Patent Application
20100099875
The present invention concerns new optically active P-chiral phosphines, their precursors and their derivatives where the phosphorus atom is a bearer of chirality and of a (hetero)aryl group functionalized in 2- or ortho-position; their preparation, the preparation of their metal complexes, and their application in asymmetric catalysis involving unsaturated compounds. This technology allows easy access to enantiomers of chiral molecules interesting in particular the pharma, agrochemical, food, and cosmetic industries.
New series of optically pure P-chiral arylphosphines, their precursors and their derivatives, possessing on the aryl in the proximity of the phosphorus atom a hydroxy-, amino- or carboxy-group, were prepared in their enantiomerically pure forms in good yields. They were easily modified in one step giving rise to a wide diversity of P-homochiral analogues. The new phosphines are easily handled due to their good air/moisture stability. In the form of their transition metal complexes, a wide variety among them exhibit superior activity and enantioselectivity in asymmetric catalysis, especially in hydrogenation, compared to well-established ligands of their type as Nobel co-laureate Knowles bis(o-anisylphenyl-phosphino)ethane (DiPAMP) ligand. For example, the asymmetric hydrogenation of itaconic acid under 1 bar of H2 with rhodium-DiPAMP complex leads to 11% enantiomeric excess (ee) and 40% conversion in 1 hour while with the new ligands of the invention, a 98.5% ee and 100% conversion were reached in 6 minutes. Consequently, the access to such a broad variety of active P-chiral phosphine ligands from a common structure, permits fine-tuning of the catalyst for a given application, a reduced amount of the catalyst is needed, and the desired molecules are obtained at a faster rate and with higher optical purity.
Catalysis mediated by transition-metal complexes of optically active phosphine ligands is an interesting technology for the synthesis and production of enantiomers of chiral molecules. Despite all strides, still no universal phosphine exists for the sought C═C, C═O, and C═N bond transformation reactions requiring cost-effective catalysts which possess high activity and attain 100% enantioselectivity. The known syntheses of efficient ligands are either restricted to the access to one antipode (e.g. tBuBisP*, MiniPHOS, TangPHOS), not trivial (e.g. DuPHOS-type ligands, NORPHOS, PhanePHOS), or a multistep synthesis is required for the preparation of a new modified parent diphosphine with different substituents either on the phosphorus atom or at the backbone.
It has been found that a close proximity of the chirality of the ligand to the catalyst metal center increases stereoselectivity. Amongst the existing phosphines, the P-chiral ones are rare and few research groups have been involved in their preparation (Mislow et al, J. Am. Chem. Soc. 1968, 90(18), 4842-4846; Knowles, Angew. Chem. Int. Ed. 2002, 41, 1998-2007; Imamoto et al, J. Am. Chem. Soc. 1990, 112, 5244-5252; Eur. J. Org. Chem. 2002, 2535-2546; Jugé et al, Tetrahedron Lett. 1990, 31(44), 6357-6360; FR 91/01674; WO 91/00286; Brown et al, Tetrahedron 1990, 46(13/14), 4877-4886; J. Chem. Soc., Perkin Trans. 1 1993, 831-839). In general, optically pure P-chiral phosphines could be prepared either according to Mislow or to Imamoto procedures through the separation of diastereomeric phosphinate or phosphinite-borane intermediates, respectively. In particular, the asymmetric strategy relying on the use of a chiral inductor derived from an aminoalcohol as (+)- or (−)-ephedrine developed by Jugé et al and by Brown et al proved to be advantageous for the practical preparation of both enantiomers of several P-chiral phosphines. However, still the synthesis of a new modified parent phosphine requires several steps starting from a common intermediate.
Following the results of his assessment tests of a variety of ortho-functionalized mono- and di-arylphosphines, Knowles has emphasized on the importance of the o-anisyl group in DiPAMP to attain high enantioselectivity (Advances in Chemistry 1982, 196, Catalysis Aspects Met. Phosphine Complexes, 325-336). However since then, no conclusive work based on a structural modification of its methoxy group has been undertaken. Also, few modifications were carried out to replace the o-anisyl group by other groups. As described within this invention, a striking improvement in activity and stereoselectivity was obtained by the appropriate modification of the methyl of the methoxy group. This result shows that the chiral induction is not only influenced by the methoxy group but more importantly by the bulkiness—and probably by the electronic structure—of the substituent of its oxygen atom.
In 1982, Knowles prepared (R,R)-bis(o-hydroxyphenyl-phenylphosphino)ethane by demethylation of (R,R)-DiPAMP with Ph2PLi. The results of its use and the use of its acylated derivative in asymmetric hydrogenation were not better than those obtained with the mother ligand DiPAMP. Also in 2001, Pizzano and Suarez prepared (S)-o-(methylphenyl-phosphino)phenol by demethylation of commercially available (S)-phenyl-o-anisylmethyl-phosphine (PAMP), using BBr3 followed by a basic workup. Phosphine-phosphites were prepared by coupling it with chlorophosphites (Tetrahedron: Asymm 2001, 12, 2501-2504). However, the attempts of the present inventors to functionalize the hydroxy group of the demethylated PAMP with activated alkyls (addition of 1 equivalent iPrI) failed but yielded instead impure phosphonium salts as shown by 1H and 31P NMR. Also, Jugé et al prepared chiral 2-hydroxyphenyl and 2-hydroxynaphth-1-yl substituted phosphine-boranes through Fries type rearrangement of the corresponding 2-(1-bromoaryl) phosphinite-borane (Tetrahedron: Asymm 2000, 11(19), 3939-3956). However, this route is not general for the preparation of optically pure ortho-functionalized P-chiral arylphosphines and has a major drawback for the preparation of optically pure ortho-functionalized DiPAMP-type diphosphines due to decrease in optical purity in the preparation of the required o-(methylphenylphosphino-borane)phenol intermediate for their synthesis.
Our invention concerns the synthesis of optically active—more particularly with 95% optical purity—P-chiral arylphosphines functionalized in 2- or ortho-position, of their precursors and derivatives of general formula (I). It concerns as well the preparation and the use of their metal complexes in asymmetric catalysis.
wherein:
wherein:
wherein:
wherein:
The invention is embodied by the preparation of P-chiral ortho-hydroxy-, amino-, carboxy-arylphosphines, their precursors and derivatives of general formula (I), starting from an optically active oxazaphosphacycloalkane-borane of formula (Ib) derived from an optically active aminoalcool HN(R06)-Q02*—0H,
wherein:
The synthetic strategy—
The adopted experimental procedures to prepare compounds of general formula (I) according to the claimed process are in general dictated by the chemical nature of starting material. Performing such reactions is for those skilled in the art. Optically pure oxazaphos-phacycloalkane-borane of formula (Ib) may be prepared as described by Jugé et al or Brown.
Thus, for example the cycle of oxazaphospholidine-borane complex 1 derived from optically pure ephedrine, was opened with various functionalized organo(di)metallics prepared from ortho-Z(CR03R04)n—-ArBr or Z(CR03R04)n—ArH (n=0 or 1) either by transmetallation with for example butyllithium (1-2 equivalents) or by reaction with a base such as MH (M=Li, Na, K) (˜1 equivalent) followed by butyllithium (1 equivalent), to yield the corresponding ortho-Z(CR03R04)n—Ar-aminophosphine-borane 2 in high yield. 1H NMR showed the formation of a single diastereomer, and the X-ray diffraction analysis provided the structures of the aminophosphine-boranes 2a and 2b, derived from o-bromophenol and 2-bromo-1-naphthol, respectively. These aminophosphine-boranes (Ic) constitute the precursors of various phosphinite-boranes and halogenophosphine-boranes (Id).
Acid alcoholysis with for example methanol/sulfuric acid, or the P—N bond cleavage of 2 by an alcohol, e.g. methanol, assisted by BF3 afforded the correponding methyl phosphinite-borane 3 in high yield and >99% ee according to HPLC analysis. The X-ray diffraction analysis of the o-(methyl phenylphosphinito-borane)phenol (S)-Mosher acid ester 3an provided the absolute configuration of the phosphorus atom. 1H and 19F NMR showed the formation of single diastereomer. In addition, BF3 assisted P—N bond cleavage of 1 in methanol afforded a diastereomerically pure phosphonite-borane as shown by 1H, 13C and 31P NMR. The P—N bond rupture of 2 in an aprotic solvent by an acid halide as HCl, leads to the corresponding chlorophosphine-borane 3′ in high yield. These phosphinite-boranes and chlorophosphine-boranes (Id) constitute the precursors of various phosphine-boranes (Ie).
The displacement of the methoxy group in 3 was carried out by the action of either an alkyl- or aryllithium (1-2 equivalents), or by the prior treatment with a base such as MH (M=Li, Na, K) (˜1 equivalent) followed by the alkyl- or aryllithium (1 equivalent). The corresponding phosphine-borane 4 was obtained in high yield. The enantiomeric purity >99% was confirmed by 1H and 19F NMR of o-(methylphenylphosphino-borane)phenol (S)-Mosher acid ester 4an and by transforming 4a into PAMP.BH3 (4aa) and HPLC analysis. Also, chlorophosphine-borane 3′ reacts with organometallics leading to the corresponding phosphine-borane 4 or reacts with a hydroxyarene leading to the corresponding aryl phosphinite-borane. These phosphine-boranes (Ie) may be also prepared by action of functionalized organometallics with phosphinite-boranes or chlorophosphine-boranes prepared following Jugé et al route.
As example of α-functionalization of the phosphorus atom (preparation of (If), (Ig), (Ih) and (Ii)), the methyl of methylphosphine-borane 4 was deprotonated with a strong base as sec-butyllithium (addition of 1-2 equivalents of the organolithium) or by the prior treatment with a base such as MH (M=Li, Na, K) (˜1 equivalent) followed by sec-butyllithium (1 equivalent). This anion 4-Li was dimerized to 5 by anhydrous Cu(II) salt or condensed on a (R′R″)SiCl2 (e.g. Me2SiCl2, Ph2SiCl2) leading to (—CH2Si(R′R″)CH2—)-bridged diphosphine-borane 6, 7 in good yields. Also, this anion 4-Li was reacted with electrophiles (according to Imamoto et al, J. Am. Chem. Soc. 1990, 112, 5244-5252; Jugé et al, Tetrahedron: Asymm 2004, 15, 2061-2065) yielding a phosphine-borane possessing a R05 arm, e.g. R05═CH2OH 8, or a (—CH2—)-bridged diphosphine-borane, e.g. R05═P(BH3)Ph2 9.
In particular, the (o-hydroxyaryl)phenylphosphine-borane 4, its precursors and derivatives are crystallin and are obtained in high chemical and optical purities.
Under the action of a base (carbonate, hydride, organometallic—the metal selected among Li, Na, K, Cs—, amine optionally on solid support), the Z function of phosphines, their precursors and derivatives, could be modified—as well as the functionalized R05 arm on α of P* as CH2OH—with various groups possessing different properties such as alkyls, activated aryls, fluoroalkyls, fluorobenzyls, silyls, acyls, aroyls, acetates, phosphates, phosphites, triflate, sulfonates, alkylammoniums, rendering them as well as their metal complexes, more soluble in the reaction medium (water, alcohols, ionic liquids, perfluorinated solvents, etc) or recyclable by solid-liquid or liquid-liquid phase separation (scheme 2: example with (o-hydroxyaryl)phenylphosphino-borane).
For example, the aromatic hydroxy group of (o-hydroxyaryl)-N-ephedrinophosphine-borane 2 (Z═OH, n=0), methyl (o-hydroxyaryl)phosphinite-borane 3 (Z═OH, n=0), (o-hydroxyaryl)phenylphosphine-borane 4 (Z═OH, n=0) and bis((o-hydroxyaryl)phenyl-phosphino-borane)alkane 5-7 (Z═OH, n=0), was easily functionalized under standard conditions in high yield. In the same manner, bis or poly(o-O-aryl)phenylphosphine-boranes (Z═OR05, n=0; R05=bis or poly-linker) were prepared in high yields by condensation of (o-hydroxyaryl)phenylphosphine-borane 4 (Z═OH, n=0) on a bifunctional alkane or heteroalkane (e.g. ethylene glycol ditosylate, diethylene glycol ditosylate), or a polyfunctional arylalkane (e.g. 2,4,6-tris(bromomethyl)mesitylene).
The (o-R05O-aryl)phosphine-boranes 4 (Z═OR05, n=0) and bis((o-R05O-aryl)-phosphino-borane)alkanes 5-7 (Z═OR05, n=0) were decomplexed at 0 to 75° C.—for example with an amine or an acid as HBF4 followed by a basic treatment (Imamoto et al, ibid; Livinghouse et al, Tetrahedron Lett. 1994, 35, 9319)—affording the corresponding phosphines 4′-7′ with high yields. This decomplexation could be applied to the other phosphine-boranes.
The inventors have found other access routes to 5a starting from DiPAMP (5′aa) or its BH3 adduct 5aa by demethylation of the o-anisyl group with BBr3 followed by complexation with BH3 (scheme 3). This route is also applicable to the synthesis of o-(methylphenyl-phosphino-borane)phenol 4a via o-(methylphenylphosphino)phenol 4′a. Demethylation of the o-anisyl group could be achieved under other conditions as described by Greene and Wuts (Protective groups in organic synthesis, John Wiley & Sons 1999).
The ortho-functionalized P-chiral arylphosphines could be modified on the phosphorus is atom by other groups than BH3 as O or acid such as HBF4, TfOH, HClO4, HPF6, HBr, HI.
The new chiral structures part of the invention 5′a, 5′ab, 5′ac, 5′b, 6′a, Ta and 10′a can be denoted by the acronyms mentioned hereinafter:
The present invention aims as well the use of optically active compounds of general formula (I) for the preparation of coordination metal complexes useful as catalysts to perform asymmetric syntheses in organic chemistry. These metal complexes prepared in an appropriate solvent are based on a transition metal and as ligand of the metal, at least an optically active form of a compound of general formula (I) wherein E and/or E′ represent 2e−; and as example of neutral, cationic or anionic metal complexes, one can mention especially those of the general formula (III),
MpLq(X′)r(Sv)s(Sv′)s′Ht (III)
wherein:
The catalyst may be prepared from optically active P-chiral compounds of general formula (I) in association with a compound provider of the metal (catalyst precursor) in an appropriate solvent according to literature protocoles (Osborn et al, J. Am. Chem. Soc. 1971, 93, 2397; Genêt, Acros Organics Acta 1994, 1(1), 1-8). According to the invention, the catalyst may consist of a preformed metal complex as defined previously, may be generated in situ in the reaction medium optionally in the presence of a substrate, or activated prior to use. The optimum proportion of optically active ligand to the metal may vary according to the ligand and the metal and may be easily determined experimentally; for example, the quantity of optically active ligand to be added may vary from 1 to 4 equivalents to the metal. It is understood that when one enantiomer is used, the other enantiomer is similarly applicable.
The present invention describes also a process to prepare rhodium catalysts from optically active P-chiral compounds of general formula (I) and a precursor as [(diene)2Rh]X where the diene may be 2,5-norbomadiene, 1,5-cyclooctadiene and X may be BF4, OTf and it also describes a process to prepare ruthenium catalysts by addition of optically active P-chiral compounds of general formula (I) to a precursor as [(diene)RuX2]x or [(diene)(1,3,5-cyclooctatriene)RuH]X where the diene may be 1,5-cyclooctadiene, 2,5-norbornadiene and X may be Cl, Br, I, BF4, OTf, PF6 and x is a number equal to 1 or 2. The last precursors were prepared from [(diene)ruthenium(2-methylallyl)] and the corresponding acid in presence or not of a diene.
Another aim of the present invention is the use of the mentioned complexes to perform asymmetric syntheses in organic chemistry. In fact, asymmetric transformation such as hydrogenation, transfer hydrogenation, hydrosilylation, hydroboration, hydroformylation, isomerization of olefins, hydrocyanation, hydrocarboxylation, electrophilic allylation, implicating prochiral molecules which possess one or several C═C, C═O and/or C═N bonds, may be carried out with catalysts containing at least an optically active form of a compound of general formula (I) (E and/or E′ represent 2e−), in association with a transition metal derivative as described previously. These asymmetric transformations may be performed under known conditions, or which could be determined, by the man of the art according to described procedures with other phosphines (Pfaltz et al, Comprehensive Asymmetric Catalysis, Springer Verlag 1999, vol. I-III; Noyori, Asymmetric Catalysis in Organic Synthesis, John Wiley & Sons 1994). The asymmetric reduction takes place in general in an organic solvent at a temperature ranging between −10° C. and 100° C., in the presence of either H2 gas under 1 to 150 bars, a hydrogen donor, a reducing agent such as a borane, a silane, or in the presence of a selected combination among all what preceded. The catalyst may be used at 0.00001 to 5% to the substrate and this amount could be easily determined experimentally. The appropriate prochiral substrates to the asymmetric reduction using metal complexes according to the invention, and which contain C═C, C═O, and/or C═N bonds, include, but are not limited to prochiral olefins as glycine alkylidene derivatives optionally substituted, α- and/or β-substituted maleic acid derivatives, succinic acid alkylidene derivatives, α- and/or β-substituted cinnamic or acrylic acid derivatives, derivatives of ethylene, enamides, enamines, enols, enol ethers, enol esters, allylic alcohols, prochiral ketones optionally substituted and/or α-unsaturated, α- or β-ketoacid derivatives, diketones and derivatives, prochiral imine derivatives, oximes, also their salts, mono/di -esters or -amides, and substituted derivatives of the mentioned substrates.
This transformation may be conducted also with racemic substrates possessing C═C, C═O, or C═N bonds according to the principle of dynamic kinetic resolution. The result of these transformations is the preparation of enantiomerically enriched products following the modification or saturation of C═C, C═O, or C═N bonds, for example preparation of optically active derivatives of α- or β-amino acids, acids or diacids, amines, alcohols, alkanes. The asymmetric reduction was carried out, illustratively and not limitedly, on model substrates.
The present invention is described in more detail by the following EXAMPLES, which are not to be construed as limitative.
All operations were conducted under N2 or Ar atmosphere using anhydrous and degassed solvents. The synthesis of various noncommercially available chemicals as o-bromophenols, o-bromoanilines, o-bromobenzylamines, o-bromobenzamides, etc, was according to known procedures. L* stands for the P-chiral ligand. 1H (300 MHz, internal Me4Si), 13C (75 MHz, internal CDCl3), 19F (282 MHz, internal CFCl3), and 31P NMR (120 MHz, external 85% H3PO4) were recorded for solutions in CDCl3 if not stated otherwise (J in Hz).
To a cold (0° C.) solution of bromoarene (or arene having an ortho directing group) (1.2-1.3 equiv.) in ether, cyclohexane or THF is added under stirring (A) an oil-free NaH (1.3-1.5 equiv.) followed by n- or sec-BuLi (1.2-1.3 equiv.) or (B) n-, sec- or tert-BuLi (1.2-1.3 equiv. in case a monoanion is to be generated; 2.4-2.6 equiv. for a dianion). The mixture is left at room temperature (or refluxed) until the transmetallation is complete. To this mixture at −30° C., a THF (or ether) solution of oxazaphospholidine-borane 1 is slowly added and the resulting mixture left to warm up to room temperature. The reaction is hydrolyzed with water after disappearance of the starting 1 as monitored by thin layer chromatography (TLC). The mixture is concentrated, and water (or acidified water until neutral pH is reached) added and the residue is extracted with CH2Cl2. Drying over Na2SO4, concentration and purification of the residue on silica gel and/or by crystallization affords compound 2 in 75-90% yield.
2a according to 1(A) or (B). 1H NMR δ 0.35-1.80 (m, 3H), 1.25 (d, 3H), 1.94 (b s, 1H), 2.56 (d, 3H), 4.11 (dq, 1H), 4.80 (d, 1H), 6.84 (m, 1H), 6.99 (m, 2H), 7.26-7.49 (m, 11H), 8.1 (br s, 1H); 31P NMR δ +66.11 (m).
The enantiomer of 2a is prepared from the enantiomer of 1.
2ab according to 1(B). 1H NMR δ 0.30-1.80 (b m, 3H), 0.90 and 0.93 (2d, 6H), 1.22 (d, 3H), 1.81 (d, 1H), 2.61 (d, 3H), 4.33 (m, 1H), 4.42 (sept, 1H), 4.89 (dd, 1H), 6.81 (dd, 1H), 7.00 (m, 1H), 7.10-7.50 (m, 11H), 7.75 (m, 1H); 31P NMR δ +68.66 (m).
2b according to 1(A) or (B). 1H NMR δ 0.66-2.00 (br m, 3H), 1.27 (d, 3H), 1.82 (br s, 1H), 2.60 (d, 3H), 4.17 (m, 1H), 4.85 (d, 1H), 6.96 (t, 1H), 7.23-7.62 (m, 13H), 7.75 (dd, 1H), 8.39 (dd, 1H), 9.09 (br s, 1H); 31P NMR δ +65.44 (m).
2bba according to 1(B). 1H NMR δ 0.50-1.85 (m, 3H), 1.28 (d, 3H), 2.01 (br s, 1H), 2.36 (d, 3H), 3.01 (s, 3H), 4.58 (br s, 1H), 5.00 (d, 1H), 6.54 (m, 1H), 7.10-7.57 (m, 13H), 7.77-7.91 (m, 2H); 31P NMR δ +77.90 (br s).
2c according to 1(A) or (B). 1H NMR δ 1.29 (d, 3H), 0.90-1.93 (br m, 3H), 2.65 (d, 3H), 4.13 (m, 1H), 4.85 (d, 1H), 7.27-7.55 (m, 12H), 7.59-7.73 (m, 4H), 7.92 (br s, 1H); 31P NMR δ +65.49 (m).
2d according to 1(A) or (B). 1H NMR δ 0.50-1.70 (br m, 3H), 1.23 (d, 3H), 2.62 (d, 3H), 4.25 (m, 1H), 4.55 and 4.64 (2d, 2H), 4.89 (d, 1H), 7.13-7.63 (m, 14H); 31P NMR δ +68.90 (m).
2da according to 1(B). 1H NMR δ 0.50-1.80 (br m, 3H), 1.25 (d, 3H), 2.64 (d, 3H), 3.19 (s, 3H), 4.30 (m, 1H), 4.33 and 4.54 (2d, 2H), 4.87 (d, 1H), 7.20-7.69 (m, 14H); 31P NMR δ +68.88 (m).
2eb according to 1(B). 1H NMR δ 0.58-2.00 (br m, 3H), 1.18 (‘t’, 6H), 1.26 (d, 3H), 2.64 (d, 3H), 3.67 (m, 1H), 4.22 (m, 1H), 4.86 (d, 1H), 5.38 (br d, 1H), 6.53 (m, 1H), 6.66 (m, 1H), 6.88 (m, 1H), 7.23-7.50 (m, 11H); 31P NMR δ +66.41 (m).
2ec according to 1(B). 1H NMR δ 0.60-1.70 (br m, 3H), 0.83 (s, 9H), 1.18 (d, 3H), 2.50 (d, 3H), 4.28 (m, 1H), 4.92 (m, 1H), 7.10, 7.30 and 7.53 (3m, 14H).
2ed according to 1(B). 1H NMR δ 0.70-1.73 (br m, 3H), 1.26 (d, 3H), 1.40 (s, 9H), 1.90 (d, 1H), 2.63 (d, 3H), 4.26 (m, 1H), 4.80 (t, 1H), 6.96-7.07 (m, 2H), 7.21-7.51 (m, 11H), 8.01 (dd, 1H), 8.06 (br s, 1H).
2ee according to 1(A) or (B). 1H NMR δ 0.62-1.67 (br m, 3H), 1.26 (d, 3H), 2.69 (d, 3H), 3.00 (s, 3H), 4.13 (m, 1H), 4.93 (d, 1H), 6.92 (br s, 1H), 7.06 (m, 1H), 7.16-7.45 (m, 11H), 7.60 (m, 2H).
2el according to 1(B). 1H NMR δ 0.77-1.98 (br m, 3H), 1.22 (d, 3H), 2.41 (s, 6H), 2.60 (d, 3H), 4.35 (m, 1H), 4.96 (d, 1H), 7.12-7.58 (m, 14H); 31P NMR δ +69.56 (m).
2fb according to 1(B). 1H NMR δ 0.40-1.55 (br m, 3H), 0.93 and 1.09 (2d, 6H), 1.28 (d, 3H), 1.83 (d, 1H), 2.74 (d, 3H), 3.69 (m, 1H), 4.25 (m, 2H), 4.48 (dd, 1H), 5.04 (m, 1H), 7.21-7.58 (m, 14H); 31P NMR δ +95.73 (m).
2fe according to 1(B). 1H NMR δ 0.20-1.32 (br m, 3H), 0.95 (d, 3H), 2.53 (d, 3H), 2.57 (s, 3H), 3.15 (m, 2H), 4.00 (m, 1H), 4.98 (m, 1H), 7.07 (m, 1H), 7.30 (m, 10H), 7.63 (m, 1H), 7.73 (m, 1H), 7.88 (m, 1H).
2fl according to 1(B). 1H NMR δ 0.81-1.80 (br m, 3H), 1.22 (d, 3H), 2.19 (s, 6H), 2.74 (d, 3H), 3.39 and 3.89 (2d, 2H), 4.21 (m, 1H), 4.74 (d, 1H), 7.28 (m, 6H), 7.45 (m, 5H), 7.59 (m, 2H), 7.76 (m, 1H); 31P NMR δ +70.41 (m).
2fm according to 1(B). 1H NMR δ 0.72-1.90 (br m, 3H), 0.86 and 0.88 (2d, 12H), 1.26 (d, 3H), 2.66 (d, 3H), 2.91 (sept, 2H), 3.57 (m, 2H), 4.36 (m, 1H), 4.93 (m, 1H), 7.18-7.33 (m, 6H), 7.35-7.49 (m, 5H), 7.62 (m, 2H), 8.06 (m, 1H); 31P NMR δ +66.93 (m).
2g according to 1(B). 1H NMR δ 0.33-1.38 (br m, 3H), 0.71 (d, 3H), 1.70 (d, 1H), 2.68 (d, 3H), 3.89 (m, 1H), 4.80 (m, 1H), 6.18, 6.24 and 7.02 (3m, 3H), 7.16-7.30 (m, 5H), 7.33-7.47 (m, 8H), 7.70 (m, 2H); 31P NMR δ +55.14 (m).
2hm according to 1(B). 1H NMR δ 0.50-1.83 (br m, 3H), 1.08, 1.22, 1.42, 1.52 and 1.72 (5d, 15H), 3.10 (d, 3H), 3.48 (m, 1H), 3.59 (sept, 2H), 3.84 (m, 1H), 3.93 (sept, 2H), 5.37 (br s, 1H), 6.87 (m, 2H), 7.05-7.21 (m, 3H), 7.30-7.62 (m, 9H); 31P NMR δ 69.67 (m).
2hn according to 1(B). 1H NMR δ 1.17 (d, 3H), 1.24 and 1.44 (2s, 6H), 0.40-1.70 (br s, 3H), 2.92 (d, 3H), 3.74 and 4.10 (2d, 2H), 3.84 (m, 1H), 4.42 (d, 1H), 7.01 (m, 2H), 7.19 (m, 3H), 7.40-7.58 (m, 8H), 7.74 (m, 1H); 31P NMR δ +71.37 (m).
2i from 1 using 1.2 equiv. TMSCH2Li, or MeLi (2.2 equiv.) followed by excess of TMSCl. 1H NMR δ 0.07 (s, 9H), 0.35-1.50 (br m, 3H), 1.04 (d, 3H), 1.08 (dd, 1H), 1.39 (dd, 1H), 1.82 (d, 1H), 2.59 (d, 3H), 3.95 (m, 1H), 4.84 (t, 1H), 7.28-7.46 (m, 7H), 7.57 (m, 3H); 31P NMR δ +66.88 (m).
2j from 1 using 2.2 equiv. TMSCH2Li followed by excess of paraformaldehyde or starting from 2i using sec-BuLi (2.2 equiv.) followed by excess of paraformaldehyde. 1H NMR δ 0.19-1.39 (br m, 3H), 1.28 (d, 3H), 1.89 (d, 1H), 2.47 (d, 3H), 4.14 (m, 1H), 4.78 (m, 1H), 6.09-6.46 (m, 3H), 7.04 (m, 2H), 7.25 (m, 2H), 7.36 (m, 4H), 7.47 (m, 2H); 31P NMR δ +66.91 (m).
2k from 1 using MeLi (2.2 equiv.) followed by excess of paraformaldehyde. 1H NMR δ 0.16-1.46 (br m, 3H), 1.14 (d, 3H), 2.09-2.37 (m, 3H), 2.53 (d, 3H), 3.70-4.00 (m, 3H), 4.76 (d, 1H), 7.25-7.42 (m, 10H); 31P NMR δ +66.76 (m).
2m from (S)-PAMP.BH3 anion and 1. 1H NMR δ 0.05-1.60 (br m, 6H), 1.17 (d, 3H), 1.90 (br s, 1H), 2.89 (d, 3H), 2.96 (m, 1H), 3.64 (m, 1H), 3.79 (s, 3H), 3.98 (m, 1H), 5.07 (br s, 1H), 6.92 (m, 1H), 7.10 (m, 1H), 7.17-7.68 (m, 16H), 8.05 (ddd, 1H); 31P NMR δ +11.49 (br s), +66.92 (br s).
Y═OMe : To aminophosphine-borane 2 in MeOH (or MeOH/CH2Cl2) at room temperature is added (A) BF3 etherate or BF3 in MeOH (˜1 equiv.) or (B) anhydrous H2SO4 (≦1 equiv.) under stirring. Following the disappearance of 95-98% the starting material indicated by TLC, the reaction mixture is filtered on a short bed of silica gel and concentrated. The residue is partitioned between water/CH2Cl2, the organic layer dried over Na2SO4, and concentrated. The residue is purified on silica gel and/or by crystallization to afford compound 3 in 85-95% yield. HPLC analysis of 3a and 3b showed >99% ee.
Y═Cl : To aminophosphine-borane 2 in aprotic solvent (as toluene, CH2Cl2, THF) at 0° C., a HCl solution in aprotic solvent is added. After 1 hour, ephedrine hydrochloride is filtered off on a sintered-glass filter and the filtrate concentrated to yield the chlorophosphine-borane as a viscous oil (90-95% yield).
3a according to 2(A) or (B). 1H NMR δ 0.45-1.80 (br m, 3H), 3.79 (d, 3H), 6.97 (m, 2H), 7.41-7.57 (m, 5H), 7.70 (m, 2H); 31P NMR δ +109.37 (m); HPLC analysis on Daicel Chiralcel® OJ (hexane/PrOH 70:30, 0.9 ml/min, λ=282 nm): t(S)=14.9 min, t(R)=22.3 min; [α]D30 23.5 (c 1, MeOH).
The enantiomer of 3a is prepared from the enantiomer of 2a.
3b according to 2(A) or (B). 1H NMR δ 0.66-1.87 (br m, 3H), 3.79 (d, 3H), 7.25-7.80 (m, 10H), 8.39 (d, 1H), 8.60 (s, 1H); 31P NMR δ +105.99 (m).
3c according to 2 (B). 1H NMR δ 0.45-1.85 (br m, 3H), 3.37 (s, 3H), 3.65 (d, 3H), 6.66 (dd, 1H), 7.32-7.50 (m, 5H), 7.57-7.68 (m, 3H), 7.99 (m, 1H), 8.26 (ddd, 1H); 31P NMR δ +103.65 (m).
3d according to 2 (B). 1H NMR δ 0.45-1.80 (br m, 3H), 5.55 (m, 2H), 7.38-7.68 (m, 9H); 31P NMR δ +124.68 (m); [α]D+55.1 (c 1, CHCl3).
3e according to 2 (B). 1H NMR δ 0.42-1.77 (br m, 3H), 1.37 (s, 9H), 3.81 (d, 3H), 7.19 (m, 1H), 7.40-7.66 (m, 7H), 7.80 (ddd, 1H), 7.93 (dd, 1H); 31P NMR δ+110.33 (m).
3′a prepared in CH2Cl2 according to 2 with HCl in toluene. 1H NMR δ 0.45-1.75 (br m, 3H), 6.89 (dd, 1H), 6.96 (dt, 1H), 7.33-7.51 (m, 4H), 7.53-7.74 (m, 3H), 8.20 (br s, 1H); 31P NMR δ+95.50 (m).
3′ab prepared in toluene according to 2 with HCl in toluene. 1H NMR δ 0.60-2.00 (br m, 3H), 1.00 (‘t’, 6H), 4.50 (sept, 1H), 6.85 (dd, 1H), 7.07 (dt, 1H), 7.41-7.58 (m, 4H), 7.75 (m, 2H), 8.01 (ddd, 1H); 31P NMR δ+91.46 (m).
To a cold (−20° C.) solution of methyl phosphinite-borane 3 in THF is added under stirring (A) an oil-free NaH (1.1-1.2 equiv.) followed by the organolithium (1.0-1.1 equiv.) or (B) the oganolithium (2.0-2.1 equiv.). The resulting mixture is left to warm up to room temperature. The reaction is hydrolyzed with water after disappearance of the starting 3 as monitored by TLC. After concentration, water (or acidified water until neutral pH is reached) is added and the residue is extracted with CH2Cl2. Drying over Na2SO4, concentration and purification of the residue on silica gel and/or by crystallization affords compound 4 in 90-99% yield. A similar procedure is adopted with chlorophosphine-boranes 3′.
4a according to 3(A) or (B) from 3a or from 3′a. 1H NMR δ 0.50-1.80 (br m, 3H), 1.92 (d, 3H), 6.92 (ddd, 1H), 6.98 (tt, 1H), 7.34-7.50 (m, 5H), 7.61 (dd, 1H), 7.63 (dd, 1H); 31P NMR δ +4.38 (m).
The enantiomer of 4a is prepared from the enantiomer of 3a.
4b according to 3(A) or (B). 1H NMR δ 0.71-1.95 (br m, 3H), 1.96 (d, 3H), 7.16 (m, 1H), 7.36-7.66 (m, 1H), 7.76 (m, 1H), 8.37 (m, 1H), 8.72 (s, 1H); 31P NMR δ +2.66 (m).
The enantiomer of 4b is prepared from the enantiomer of 3b.
4c according to 3(A) or (B). 1H NMR δ 1.04-2.28 (br m, 3H), 6.84 (m, 2H), 7.06 (m, 1H), 7.20 (m, 1H), 7.33-7.72 (m, 9H), 7.89 (m, 1H), 8.00 (m, 1H), 8.18 (m, 1H); 31P NMR δ +13.96 (m).
4d according to 3(A) or (B). 1H NMR δ 0.81-2.08 (br m, 3H), 0.93 and 1.02 (2d, 6H), 4.51 (sept, 1H), 6.83-7.02 (m, 4H), 7.13 (m, 1H), 7.32-7.64 (m, 8H), 7.66 (s, 1H); 31P NMR δ+10.96 (m).
4e according to 3(B). 1H NMR δ 0.45-1.68 (br m, 3H), 1.89 (d, 3H), 2.19 (t, 1H), 4.40 (dd, 1H), 4.71 (dd, 1H), 7.39-7.67 (m, 9H); 31P NMR δ +10.70 (m).
4f according to 3(A). 1H NMR δ 0.67-2.05 (br m, 6H), 4.13, 4.54, 4.57 and 4.67 (4m, 8H), 6.81-7.01 (m, 6H), 7.31-7.48 (m, 12H), 7.59 (br s, 2H); 31P NMR δ +8.82 (br s).
To a cold (0° C.) solution of phosphine-borane 4 (R=Me) in THF is added under stirring (A) an oil-free NaH (1.1-1.2 equiv.) followed by sec- or tert-BuLi (1.0-1.05 equiv.), (B) sec- or tert-BuLi (2.0-2.05 equiv.) or (C) sec- or tert-BuLi (1.0-1.05 equiv.). After leaving the resulting mixture at 0° C. for 1 h, anhydrous CuCl2 (1.05 equiv.) or (R′R″)SiCl2 (0.5 equiv.) is added at −30 to −40° C.; or an electrophile (0.5-1.2 equiv.) at −20 to 0° C. The reaction is left to warm up to room temperature and water (or acidified water until neutral pH is reached) is added. The mixture is concentrated, extracted with CH2Cl2, dried over Na2SO4, and concentrated. In case of reaction with CuCl2, the residue is filtered on a bed of silica gel eluting with EtOAc. The pure product 5-13 is obtained in 65-90% yield after purification on silica gel and/or crystallization.
5a according to 4(A) or (B) from 4a. 1H NMR δ 0.43-1.78 (br m, 6H), 2.51 (m, 4H), 6.88 (m, 2H), 6.94 (br s, 2H), 6.97 (tm, 2H), 7.32-7.53 (m, 10H), 7.64 (m, 4H); 31P NMR δ+18.48 (m).
5b according to 4(A) or (B) from 4b. 1H NMR δ 0.70-2.10 (br m, 6H), 2.41 and 2.59 (2m, 4H), 6.98 (m, 2H), 7.27 (d, 2H), 7.38-7.65 (m, 12H), 7.75 (d, 2H), 8.32 (d, 2H), 8.60 (s, 2H); 31P NMR δ +11.03 (m).
5ab (o-Z(R03R04C)n═OiPr) according to 4(C) from 4ab or also according to 6(B) from 5a.
6a according to 4(A) or (B) from 4a. 1H NMR δ −0.02 (s, 6H), 0.65-1.77 (br m, 3H), 1.68 (t, 2H), 1.91 (dd, 2H), 6.85 (m, 2H), 6.95 (m, 2H), 7.40 (m, 10H), 7.61 (m, 4H); 31P NMR δ +7.58 (m).
7ab (o-Z(R03R04C)n═OiPr) according to 4(C) from 4ab. 1H NMR δ 0.42-1.60 (br m, 6H), 0.73 and 1.10 (2d, 12H), 2.97 (m, 4H), 4.34 (sept, 2H), 6.52 (m, 4H), 7.05 (m, 2H), 7.15 (m, 6H), 7.34 (m, 8H), 7.54 (m, 4H); 31P NMR δ +14.06 (m).
8a according to 4(A) or (B) from 4a and paraformaldehyde. 1H NMR δ 0.40-1.72 (br m, 3H), 2.56 and 2.89 (2m, 2H), 3.87 (m, 2H), 6.78 (m, 1H), 6.94 (m, 1H), 7.36 (m, 4H), 7.64 (m, 3H); 31P NMR δ +8.13 (m).
9a according to 4(A) or (B) from 4a and Ph2PCl. In this case, after 12 hours at room temperature, BH3.Me2S (1 equiv.) is added at 0° C. to the mixture. After 1 hour, water is added and the mixture concentrated. The residue is extracted with CH2Cl2, dried over Na2SO4, and concentrated. The pure product is obtained in 68% yield after purification over silica gel eluting with toluene/EtOAc 20:1. 1H NMR δ 0.20-1.55 (br m, 6H), 3.20 and 3.77 (2m, 2H), 6.74 (ddd, 1H), 6.89 (m, 1H), 7.25 (m, 1H), 7.30-7.53 (m, 10H), 7.60-7.73 (m, 6H); 31P NMR δ+11.01 (m), +14.62 (m).
9ab according to 4(C) from 4ab, Ph2PCl and BH3.Me2S as for 9a. The product is obtained in 75% yield after purification over silica gel eluting with toluene. 1H NMR δ 0.15-1.50 (br m, 6H), 0.86 and 1.28 (2d, 6H), 3.22 and 3.91 (2m, 2H), 4.52 (sept, 1H), 6.74 (dd, 1H), 6.89 (ddt, 1H), 7.27-7.55 (m, 14H), 7.68 (m, 3H); 31P NMR δ +13.55(m), +14.45(m)
10ab according to 4(C) from 4ab and 3′ab. 31P NMR δ +13.61 (m).
11af according to 4(A) or (B) from 4a and 3 equiv. TMSCl. 1H NMR δ −0.03 (s, 9H), 0.05 (s, 9H), 0.47-1.30 (br m, 3H), 1.51 (‘t’, 1H), 2.04 (dd, 1H), 6.76 (ddd, 1H), 7.08 (ddt, 1H), 7.31-7.51 (m, 6H), 8.02 (ddd, 1H); 31P NMR δ +12.98 (m).
11a from 11af heating at 50° C. for 1 hour lla in MeOH in presence of silica gel. 1H NMR δ 0.03 (s, 9H), 0.62-1.82 (br m, 3H), 1.53 (‘t’, 1H), 1.74 (dd, 1H), 6.88-6.98 (m, 2H), 7.31-7.47 (m, 5H), 7.60-7.68 (m, 2H); 31P NMR δ +6.90 (m).
12a according 4(A) or (B) from 4e. 1H NMR δ 0.45-1.80 (br m, 6H), 2.19-2.37 (m, 4H), 2.62 (m, 2H), 4.35 and 4.65 (2dd, 4H), 7.32-7.66 (m, 18H); 31P NMR δ +16.39 (m).
13a according to 4(A) from 3d. 1H NMR δ 0.44-1.55 (br m, 6H), 0.76 (d, 3H), 1.09 (d, 3H), 2.07 (br s, 1H), 3.07 (ddd, 1H), 3.45 (dt, 1H), 4.30 (sept, 1H), 4.59 (d, 1H), 4.85 (dd, 1H), 6.58 (dd, 1H), 6.99 (ddt, 1H), 7.09-7.62 (m, 15H), 7.94 (ddd, 1H); 31P NMR δ +14.58 (m), +17.32 (m).
BBr3 (75 μl, 7 equiv.) is added to (R,R)-DiPAMP (5′aa) (50 mg, 0.11 mmol) in CH2Cl2 (2 ml) at −20° C. and the mixture left 1 h at room temperature. MeOH (2 ml) is added at 0° C. and the mixture refluxed for ˜2 h monitoring the reaction by 31P NMR. The mixture is then concentrated and carefully basified. (R,R)-5′a is extracted with a water/CH2Cl2 mixture, dried and concentrated. To (R,R)-5′a in THF is added Me2S.BH3 (2.1 equiv.) at 0° C. and the dried and concentrated. To (R,R)-5′a in THF is added Me2S.BH3 (2.1 equiv.) at 0° C. and the mixture left to warm up to room temperature, then concentrated and recrystallized to yield (R,R)-5a in 90% yield. 1H and 31P NMR are identical to the product prepared according to 4.
Similarly as above, (R)-o-(methylphenylphosphino)phenol (4′a) (108 mg, 0.5 mmol) led to (R)-o-(methylphenylphosphino-borane)phenol (4a) (109 mg) in 95% yield using BH3.THF (1.1 equiv.). 1H and 31P NMR are identical to the product prepared according to 3.
(A) To a cold (0° C.) solution of starting 2, 3, 4, 5 or 12 (Z═OH, n=0) in THF or ether is added oil-free NaH (1.0-1.3 equiv./P*) and a reagent R05X (1-5 equiv./P* of a mono-functional reagent and <0.5 equiv./P* for a bi-functional reagent). The mixture is stirred at room temperature until disappearance of the starting material as indicated by TLC. The concentrated mixture is extracted with CH2Cl2 and dried over Na2SO4. Concentration and purification of the residue on silica gel and/or crystallization affords the OH-functionalized compound in 75-90% yield. (B) A mixture of starting 2, 3, 4, 5 or 6 (Z═OH, n=0), a reagent R05X (5 equiv./P* of a mono-functional reagent and <0.5 equiv./P* for a bi-functional reagent) and K2CO3 (3 equiv.) in acetone (or DMF) is heated at 50° C. (or refluxed) until disappearance of starting material as indicated by TLC. Insolubles are filtered off and the filtrate concentrated. Purification of the residue on silica gel and/or crystallization affords the OH-functionalized compound in 60-95% yield (Tables 1 and 2).
2aa according to 6(B) from 2a and MeI. 1H and 31P NMR spectra are identical to the literature.
2ab according to 6(B) from 2a and isopropyl iodide. 1H and 31P NMR spectra are identical to the product prepared from 1 and o-iPrOPhLi according 1(A) or (B).
3aa according to 6(B) from 3a and MeI. 1H and 31P NMR spectra are identical to the literature.
The enantiomer of 3aa is prepared from the enantiomer of 3a.
3ab according to 6(B) from 3a and isopropyl iodide. 1H NMR δ 0.20-1.77 (br m, 3H), 0.98 and 1.07 (2d, 6H), 3.71 (d, 3H), 4.47 (sept, 1H), 6.81 (dd, 1H), 7.02 (tdd, 1H), 7.34-7.51 (m, 4H), 7.74 (m, 2H), 7.84 (ddd, 1H); 31P NMR δ +106.30 (m).
3an according to 6(A) from 3a and (R)-Moscher acid chloride. 1H NMR δ 0.28-1.78 (br m, 3H), 3.32 (q, 3H), 3.47 (d, 3H), 7.19 (ddd, 1H), 7.31-7.70 (m, 12H), 8.04 (ddd, 1H); 19F NMR δ −71.96 (s); 31P NMR δ +110.25 (m).
3bd according to 6(A) from 3b and triflic anhydride (Tf2O) in ether. 1H NMR δ 0.40-1.85 (br m, 3H), 3.86 (d, 3H), 7.41-7.57 (m, 3H), 7.63-7.83 (m, 5H), 7.90 (m, 2H), 8.17 (m, 1H); 19F NMR δ −72.06 (s); 31P NMR δ +112.95 (m).
4aa according to 6(A) or (B) from 4a and Md. 1H and 31P NMR spectra are identical to the literature. HPLC analysis on Daicel Chiralcel® OJ (hexane/iPrOH 70:30, 0.9 ml/min, λ=282 nm): t(R)=14.4 min, t(S)=26.8min
4ab according to 6(B) from 4a and isopropyl iodide. 1H NMR δ 0.24-1.64 (br m, 3H), 0.90 and 1.20 (2d, 6H), 1.95 (d, 3H), 4.52 (septd, 1H), 6.82 (dd, 1H), 7.02 (m, 1H), 7.37 (m, 3H), 7.46 (m, 1H), 7.57 (m, 2H), 7.93 (ddd, 1H); 31P NMR δ +9.04 (m).
4ad according to 6(A) from 4a and triflic anhydride (Tf2O). 1H NMR δ 0.30-1.70 (br m, 3H), 2.04 (d, 3H), 7.40-7.64 (m, 7H), 8.08 (ddd, 2H).
4al according to 6(A) from 4a and C6F6 in DMF. 1H NMR δ 0.25-1.75 (br m, 3H), 2.05 (d, 3H), 6.57 (m, 1H), 7.29 (md, 1H), 7.42 (m, 4H), 7.64 (m, 2H), 8.03 (ddd, 1H); 19F NMR δ −153.94 (d, 2F), −158.87 (t, 1F), −161.63 (m, 2F).
4an according to 6(A) from 4a and (R)-Moscher acid chloride. 1H NMR δ 0.25-1.50 (br m, 3H), 1.71 (d, 3H), 3.37 (q, 3H), 7.23-7.45 (m, 12H), 7.61 (m, 1H), 7.99 (ddd, 1H); 19F NMR δ −70.91 (s); 31P NMR δ +12.91 (m).
4at according to 6(B) from 4a and 2,4,6-tris(bromomethyl)mesitylene. 1H NMR δ 0.40-1.30 (br m, 9H), 1.71 (d, 9H), 1.88 (s, 9H), 4.88 and 5.02 (2d, 6H), 7.13 (m, 12H), 7.37 (m, 9H), 7.58 (m, 3H), 7.79 (m, 3H); 31P NMR δ +9.14 (s).
4av according to 6(B) from 4a and ethyl α-bromo(dimethylacetate). 1H NMR δ 0.50-1.80 (br m, 3H), 1.15 (t, 3H), 1.28 and 1.36 (2s, 6H), 1.96 (d, 3H), 4.14 (q, 2H), 6.52 (m, 1H), 7.05 (m, 1H), 7.35-7.58 (m, 6H), 7.91 (ddd, 1H); 31P NMR δ +9.85 (m).
4ea according to 6(A) from 4e and Md. 1H NMR δ 0.42-1.73 (br m, 3H), 1.89 (d, 3H), 3.10 (s, 3H), 4.20 and 4.47 (2d, 2H), 7.38-7.75 (m, 9H).
4ee according to 6(A) from 4e and mesyl chloride. 1H NMR δ 0.15-1.65 (br m, 3H), 1.92 (d, 3H), 2.75 (s, 3H), 5.13 and 5.35 (2d, 2H), 7.42-7.75 (m, 9H).
5aa according to 6(B) from 5a and Md. 1H and 31P NMR spectra are identical to the literature.
5ai according to 6(B) from 5a and 9-(chloromethyl)anthracene. 1H NMR δ 0.05-1.50 (br m, 6H), 2.04-2.33 (m, 4H), 5.63 (s, 4H), 6.23 (tm, 4H), 6.53 (tm, 2H), 6.71-6.84 (m, 4H), 7.12 (m, 4H), 7.29-7.48 (m, 8H), 7.55 (dt, 2H), 7.78 (dm, 4H), 7.87 (m, 2H), 7.97 (dm, 4H), 8.44 (s, 2H); 31P NMR δ +17.48 (m).
iBu
tBu
iPr
iPr
iPr
iPr
5ak according to 6(A) from 5a and (PhO)2P(O)Cl. 1H NMR δ 0.25-1.75 (br m, 6H), 2.71 (m, 4H), 6.97 (m, 8H), 7.09-7.39 (m, 20H), 7.44 (td, 2H), 7.62 (m, 6H), 7.93 (m, 2H); 31P NMR δ +19.27 (m), −17.88 (s).
5abe according to 6(B) from 5a and 3-bromocyclohexene. 1H NMR δ 0.30-2.11 (m, 18H), 2.62 (m, 4H), 4.64 (br s, 2H). 5.35-5.92 (m, 4H), 6.79 (m, 2H), 6.99 (m, 2H), 2.11 (m, 18H), 2.62 (m, 4H), 4.64 (br s, 2H), 5.35-5.92 (m, 4H), 6.79 (m, 2H), 6.99 (m, 2H), 7.37 (m, 8H), 7.61 (m, 4H), 7.93 (m, 2H); 31P NMR δ +19.61 (m).
The phosphine-borane 4-12 yields the corresponding phosphine 4′-12′ after 2-12 hours in refluxing Et2NH as solvent under inert atmosphere. After concentration and purification of the residue on silica gel and/or crystallization under inert atmosphere, the phosphine is obtained in 85-95% yield (Table 3).
tBu
tBu
iPr
iPr
4′ac according to 7 from 4ac. 1H NMR δ 1.27 (s, 9H), 1.55 (d, 3H), 7.04 (m, 1H), 7.22 (m, 2H), 7.34 (m, 6H); 31P NMR δ −38.14 (s).
4′ak according to 7 from 4ak. 1H NMR δ1.54 (d, 3H), 7.10-7.54 (m, 19H); 31P NMR δ −17.74 (s), −36.27 (s).
4′ao according to 7 from 4ao. 1H NMR δ 1.54 (d, 6H), 4.92 (m, 4H), 6.84 (m, 2H), 6.94 (t, 2H), 7.15 (m, 2H), 7.21-7.40 (m, 16H); 31P NMR δ −35.81 (s).
4′ap according to 7 from 4ap. 1H NMR δ 1.58 (d, 6H), 3.85-4.15 (m, 4H), 6.77 (dd, 2H), 6.92 (t, 2H), 7.09 (m, 2H), 7.32-7.41 (m, 8H), 7.46 (m, 4H); 31P NMR δ −34.02 (s).
4′aq according 7 from 4aq. 1H NMR δ 1.59 (d, 6H), 3.65 (t, 4H), 4.01 (m, 4H), 6.83 (dd, 2H), 6.92 (tt, 2H), 7.08 (m, 2H), 7.31 (m, 8H), 7.44 (m, 4H); 31P NMR δ −35.81 (s).
4′dc according 7 from 4dc. 1H NMR δ 1.07 and 1.10 (2d, 6H), 1.13 (s, 9H), 4.48 (sept, 1H), 6.70-6.86 (m, 4H), 7.04-7.14 (m, 2H), 7.24-7.38 (m, 7H); 31P NMR δ −24.89 (s).
4′dy according to 7 from 4dy. 1H NMR δ 0.93 and 1.11 (2d, 6H), 1.24 (s, 9H), 4.37 (m, 2H), 4.46 (sept, 1H), 6.68 (br s, 1H), 6.70-6.95 (m, 6H), 7.25-7.39 (m, 7H); 31P NMR δ −25.04 (s).
4′fb according to 7 from 4fb. 1H NMR δ 0.71 and 1.19 (2d, 12H), 2.35, 3.47 and 4.12 (3m, 6H), 4.31-4.43 (m, 4H), 6.65-6.83 (m, 6H), 7.14-7.30 (m, 8H), 7.35-7.44 (m, 4H); 31P NMR δ −26.13 (s).
4′fbd according to 7 from 4fbd. 1H NMR δ 0.36 and 0.90 (2t, 12H), 1.22 and 1.56 (2m, 8H), 4.01 (quin, 2H), 3.43, 4.10, 4.38 and 4.42 (4m, 8H), 6.67 (dd, 2H), 6.75 (m, 4H), 7.14-7.29 (m, 8H), 7.40 (m, 4H); 31P NMR δ −26.67 (s).
DiPMP (5′a) according to 7 from 5a. In this case, a Et2NH adduct precipitates. 1H NMR (DMSO-d6) δ 1.00 (t, 6H), 1.83 and 2.18 (2m, 4H), 2.53 (q, 4H), 6.79 (m, 6H), 7.14 (m, 2H), 7.21-7.39 (m, 10H); 31P NMR (DMSO-d6) δ −21.17 (s). The free diphosphine is obtained quantitatively by capture of Et2NH by a weakly acidic resin as Amberlite® IRC-50 H in MeOH. 1H NMR δ 2.15 (m, 4H), 6.46 (br s, 2H), 6.91 (m, 4H), 7.06 (m, 2H), 7.30 (m, 12H); 31P NMR δ −39.23 (s).
SMS-PiP (5′ab) according to 7 from 5ab. 1H NMR δ 1.03 and 1.17 (2d, 12H), 1.95 and 2.28 (2m, 4H), 4.47 (sept, 2H), 6.75 (dm, 2H), 6.97 (td, 2H), 7.05-7.39 (m, 14H); 31P NMR δ −19.13 (s).
SMS-Piv (5′ac) according to 7 from 5ac. 1H NMR δ 1.25 (s, 18H), 2.02 (m, 4H), 7.01 (m, 2H), 7.13 (m, 4H), 7.20-7.38 (m, 12H); 31P NMR δ −25.30 (s).
5′af according to 7 from 5af. 1H NMR δ 1.01 and 1.02 (2d, 36H), 1.22 (sept, 6H), 1.87 and 2.15 (2m, 4H), 6.75 (dm, 2H), 6.82 (td, 2H), 6.95 (m, 2H), 7.15 (m, 2H), 7.23 (m, 10H); 31P NMR δ −23.86 (s).
5′ag according 7 from 5ag. 1H NMR δ 0.28 (s, 18H), 2.19 and 2.54 (2m, 4H), 3.78 (s, 4H), 7.13 (dt, 2H), 7.22 (d, 2H), 7.28 (m, 2H), 7.55 (m, 12H); 31P NMR δ −21.25 (s).
5′ah according to 7 from 5ah. 1H NMR δ 1.83 and 2.08 (2m, 4H), 4.98 (m, 4H), 6.94 (m, 4H), 7.05-7.40 (m, 14H); 19F NMR δ −142.22 (m, 4F), −153.57 (m, 2F), −162.21 (m, 4F); 31P NMR δ −20.90 (s).
5′aj according to 7 from 5aj. 1H NMR δ 1.42 (s, 18H), 1.99 and 2.38 (2m, 4H), 4.42 (s, 4H), 6.65 (dm, 2H), 6.86 (td, 2H), 6.97 (m, 2H), 7.16-7.43 (m, 12H); 31P NMR δ −20.96 (s).
5′ap according to 7 from 5ap. 1H NMR δ 1.94 and 2.27 (2m, 4H), 3.31 (s, 6H), 3.30 (t, 4H), 3.99 (m, 4H), 6.81 (d, 2H), 6.87 (td, 2H), 7.04 (m, 2H), 7.22-7.40 (m, 12H); 31P NMR δ −20.24 (s).
5′bb according to 7 from 5bb. 1H NMR δ 1.30 and 1.36 (2d, 12H), 2.19 (m, 4H), 4.79 (m, 2H), 7.06 (dt, 2H), 7.22-7.56 (m, 16 H), 7.75 (m, 2H), 8.16 (m, 2H); 31P NMR δ −23.31 (s).
5′bc according to 7 from 5bc. 1H NMR δ 1.48 (br s, 18H), 2.14 (m, 4H), 6.83-7.85 (m, 22H); 31P NMR δ −27.98 (m).
5′az according to 7 from 5az. 1H NMR δ 2.06 and 2.34 (2m, 4H), 6.75 (m, 4H), 6.94-7.42 (m, 24H); 31P NMR δ −22.53 (s).
5′abc according to 7 from 5abc. 1H NMR δ 0.85 and 0.87 (2d, 12H), 1.88 (m, 2H), 1.96 and 2.31 (2m, 4H), 3.61 (m, 4H), 6.76 (m, 2H), 6.82 (m, 2H), 6.99 (m, 2H), 7.19-7.35 (m, 12H); 31P NMR δ −20.29 (s).
5′abf according to 7 from 5abf. 1H NMR δ 1.08-2.46 (m, 24H), 4.20 (m, 2H), 6.73-6.83 (m, 4H), 7.02 (m, 2H), 7.17-7.40 (m, 12H); 31P NMR δ −19.28 (s).
5′abb according to 7 from 5abb. 1H NMR δ 1.16-1.34 (m, 24H), 1.89 and 2.31 (2m, 4H), 4.49 and 4.76 (2sept, 4H), 6.49 (m, 2H), 6.79-6.89 (m, 4H), 7.22-7.38 (m, 10H); 31P NMR δ −21.43 (s).
5′abbb according to 7 from 5abbb. 1H NMR δ 1.10 (d, 6H), 1.22 (m, 18H), 1.32 (d, 6H), 1.34 (d, 6H), 1.91 (m, 2H), 2.19 (m, 2H), 4.30 (sept, 2H), 4.49 (sept, 2H), 4.87 (sept, 2H), 6.48-6.60 (m, 4H), 7.23-7.37 (m, 10H); 31P NMR δ −22.56 (s).
5′ae according to 7 from 5ae. 1H NMR δ 1.88 (m, 4H), 2.38 (s, 6H), 6.98 (m, 2H), 7.06-7.35 (m, 20H), 7.76 (m, 4H); 31P NMR δ −24.72 (s).
5′acb according to 7 from 5acb. NMR 1H δ 1.89-2.24 (m, 4H), 7.11-7.29 (m, 16H), 7.34-7.44 (m, 6H), 7.55 (m, 2H), 7.96 (m, 4H); 31P NMR δ −23.48 (s).
5′akb according to 7 from 5akb. 1H NMR δ 1.86-2.22 (m, 4H), 6.96 (m, 4H), 7.11-7.58 (m, 26H), 7.69 (m, 4H), 7.96 (m, 4H); 31P NMR δ −24.43 (s), +31.20 (s).
5′abd according to 7 from 5abd. 1H NMR δ 0.67 and 0.85 (2t, 12H), 1.44 and 1.55 (2m, 8H), 1.95 and 2.31 (2m, 4H), 4.10 (quin, 2H), 6.74 (m, 2H), 6.80 (m, 2H), 7.04 (m, 2H), 7.18-7.38 (m, 12H); 31P NMR δ −20.16 (s).
5′abh according to 7 from 5abh. 1H NMR δ 1.36 (s, 18H), 1.86 and 2.28 (2m, 4H), 6.82-7.02 (m, 6H), 7.17 (m, 2H), 7.22-7.35 (m, 10H); 31P NMR δ −19.85 (s).
5′ay according to 7 from 5ay. 1H NMR δ 1.33 (s, 18H), 2.02 and 2.19 (2m, 4H), 4.27 and 4.35 (2d, 4H), 6.70 (br s, 2H), 6.80 (m, 2H), 6.98 (m, 2H), 7.09 (m, 2H), 7.31 (m, 12H); 31P NMR δ −24.44 (s).
7′ab according to 7 from 7ab. 1H NMR δ 0.89 and 1.03 (2d, 12H), 1.63 (d, 2H), 1.97 (d, 2H), 4.32 (sept, 2H), 6.60 (m, 2H), 6.78 (m, 2H), 7.04-7.27 (m, 20 H), 7.37 (m, 4H); 31P NMR δ −29.14 (s).
12′aa according to 7 from 12aa. 1H NMR δ 2.09 (m, 4H), 3.29 (s, 6H), 4.53 and 4.75 (2d, 4H), 7.16-7.47 (m, 18H); 31P NMR δ −24.77 (s).
To DiPAMP (5′aa) (50 mg) in ether is added HBF4 50% in ether (2.2 equiv.). The white precipitate is filtered, rinsed with ether and dried under vacuo. 1H NMR δ 3.25 (m, 4H), 3.99 (s, 6H), 7.06 (m, 2H), 7.24 (m, 2H), 7.57-7.78 (m, 8H), 7.96 (m, 6H); 19F NMR δ −149.49 (s, 1F), −149.54 (s, 3F); 31P NMR δ +8.39 (m).
Following the above procedure from SMS-PiP (5′ab) (50 mg). 1H NMR δ 1.23 and 1.30 (2d, 12H) 3.25 (m, 4H), 4.68 (sept, 2H), 7.02 (m, 2H), 7.23 (m, 2H), 7.63 (m, 4H), 7.71 (m, 4H), 7.93 (m, 6H); 19F NMR δ −149.10 (s, 1F), -149.16 (s, 3F); 31P NMR δ +2.41 (m).
To o-(methylphenylphosphino)phenol (4′a) (25 mg) in THF is added at room temperature an aqueous solution of 30% H2O2 (200 μl). After 10 min, the mixture is concentrated yielding quantitatively 4′a-oxide as a white solid. 1H NMR δ 2.10 (d, 3H), 6.86 (ddt, 1H), 6.94 (ddd, 1H), 7.06 (m, 1H), 7.39 (m, 1H), 7.52 (m, 3H), 7.77 (m, 2H), 11.10 (br s, 1H); 31P NMR δ +43.38 (br s) ; [α]D 58 (c 1, MeOH).
All operations were conducted under Ar atmosphere with dried and degassed solvents. The metal precursors, bis(2,5-norbomadiene)rhodium tetrafluoroborate [(nbd)2Rh]BF4, (2,5-norbomadiene)ruthenium dichloride polymer [(nbd)RuCl2]n, and bis(2-methylallyl)(1,5-cyclooctadiene)ruthenium [(cod)Ru(C4H7)2] are commercially available.
To a solution of [(nbd)2Rh]BF4 (2.8 mg, 1% Rh) in MeOH (0.5 ml), a solution of the ligand L*(2 equiv. in case of monophosphines; 0.75 equiv. with diphosphines) in MeOH (0.5 ml) or CH2Cl2 (0.5 ml) is added dropwise at room temperature. The mixture is hydrogenated at 1 atm H2 for 15 min, filtered on a sintered glass, and the filtrate containing the catalyst Rh-L* is used directly in the tests. For example: Rh-(5′ab) complex prior to hydrogenation: 31P NMR (MeOH) δ +52.99 (d, J 158.08).
To a solution of [(cod)Ru(C4H7)2] (160 mg, 0.5 mmol) in acetone (3 ml), a 0.2 M FIX (X═Cl, Br, I) in acetone (5 ml, 1 mmol) is added at room temperature. The [(cod)RuX2]x complexes precipitate, are filtered, rinsed with acetone and dried in vacuum (75-85% yield).
To a cold (0° C.) solution of [(cod)Ru(C4H7)2] (160 mg, 0.5 mmol) and 1,5-cyclooctadiene (185 μl, 1.5 mmol) in ether (3 ml) is slowly added triflic acid (44 μl, 0.5 mmol). The [(cod)(cot)RuH]OTf precipitates, is filtered, rinsed with ether and dried (185 mg, 80% yield).
To a solution of the substrate (0.5 mmol) in MeOH (7 ml), a solution of the Rh-L* catalyst in MeOH (prepared as above) is added under Ar, then a vacuum/H2 cycle is applied. The mixture is stirred at room temperature under 1 atm of H2 (10 bars for atropic acid) until uptake H2 ceased. The solution is analyzed by GC on Lipodex E, Chiralsil-L-Val, CP-Chiralsil DEX CB columns. The acids were esterified in CH2Cl2 using TMSCH2N2 (hexanes) prior to analysis 25 (Tables 4, 5 and 6). The results show that using the ligands of the present invention, it is possible to significantly increase the reaction rate and the ee of the product.
(5-10 bars)
(10 bars)
A) A solution of [(cod)RuX2]x (10 μmol) (prepared as above) and the L* (10 μmol) in acetone (1 ml) is stirred for 30 min at room temperature then concentrated. A solution of the substrate (1 mmol) in MeOH (2 ml) is added and the solution is hydrogenated as indicated. B) To a mixture of [(cod)Ru(C4H7)2] (3.2 mg, 10 μmol) and the L* (10 μmol) in acetone (1 ml), a solution of 0.22 M HX (22 μmol, 2.2 equiv.) (X═Cl, Br, I) in MeOH (100 μl) is added at room temperature. After stirring for 30 min, the mixture is concentrated. To the residue is added a solution of the substrate (1 mmol) in MeOH (2 ml). The mixture is hydrogenated as indicated in table 7. The crude is analyzed by GC on CP-Chiralsil DEX CB.
A mixture of [(cod)RuCl2]2 (2.8 mg, 5 μmol, as described above) and the ligand L* (10 μmol) in acetone (0.5 ml) is stirred for 30 min at 40° C. and concentrated. The residue is transferred in DMF (0.5 ml) to 1,2-diphenylethylenediamine (DPEN) (2.1 mg, 10 μmol) and stirred for 1 h before concentration. A solution of acetophenone (120 mg, 1 mmol) and tBuOK (3.4 mg, 30 μmol) in iPrOH (1 ml) is added and hydrogenated at room temperature under 10 bars for 3 h. The crude is analyzed by GC on CP-Chiralsil DEX CB at 120° C.: t(R)=6.5 min, t(S)=7.0 min
To a solution of [(nbd)2Rh]BF4 (1.9 mg, 5 μmol) in THF (0.5 ml), a solution of the L* (1.1 equiv. to Rh atom) in THF (0.5 ml) is added at room temperature and the mixture stirred for 15 min Acetophenone (58 μl, 0.5 mmol) is added at 0° C. then Ph2SiH2 (138 μl, 0.75 mmol). After 2.5 h, K2CO3 (0.5 mg) in MeOH (0.5 ml) is added and the mixture stirred at room temperature for 3 h, then concentrated. The crude is analyzed on CP-Chiralsil DEX CB.
| Number | Date | Country | Kind |
|---|---|---|---|
| 0506226 | Jun 2005 | FR | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/FR2006/001394 | 6/20/2006 | WO | 00 | 12/31/2009 |
