantioselectivites, in some cases better than those methods reported to date.
The present invention provides an effective means of accessing an enantiomerically enriched chiral amine of formula (10), or the opposite enantiomer thereof, from an imine of formula (11), according to the following reaction:
wherein the catalyst is shown for the purpose of illustration, (i) R
1
is aryl, R
2
is alkyl and R
3
is aryl or aryl-CH
2
—, or (ii) R
2
is linked with R
1
and/or R
3
to form one or more rings and R
3
or R
1
(if not in a ring) is H or a non-interfering organic group, the number of C atoms in each of R
1
, R
2
and R
3
being up to 30. The novel process comprises asymmetric hydrogenation of the imine in the presence of a base and, as catalyst, a ruthenium complex of a chiral diphosphine and a chiral diamine.
DESCRIPTION OF THE INVENTION
In the illustrative reaction shown above, (DIP)RuX
2
(DIA) represents the ruthenium complex that, following activation with base, catalyses the asymmetric hydrogenation process. DIP is a bis-tertiary phosphine in which the two phosphorus atoms are linked by a C
2-7
carbon chain such that they form a 5-10 membered ring with the Ru atom, DIA is a diamine (typically vicinal) with any aromatic, alkyl or hydrogen substituent on the C
2
— carbon chain linking the nitrogen atoms, and X is halide or carboxylate, preferably halide (Cl, Br, I or F) and more preferably chloride. Both DIP and DIA are chiral and substantially in the form of a single enantiomer.
In preferred embodiments of the present invention, DIP in the complex (DIP)RuX
2
(DIA) is selected from one of two sub-classes of bis-tertiary phosphine. Firstly, an atropisomeric bis-tertiary phosphine may be used, in which the two phosphorus atoms are linked by a biaryl backbone. Representative members of this subclass include the BINAP ligands depicted above, and ligands based on a biphenyl backbone, such as the BIPHEP/BIPHEMP (respectively Y═OMe/Y═Me) series of for

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