MXPA00004630A - Transition metal-catalyzed reactions based on chiral amine oxazolinyl ligands - Google Patents

Abstract

The invention is drawn to novel transition metal catalysts for the pratical synthesis of important chiral molecules. The transition metal catalysts comprise chiral ligands based on chiral amine oxazolinyl ligands. The invention includes methods of making the catalysts, and methods of performing reactions using the catalysts.

Description

CATALYZED REACTIONS BY TRANSITION METALS BASED ON QUIRAL LAMPS OF AMINE OXAZOLINILO BACKGROUND OF THE INVENTION Molecular chirality plays an important role in science and technology. The biological activities of many pharmaceuticals, fragrances, food additives and agro-chemicals are often associated with their absolute molecular configuration. While one enantiomer provides a desired biological function through interactions with the natural agglutination sites, another enantiomer does not normally have the same function and sometimes has deleterious side effects. A growing demand e? The pharmaceutical industries is to market a chiral drug in its enantiomerically pure form. To meet this fascinating challenge, chemists have explored many advances in acquiring enantiomerically pure compounds ranging from optical resolution and structural modification of naturally occurring chiral substances to asymmetric catalysis using enzymes and synthetic chiral catalysts. Among these methods, asymmetric catalysis is perhaps the most efficient because a small amount of chiral catalyst can be used to produce a large amount of target chiral molecule. During the last decades, it has been dedicated REF .: 119882 *? ._ great attention to the discovery of new catalysts > Commercial asymmetric step key in the production of enantiomerically pure compounds. Worldwide sales of chiral drugs in 1997 was almost $ 90 billion. Many chiral phosphines (as shown 1, in Figure 1) have been made to facilitate the asymmetric reactions. Among these ligands, BINAP is one of the most frequently used chiral and dentate phosphines. The fully aromatic, axially dissymmetric BINAP ligand has been shown to be effective for many asymmetric reactions. DUPHOS and related ligands also show impressive enantioselectivities in various reactions. However, these phosphines are difficult to make and some of them are sensitive to air. Recently, they have been extensively studied for their asymmetric reactions. Particularly, oxazolinyl derivatives of chiral amino alcohols are popular ligands. The recognition of secondary interactions between ligands and substrates has also been used to design asymmetric catalysts. For example, primary and secondary amines can form H-bonds with substrates.

BRIEF DESCRIPTION OF THE INVENTION An objective of the present invention is the development of transition metal complexes with new families of oxazolinyl amine ligands for practical asymmetric synthesis. Various new families of chiral oxazolinyl amine ligands are incorporated herein for asymmetric catalysis, including secondary oxazolinyl amine ligands, and oxazolinyl amine ligands having more than one oxazolinyl group. Another object of the invention is the preparation of chiral oxazolinyl from chiral amino alcohols. Another objective of the invention is the discovery of tridentate and tetradentate chiral ligands suitable for asymmetric catalysis. Particularly, it has been shown that these ligands are highly effective for the hydrogenation of Ru catal catalyzed transfer of ketones and imines. Another object of the invention is the improved catalysis of reactions accelerated by transition metals such as hydrogenation, hydride transfer reaction, hydrosilylation, hydroboration, hydrovinylation, hydroformylation, hydrocarboxylation, alkylation, cyclopropanation, Diels-Alder reaction, reaction from Aldol, Heck reaction, Michael addition, and reconfiguration reactions, which leads to efficient and practical methods to produce drugs and important chiral agrochemicals.

In order to achieve the objectives and in accordance with the purpose of the invention as embodied and described broadly herein, the invention comprises a chiral ligand forming a catalyst that provides unattained enantiomer selectivity in asymmetric reactions, and having a structure selected from the group consisting of enantiomers of the following formulas (I) through (IV): R, wherein R, R1 R2, R3, R, R5, Re and 7 are each independently hydrogen, alkyl, aryl, substituted alkyl or substituted aryl, wherein any of two between Ri, R2, R3, R4, can be link to each to form annular structures, where either of two between R5, Re and R7 can be linked to each to form a \ nular structure, and where n is 1 or 2.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows a general route for the synthesis of a bis (oxazolinylmethyl) amine ligand hereafter ("AMBOX") in a preferred embodiment of the present invention. Figure 2 shows the general structure of several chiral ligands according to the preferred embodiments of the present invention. Figure 3 shows specific examples of; the chiral ligands according to the preferred embodiments of the present invention. Figure 4 is a schematic representation of the transition metal catalysts of tridentate chiral nitrogen ligands with an NH function, showing the cyclic transition state that is obtained in the hydrogenation of transfer of the prochiral ketones.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES The hydrogenation of asymmetric catalytic transfer using 2-propanol as a source of hydrogen offers an attractive route to reduce asymmetric ketones in chiral alcohols. Among the efficient chiral catalysts based on newly developed transition metals, the most notable is the Ru (II) -Ts-DPE (N- (p-tolylsulfonyl) -1,2-diphenylethylene diamine) system reported by R. Noyori et al. al., "Assymmetric Transfer Hydrogenation Catalyzed by Chral Ruthenium Complexes", Acc. Chem. Res. , Vol. 30, No. 2, 99. 97-102 (1997) and K. Haacj et al., "The Catalyst Precursor, Catalyst and Intermediate in 'V the Ru" - Promated Assymmetric Hydrogen Transfer Between Alcohols and Retoñes ". , Angew, Chem. In t. Engl., Vol., 36, No. 3. Pp. 285-288 (1997), which are incorporated herein in their entirety, suggest that an NH portion in the ligand may promote a of cyclic transition by hydrogen bonding to a ketone substrate, which greatly increases the affinity of the substrate to the active site of the catalyst, thus inducing high optical purity activity.Mother reports show a similar "NH effect", for example , J. Gao et al., "A Ruthenium (II) t Complex with a C2 symmetric Diphosphine / Diamine Tetradentate Ligand of Asymmetric Transfer Hydrogenation of Aromatic Retoñes", Organometallics, Vol. 15, No. 4, pp. 1087-1089 ( 1996) and P. Gamez et al., "Assymmetric Catalytic Reduction of Carbonyl Compounds Using C2 symmetric Diamines as Chiral Liga nds ", Tetraedron: Assymmetry, Vol. 6, No. 3, pp. 705-71! (1995), which are incorporated here in their entirety. In an effort for tridentate chirals for asymmetric catalysis, we have designed the bis (oxazolinylmethyl) amine - ("AMBOX") ligand system. Tridentate chiral ligands tend to form a deep chiral gap around the metal center once it has been coordinated to a transition metal. A good example is the well known PYBOX ligand family, described, for example, by H. Nishiyama, "Chiral and C £ -Symmetrical Nis (oxazolinylpyridine) rhodium (III) Complexes: Effective Catalysts for Asymmetric Hydrosylation of Retoñes ", Organome tal l ics, Vol. 8, No. 3, pp. 846-48 (March 1989).

This catalyst is successfully used for the catalysis of asymmetric reactions. The two R groups in the oxazolino rings of PYBOX form a highly enantoselective "chiral barrier", which allows a better differentiation of the Re and Si fronts of incoming substrates. By replacing the pyridine backbone of PYBOX with an amine function, the new AMBOX ligand undergoes cyclic transition states similar to those suggested in the Noyori and Haack articles cited above and effectively catalyzes asymmetric transformations - for example, the reduction of transfer of the hydride of the ketones. Figure 4 is a schematic representation of the cyclic transition state that is obtained in the transfer hydrogenation in the pro-chiral ketones. Figure 1 represents a preferred synthetic route for bis [4- (R) -phenyloxazolin-2-yl-methyl] amine (hereinafter "(R) -Ph-AMBOX"), a preferred embodiment of the present invention . A cyanoamide is reacted in a with HCl and methyl alcohol to form an imidate ester hydrochloride in 75% crude yield. The imidate hydrochloride obtained is reacted in b without further purification with a (R) -phenyl-glycinol in dichloromethane between 0 ° C and room temperature for twelve hours. You get (R) -Ph-AMBOX in 15% production. A previous attempt to synthesize (R) -Ph-AMBOX was unsuccessful. Yutong, J., et al., Tetrahedron Letters, Vol. 38, No. 37, pp. 6565-6568 (1997). The chirality of the oxazolinyl amine product as well as the identity of the substituents can be determined by choosing a different amino alcohol for step b. For example, to form the preferred structure (XI) shown in Figure 3, the amino alcohol i can be used in step b. In the scheme 'exposed in Figure 1, the amino alcohol (S) can be used to produce a product with the opposite chirality. The catalysts of the present invention are produced by complexing the amino-oxazolinyl ligands described herein with a transition metal. Suitable precursors of transition metal catalysts to complex them with the ligands of the present invention are know by those skilled in the art. For example, [Rh (cod) Cl] 2 / [Rh (cod)] X, [Ir (cod) Cl] :, [Ir (cod);] X, Ru (cod) Cl2, where "cod" means 1,5-cyclooctadiene and X means BF4, C104, SbFD, CF3SO3,, or equivalents, which may be used. Alternatively, RuCl2 (PPh3) 3, RuHCl (PPh3) 3, RuX (PR3) 3l, RuHX (PR3) 3, RuX can be used; , and other equivalents, wherein X is halogen and R is a substituted or unsubstituted alkyl or an aryl group.

Jl . { Optimization of the Catalyst The initial results of the transfer analysis and hydrogenation of acetophenone in 2-p -ropanol, using in-situ catalysts with AMBf) X, and various transition metal precursors commonly used were disappointing. A poor enantoselective performance prevailed among all these catalysts, with the largest enantioeric excess (alternatively referred to as > • "ee") of less than 50% obtained using RuCX (PPh3) 5. Table 1 represents the results of the optimization of the catalytic conditions for the transfer hydrogenation of acetophenone using (R) -Ph-AMBQX. The reaction (1) is then carried out in a 0.1M solution of acetophenone in 5mL of 2-propanol. The ketone ratio: Ru11: (R) -Ph-AMBOX was 100: 1: 1.1.

Ph (D TABLE 1 Input PPh. ' NaOPr- T t Production Ee of free Equivalent1 ° C h Data 82 0.5 96 45 2 '15 82 0.25 92 60 3 1.0 82 1 67 84 4 1.0 82 0.17 \ 91 9 ~ 5 0.5 82 1 V 26 95 6 0 82 1 \ ° N / A 7 2.0 82 0.17 T4 68 1.0 23 22. 91 95 to. "+" indicates that free PPh3 existed in the reaction mixture; "-" indicates that free PPh3 was leached with ether after the catalyst formed, before adding acetophenone and NaOPr1 b. Base Equivalents for Ru11? c. % Of production and% of enantiomeric excess was determined by GC analysis with a chiral capillary column Supelco ß-DEX 120. The absolute configurations were determined by comparing the optical rotations with the values of the literature. All major secondary f-alcohol products are isomers (S). d. The catalyst is made by stirring the mixture of (R) -Ph-AMBQX and RuCl2 (PPh3) 3 at room temperature overnight, e. For data entries 2-8, the catalysts are prepared by refluxing (R) -Ph-AMBOX and RuCi? PPh3) 3 at 82 ° C for 2 hours.

It is discovered that a catalyst in itself made by refluxing AMBOX and RuCl2 (PPh3) 3 in 2-propanol is much more effective than up to the catalyst made at room temperature.

For data entries 2 and 8 in "Table 1, the catalysts are prepared by refluxing the precursor of RuCl2 (PPh3) 3 at 82 ° C for 2 hours.This catalysts produce a greater enantiomeric excess than the catalysts that are prepared The corresponding catalysts are prepared by refluxing the 2-propanol at boiling temperature. drastically both the catalytic activity and the enantoselectivity is the removal of the free ligand of diphenylphosphine that is released during the formation of complexes of AMBOX before the introduction of the acetophenone and the base (NaOPr1) - The free PPh0 can interfere in the reaction due to its ability to reshape complexes with the Ru center The free PPh removal reduces unfavorable competition for the enantosele catalytic process Preferably, according to the invention, a mixture of the precursor RuCi? PPh3) 3 is heated with .R-Ph-AMBOX for 2 hours, yielding a green solution. After the solvent is removed in a vacuum, the resulting greenish residue is washed with ether to remove any free PPh3. The solid is re-dissolved in 2-propanol, followed by an addition of the substrate and NaOPr1 . Enantiomeric excess increases dramatically from 84% to 97% at the time of such treatment, as can be seen when comparing data entries 3 and 4 of the Table 1. . { s Another important factor that can enhance activity and enantoselectivity is the molar ratio of NaOPr1 to catalyst. This ratio should be approximately 1.0. When 0.5 molar equivalent base is used, the reaction becomes too slow, although the enantiomeric excess remains high (data entry 5, Table 1).

When 2.0 molar equivalents of baa ie are used, the reaction is accelerated, but is accompanied by severe erosion of the enantiomeric excess (data entry 7, Table 1). Figure 4 represents the presumed conformation of the active catalyst type, where L represents PPh3 and X represents chlorine. The type in Figure 4 is probably formed after an HCl is extracted by NaOPr1 from the putative precursor of RuCl2PPh3 (AMBOX), followed by an absorption of a proton and a hydride of 2-propanol. Chloride through the apical PPh3 should preferably be removed together with the NH proton, considering a strong cross effect of PPh3. However, if more than one molar equivalent of base is introduced, the chloride through the NH can also be removed, resulting in possible pathways that favor the inverse reaction of the ketone reduction, and therefore a rapid loss of excess enantiomeric PPh3 1ibr can also interfere with the reaction, due to its ability to form complexes again with the ruthenium center i Therefore, \ the removal of the free PPh3 gives a decreased unfavorable competition of the catalytic process enantoselectivok In fact, the excess enantiomeric increased dramatically from 84% to 97% in such treatment ._ (see data entry 3-4 in Table 1). Table 2 represents the reduction of a variety of aromatic ketones to their secondary alcohols under optimized conditions using the catalyst of the present invention, with a high enantiomeric excess and a mainly satisfactory production. The generic reaction (2) was carried out (except if indicated otherwise) using a 0.1M solution of ketone in 5mL of 2-propanol. The ketone ratio: Ru: (R) -Ph-AMBOX: NaOEr1 is 100: 1: 1.1: 1.0 O OH fRVPívAMBOX- [RuOjíPPrijy OH. »- or Ar- ^ R NaOPr (2) Ar) R - ^ Table 2 shows various changes in substrates and catalytic reactions.

TABLE 2 Input of t production Ketone ee ° Data min 1 0 X = CH3 5 (10) 80 (91) 98 (97) 2 f¿ ^ ~ - ~ XX = Et 10 (20) 77 (92) 95 (92) 3 X = i-Pr 10 15 '. 78 4) 9 X = CH3O 7 (10) 91 (94) 95 (93) 10 O X = CH3 24h / rt 61 96 I 11 1 X = C1 10 97 90 X '"" "- 12 X = CH3O 10 41 98 2 (7) 55 (91) 90 (92) The% of production and% of enantiomeric excess is determined by means of a GC analysis with a chiral capillary column Supelco ß-DEX determine the absolute configurations when sharing the optical and rotations with the values of the literature. All the main products of secondary alcohols are isomers (S).

Both the enantiomeric excess and the chemical production are delicately affected by the electronic and spatial properties of the substrates. The inhibitory spatial effect of the alkyl sides of the ketone substrates is apparent when their results are compared for the methyl, ethyl and isopropylphenyl ketones (data entry 1 to 3, Table 2). When replacing the for substituent of chloride with a methoxyl group, the enantiomeric excess improves but with a tremendous drop in the conversion (data entry 11, 12, Table 2). The erosion of the enantiomeric excess product with an increasing conversion is moderate for most of the ketones being analyzed, especially for ortho-methyl and chloro-substituted acetophenones, which have hardly witnessed any erosion at all throughout the reaction (entry of data 4, 5, Table 2). However, when the ortho phenyl group is methoxy, very poor results are obtained (data entry 6, Table 2).

V Formulas (I) to (IV) of Figure 2 are non-limiting examples of the preferred ligands eg compliance with the present invention. As shown in * 3, to Figure 2, all preferred ligands according to the present invention comprise an oxazole substituted in the two-position alkyl amine or substituted alkyl amine. As you can see, in the Formula (I) for example, the alkylamine substituted at position two of the oxazole can be, for example, a methylamma or a substituted methylamine. Moreover, the amine can be primary, secondary or tertiary as shown in Figure 2. - In Figure 2, R, R1 R2, R3, R4, R5, R1 and RT can be the same or different and can to be hydrogen, alkyl, aryl, substituted alkyl or substituted aryl. Also within the scope of the invention are embodiments wherein any two of Ri, R2, R3, and R4, can be linked to form an annular structure, wherein any two of R5, Re, and R- can be linked together to form an annular structure. an annular structure. For example, in Formula (II), when one of Ri and R3 is methyl and the other is hydrogen and one of R_ and R1 is phenyl and the other is hydrogen, a structure having the configuration of Formula (XI) it is formed when R is hydrogen and n is 1. Similarly, one of ordinary skill in the art recognizes many annular structures that are made possible by joining R; to R4 in Formulas (I) through (IV). Alternately, a ring that forms at the - - * - joining R5 and R6 can form a structure as shown in Formula (VI). f Although only certain enantiomeric configurations are shown in the figures, the enantiomeric orientation of the ligands can be manipulated using different reagents during the synthesis. The enantiomers of the represented formulas are also within the scope of? the invention. Figures (V) through (XI) of Figure 3 denote particularly preferred embodiments of the chiral oxazolinyl amine compounds of the present invention, such as, oxazolin-2-yl-methylamine, which can be substituted in the oxazole or in the methyl as shown in Figure f (V), or the 2-oxazolin-2-yl-azacyclopentane which can be substituted in the oxazole as shown in Figure (VIJ, or the bis [4- (R) -phenyloxazolin-2-yl-methyl] amine, previously described, which can be derived from Formula (VII).

In summary, this invention includes novel tridentate chiral ligands that form highly efficient catalysts with RuCl2 (PPh3) 3 and other catalyst precursors for the hydrogenation of transferring a range of ketones and other reactions. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims (20)

CLAIMS. Having described the invention as above, the content of the following claims is claimed as property:

1. A chiral ligand that forms a catalyst that provides enhanced enantiomeric selectivity in asymmetric reactions, characterized in that it has a structure selected from the group consisting of enantiomers of the following Formulas (I) through (-IV):

(ll)

wherein R, Ri, R;, R3, R., R5, R6 and R- are independently hydrogen, alkyl, aryl, substituted alkyl or substituted aryl wherein any two of Ri, R2, R3, and EX are can join each of the others to form an annular structure, where either of the two between Rs, i

R? Or R? they can be attached to each other to form an annular structure, and where n is 1 or 2.

2. The chiral ligand according to claim 1, characterized in that this ligand forms complexes with a transition metal. * "

3. The chiral ligand according to claim 2, characterized in that this transition metal is selected from the group consisting of rhodium, iridium, ruthenium and palladium.

4. The chiral ligand according to claim 1, characterized in that this ligand forms complexes with a precursor of the transition metal catalyst selected from the group consisting of [Rh (cod) Cl];, l [Rh (cod); ] X, [Ir (cod) Cl] 2, [Ir (cod) 2] X, Ru (cod) CX, where t "cod" means 1, 5-cyclooctadiene and X means BF4, C10,

SbF. or CF3SO3.

5. The chiral ligand according to claim 1, characterized in that this ligand forms complexes with a precursor of the transition metal catalyst selected from the group consisting of RUCXÍPPITX -. , RuHCl (PPh3) 3, RuX; (PR3) 3, RuHX (PR3) 3, RuX; , wherein X is halogen and R is an unsubstituted or substituted alkyl or aryl group.

6. The chiral ligand according to claim 1, characterized in that this ligand is selected from the group consisting of the following ^ Formulas (V) through V (XI):

(SAW)

X The chiral ligand forming a catalyst "which provides an enantiomeric selectivity in the asymmetric reactions, characterized in that this chiral ligand comprises a bis (oxazolinyl) amine.

A chiral ligand according to claim 1, characterized in that this chiral ligand is bis [4- (R) -L-phenyloxazolin-2-yl-methyl] amine. 9. A process for making a catalyst provided with an enhanced enantiomeric selectivity in asymmetric reactions, characterized in that it comprises reducing an imidate ester with a chiral alcohol to obtain the chiral ligand i according to claim 1.

10. A process in accordance with claim 9, characterized in that it further comprises complexing this chiral ligand with a precursor of the catalyst comprising a transition metal. =?

11. A process for making a catalyst according to claim 10, characterized in that this precursor of the catalyst further comprises triphenylphosphin, and wherein this process for making the catalyst invests to remove the free triphenylphosphine that is released during the complex formation of the chiral ligand. with the catalyst precursor. i

12. A process for making a catalyst according to claim 10, characterized in that this precursor: the catalyst and this chiral ligand are refluxed with alcohol at the reflux temperature of the alcohol.

13. A process for making a catalyst according to claim 10, characterized in that this transition metal is selected from the group consisting of rhodium, iridium, ruthenium and palladium.

14. A process for making a catalyst according to claim 10, characterized in that this% catalyst precursor is selected from the group consisting of [Rh (cod) Cl] 2, [Rh (cod):] X, [Ir (cod) Cl] 2, # [Ir (cod) 2] X, where "cod" means 1, 5-cyclooctad? ene and c X s ignicible BF4, C104, SbF6, CF3SO3"

15. A process for making a catalyst according to claim 10, characterized in that "this catalyst precursor is selected from the group consisting of RuCl2 (PPh3) 3, RuHCl (PPh3) 3, RuX: (PR3) 3, RuHX ( PR3) 3, RuX:, wherein X is halogen and R is an unsubstituted or substituted alkyl or aryl group.

16. A method for enhancing the enantiomeric selectivity of a chemical reaction, characterized in that it comprises contacting a substrate with the catalyst comprising the chiral ligand in accordance with claim 1.

17. A method according to claim 16, characterized in that this reaction is selected from the group consisting of hydrogenation, hydride transfer reaction, hydrosilylation, hydroboration, hydrovinylation, hydroformylation, hydrocarboxylation, allyl alkylation, cyclopropanation, Diels reaction. -Alder, reaction of Aldol, reaction Xde Heck, addition and reconfiguration of Michael. 7,

17 of

A method according to claim 1 characterized in that the contact of the substrate with the catalyst further comprises putting on substrate and this catalyst with a molar proportion base of this base with this catalyst e? between 0.5 and 2.0.

20. A method according to claim 19, characterized in that this molar ratio is approximately 1.0.