CZ20001743A3 - Reactions catalyzed by transient metal based on chiral amine oxazolinyl ligands - Google Patents

Abstract

Catalysts based on transition metal are proposed practical synthesis of important chiral molecules. The transition metal catalysts include chiral ligands based on chiral aminoxazoline ligands formulas I, II, III and IV, wherein the general substituents are specific meanings. The solution includes methods for preparing catalysts a methods for carrying out reactions using these catalysts.

Description

Transition catalyzed reactions based on chiral aminoxazolinyl ligands

Technical field:

(This application claims priority from US Application 60/065502, filed November 12, 1997, which is hereby incorporated by reference in its entirety.

The invention relates to the chiral ligand that it forms; (a catalyst providing increased enantiomeric selectivity in asymmetric reactions, a process for producing the same and a process; (increasing the enantiomeric selectivity of asymmetric reactions).

BACKGROUND OF THE INVENTION;

Molecular chirality plays an important role in science and; The biological activities of many medicinal products, fragrances, food ingredients and agrochemicals are often associated with their absolute molecular configuration. While one enantiomer provides the desired biological function by interacting with natural binding sites, the other enantiomer usually does not have the same function and sometimes has detrimental: (side effects. An increasing demand from the pharmaceutical industry is the preparation of chiral drugs in enantiomerically pure; (form. To achieve this goal, chemists have explored many approaches for obtaining enantiomerically pure compounds from; (using synthetic chiral catalysts and enzymes. Asymmetric catalysis is perhaps the most effective among these methods, because to produce large quantities of chiral target molecules, t using a small amount of a chiral, (catalyst. Over the last several decades, great attention was paid exploring new asymmetric;

·· · • »· Catalysts and over half a dozen commercial industries! The processes used asymmetric analysis as a key step in the production of enantiomerically pure compounds. Worldwide sales! of their chiral drugs reached nearly $ 90 billion in 1997.

Many chiral phosphines have been prepared to facilitate asymmetric reactions. Among these ligands, BINAP is one of the most commonly used bidentate chiral phosphines. It was! It has been shown that the axially chiral, fully aromatic BINAP ligand is highly effective in many asymmetric reactions. DUPHOS and related ligands also exhibited significant enantioselectivity in numerous reactions. However, these phosphines are! difficult to prepare and some of them sensitive to air. Recently, chiral ones have been extensively investigated! nitrogenous ligands for use in asymmetric reactions. Particularly popular ligands are oxazolinyl derived from; ichiral aminoalcohols. Secondary cognition was also used to create asymmetric catalysts. interactions between ligands and substrates. For example, primary and secondary amines can form H-bonds to substrates.

SUMMARY OF THE INVENTION It is an object of the present invention to provide novel transition metal complexes with new series; ioxazolinylamine ligands for practical asymmetric syptesis. Here are some new chiral series! aminoxazolinyl ligands, including secondary aminoxazolinyl ligands and oxazolinylamine ligands; Sintering more than one oxazolyl group.

Another object of the present invention is to prepare a chiral! Oxazolinyl from chiral amino alcohols.

Another object of the present invention is the discovery of chiral; itridentate and tetradentate ligands suitable for asymmetric catalysis. It has been shown that especially these!

ligands are highly effective in hydrogenating ketones and imines!

(catalyzed by ruthenium.

Another object of the present invention is to improve catalysis. reactions mediated by transition elements such as hydrogenation, hydridtransfer reaction, hydrosilylation; hydroboration, hydrovinylation, hydroformylation, hydrocarboxylation, allyl alkylation, cyclopropanation, Diels-S Alder reaction, aldol reaction, Heck reaction,

Michael addition and rearrangement reactions that lead to effective! and practical ways of preparing important chiral drugs and agrochemicals.

(To achieve these objectives and in accordance with the purpose of this invention, as disclosed and described in detail herein, the invention comprises a chiral ligand which forms a catalyst providing enhanced enantiomeric selectivity in (asymmetric reactions) having a structure selected from the group consisting of enantiomers of the following formulas (1)!

(to (IV):

o (O)

wherein R 1, R ₂ , R ₃ , R ₅ R ₅ , R ₅ and ^R 7 are independently hydrogen, alkyl, R ₂ , R ₃ , R ₃ , R 8, ^R 8 and ^R 7. aryl, substituted alkyl, or substituted aryl, wherein any two of R 1, R ₂ , R 3, and R 4 may be substituted; linked to each other to form a ring structure, wherein any two substituents R 5, R 8 and R 7 may be linked to each other to form a ring structure, and wherein η = 1 or 2.

Description of the drawings!

Figure 1 shows the general synthesis pathway!

bis (oxazolinylmethyl) amine ligands (hereinafter referred to as "AMBOX") in a preferred embodiment of the present invention. invention.

Figure 2 shows the general structure of several chiral ligands according to a preferred embodiment of the present invention.

Figure 3 shows specific examples of chiral ligands according to a preferred embodiment of the present invention.

Figure 4 is a schematic representation of transition metal catalysts with chiral tridentate ligands having an NH functional group, showing the cyclic transition state obtained by transfer hydrogenation of prochiral ketones.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Asymmetric catalytic transfer hydrogenation using 2-propanol as a hydrogen source offers an attractive way to reduce unsymmetrical ketones to chiral! alcohols. Among the recently developed efficient chiral transition metal catalysts, it is most prominent! The Ru (II) -TsDPEN (N- (p-tolylsulfonyl) -1,2-diphenylethylenediamine) system described in R. Noyori et al. Asymmetric Transfer Hydrogenation Catalyst by Chiral Ruthenium Complexes, Acc. Chem. Res., Vol. 30, No. 2, pp. 97-102 (1997) and K. Haack et al. "The Catalyst Precursor, Catalyst and Intermediate in the Rui ^{: i} -promoted Asymmetrici Hydrogen Transfer Between Alcohols and Ketones, Angew.i iChem. Int. Engl., Vol. 36, No. 3, pp. 285-288 ¢ 1997), which are hereby incorporated by reference in their entirety. Above! The aforementioned authors suggest that the NH moiety in the ligand can promote a cyclic transition state through! Binding of hydrogen to the ketone substrate, which greatly increases the substrate affinity for the active site of the catalyst. causes a high activity and optical purity, other publications disclose a similar "NH effect", for example, in Ji Gao et al. "A Ruthenium (II) Complex with a C ₂ Symmetric ·· · ·· · ·

9 4 4 4 4 4 9 4 4 5

4944499 4 4 44 9 9 4

9449 4 94 949 44 444

Diphosphine / Diamine Tetradentate Ligand for Asymmetric! (Transfer Hydrogenation of Aromatic Ketones, " Organometallics, Vol. 15, No. 4, pp. 1087-1089 (1996) and P. (Gamez et al., &Quot; Asymmetric Catalytic Reduction of Carbonyl Compounds Using C ₂ Symmetric Diamines as Chiral Ligands, "(Tetrahedron: Asymmetry, Vol. 6, No. 3, pp. 705-718 (1995), all of which are hereby incorporated by reference in their entirety!).

(In an effort to develop chiral tridentate ligands for asymmetric catalysis, the inventors have created!

(bis (oxazolinylmethyl) amine ("AMBOX") ligand system. Chiral tridentate ligands tend to form! (a deep chiral pocket around the center of a once-assigned transition metal. A good example is the known PYBOX ligand series described, for example, in H. Nishiyama, "Chiral and C ₂ Symmetrical Bis (oxazolinylpyridine) rhodium (III) Complexes (Effective Catalysts for Asymmetric Hydrosilylation of Ketones, " Organometallics, Vol. 8, No. 3, pp. 846-48!) (March 1989). Two R groups on the oxazoline rings of PYBOX form a highly enantioselective "chiral fence" that allows better (differentiation of the orientation of Re and Si entering substrates).

When replacing the pyridine chain of PYBOX with an amine. (The new AMBOX ligand undergoes cyclic transition states similar to those in the articles! (Noyori and Haack cited above) and effectively catalyzes asymmetric transformations - e.g., hydridtransfer! (ketone reduction. Figure 4 is a schematic representation of the cyclic transition state obtained in (by hydrogenation of prochiral ketones.

Figure 1 shows a preferred route for the synthesis of bis [4- (R) -1-phenyloxazolin-2-ylmethyl] amine (hereinafter referred to as "(R) -PhAMBOX"), a preferred embodiment of the invention. Cyanoamine ·· 4

4 4 4

4 4 4

4 4 · 4444 • 4

It was reacted with HCl and methanol to give imidatester hydrochloride in a crude product yield of 76%. The obtained imidate hydrochloride without further purification was reacted in step b with (R) -phenylglycinol in dichloromethane at a temperature between 0 ° C and room temperature after ^; for 12 hours. (R) -Ph-AMBOX was obtained in 15% yield.

The chirality of the oxazolinylamine product as well as the identity of the substituent can be verified by selecting different aminoalcohols in step b. For example, to prepare the preferred structure XI shown in Figure 3, an aminoalcohol can be used.

OH in step b. In the scheme shown in Figure 1, it can be used to prepare a product with opposite chirality (S) aminoalcohols.

The catalysts of the present invention are prepared by forming a complex of a transition metal oxazolinylamine ligand described herein. Suitable transition metal catalyst precursors for complexing with the chiral ligand of the invention are known to those skilled in the art. For example, ¹ can be used ^: [Rh (cod) Cl] ₂ , [Rh (cod) ₂ ] X, [Ir (cod) Cl] ₂ , [Ir (cod) ₂ ] X, Ru (cod) Cl ₂ , where Cod is 1,5-cyclooctadiene, and X is BF ₄ , C10 ₄ , SbF ₆ , CF ₃ SO 3 or equivalents thereof. Alternatively, RuC1 ₂ (PPh ₃ ) ₃ , RuHCl (PPb.3) 3, RuX ₂ (PR ₃ ) ₃ can be used, »»

RuHX (PR ₃ ) ₃ , RuX ₂ and other equivalents, wherein "X is halogen and""R" is a substituted or unsubstituted alkyl or aryl group.

• ·

• 99 ····

• · ·

• © • ·

Φ

9 9 9

9 «• Φ Φ · (9 • 49 49

Catalyst optimization

Initial results of acetophenone transfer hydrogenation tests in 2-propanol using in situ catalysts with AMBOX and various commonly used transition metal precursors were unsatisfactory. All these catalysts had poor enantioselective activity, with the highest enantiomeric excess (alternatively hereinafter referred to as "ee") of less than 50% obtained using RuCl ₂ (PPh ₃ ) ₃ .

Table 1 shows the results of the optimization of the catalytic conditions for the transfer hydrogenation of acetophenone using (R) -Ph-AMBOX. Reaction (1) below was carried out in a 0.1 M acetophenone solution in 5 ml of 2-propanol. The ratio of ketone Ru ¹¹ : (R) -Ph-AMBOX was 100: 1: 1.1.

OH (R) Ph AMBOX [RuCIstPPhsfe]

OH

NaOPř

Ph '

Ph '(s;

0)

»·

Table 1

Try Free PPh ₃ ^a NaOPr ¹ eq. ^b T ° c t h yield ^c % ee ^c % l ^d + 15 Dec 82 0.5 96 45 2 ^e + 15 Dec 82 0,025 92 60 3 + 1.0 82 1 67 84 4 - 1.0 82 0.17 91 97 5 - 0, 5 82 1 26 95 6 - 0 82 1 0 ON 7 - 2,0 82 0.17 94 68 8 - 1.0 23 22nd 91 95

a. + indicates that there is free PPh ₃ in the reaction mixture; means that free PPh ₃ was washed out with ether after the catalyst was formed, before the addition of acetophenone and NaOPr ¹

b. Equivalents of base to Ru ¹¹

c.% yield and% enantiomeric excess were determined by GC analysis on a Supelco β-DEX 120 chiral capillary column. Absolute configurations were determined by comparing optical rotations with literature values. All major secondary alcohol products are (S) isomers.

d. A catalyst prepared by stirring a mixture of R- (Ph) -AMBOX and RuCl ₂ (PPh ₃ ) ₃ at room temperature overnight.

e. For Experiments 2-8, the catalysts were prepared by refluxing R- (Ph) -AMBOX and RuCl ₂ (PPh ₃ ) ₃ at 82 ° C for two hours.

It was found that the catalyst prepared in situ by refluxing AMBOX and RuCl ₂ (PPh ₃ ) ₃ in 2-propanol was much more effective than the catalyst prepared at 9 4 · · ··· · · ··· 9 9 4 99 94 9 at room temperature. For experiments 2 and 8 in Table 1, the catalysts were prepared by refluxing from the precursor RuCl ₂ (PPh 3) 3 at 82 ° C for two hours. These catalysts produced a larger enantiomeric excess than the corresponding catalysts from Experiment 1, which were prepared overnight at room temperature. Thus, according to a preferred embodiment of the invention, catalysts ^{1 were} prepared by refluxing 2-propanol:

Another factor that can significantly increase both catalytic activity and enantioselectivity is the removal of free triphenylphosphine ligand released during the formation of the AMBOX complex prior to the introduction of acetophenone and base (NaOPr ¹ ). Free PPh3 may interfere with this reaction due to its ability to again form a complex with the Ru center.

Removal of free PPh3 reduces unwanted competition to the enantioselective catalytic process. Preferably, according to ^the: present invention, heating a mixture of precursor _{RuCl2 (PPh3) 3,} RPH-AMBOX for two hours to give a green solution.

Then the solution is removed under vacuum, the resulting greenish residue is washed with ether to remove any free

PPh3. The solid was dissolved in 2-propanol, followed by addition of substrate and NaOPr ¹ . After this treatment, the enantiomeric excess increased significantly from 84% to 97%, as can be seen from Comparison of Experiments 3 and 4 in Table 11. Another important factor that can increase activity and enantioselectivity is the molar ratio of NaOPr ¹ to: catalyst. This ratio should be about 1.0. When 0.5 molar equivalent of base was used, the reaction; slow, although the enantiomeric excess remained high (Experiment 5, Table 1). When 2.0 molar equivalents were used! In addition, the reaction was accelerated but was accompanied by a strong decrease in the enantiomeric excess (Experiment 7, Table 1).

• 9

9 9 9 • 999

9 9

Figure 4 shows the predicted conformation of the active catalyst particle where L is PPh ₃ and X is chlorine. The particle of Figure 4 is likely to be formed after one HCl molecule has been peeled off by one NaOPr ¹ molecule from the putative RuCl ₂ PPh ₃ precursors (AMBOX), followed by one proton and one hydride from 2-propanol. ₃ should preferably be removed together with the NH proton due to the strong trans effect from PPh _3. However, if more than one molar equivalent of base is introduced, the chloride opposite NH could also be removed, resulting in possible pathways, Free PPh ₃ can also interfere with this reaction due to its ability to recompose with Ru. Therefore, removal of free PPh ₃ should result in avoiding undesirable competition and reducing The enantioselectivity of the catalytic process increased significantly after this treatment (enantiomeric excess from 84% to 9%). (See experiments 3 to 4 in Table 1.) ((Table 2 shows the reduction of a number of aromatic ketones to their secondary alcohols under optimized conditions!). using the catalyst of the invention. This reduction proceeds with a high enantiomeric excess and mostly with a! (satisfactory yield. General reaction (2) was carried out (unless otherwise stated) using a 0.1 M solution (ketone in 5 ml 2-propanol. The ketone: Ru: (R) -Ph-Ambox: NaOPr ¹ ratio was 100: 1: 1.1: 1.0. (

O

OH (R) -PtvAMBQX- tRuqz (PPh 4 OH

(WITH)'

O

(2) »·»

9 ·

9 4 9

The various changes in the substrates and conditions of the catalytic reactions are summarized in Table 2.

9 9

Table 2

Try; .Keton t min (Yield ³ % ee ^a % 1 0 X = CH ₃ 5 (9) 80 (90) 98 (97) 2 X = B 10 (20) 77 (92) 95 (92) 3 at X = i-Pr 10 15 Dec 78 4 X o X f 40 96 98 5 AND' A ^{x = a} 10 99 • 96 6 j X = CH ₃ o 4h 3 19 Dec

7 0 1 x = ch ₃ 5 (6) 75 (90) 96 (94) 8 C/ X = CI 10 5 92 9 X = CH ₃ o 7 (10) 91 (94) 95 (92) 10 0 x = ch ₃ 24h / rt 61 96 11 X = CI 10 97 90 12 X = CH ₃ o 10 41 98

i o 10 42 95

• * ·

(5) 72 (98) 96 (94) i-13 • · ♦ φ φ φ φφφφ / “Ο

2 (7) 55 (90) 96 (91)

% yield and% enantiomeric excess were determined by GC analysis on a Supelco β-DEX 120 chiral capillary column. Absolute configurations were determined by comparing optical rotations with literature values. All major secondary! Alcohol products are (S) isomers.

Both the enantiomeric excess and the chemical yield are modestly affected by substrate, spherical and electron properties. Spherical barrier effect of alkyl chains; Skeleton substrates are evident when their results are compared for methyl, ethyl and isopropylphenyl ketones (experiments 1 to 3, Table 2). By replacing the para substituent from the chloride with a methoxy group, the enantiomeric excess improved, but the conversion greatly decreased (experiments 11, 12, Table 2).

Reducing the enantiomeric excess of the product increases!

Conversion is mild for most ketones tested, especially methyl- and chloro-substituted acetophenones in which

Almost no reduction in the course of the reaction was observed (attempts (4, 5, Table 2).) However, replacing the phenylo ortho group with a methoxy group yielded very poor results! results (item 6, table 2).

The formulas (I) to (IV) of Figure 2 are not limiting; (Examples of preferred ligands of the invention. As shown in Figure 2, all preferred ligands of the invention contain oxazole substituted in two positions by an alkylamine or substituted alkylamine. As shown (for example in Formula (I), an alkylamine substituted at position 2). the oxazole may be, for example, methylamine or substituted methylamine In addition, the amine may be a primary, secondary or tertiary amine as shown in Figure 2.

In Figure 2, R ₁ , R ₂ , R 3, R ₄ , R 5, R 6, and R 7 may be the same or different and may be selected from the group consisting of: (hydrogen, alkyl, aryl, substituted alkyl or substituted aryl. The present invention includes embodiments wherein: (any two substituents of R 1, R ₂ , R 3 and R ₄ may be joined to form a ring structure and wherein any two substituents from R 5, R ₆ , and R ₇ may be joined to form a ring structure For example, in formula (II), wherein; (R 1 and R ₃ are methyl and R ₂ and R ₄ are phenyl, a structure having the configuration of the formula (XI) Similarly, one skilled in the art can create many ring structures that would be possible by linking R 1 to R ₄ in formulas (I) to (IV). (Alternatively, the ring formed by combining R ₅ and R 8 may form a structure similar to that (Although only certain enantiomeric configurations are shown in the figures, the enantiomeric orientation of the ligands!) (may be modified using various reagents during the synthesis. within the scope of the invention.

• · · · ·

Φ Φ ♦ ·

· Φ ♦ Φ • ······ φ

Φ ΦΦΦ

Φ Φ Φ Φ

Figures (V) to (XI) of Figure 3 indicate particularly) preferred embodiments of the chiral aminoxazoline ligands of the invention, such as oxazolin-2-yl-1 (methylamine which may be substituted for oxazole or methyl as shown in the formula) (V), or 2-oxazolin-2-yl-: azacyclopentane, which may be substituted to the oxazole as shown in formula (VI), or the bis [4- (R) - ifenyloxazolin-2-yl- methyl] amine, which may be derived from formula (VII)

In summary, this invention encompasses novel chiral tridentate ligands that form highly potent; (catalyst with RuCl2 (PPh3) 3 and other catalyst precursors for the transfer hydrogenation of a number of ketones and other reactions:

Czech Republic . . . . - r. «, 5 /> Av

MbdaA. and

Claims (20)

PATENT CLAIMS 7 (/ 3poo ~ • 99 99 · 99 • 99 9999 999) 99 99 99 9999999 9 9 99 9 • 9 9 9 9 9 9999 9 99 · 9 9 99 9 51. A chiral ligand that forms a catalyst providing increased enantiomeric selectivity at asymmetric! A reaction having a structure selected from the group consisting of enantiomers of the following formulas (I) to (IV): wherein R 1, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R 7 are independently hydrogen, alkyl, aryl, substituted alkyl or substituted aryl, wherein any two of R 1, R ₂ , R 3 and R ₄ may be joined to each other to form a ring structure, wherein any two of R ₅ , R ₆ or R 7 may be joined to each other to form a ring structure, and wherein η = 1 or 2. The chiral ligand of claim 1, wherein the ligand is 1. complexly bound with transition metal. Φ Φ · · · · · · · · · • · The chiral ligand of claim 2, wherein the transition metal is; selected from the group consisting of rhodium, iridium, ruthenium and palladium / The chiral ligand of claim 1, wherein the ligand is complexed to the transition metal catalyst precursor selected; from the group consisting of [Rh (cod) Cl] ₂ , [Rh (cod) ₂ ] X, [Ir (cod) Cl] ₂ , [Ir (cod) ₂ ] X, Rh (cod) Cl ₂ , wherein the cod i is 1,5-cyclooctadiene, and X is BF _4, C10 _4, CF ₃ or SbFg SO _3rd The chiral ligand of claim 1, wherein the ligand is (i-complexed with a transition metal catalyst precursor selected from the group consisting of RuCl ₂ (PPh ₃ ) ₃ , RuHCl (PPh ₃ ) ₃ , IRu ₂ (PR ₃ ) ₃ , RuHX (PR ₃ ) ₃ , RuX ₂ , wherein X is halogen and R is a substituted or unsubstituted alkyl or aryl group / ( The chiral ligand of claim 1, wherein the ligand is selected from the group consisting of the following formulas (V) to; (Xi): ........ R 7. A chiral ligand which forms a catalyst providing a! Enhanced enantiomeric selectivity in asymmetric reactions, wherein the chiral ligand comprises! bis (oxazolinyl) amine. The chiral ligand of claim 1, wherein said chiral ligand. the iligand is bis [4- (R) -phenyloxazolin-2-ylmethyl] amine. 9. A process for the production of a catalyst providing increased catalysts. Senantiomeric selectivity in asymmetric reactions comprising reduction of the imidate ester with a chiral alcohol to obtain a chiral ligand according to claim 1 10. The process of claim 9, further comprising complexing said chiral ligand with a transition metal catalyst precursor. A process for the production of a catalyst according to claim 10, wherein the catalyst is produced. [The catalyst precursor further comprises triphenylphosphine, characterized in that the process for the preparation of the catalyst. is to remove free triphenylphosphine released during chiral ligand precursor complex formation! of the catalyst. [ A process for producing a catalyst according to claim 10, wherein the catalyst precursor and the chiral ligand are cooked. ipod reflux condenser in alcohol at boiling point of alcohol.! [ 13. The process of claim 10 wherein the transition metal is selected from the group consisting of: a. [Rhodium, Iridium, Ruthenium and Palladium. 14. The process of claim 10 wherein the catalyst precursor is selected from the group consisting of [Rh (cod) Cl] _n [Rh (cod) ₂ ] X, [Ir (cod) Cl] ₂ , i [ [Ir (cod) _2] X, where COD is 1,5-cyclooctadiene, and X is BF _4, C10 _4, SbF ₆ or CF ₃ SO ₃ .I A process for producing a catalyst according to claim 10, wherein the catalyst precursor is selected from the group consisting of: [composed of RuCl ₂ (PPh ₃ ) ₃ , RuHCl (PPh ₃ ) 3, RuX ₂ (PR ₃ ) ₃ , RuHX (PR ₃ ) ₃ ] RuX _2, wherein X is halogen and R is not substituted (unsubstituted alkyl or aryl group. 16. A method of increasing the enantiomeric chemical selectivity! The reaction comprising contacting the substrate with the chiral ligand-containing catalyst of claim 1. 17. The method of claim 16, wherein said reaction is selected from the group consisting of hydrogenation, hydrogenation, and the like. hydridtransfer reactions, hydrosilylation, hydroboration, hydrovinylation, hydroformylation, hydrocarboxylation, allyl (alkylation, cyclopropanation, Diels-Alder reactions, aldol reactions, Heck reactions, Michael additions and rearrangements) ( 18. The method of claim 17, wherein said reaction is transfer hydrogenation and said substrate is a hydrogenation reaction. (ketone or imine. 19. The method of claim 18 wherein: < tb > (Contacting the substrate with the catalyst further comprises contacting the substrate and the catalyst with a base, and wherein (the molar ratio of this base to the catalyst is between 0.5 and 2.0%). 20. The method of claim 19, wherein said molar ratio is about 1.0.