Title of Invention

CHIRAL PHOSPHINE LIGANDS,THEIR PREPARATION AND CATALYST THEREOF

Abstract

The present invention provides bipyrimidinyl diphosphine compounds of the formula, formula (I) wherein R is optionally substituted alkyl, cycloalkyl, aryl or heteroaryl; R' and R" are independently optionally substituted alkyl, cycloalkyl, aryl or heteroaryl; or an enantiomer thereof; or an enantiomeric mixture thereof. The compounds of the formula (I) are chiral atropisomeric bipyrimidinyl diphosphine compounds and, thus, may be employed as ligands to generate chiral transition metal catalysts which may be applied in a variety of asymmetric reactions, e.g., in palladium catalyzed asymmetric allylic substitution reactions. The compounds of the present invention are easily accessible a in high enantiomeric purity according to the methods disclosed herein.

Full Text

asymmetric allylic substitution reactions, and which are synthetically easily accessible in high optical purity. Accordingly, the present invention provides bipyrimidinyl diphosphine compounds of the formula wherein R is optionally substituted alkyl, cycloalkyl, aryl or heteroaryl; R' and R" are independently optionally substituted alkyl, cycloalkyl, aryl or heteroaryl; or an enantiomer thereof; or an enantiomeric mixture thereof. The compounds of the formula (I) are chiral atropisomeric bipyrimidinyl diphosphine compounds and, thus, may be employed as ligands to generate chiral transition metal catalysts which may be applied in a variety of asymmetric reactions, e.g., in palladium catalyzed asymmetric allylic substitution reactions. The compounds of the present invention are easily accessible in high enantiomeric purity according to the methods disclosed herein. Other objects, features, advantages and aspects of the present invention will become apparent to those skilled in the art from the following description and appended claims. It should be understood, however, that the following description, appended claims, and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only. Various changes and modifications within the spirit and scope of the disclosed invention will become readily apparent to those skilled in the art from reading the following. Listed below are definitions of various terms used to describe the compounds of the present invention. These definitions apply to the terms as they are used throughout the specification benzoxazolyl, benzothienyl, quinoiinyl, isoquinolinyl, benzimidazolyl, benzofuryl and the like; optionally substituted by, e.g., lower alky! or lower alkoxy. As described herein above, the present invention relates to compounds of formula (I), to methods for their preparation, and to use of such compounds in asymmetric catalysis. Compounds of the present invention are particularly useful when employed as chiral ligands in palladium catalyzed asymmetric allylic substitution reactions. When required, protecting groups may be introduced to protect the functional groups present from undesired reactions with reaction components under the conditions used for carrying out a particular chemical transformation of the present invention. The need and choice of protecting groups for a particular reaction is known to those skilled in the art and depends on the nature of the functional group to be protected (amino, hydroxy etc.), the structure and stability of the molecule of which the substituent is a part and the reaction conditions. Well-known protecting groups that meet these conditions and their introduction and removal are described, for example, in McOmie, "Protective Groups in Organic Chemistry1, Plenum Press, London, NY (1973); Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley and Sons, Inc., NY (1999). Preferred are the compounds of formula (I) wherein R is monocyclic aryl; R' and Rw are independently lower alky!; or an enantiomer thereof; or an enantiomeric mixture thereof. Further preferred are the compounds of formula (I) wherein R is phenyl; R' and R" are methyl; or an enantiomer thereof; or an enantiomeric mixture thereof. Particular embodiments of the invention are: (fl)-5,5'-bis(disubstitutedphospW 3'H)-tetrone, also designated as (R)-PM-Phos; and (S)-5,5'-bis(disubstitutedphosph^ 3'H)-tetrone, also designated as (S)-PM-Phos. The compounds of the present invention preferably have an optical purity of at least 85% enantiomeric excess (ee), more preferably at least 95% ee, and most preferably at least 98% ee. The compounds of the present invention may be employed to generate a chirai transition metal catalyst comprising a suitable transition metal bound to a compound of the formula wherein R is optionally substituted alkyi, cycioalkyl, aryl or heteroaryl; R' and R" are independently optionally substituted alkyl, cycioalkyl, aryl or heteroaryl; or an enantiomer thereof; or an enantiomeric mixture thereof. Particularly useful are the catalysts of the present invention wherein the transition metal is bound to a compound of formula (I) wherein R is monocyclic aryl; R' and R" are independently lower alkyl; or an enantiomer thereof; or an enantiomeric mixture thereof. Especially useful are the catalysts of the present invention wherein the transition metal is bound to a compound of formula (I) wherein R is phenyl; R' and R" are methyl; or an enantiomer thereof; or an enantiomeric mixture thereof. Especially useful are also the catalysts of the present invention wherein the transition metai is bound to a compound of formula (I) which is selected from the group consisting of; (R)-5,5'~bis(disubstitutedphosphinoK 3'H)-tetrone; and (S)-5,5'-bis(disubstitutedphosphino)^ 3'HHetrone. Suitable transition metals for the catalyst system of the present invention include, but are not limited to, copper (Cu), iridium (ir), nickel (Ni), palladium (Pd), platinum (Pt), rhodium (Rh) and ruthenium (Ru). Preferably, the transition metal is palladium. Particularly useful are the catalysts of the present invention wherein the transition metal is palladium, and the transition metal is bound to a compound of formula (I) wherein R is monocyclic aryl; R' and R" are independently lower alkyl; or an enantiomer thereof; or an enantiomeric mixture thereof. Especially useful are the catalysts of the present invention wherein the transition metal is palladium, and the transition metal is bound to a compound of formula (I) wherein R is phenyl; R'and R" are methyl; or an enantiomer thereof; or an enantiomeric mixture thereof. Especially useful are also the catalysts of the present invention wherein the transition metal is palladium, and the transition metal is bound to a compound of formula (I) which is selected from the group consisting of: (R)-5,5'-bis(disubsttutedphosphinoH^ 3'H)-tetrone; and (S)-5,5'-bis(disubstitutedphosphino)-1,1 '.S^'-tetraalkyM^'-bipyrimidine-a^'^.e'-i 1H, 1 'H,3H, 3'H)-tetrone. The compounds of the present invention may be prepared by deprotonating a compound of the formula wherein R' and R" have meanings as defined herein above and X represents halogen, such as iodide, bromide or chloride, with a base such as lithium diisopropylamide (LDA) or lithium wherein R( R' and R" have meanings as defined herein above. The Ullmann coupling reaction is preferably conducted at a temperature ranging from about 100 °C to about 160 °C, preferably at a temperature of about 140°C, in the presence of an inorganic salt such as sodium carbonate, potassium carbonate or sodium oxalate, or a mixture of salts thereof, to facilitate the coupling reaction. Interestingly, the coupling reaction is accompanied by the spontaneous migration of the R' and R" groups from the oxygen atoms to the nitrogen atoms. A resulting racemic compound of formula (VI) may then be resolved into its optical antipodes, i.e., enantiomers, by known methods, e.g., by separation of the diastereoisomeric salts thereof, e.g., by fractional crystallization of a (+)- or (-)-dibenzoyltartaric acid salt thereof, e.g., from a 1:1-mixture of ethyl acetate and chloroform. The optically active compound of the formula wherein R, R' and R" have meanings as defined herein above, may then be liberated, e.g., by treatment with base such as aqueous sodium hydroxide (NaOH) to afford a free compound of formula R-(VI) or S-(VI), or an enantiomeric mixture thereof. A racemic compound of formula (VI) may also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent. Finally, a compound of formula (VI), or an enantiomer thereof, or an enantiomeric mixture thereof, may be treated with a reducing agent, such as trichlorosiiane, in the presence of an organic base, such as triethylamine or tri-n-butylamine, and an aromatic hydrocarbon solvent, such as toluene or xylene, to afford a compound of formula (I), or an enantiomer thereof, or an enantiomeric mixture thereof, respectively, wherein R, R1 and R" have meanings as defined herein above. Preferably, the reduction is conducted in toluene in an autoclave, at a temperature of about 120 °C. The compounds of formula (I) may then be converted to chiral transition metal catalysts of the present invention by reacting a compound of formula (I), or an enantiomer thereof, or an enantiomeric mixture thereof, with a suitable transition metal salt, or a complex thereof, to afford a catalyst of the present invention. The choice of a suitable transition metal salt, or a complex thereof, is generally known to those skilled in the art and depends on the nature of the asymmetric reaction to be performed. A suitable transition metal salt, or a complex thereof, for the preparation of a catalyst of the present invention may be selected, e.g., from those described herein in the illustrative examples. Further examples of such transition metal salts may be found, e.g., in Seyden-Penne, "Chiral Auxiliaries and Ligands in Asymmetric Synthesis'1, John Wiley & Sons, Inc., NY (1995). A catalyst of the present invention may be generated in situ, or it may be isolated prior to use. The catalysts of the present invention obtainable as described herein may be employed for converting a racemic or a prochiral substrate to a chiral product under reaction conditions otherwise suitable for asymmetric induction. Such asymmetric reactions include, but are not limited to, catalytic hydrogenation, hydrosilylation, hydroboration, hydroformylation, hydrocarboxylation, hydroacylation, Heck reaction and allylic substitution reactions. The catalysts of the present invention are especially effective when employed in allylic substitution reactions. For example, a compound of formula (I) may be reacted with a palladium complex such as a dimer of allyl palladium chloride or tris(dibenzylideneacetone)paIIadium in a suitable organic solvent such as dichloromethane (DCM) to obtain a catalyst of the present invention. The resulting catalyst may then be used in situ in a suitable palladium catalyzed reaction, e.g., in an Similarly, the results of a palladium catalyzed allylic amination using benzylamine as the nucleophile and (R)-PM-Phos as the chiral ligand are summarized in Table 2. As exemplified in entries 1 and 2, an asymmetric allylic amination employing a catalyst of the present invention provides chiral allylic amines with considerably higher catalytic activity and enantioseiectivity than that obtained with the well known diphosphine iigand BINAP under identical reaction conditions. The following Examples are intended to further illustrate the invention and are not to be construed as being limitations thereon. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 5 and 50 mmHg. The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis, melting point, and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art. To a magnetically stirred solution of 8.2 mL (58.4 mmol) of diisopropylamine in 50 mL of dried THF at 0°C is dropwisely added 34.2 mL (54.7 mmol) of a solution of n-BuLi (1.6 M) in hexane. After the addition, the resulting solution is maintained at room temperature for 1 h, then cooled down to -78 °C. To the above LDA solution, a solution of 5-bromo-2,4-dimethoxypyrimidine (10 g, 45.6 mmol) in 50 mL of THF is dropwisely added in 1 h. The temperature is allowed o rise a little until the color of the solution became dark brown, and then cooled down to -78 °C again. A solution of CIPPh2 (10 mL, 55.5 mmol) in 50 mL of THF is dropwisely added to the above solution. And finally the temperature is allowed to naturally rise to room temperature. The reaction mixture is stirred at ambient temperature for additional 12 h. At the end, the reaction mixture is poured into 300 mL of water with vigorous stirring. The product is extracted with DCM (3 x 50 mL). The combined extract is washed with water for 3 times and dried with anhydrous sodium sulfate. The solvent is removed off in vacuo to give a crude product which is purified by flash chromatography with DCM as eiuant and then by recrystaliization in a 1:1 mixture of methanol and acetone to give pure, white powdery 4-bromo-5-(diphenylphosphino)-2l6-dimethoxypyrimidine: 1H NMR (500 MHz) (CDCi3) 8 3.55 (s, 3H, OCH3), 4.02 (s, 3H, OCH3), 7.31-7.38 (m, 10H, PhH); 13C-NMR (126 MHz) (CDCI3) 5 54.4, 55.8, 110.9 (d, J = 24.0 Hz), 128.4 (d, J= 5.7 Hz), 128.6, 132.6 (d, J = 20.1 Hz), 135.3 (d, J = 10.6 Hz), 162.6 (d, J = 41,5 Hz), 165.0, 172.3 (d, J = 2.9 Hz); 31P-NMR (202 MHz) (CDCI3) 5 -9.0 (s). A round bottom flask with a magnetic stirrer is charged with 4-bromo-5-(diphenylphosphino)~ 2,6-dimethoxypyrimidine from Example 1 (13 g) and 150 mL of acetone, the reaction mixture is stirred vigorously and cooled down to 0 °C, To this mixture is slowly added 15 mL of ca. 35% hydrogen peroxide. The reaction is monitored by TLC. After the solid is completely dissolved, the reaction is completed. After adding 100 mL of water, the product is extracted with DCM (3 x 50 mL). The combined extract is washed with water for three times and dried with anhydrous sodium sulfate. The solution is concentrated-//? vacuo to give a crude product which is purified by recrystallization from a 1:1 mixture of ethyl acetate and hexane to afford pure, colorless crystalline 4-bromo-5-(diphenylphosphinoyl)-2,6-dimethoxypyrimidine: 1H NMR (500 MHz) (CDCfe) 6 3.49(s, 3H), 4.02 (s, 3H), 7.43-7A6 (m, 4H), 7.50-7.54 (mt 2H), 7.67-7.72 (m, 4H); 13C-NMR (126 MHz) (CDCI3) 8 54.7, 56.1, 128.6 (d, J= 12.6 Hz), 131.5 (d, J= 10.6 Hz), 132.0, 133.1, 134.0, 158.8 (d, J= 6.8 Hz), 165.2, 172.3 (d, J = 5.8 Hz): 31P-NMR (202 MHz} fCDCW 5 24.8 fs^. What is claimed is: wherein R is optionally substituted alkyl, cycloalkyl, aryl or heteroaryi; R' and R" are independently optionally substituted alkyl, cycloalkyl, aryl or heteroaryi; or an enantiomer thereof; or an enantiomeric mixture thereof. 2. A compound according to claim 1, wherein R is monocyclic aryl; R' and Rn are independently lower alkyl; or an enantiomer thereof; or an enantiomeric mixture thereof. 3. A compound according to claim 2, wherein R is phenyl; R' and Rw are methyl; or an enantiomer thereof; or an enantiomeric mixture thereof. 4. A compound according to claim 2, which is selected from the group consisting of: (R)-5,5'-bis(disubstitutedphosphino)-1,1 'I3,3'-tetraalkyl-4l4,.bipyrimidine-2,2',6,6,-(1 H, 1 'H,3H, 3'tf)-tetrone; and (S)~5,5'-bis(disubstitutedphos 3'H)«tetrone. 5. A catalyst comprising a transition metal bound to a compound of the formula wherein R is optionally substituted alkyl, cycloalkyl, aryl or heteroaryl; R' and R" are independently optionally substituted alkyl, cycloalkyl, aryl or heteroaryl; or an enantiomer thereof; or an enantiomeric mixture thereof. 6. A catalyst according to claim 5, wherein R is monocyclic aryl; R' and R" are independently lower alkyl; or an enantiomer thereof; or an enantiomeric mixture thereof. 7. A catalyst according to claim 6, wherein R is phenyl; R' and R" are methyl; or an enantiomer thereof; or an enantiomeric mixture thereof. 8. A catalyst according to claim 6, wherein the compound of formula (I) is selected from the group consisting of: (R)-5,5r-bis(disubstiM^^ 3fH)-tetrone; and (S^S'-bistdisubstitutedphosp 3'H)-tetrone. 9. A catalyst according to claim 5, wherein the transition metal is selected from the group consisting of copper, iridium, nickel, pafladium, platinum, rhodium and ruthenium. 10. A catalyst according to claim 9, wherein the transition metal is palladium. 11. A catalyst according to claim 10, wherein R is monocyclic aryl; R' and R* are independently lower alkyl; or an enantiomer thereof; or an enantiomeric' mixture thereof. 12. A catalyst according to claim 11, wherein R is phenyl; R' and R" are methyl; or an enantiomer thereof; or an enantiomeric mixture thereof. 13. A catalyst according to claim 11, wherein the compound of formula (!) is selected from the group consisting of: (tf)-5,5 ~bis(disubstitutedphosphino)-1,1 '^^'-tetraalkyM^bipyrimidine-a^'^^'^l H,VH,ZH, 3'W)-tetrone; and (S)-5,5'-bis(disubstituted^ 3'H)-tetrone. 14. A method for converting a racemic or prochiral substrate to a chiral product by an asymmetric allylic substitution reaction in the presence of a catalyst comprising a transition metal bound to a compound of the formula wherein R is optionally substituted alkyl, cycloalkyl, aryl or heteroaryl; R' and R" are independently optionally substituted alkyl, cycloalkyl, aryl or heteroaryl; or an enantiomer thereof; or an enantiomeric mixture thereof. 15. A method according to claim 14, wherein the transition metal is palladium. 16. A catalyst according to claim 15, wherein R is monocyclic aryl; R' and R" are independently lower alkyl; or an enantiomer thereof; or an enantiomeric mixture thereof. 17. A catalyst according to claim 16, wherein R is phenyl; R' and R" are methyl; or an enantiomer thereof; or an enantiomeric mixture thereof. 18. A catalyst according to claim 16, wherein the compound of formula (I) is selected from the group consisting of: (R)-5,5'-bis(disubstitutedphosphinoM ,1 '.S^'-tetraalkyM^'-bipyrimidine^^'.e^'-CI H.1 'H.3H, 3'H)-tetrone; and (S)-5,5'-bis(disubstitutedphosphino)-1 ,1 '.S^'-tetraalkyM.^-bipyrimidine-Z^'^.e'^l H, 1U3H, 3'H)-tetrone. 19. A method for preparing a compound of the formula wherein R is optionally substituted alkyl, cycloalkyl, aryl or heteroaryl; R' and R" are independently optionally substituted alkyl, cycloalkyl, aryl or heteroaryl; or an enantiomer thereof; or an enantiomeric mixture thereof; which method comprises treating a compound of the formula wherein R is optionally substituted alkyl, cycloalkyl, aryl or heteroaryl; R' and R" are independently optionally substituted alkyl, cycloalkyl, aryl or heteroaryl; or respectively, an enantiomer thereof; or an enantiomeric mixture thereof, with a reducing agent in the presence of an organic base and an aromatic hydrocarbon solvent to afford a compound of formula (I). 20. A method according to claim 19, wherein the reducing agent is trichiorosilane, the organic base is triethylamine, the aromatic hydrocarbon solvent is toluene and the reduction reaction is carried out in an autoclave. 21. A method according to claim 19, wherein a compound of formula R-(VI); or an enantiomer thereof; or an enantiomeric mixture thereof; is prepared by a process comprising: (a) converting a compound of the formula wherein R, R' and R" have meanings as defined in said claim and X represents halogen; to a compound of the formula

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