Patent Application
20110004005
The present invention is directed to rhodium-phosphorus complexes and their use as catalysts in the ring opening reaction of heteronorbornenes and other α,β-unsaturated compounds.
The efficient construction of stereochemically complex carbocyclic compounds through the ring opening of heterobicyclic alkenes has become an important reaction for C—C and C—X bond formation. Pioneering work in this field as well as the exploration of its synthetic potential in enantioselective synthesis and synthesis of natural products was first described by Lautens and co-workers [For natural product synthesis, see: Lautens, M.; Rovis, T. J. Org. Chem. 1997, 62, 5246-5247. Lautens, M.; Rovis, T. Tetrahedron 1999, 8967-8976. Lautens, M.; Colucci, J. T.; Hiebert, S.; Smith, N. D.; Bouchain, G. Org. Lett. 2002, 4, 1879-1882. Lautens, M.; Fagnou, K.; Zunic, V. Org. Lett. 2002, 4, 3465-3468].
Particular attention has been placed on the desymmetrization of oxobenzonorbornadiene 1, as the products are precursors to the medicinally important tetrahydronaphthalene moiety [Snyder, S. E.; Aviles-Garay, F. A.; Chakraborti, R.; Nichols, D. E.; Watts, V. J.; Mailman, R. B. J. Med. Chem. 1995, 38, 2395-2409. Kamal, A.; Gayatri, N. L. Tetrahedron Lett. 1996, 37, 3359-3362. Kim, K.; Guo, Y.; Sulikowski, G. A. J. Org. Chem. 1995, 60, 6866. Perrone, R.; Berardi, F.; Colabufo, N. A.; Leopoldo, M.; Tortorella, V.; Fiorentini, F.; Olgiati, V.; Ghiglieri, A.; Govoni, S. J. Med. Chem. 1995, 3, 8, 942-949].
The following scheme shows the huge synthetic potential of oxabenzonorbornadiene 1.
Among the carbon nucleophiles capable of inducing ring opening of heterobicyclic alkenes, organolithium [Caple, R.; Chen, G. M.-S.; Nelson, J. D. J. Org. Chem. 1971, 36, 2874-2876. Arjona, O.; de la Pradilla, R. F.; Garcia, E.; Martin-Domenech, A.; Plumet, J. Tetrahedron Lett. 1989, 30, 6437-6440. Lautens, M.; Gajda, C.; Chiu, P. J. Chem. Soc., Chem. Commun. 1993, 1193-1194] and cuprate [Lautens, M.; Smith, A. C.; Abd-El-Aziz, A. S.; Huboux, A. H. Tetrahedron Lett. 1990, 31, 3523] reagents were the first class of nucleophiles used, affording the corresponding syn addition products. Later, softer organometallic species such as phenylstannane [Fugami, K.; Hagiwara, S.; Oda, H.; Kosugi, M. Synlett 1998, 477-478], alkylaluminums [Millward, D. B.; Sammis, G.; Waymouth, R. M. J. Org. Chem. 2000, 65, 3902-3909], dialkylzincs [Lautens, M.; Hiebert, S.; Renaud, J.-L. Org. Lett. 2000, 2, 1971-1973. Lautens, M.; Renaud, J.-L.; Hiebert, S. J. Am. Chem. Soc. 2000,122, 1804-1805. Lautens, M.; Hiebert, S.; Renaud, J.-L. J. Am. Chem. Soc. 2001, 123, 6834-6839] alkylzinc halides [Rayabarapu, D. K.; Chiou, C.-F.; Cheng, C.-H. Org. Lett. 2002, 4, 1679-1682] and arylboronic acids [Murakami, M.; Igawa, H. Chem. Commun. 2002, 390-391. Lautens, M.; Dockendorff, C.; Fagnou, K.; Malicki, A. Org. Lett. 2002, 4, 1311-1314] in the presence of a variety of metal catalysts, also proved to be efficient reagents for the syn-stereoselective ring-opening addition.
On the other hand, the rhodium-catalyzed asymmetric ring-opening of oxabenzonorbornadiene with alcohols and phenols produces hydronaphtalenes in high yields and with excellent enantioselectivities by means of an anti addition [Lautens, M.; Fagnou, K.; Rovis, T. J. Am. Chem. Soc. 2000, 122, 5650. Lautens, M.; Fagnou, K.; Taylor, M. Org. Lett. 2000, 2, 1677. Lautens, M.; Fagnou, K.; Taylor, M.; Rovis, T. J. Organomet. Chem. 2001, 624, 259. Lautens, M.; Fagnou, K.; Hiebert, S. Acc. Chem. Res. 2003, 36, 48]. Also, rhodium-catalyzed ring-openings of oxabicyclic alkenes with amines [Lautens, M.; Fagnou, K. J. Am. Chem. Soc. 2001, 123, 7170], carboxilates [Lautens, M.; Fagnou, K. Tetrahedron 2001, 57, 5067], 1,3-dicarbonyl nucleophiles [Lautens, M.; Fagnou, K.; Yang, D. J. Am. Chem. Soc. 2003, 125, 14884] and sulfur nucleophiles [Leong, P.; Lautens, M. J. Org. Chem. 2004, 69, 2194] have been reported as anti-stereoselective reactions.
Azabicyclic alkenes, including azabenzonorbornadienes, were found to be less reactive than the corresponding oxabicyclic alkenes. The first example of the transition metal-catalyzed ring-opening reaction of azabicyclic alkenes is the palladium-catalyzed alkylative ring-opening of N-substituted azabenzonorbornadienes [Lautens, M.; Hiebert, S.; Renaud, J. Org. Lett. 2000, 2, 1971. Cabrera, S.; Arrayas, R. G.; Carretero, J. C. Angew. Chem., Int. Ed. 2004, 43, 3944]. Rhodium-catalyzed ring-opening addition of aliphatic and cyclic amines to azabicyclic substrates has also been reported [Lautens, M.; Fagnou, K.; Zunic, V. Org. Lett. 2002, 4, 3465. Cho, Y-h.; Zunic, V.; Senboku, H.; Olsen, M.; Lautens, M. J. Am. Chem. Soc. 2006, 128, 6837].
WO2001030734 (Fagnou, K.; Lautens, M.) discloses a procedure for making an enantiomerically enriched compound containing a hydronaphthalene ring structure. The process involves reacting oxabenzonorbornadiene compounds with nucleophiles using rhodium as a catalyst and in the presence of a phosphine ligand. The compounds synthesized may be used in pharmaceutical preparations. The catalyst used in this document is [Rh(COD)Cl]2/PPF-tB2.
Nevertheless, Lautens disclosed later a halide exchange protocol in order to achieve better activity and enantioselectivity, specially for other than alcohols or phenolic nucleophiles [Lautens, M.; Fagnou, K.; Yang, D. J. Am. Chem. Soc. 2003, 125, 14884]. Even though the new catalyst, [RhI(PPF-tB2)], improved the efficiency of such reactions, high temperatures (always 80° C. or above) were still required.
On the other hand, EP 1 225 166 (Degussa AG) is directed to enantiomerically enriched N-acylated β-amino acids synthesized by catalytic enantioselective hydrogenation of E-isomers and Z-isomers of 3-amino acrylic acid derivatives in the presence of a pre-catalyst such as [Rh(MeDuPHOS)COD]BF4. The inventors propose this pre-catalyst is first converted to a solvent complex ([Rh(MeDuPHOS)(MeOH)2]BF4) which is actually the catalytically active species by pre-hydrogenation of the diolefinic ligand.
Heller and co-workers have also explored the asymmetric hydrogenation of prochiral substrates in presence of Rh(diolefin) complexes with chiral phosphines. These complexes are hydrogenated in parallel to the asymmetric reaction obtaining thus the true catalytic species, [Rh(chiral diphosphine)(MeOH)2]BF4 [Tetrahedron Lett. 2001, 42, 223; J. Organomet. Chem. 2001, 621, 89; Dalton Trans. 2003, 1606].
It would be highly desirable to develop new catalysts which overcome the problems raised in ring opening reactions. In particular, lower reaction temperatures together with lower amounts of substrates would facilitate the industrial application of these processes.
The authors of the present invention have surprisingly found that a cationic solvent complex, represented by the general formula [RhPP(solv)2]X, presents excellent behaviour in ring opening reactions, improving significantly the results obtained when compared to the complexes previously described in the prior art. In particular, the application of these cationic solvent complexes in the asymmetric version of this reaction (asymmetric ring opening, ARO) provides higher enantioselectivities and complete conversions whereas it allows lowering the substrate/nucleophile ratio. In addition, such complexes enable lower reaction temperatures and shorter reaction times.
A first aspect of the present invention refers to the use of a rhodium-phosphorus complex of formula (I):
[Rh(PP)(solv)2]X (I)
wherein:
PP is a bidentate phosphorus ligand or two monodentate phosphorus ligands;
solv is a coordinating solvent; and
X is an anionic counterion,
as catalyst in a ring opening reaction.
A second aspect of the present invention is a process for the catalytic ring opening of α,β-unsaturated compounds of formula (II) and (III):
In another aspect the present invention is directed to a rhodium-phosphorus complex of formula (I′):
[Rh(PP′)(solv)2]X (I′)
wherein
PP′ is a metallocene-type diphosphine ligand,
solv is a coordinating solvent, and
X is an anionic counterion.
with the proviso that [Rh(PPF-PCy2)(MeOH)2]BF4 is not included.
Another aspect of the present invention is a process for the preparation of a rhodium-phosphorus complex (I′) as defined in the paragraph above, which comprises the hydrogenation of a metal diolefin complex of formula (IV) in the presence of a suitable coordinating solvent (solv),
[Rh(PP′)(diolefin)]X (IV)
wherein PP′, X and solv have the same meanings as defined for (I′) and diolefin represents a diolefin molecule or two monoolefin molecules.
According to a further aspect, the present invention refers to the process described in the paragraph above which further comprises the subsequent addition of a compound of formula (II) or (III) as defined previously and a nucleophile to promote the ring opening reaction of said compound of formula (II) or (III).
Finally, another aspect of the present invention is the rhodium-phosphorus complex (I′) obtainable by the process as defined above.
In the context of the present invention, the following terms have the meaning detailed below:
“Alkyl” refers to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no unsaturation, having one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e. g., methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl or n-pentyl. Alkyl radicals may be optionally substituted by one or more substituents such as an aryl, halo, hydroxy, alkoxy, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto or alkylthio.
“Alkenyl” refers to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing one or more unsaturated bonds, having at least two carbon atoms and which is attached to the rest of the molecule by a single bond, e. g., vinyl or allyl. Alkenyl radicals may be optionally substituted by one or more substituents such as an aryl, halo, hydroxy, alkoxy, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto or alkylthio.
“Cycloalkyl” refers to a stable 3-to 10-membered monocyclic or bicyclic radical which is saturated or partially saturated, and which consist solely of carbon and hydrogen atoms, such as cyclohexyl or adamantyl. Unless otherwise stated specifically in the specification, the term “cycloalkyl” is meant to include cycloalkyl radicals which are optionally substituted by one or more substituents such as alkyl, halo, hydroxy, amino, cyano, nitro, alkoxy, carboxy or alkoxycarbonyl.
“Aryl” refers to single and multiple aromatic hydrocarbon radicals, including multiple ring radicals that contain separate and/or fused aryl groups. Typical aryl groups contain from 1 to 3 separated or fused rings and from 6 to about 18 carbon ring atoms, such as phenyl, naphthyl, indenyl, fenanthryl or anthracyl radical. The aryl radical may be optionally substituted by one or more substituents such as hydroxy, mercapto, halo, alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino, aminoalkyl, acyl or alkoxycarbonyl.
“Heterocyclyl” refers to a stable 3- to 15-membered ring which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, preferably a 4-to 8-membered ring with one or more heteroatoms, more preferably a 5-or 6-membered ring with one or more heteroatoms. For the purposes of this invention, the heterocycle may be a monocyclic, bicyclic or tricyclic ring system, which may include fused ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidised; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated or aromatic. Examples of such heterocycles include, but are not limited to, azepines, benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole and tetrahydrofurane.
“Alkoxy” refers to a radical of the formula —ORa where Ra is an alkyl radical as defined above, e.g., methoxy, ethoxy or propoxy. “Aryloxy” refers to a radical of formula —ORb wherein Rb is an aryl radical as defined above.
“Alkylamine” refers to a radical of the formula —NHRa or —NRaRb, optionally quaternized, wherein Ra and Rb are independently an alkyl radical as defined above. The alkyl radical may be optionally substituted by one or more substituents such as an aryl, halo, hydroxy, alkoxy, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto or alkylthio.
“Arylamine” refers to a radical of the formula —NHRa or —NRaRb, optionally quaternized, wherein Ra and Rb are independently an aryl radical as defined above. The aryl radical may be optionally substituted by one or more substituents such as hydroxy, mercapto, halo, alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino, aminoalkyl, acyl or alkoxycarbonyl.
“Amino protecting group” refers to a group that blocks the NH2 function for further reactions and can be removed under controlled conditions. The amino protecting groups are well known in the art, representative protecting groups are carbamates and amides such as substituted or unsubstituted or substituted acetates. Also different alkyl moeties may serve as amino protecting groups. Additional examples of amino protecting groups can be found in reference books such as Greene and Wuts “Protective Groups in Organic Synthesis”, John Wiley & Sons, Inc., New York, 1999.
“Halogen” or “halo” refers to bromo, chloro, iodo or fluoro.
The term “complex” means a molecular structure in which neutral molecules or anions (called ligands) bond to a central metal atom (or ion) by coordinate covalent bonds. Extensive descriptions of terms related to coordination chemistry in reference books such as Robert H. Crabtree “The Organometallic Chemistry of the Transition Metals”, Wiley-Interscience; 4 ed., 2005.
The term “catalyst” is recognized in the art and means a substance that increases the rate of a reaction without modifying the overall standard Gibbs energy change in the reaction and without itself being consumed in the reaction. The changing of the reaction rate by use of a catalyst is called catalysis. As used herein, the catalyst is used in a substoichiometric amount relative to a reactant, i.e. a catalytic amount. A preferred catalytic amount is considered herein from 0.0001 to 10 mol % of catalyst relative to the substrate to be opened, more preferably from 0.001 to 1 mol %, more preferably from 0.005 to 0.05 mol % and even more preferably is 0.01 mol %.
The term “ligand” refers to a molecule or ion that is bonded directly (i.e. covalently) to a metal center. As used herein in reference to a ligand or metal complex, the term “asymmetric” means that the ligand or complex comprises chiral centers that are not related by a plane or point of symmetry and/or that the ligand or complex comprises an axis of asymmetry due to, for example, restricted rotation, planarity, helicity, molecular knotting or chiral metal complexation.
The term “chiral” refers to molecules which have the property of non superimposability of the mirror image partner.
The term “stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
A “stereoselective process” or an “asymmetric process” is one which produces a particular stereoisomer of a reaction product in preference to other possible stereoisomers of that product.
An “enantioselective reaction” is a reaction that converts an achiral reactant to a chiral, non-racemic product that is enriched in one enantiomer. Enatioselectivity is generally quantified in terms of “enantiomeric excess” (“e. e.”), defined as:
where A and B are the amounts of enantiomers formed. An enantioselective reaction yields a product with an e.e. greater than zero. Preferred enantioselective reactions yield an e. e. greater than 80%, more preferably greater than 90%, even more preferably greater than 95% and most preferably greater than 98%.
“Ring opening reaction” is recognized in the art and intended to mean a transition-metal catalyzed process in which a nucleophile reacts with a heterocyclic molecule which has at least a double bond, specifically with a double bond situated in position 2 to a heteroatom, and so the pair of electrons of the double bond is displaced, breaking the heteroatom-carbon bond and thus opening the heterocycle.
As mentioned previously, an aspect of the invention is the use of a rhodium-phosphorus complex of formula (I):
[Rh(PP)(solv)2]X (I)
wherein:
PP is a bidentate phophorus ligand or two monodentate phosphorus ligands;
solv is a coordinating solvent; and
X is an anionic counterion,
as catalyst in a ring opening reaction.
Next, the different components of the complex that are advantageously employed in ring opening reactions will be comprehensively described.
Phosphorus ligand represents a ligand covalently bonded to the rhodium by one or two phosphorus atoms. So, both monodentate and bidentate phosphorus ligands are suitable for the present invention. In this sense a “monodentate phosphorus ligand” refers to a molecule containing one phosphorus atom that is covalently bonded to the rhodium, whereas a “bidentate phosphorus ligand” refers to a molecule containing two phosphorus atoms that are covalently bonded to the rhodium. In a preferred embodiment of the invention, the bidentate phosphorus ligand is a diphosphine ligand containing two phosphine groups that are covalently bonded to the rhodium.
The phosphorous ligands used in the present invention are commonly used in organic catalysis by a skilled person. For example, phosphines, phosphinites, phosphonites, phosphites, phosphine-phosphinites, aminophosphines, diaminophosphines are included in the scope of the present invention.
Likewise, both chiral and non-chiral phosphorus ligands are suitable for the present invention.
In a particular embodiment of the invention, the phosphorus ligand is a non-chiral phosphorus ligand. Typical non-chiral phosphorus ligands are PPh3, P(o-Tol)3, P(n-Bu)3, PCy3, P(OEt)3, 1,2-bis(diphenylphosphino)ethane (dppe), 1,4-bis(diphenylphosphino)butane (dppb), 1,1′-bis(diphenylphosphino)ferrocene (dppf).
In another particular embodiment, the phosphorus ligand is a chiral phosphorus ligand, preferably a chiral bidentate phosphorus ligand, even more preferably a chiral diphosphine ligand. Handbook of Reagents for Organic Synthesis, Chiral Reagents for Asymmetric Synthesis Leo A. Paquette (Wiley; 1 edition (Aug. 15, 2003) covers a broad list of chiral phosphines, which are herein incorporated by reference. Many chiral diphosphine ligands may be purchased from well-known commercial sources such as Sigma Aldrich or Strem.
More preferably, the chiral diphosphine is selected from BPPFA, Ferrophos, FerroTANE, Josiphos, Mandyphos (Ferriphos), Taniaphos, TRAP, Walphos, BICP, Binap, BPE, BPPM, Chiraphos, Deguphos, Diop, DIPAMP, Duphos, Norphos, Pennphos, Phanephos, PPCP, Prophos, Seguphos, and derivatives thereof. These diphosphine ligands are shown in the following scheme:
wherein Rx and Ry are, but not limiting to, substituted or unsubstituted alkyl, such as methyl, ethyl, i-propyl, t-butyl or benzyl; cycloalkyl, such as cyclohexyl; substituted or unsubstituted aryl, such as phenyl, tolyl, 3,5-(Me)2-4-(MeO)C6H2, 3,5-(Me)2C6H3; substituted or unsubstituted heteroaryl, such as 2-furyl.
Examples of these diphosphine ligands include, respectively:
In a preferred embodiment of the invention, the diphosphine ligand is a metallocene-type diphosphine ligand. “Metallocene-type diphosphine ligand” means a diphosphine ligand with a metallocene scaffold. A metallocene is an organometallic coordination compound in which one atom of a transition metal is bonded to and only to the face of two cyclopentadienyl [η5-(C5H5)] anions which lie in parallel planes. When the transition metal is iron the metallocene is called ferrocene.
More preferably, the diphosphine ligand is a ferrocene-based diphosphine ligand. In an even preferred embodiment the ferrocene-based diphosphine ligand is selected from the following compounds:
Among all the ferrocene-based diphosphine ligands the two following cores are preferred structures:
Even more preferably, the diphosphine ligands are PPF-tBu2 and BPPFA.
A “coordinating solvent” is one which can act as a ligand forming a covalent bond with a transition metal. Typical coordinating solvents are alkanols and ethers, which have atoms with at least one free electron pair through which they coordinate to the transition metal.
As it will be appreciated, the coordinating solvent in the context of the invention comes from the solvent in which the complex is formed. The coordinating solvent of the rhodium-phosphorus complex of formula (I) is coordinating to the metal by means of an oxygen atom. This solvent is selected from an ether and an alkanol. The ether is preferably selected from tetrahydrofurane, tetrahydropyrane, dioxane, dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether and dibutyl ether whereas the alkanol is preferably selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol and tert-butanol. More preferably, the coordinating solvent is tetrahydrofurane or methanol.
An “anionic counterion” is an ionic species with negative charge that accompanies a cationic transition metal complex, without coordinating to the metal, in order to maintain electric neutrality.
In a particular embodiment of the invention the anionic counterion is selected from BF4−, PF6−, SbF6−, AsF6−, ClO4−, CH3SO3−, CF3SO3−, HSO4−, BPh4− and B[bis-3,5-trifluoromethyl)phenyl]4−. Preferably, the anionic counterion is BF4−.
Accordingly to the above descriptions, preferred rhodium-phosphorus complexes of formula (I) of the invention are selected from [Rh(PPF—PtBu2)(THF)2]X, [Rh(BPPFA)(THF)2]X, [Rh(PPF—PtBu2)(MeOH)2]X and [Rh(BPPFA)(MeOH)2]X, wherein X is preferably BF4.
The ring opening reaction may be carried out in the presence of a chiral or non-chiral complex, thus leading to an asymmetric or non-asymmetric ring opening reaction, respectively. However, in a preferred embodiment, the ring opening reaction is asymmetric. As stated in the examples below, the process of the invention provides advantageously high enantioselectivities, typically above 98%, and complete conversions, while requiring lower reaction temperatures and shorter reaction times in relation to prior art.
The ring opening involves reacting a α,β-unsaturated compound of formula (II) and (III):
or a stereoisomer, salt or solvate thereof,
wherein the dotted line represents no bond, a single bond or a double bond;
X is oxygen, sulfur or NR, being R hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl or a suitable amino protecting group;
In the context of the present invention, the term “nucleophile” refers to a reagent that forms a chemical bond to its reaction partner (the electrophile) by donating both bonding electrons. Both neutral and anionic nucleophiles are considered in the present invention [for references related to nucleophilicity, please see: Phan T. B.; Breugst, M.; Mayr, H. Angew. Chem. Int. Ed. 2006, 45, 3869-3874. Mayr, H.; Patz, M. Angew. Chem. Int. Ed. Engl. 1994, 33, 938-957].
Non-limiting examples of nucleophiles used in this process are for instance an halogen; a carbon nucleophile selected from 3-indol and activated methylene group; a boronic acid; an oxygen nucleophile selected from water, an alcohol, an ether and a carboxylate; a nitrogen nucleophile selected from ammonia, an amine, an azide, cyanide, isocyanate and isothiocyanate; a sulphur nucleophile selected from a thiol and a thioether; selenocyanate or a phosphine.
Activated methylene groups have electron withdrawing groups in the a-position, such as carbonyl or ester groups, such as in acetoacetates.
Preferred nucleophiles are alcohols, ethers and amines.
The ring opening reaction is advantageously carried out in the presence of a solvent selected from an ether, an alcohol, a ketone, an ester, an amine, a chlorine-containing solvent, an aromatic solvent, an aprotic polar solvent and mixtures thereof.
In a particular embodiment of the invention the solvent is selected from tetrahydrofurane, tetrahydropyrane, dioxane, dimethyl ether, diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyl tert-butyl ether, dibenzyl ether, anisol, triethylamine, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, acetone, ethyl acetate, triethylamine, piperidine, pyridine, tetrachloromethane, dichloromethane, chloroform, 1,2-dichloroethane, benzene, toluene, xylene, dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, benzonitrile, nitromethane, propylene carbonate or mixtures thereof.
In another particular embodiment the solvent of the ring opening reaction is also the nucleophile.
In a particular embodiment of the invention, the α,β-unsaturated compound is an alkene of formula (IIa):
More preferably, the α,β-unsaturated compound is an alkene of formula (IIa) wherein N, O, P and Q are independently hydrogen, methyl, methoxy and halogen.
Another aspect of the present invention is directed to a rhodium-phosphorus complex of the formula (I′):
[Rh(PP′)(solv)2]X (I′)
wherein
PP′ is a metallocene-type diphosphine ligand,
solv is a coordinating solvent, and
X is an anionic counterion,
with the proviso that [Rh(PPF-PCy2)(MeOH)2]BF4 is not included.
The solvent (solv) and the conterion (X) have the meaning previously defined for the complex of formula (I), whereas PP′ is a metallocene-type diphosphine ligand.
In a particular embodiment, the metallocene-type diphosphine ligand is preferably a ferrocene-based diphosphine ligand. According to this definition, the ferrocene-based diphosphine ligand is selected from the following compounds:
and any stereoisomer, salt or solvate thereof,
wherein
R1 to R10 are each independently selected from the group consisting of linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
As stated above, among all the ferrocene-based diphosphine ligands, the two following compounds are preferred structures:
and any stereoisomer, salt or solvate thereof,
wherein R1 to R4 are as defined above.
Even more preferably, the diphosphine ligand is selected from PPF-PtBu2 and BPPFA.
or a stereoisomer, salt or solvate thereof,
Likewise, preferred rhodium-phosphorus complexes of formula (I′) of the invention are selected from [Rh(PPF-PtBu2)(THF)2]X, [Rh(BPPFA)(THF)2]X, [Rh(PPF-PtBu2)(MeOH)2]X and [Rh(BPPFA)(MeOH)2]X, wherein X preferably is BF4.
In another aspect, the present invention refers to a process for the preparation of a rhodium-phosphorus complex of formula (I′) as defined above, which comprises the hydrogenation of a rhodium diolefin complex of formula (IV) or a rhodium mono-olefin complex of formula (V) in the presence of a suitable coordinating solvent (solv),
[Rh(PP′)(diolefin)]X (IV)
[M(PP′)(mono-olefin)2]X (V)
wherein PP′, X and (solv) have the meanings as defined above for the complex of formula (I′).
In a particular embodiment, the diolefin is selected from the group consisting of 1,3-cyclooctadiene, 1,4-cyclooctadiene, 1,5-cyclooctadiene (COD), 2,5-norbornadiene (NBD), 1,5-hexadiene and 1,6-heptadiene. In another particular embodiment, the mono-olefin is selected from ethylene, hexane and octene.
The suitable coordinating solvent is incorporated to the complex displacing the diolefin or mono-olefin after the hydrogenation thereof.
In a particular embodiment, once the rhodium-phosphorus complex is obtained, said process further comprises the subsequent addition of a compound of formula (II) or (III) as defined above and a nucleophile to promote the ring opening reaction of said compound of formula (II) or (III).
Tyipical nucleophiles for this process are alcohols, phenols, amines, and stabilized carbanions such as malonates and derivatives.
In a preferred embodiment, the nucleophile is an alcohol or an amine, preferably is methanol or dimethylamine.
In a preferred embodiment, the compound of formula (II) is a compound of formula (IIa′):
In a more preferred embodiment, the compound of formula (IIa′) is that wherein N is hydrogen, methyl, methoxy or halogen, and O, P and Q are hydrogen.
As mentioned above, the ring opening reaction can be asymmetric or non-asymmetric depending on the presence or absence of chirality in the rhodium complex used in the reaction. However, in the context of the present invention, it is particularly preferred the execution of an asymmetric ring opening reaction.
A simplified version of the proposed asymmetric catalytic pathway for this transformation is the following: firstly, the chiral rhodium complex binds to the heteroatom and the alkene; afterwards, oxidative insertion of rhodium catalyst to carbon-heteroatom bond and an SN2′ displacement of the rhodium catalyst by the nucleophile gives the product and regenerates the catalyst. Nucleophilic attack with inversion provides the product in an SN2′ fashion relative to the metal.
In a particular embodiment, the product obtained after the asymmetric ring opening reaction takes place is selected from:
Finally, another aspect of the present invention describes a rhodium-phosphorus complex (I′) obtainable by the process which comprises the hydrogenation of a metal diolefin complex of formula (IV) or a metal mono-olefin complex of formula (V) in the presence of a suitable coordinating solvent (solv),
[Rh(PP′)(diolefin)]X (IV)
[M(PP')(mono-olefin)2]X (V)
wherein PP′, X and (solv) have the meanings as defined above for the complex of formula (I′).
The following non-limiting examples will further illustrate specific embodiments of the invention.
[Rh((S,R)-PPF-PtBu2)(NBD)]BF4 or [Rh((S,R)-PPF-PtBu2)(COD)]BF4 (0.01 mmol) is dissolved in 3 mL of THF-d8 or MeOH-d4 under argon atmosphere. Hydrogen is pressed on the solution, which is then allowed to stir under hydrogen atmosphere for ca. 5 min.
[Rh((S,R)-PPF-PtBu2)(MeOH)2]BF4
1H-NMR: 8.59-8.51 (2H, m); 7.67-7.56 (5H, m); 7.46-7.39 (3H, m); 4.96-4.89 (m); 4.63 (1H, br. s); 4.35 (1H, br. s); 4.17 (1H, br. s); 3.81-3.74 (5H, m); 3.39-3.31 (m); 2.88-2.82 (1H, m); 2.00-1.95 (3H, m); 1.71-1.66 (10H, m); 1.34-1.28 (10H, m).
31P-NMR (in MeOH-d4): 112.3 (J=213.2/54.7 Hz); 49.6 (J=211.5/54.6 Hz)
[Rh((S,R)-PPF-PtBu2)(THF)2]BF4
1H-NMR: signals (except for arene protons) covered by solvent signals
31P-NMR (in THF-d8): 113.2 (J=206.7/54.7 Hz); 51.0 (J=230.2/53.9 Hz)
[Rh(DPPF)(NBD)]BF4 or [Rh(DPPF)(COD)]BF4 (0.01 mmol) is dissolved in 3 mL of MeOH-d4 under argon atmosphere. Hydrogen is pressed on the solution, which is then allowed to stir under hydrogen atmosphere for ca. 5 and 45 min, respectively.
[Rh(DPPF)(MeOH)2]BF4
1H-NMR (in MeOH-d4): 7.96-7.89 (8H, m); 7.55-7.41 (12H, m); 4.90 (s); 4.39-4.37 (4H, m); 4.29-4.26 (4H, m); 3.33-3.31 (m). (in NMR also signals of norbornadiene)
31P-NMR (in MeOH-d4): 54.9 (213.7 Hz).
[Rh((S,R)-PPF-PtBu2)(NBD)]BF4 (0.01 mmol) is dissolved in 3 mL of THF under argon atmosphere. Hydrogen is pressed on the solution, which is then allowed to stir under hydrogen atmosphere for ca. 5 min. Hydrogen is exchanged by argon by freezing the solution and securating the gas phase above the solution with argon. This procedure is repeated 3 times. To the cold solvent complex a solution of the substrate (1 mmol) dissolved in 3 ml of THF is added via cannula. The nucleophile (1 mmol) is added to the cool substrate complex solution a) directly via syringe (in case of liquids) or b) as a THF (ca. 4 ml) solution via cannula from a separate flask (in case of solids). The reaction mixture was then heated at 50° C. until the reaction was finished (as judged by TLC or determined separately by HPLC). The solvent was then removed in vacuo and the resulting mixture purified by flash chromatography.
For comparative purposes, other diphosphine complexes of the art have also been tested in the asymmetric ring opening reaction of oxobenzonorbornadiene.
As it is shown, the rhodium solvent complex of the invention provides better results than the complex used in the prior art. Specifically, the transformation runs at lower temperatures and in less than one hour. Also, there is no need of using large amount of nucleophile, since the reaction takes place with complete conversions and excellent enantioselectivities with only one equivalent of nucleophile.
| Number | Date | Country | Kind |
|---|---|---|---|
| 07380349.6 | Dec 2007 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP08/66693 | 12/3/2008 | WO | 00 | 9/23/2010 |
