EP1899358A2 - Neue p-chirale funktionalisierte arylphosphine und derivate, ihre herstellung und ihre verwendung zur asymmetrischen katalyse - Google Patents

Neue p-chirale funktionalisierte arylphosphine und derivate, ihre herstellung und ihre verwendung zur asymmetrischen katalyse

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Publication number
EP1899358A2
EP1899358A2 EP06778624A EP06778624A EP1899358A2 EP 1899358 A2 EP1899358 A2 EP 1899358A2 EP 06778624 A EP06778624 A EP 06778624A EP 06778624 A EP06778624 A EP 06778624A EP 1899358 A2 EP1899358 A2 EP 1899358A2
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European Patent Office
Prior art keywords
phenyl
denotes
methyl
optionally substituted
nmr
Prior art date
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EP06778624A
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English (en)
French (fr)
Inventor
Michel Stephan
Barbara Mohar
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PHOSPHOENIX SARL
National Institute of Chemistry
Kemijski Institut
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PHOSPHOENIX SARL
National Institute of Chemistry
Kemijski Institut
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    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
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    • B01J31/2447—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring
    • B01J31/2452—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring with more than one complexing phosphine-P atom
    • B01J31/2457—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring with more than one complexing phosphine-P atom comprising aliphatic or saturated rings, e.g. Xantphos
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Definitions

  • New ortho-functionalized P-chiral arylphosphines and their derivatives their preparation and use in asymmetric catalysis
  • the main subject of the present invention is new optically active P-chiral phosphines, their precursors and their derivatives, the phosphorus atom of which carries chirality and a (hetero) aryl group functionalized in the ortho or 2 position thereof. ; their preparation, the preparation of their metal complexes and their application in asymmetric catalysis of unsaturated compounds. This technique allows easy access to the enantiomers of chiral molecules of interest in particular the pharmaceutical, food and cosmetic industries.
  • transition metal complexes In their form of transition metal complexes, a wide variety of them exhibit increased activity and enantioselectivity in asymmetric catalysis, particularly in hydrogenation, compared to well known ligands of the same type such as bis (o-anisyhnethylphenylphosphino). ethane (DiPAMP); the latter was invented by Knowles, co-winner of the 2001 Nobel Prize in Chemistry.
  • the asymmetric hydrogenation of itaconic acid at 1 bar of 2 with a rhodium-DiPAMP complex results in an enantiomeric excess (ee) of 11% and a conversion of 40% in 1 hour, while with New ligands of the invention, a 98.5% ee and a 100% conversion were achieved in 6 minutes. Therefore, access to such a wide variety of highly active P-chiral phosphorous ligands from a common structure results in the possibility of "leakage control" of the catalyst for a particular application, a lesser amount of the catalyst is and the desired molecules are obtained faster with better optical purity.
  • the current syntheses of the effective ligands are restricted to the access of an antipode (eg 1 BuBiSP *, MiniPHOS, TangPHOS), difficult to access (eg ligands like DuPHOS, NORPHOS, PhanePHOS), or a multi-step synthesis is necessary for the preparation of a new "modified parent diphosphine" with different substituents on the phosphorus atom or on the side chain.
  • an antipode eg 1 BuBiSP *, MiniPHOS, TangPHOS
  • difficult to access eg ligands like DuPHOS, NORPHOS, PhanePHOS
  • a multi-step synthesis is necessary for the preparation of a new "modified parent diphosphine" with different substituents on the phosphorus atom or on the side chain.
  • Phosphine phosphites have been prepared by coupling with chlorophosphites (Tetrahedron: Asymm 2001, 12, 2501-2504).
  • chlorophosphites Tetrahedron: Asymm 2001, 12, 2501-2504
  • the attempts of the present inventors to functionalize the hydroxyl group of the PEM demethylated by alkyl failed, leading to a mixture of phosphonium salts as shown by NMR 1 H and 31 P.
  • Our invention relates to the synthesis of optically active P-chiral arylphosphines - more particularly having an optical purity> 95% - functionalised in the ortho or 2 position, of their precursors and derivatives which correspond to the general formula (I).
  • Our invention also relates to the preparation and use of their metal complexes in asymmetric catalysis.
  • - m is an integer greater than or equal to 1
  • n is an integer equal to zero or 1
  • P * symbolizes an asymmetric phosphorus atom; with m> 1, the atoms P * preferentially have the same absolute configuration,
  • Ar symbolizes a C 4-14 aromatic or polyaromatic group bonded to the atom P * by the bond (x) and to the group Z- (CR 03 R 04 ) n by the bond (y) such that the grouping Z- (CR 03 R 04 ) n is in the ortho position or 2 of the atom P *;
  • Ar includes or otherwise one or more heteroatoms such as N, O, S, or may optionally bear one or more heteroatoms such as N, O, Si 5 halogen, and / or Ar may be optionally substituted by one or more alkyl and / or Cno alkoxys also optionally substituted or which may form a ring with each other; such that phosphino-Ar may be phosphinobenzene, 1-phosphinonaphthalene, 2-phosphinonaphthalene, N- (R 05 ) -2-methyl-7-phospbinomdole, N- (R 05 ) -7-phosphinoindoline,
  • Z may represent a group R 05 linked at the end of the chain (s) to O-, S-, N-, NC (O) -terminals, optionally interrupted by heteroatoms such as N, O, S, Si, P; or else R 05 may represent a chiral hydrocarbon chain, a polymer, a resin, a gel, a siloxane, or a spacer arm (spacer) between these and the O-, S-, N-, NC (O) - terminals; by way of example R 05 may represent a skeleton of formula (II),
  • a symbol represents a carbon atom, O, S, or a group Ts-N, CH, CH 2 , (-Si (R 051 ) 2 O- Si (R 051 ) 2 ) m ', an aromatic such as benzene, pyridine, where R 05 'represents a C 1-10 alkyl radical and m' an integer greater than or equal to 1,
  • R 08 and R 09 independently of one another represent a C 1 -C 5 alkyl, C 5-8 cycloalkyl or C 8 -w aryl radical, where appropriate substituted with alkyls, alkenyls or aryls, and / or contain heteroatoms such as O, N, Si, P, halogen,
  • - k 01 , k 02 , k 03 , k 04 are independently of each other integers varying from zero to 10, and I 01 , 1 02 , 1 03 , 1 04 are independently one of the other integers ranging from zero to 1,
  • (y 03 ), (y 04 ) respectively identify the links established between A 01 , A 02 , A 03 , A 04 and the O-, S-,
  • R 05 may be a Merrifield or Wang resin, a (CH 2 ) 2 , (CH 2 ) 3 , (- CH 2 CH 2 ) 2 O, (-CH 2 CH 2 ) 2 NTs ⁇ , ⁇ '-o-xylyl, 2,6-bis (methyl) pyridine, 1,2,4,5- (tetramethylene) benzene, diglycolyl, phthaloyl, trimesoyl, 2,6- (pyridine) dicarbonyl, (benzene) - disulfonyl, 1,2-bis (dialkylsilyl)
  • OR 05 represents a negatively charged oxygen atom, a hydroxyl, a linear or branched, cyclic or polycyclic C 1-1 2 alkoxy, saturated or unsaturated, optionally substituted with one or more (hetero) aryls in C 4-14 - all these radicals possess or not one or more asymmetric carbon atoms each symbolized by C *; or OR 05 represents a Cs- 14 (hetero) aryloxy radical which optionally contains fluorine atoms, one or more nitro, cyano, trifluoromethyl and the like; R 05 optionally contains heteroatoms such as O, N, Si, halogen such as fluorine, and / or a functional group such as unsaturation, a hydroxyl, an amino, a (di) alkylamino, a carboxyl, an ester, an amide, an ammonium, a sulphonate, a sulphate, a phosphit
  • P 01 * symbolizes an asymmetric phosphorus atom with the atoms P * and P 01 * having the same absolute configuration
  • R 05 "represents a hydrogen atom, a C 1-1 O radical such as methyl or tert-butyl,
  • R 01 and R 02 have the same meanings as in formula (T) and are defined below,
  • R 05 is as defined above and in particular hydrogen, an isopropyl, tert-butyl or C 6-10 aryl radical optionally substituted by one or more C 1 -C 10 alkyl or C 5 -C 1 aryl groups; o, or with heteroatoms such as O, N, Si, halogen,
  • R 05 represents an isopropyl, tert-butyl or C 5-6 cycloalkyl radical, a dialkylamino
  • R 06 and R 07 represent, independently of one another, what is defined previously for R 05 and in particular a hydrogen, a linear or branched chain in C 1 -10 , a C 5-8 cycloalkyl radical; or R 06 and R 07 may be bonded together to form an optionally substituted C 4-7 ring; or else C (O) N (R 06 R 07 ) represents an oxazoline substituted in the 4-position by one or two C 1 + alkyl or aryl groups,
  • R 10 represents a hydrogen, a halogen such as Cl, Br, I or F, especially a Cl, a C 1-18 alkyl radical, a C 7 -7 cycloalkyl, a C 4-14 aryl or heteroaryl, substituted optionally by one or more alkyl, alkoxy or aryl groups and / or by heteroatoms such as O, N, Si, P, halogen; or else R 01 represents a C 5-14 aryloxy group, C 1-18 alkoxy - optionally having one or more asymmetric carbon atoms each symbolized by C * or substituted by one or more halogens -, a nitrogen group being part of of a C 4-6 aliphatic ring, or a (di) alkylamino at CH 8 - where the alkyls, different or identical, have or not one or more asymmetric carbon atoms each symbolized by C * and optionally substituted by heteroatoms -; R 01 still represents a group Z '- (CR
  • R 02 is different from R 01 and represents a C 1-18 alkyl, a C 5-7 cycloalkyl, a C 4-14 aryl or heteroaryl, optionally substituted with one or more alkyl, alkoxy or aryl groups; and / or by heteroatoms such as O, N, Si, P, halogen;
  • R 02 also represents a vinyl; in the particular case where R 02 may represent an alkoxy group, R 01 and R 02 are bonded to each other and form a C 2-3 aminoalkoxy hydrocarbon chain containing one or more C * asymmetric carbon atoms; or R 02 represents a backbone of general formula (T) bonded to the atom P * of (I) via the bond (w), in which :
  • n ' is an integer equal to zero or 1
  • P 1 * symbolizes an asymmetric phosphorus atom; with m> 1, the atoms P * and P '* preferentially have the same absolute configuration, - E' denotes, independently of E, what is defined previously for E, and E 'also denotes an oxygen atom,
  • R 03 'and R 04 ' represent independently of each other and R 03 and R 04 which is defined above for R 03 and R 04 , and particularly (CR 03l R 04 ') n . and (CR 03 R 04 ) n are identical,
  • Z represents independently of Z what is defined previously for Z
  • R 01 ' represents independently of R 01 which is defined previously for R 01 , and more particularly R 01 ' and R 01 are identical,
  • Q represents a hydrocarbon-based chain optionally interrupted by heteroatoms such as -C (R 08 R 09 ) -, (-CH (R 08 )) 2 (in this case, the radicals R 08 may be linked to form an optionally substituted ring) , (-CH (R 08 )) 2 CH 2 , (-CBb) 2 Si (R 08 R 09 ), (-CH 2 ) 2 P (E ") (R 08 ), - CH (R 08 ) CH 2 CH 2 CH (R 08 ) -, (-CH (R 08 ) CH 2 ) 2 O, (-CH (R 8 ) CH 2 O) 2 P (E ") (R 0 S ), or a 1, 2- phenylene, ferrocene-1,1-diyl, 2,6-bis (dimethylene) pyridine, N- (R 5 O) -pyrrolidine-3,4-diyl, wherein N- (R 05 ) -, R 08 and R 09 represent as previously described,
  • R 01 denotes a phenyl
  • R 02 denotes an o-anisyl
  • Z- (CR 03 R 04 VAr denotes a 2- (hydroxy) -1-naphthyl, 2- (O-acetyllactoxy) ) -l-na ⁇ htyle
  • R 01 denotes a phenyl
  • R 02 denotes a methyl
  • Z- (CR 03 R 04 VAr denotes a 2-methoxy-1-naphthyl, 2-acetoxy-1-naphthyl,
  • R 01 denotes a phenyl
  • R 02 denotes a methyl
  • Z- (CR 03 R 04 VAr denotes a 2-hydroxyphenyl, 2- (3,3 ', 5,5'-tetra- tert-Buryl-1, r-bisphenyl-2,2 l -phosphine) phenyl, 2- (3,3'-di-tert-butyl-5,5,6,6'-tetamethyl-1,1'-bisphenyl) 2,2'-phosphite) phenyl, 2,7-di-tert-butyl-9,9-dimethyl-5- (methylphenylphosphino-EO 2 ) xanth-4-yl
  • E 02 denotes 2e " , BH 3 or O
  • Z- (CR 03 R 04 VAr denotes an oxazoline substituted in the 4-position by methyl, isopropyl, tert-butyl, phenyl,
  • R 01 denotes a phenyl
  • R 02 denotes 1-naphthyl, 2-naphthyl, 2-biphenylyl, • with E and K identical designating 2e " or BH 3 :
  • Q denotes CH 2 CH 2 ,
  • Z- (CR 03 R 04 VAr and ZKCR 031 R 041 VAr 1 identical are ortho-anisyl, R 01 and R 01 'are identical and denote an ethyl, cyclohexyl, phenyl, 2-naphthyl, anisyl, chlorophenyl, (methanesulfonyl) phenyl p- (N, N-dimethylamino) phenyl, thioanisyl,
  • R 04 % -Ar l are the same as o-hydroxyphenyl, o-thioanisyl, o- (methanesulfonyl) phenyl, o-acetylphenyl, 2- methoxy-4- (sodium sulfonyl) phenyl, 2-methoxy-4- (N, N-dimethylaminosulfonyl) phenyl,
  • Q denotes CH 2 SiMe 2 CH 2 , CH 2 SiPh 2 CH 2 , CH 2 SiBn 2 CH 2 , 1,1-ferrocenyl, 2,6-bis (dimethylen) pyridine, N- (R 05 ) -pyrrh 'dine-3,4-diyl.
  • Our invention is illustrated by the preparation of ortho-hydroxy-, amino-, carboxy-arylphosphines, their precursors and P-chiral derivatives of the general formula (T), from an optically active oxazaphosphacycloalkane-borane of the general formula ( Ib) derived from an optically active amino alcohol HN (R 06 > Q 02 * -OH,
  • R 10 represents a methyl, (trimethylsilyl) methyl, isopropyl, tert-butyl, adamantyl, C 5-7 cycloalkyl, an optionally substituted C 4 -4 aryl, an ormo-Z (CR & 3 R 04 ); n -Ar as defined above and in particular an orfho- (R 05 O (CH 2 ) n ) -Ar where n is equal to 0 or 1, R 05 represents a hydrogen atom, an isopropyl, tert-butyl or cyclohexyl and Ar represents a phenyl or naphthyl optionally substituted with one or more Cno alkyls and / or alkoxys, also optionally substituted or may form a ring with each other, - Q 02 * represents a C 2-3 alkyl chain containing one or more asymmetric carbon atoms, and which can also be linked to N by R 06 , R 06 ,
  • the optically pure oxazaphosphacycloalkane-borane of general formula (Ib) can be prepared as described by Jugé et al or Brown.
  • organo * (di) functionalized metal prepared from ortho-Z (CR 03 R ° 4 ) n
  • aminophosphine- boranes 2a and 2b respectively derived ro-bromophenol and 2-bromo-l naphthol.
  • aminophosphine boranes (Ic) are precursors of various phosphinite boranes and halophosphine boranes (Id).
  • chlorophosphine-borane 3 f reacts with an organometallic to yield the corresponding phosphine borane 4 or reacts with a hydroxyarene to yield the corresponding aryl phosphinite-borane.
  • phosphine boranes (Ie) can also be prepared by reacting the functionalized organometallic with phosphinite boranes or chlorophosphine boranes prepared according to the method of Jugé et al.
  • the Z function of the phosphines, their precursors and derivatives can be modified - just as the functionalized arm R 05 in ⁇ of P * such CH 2 OH - with various groups possessing different properties such as alkyls, activated aryls, fluoroalkyls, fluorobenzyls, silyls, acyls, aroyles, acetates, phosphates, phosphites , triflate, sulphonates, ammonium salts, rendering them as well as their metal complex, more soluble in the reaction medium (water, alcohols, ionic liquids, perfluorinated solvents, etc.) or recyclable by separation of the solid-liquid or liquid-liquid phases (Scheme 2: Example with (o-hydroxyaryl) phenylphosphino borane).
  • a bifunctionalized alkane or heteroalkane eg ethylene glycol ditosylate, diethylene glycol ditosylate
  • a polyfunctionalized arylalkane eg 2,4 6- Tris (bromomethyl) mesitylene
  • the inventors have also found other pathways to 5a from the DIPAMP (5'aa) or from its complex BH 3 5aa by demethylation of o-anisyl group with BBr 3 followed by complexation with BH 3 (scheme 3).
  • This route also applies to the synthesis of poly (phenylphenylphosphoroborane) phenol 4a via o- (methylphenylphosphino) phenol 4'a.
  • the demethylation of the o-anisyl group can also be carried out according to conditions described by Greene and Wuts (Protective Groups in Organic Synthesis, John Wiley & Sons 1999).
  • ortho-functionalized P-chiral arylphosphines may be modified on the phosphorus atom by groups other than BH 3 such as oxygen or acid, for example HBF 4 , TfOH, HClO 4 , HPF 6 , HBr, HL.
  • the present invention also relates to the use of optically active compounds of general formula (T) for the preparation of catalytic metal complex ligands useful for carrying out asymmetric syntheses in organic chemistry.
  • Said metal complexes prepared in a suitable solvent are based on a transition metal and, as ligand of said metal, at least one optically active form of a compound of general formula (I) in which E and / or E 'represent 2e ", and as examples of neutral, cationic or anionic metal complexes, mention may be made especially of those corresponding to the general formula (DI), (m) H t in which
  • M represents a transition metal chosen from rhodium, ruthenium, iridium, cobalt, palladium, platinum, nickel or copper,
  • L represents an optically active compound of general formula (T) as defined previously in which E and / or E 'represent 2e " , and E and / or E 01 represent 2e "
  • X 1 represents a coordinating anionic ligand such as the halide ions Cl, Br or I, an anionic group such as OTf, BF 4 , ClO 4 , PF 6 , SbF 6 , BPh 4 , B (C 6 F 5 ) 4 , B (3,5-di-CF 3 -C 6 H 3 ) 45 p-TsO, OAc, or CF 3 CO 2 or even ⁇ -allyl, 2-methylallyl, and when the complex is anionic, X 1 represents a cation such as Li, Na, K, ammonium substituted or not with alkyls,
  • - S v and Sy represent, independently of one another, a ligand molecule such as H 2 O, MeOH, EtOH, amine, 1,2-diamine (chiral or non-chiral), pyridine, a ketone such as acetone, an ether such as THF, a sulfoxide such dimethylsulfoxide, an amide such as dimethylformamide or N-methylpyrrolidinone, an olefin such as ethylene, 1,3-butadiene, cyclohexadiene, 1,5-cyclooctadiene, 2,5-norbornadiene, 1,3,5- cyclooctatriene, or an unsaturated substrate, a nitrile such as acetonitrile, benzonitrile, arene or C 5-12 aryl optionally substituted with one or more C1-C5 alkyls, iso- or tertioalkyls, such as benzene, p-cymene
  • - H represents a hydrogen atom
  • - p is an integer equal to 1 or 2
  • q is an integer ranging from 1 to 4
  • r is an integer ranging from 0 to 4
  • s and s 1 independently of one another are integers ranging from 0 to 2
  • t is an integer ranging from 0 to 2.
  • the catalyst can be prepared from optically active P-chiral compounds of general formula (I) in combination with a metal donor compound (catalyst precursor) in a suitable solvent according to protocols known in the literature (Osborn et al, J. Am., Chem Soc., 1971, 93, 2397; Genet, Acros Organics Acta 1994, 1 (1), 1-8).
  • the catalyst may consist of a preformed metal complex as defined above, may be generated in situ in the reaction medium optionally in the presence of the substrate, or even activated before use.
  • the optimum ratio of the optically active ligand to the metal may vary depending on the ligand and the metal and can be easily determined experimentally; for example, the amount of the optically active ligand to be added may vary from 1 to 4 equivalents relative to the metal. It is understood that when one enantiomer is used, the other enantiomer is similarly applicable.
  • the present invention also provides a process for preparing rhodium catalysts from an optically active P-chiral compound of general formula (!) And a precursor such as
  • [(diene) 2 Rh] X where the diene can be 2,5-norbornadiene, 1,5-cyclooctadiene and X can be BF 4 , OTf and also a process for preparing ruthenium catalysts by adding a optically active P-chiral compound of general formula (I) with a precursor such as [(diene) RuX 2 ] x or [(diene) (1,3,5-cyclooctatriene) RuH] X where the diene may be 1.5 -cyclo-octadiene, 2,5-norbornadiene and X can be Cl, Br, I, BF 4 , OTf, PF 6 and x an integer equal to 1 or 2. These latter precursors were prepared from [(diene) ruthenium (2-methyl-allyl)] and the corresponding acid in the presence or absence of a diene.
  • a precursor such as [(diene) RuX 2 ] x or [(diene) (1
  • Another object of the present invention is the use of said complexes to perform asymmetric syntheses in organic chemistry.
  • These asymmetric transformations can be carried out under well known conditions, or which can be determined by those skilled in the art according to well described 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 is generally carried out in an organic solvent at a temperature of between -10 ° C. and 100 ° C., in the presence of either hydrogen at 1 to 150 bar, a hydrogen donor, or another reducing agent such as borane. , a silane, or in the presence of a combination selected from all the above.
  • prochiral olefins such as optionally substituted alkylidene glycine derivatives
  • the asymmetric reduction has been carried out, by way of illustration and without limitation, on model prochiral substrates.
  • the present invention is described in more detail, by way of illustration and without limitation, by the
  • the compound 2 is obtained with a yield of 75-90%.
  • Example 1. 2a is prepared according to 1 (A) or (B). 1 H NMR ⁇ 0.35-1.80 (m, 3H), 1.25 (d, 3H), 1.94
  • Example 2 The enantiomer of 2a is prepared from the enantiomer of 1.
  • Example 3ab is prepared according to 1 (B). 1 H NMR ⁇ 0.30-1.80 (1 m, 3H), 0.90 and 0.93 (2d, 6H),
  • Example 4. 2b is prepared according to 1 (A) or (B). 1 H NMR ⁇ 0.66-2.00 (1 m, 3H) 5 1.27 (d, 3H) 5
  • Example 5 2bba is prepared according to 1 (B). 1 H NMR ⁇ 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 5.00 (d, IH) 5 6.54 (m, IH), 7.10-7.57 (m, 13H) 5 7.77-7.91 (m, 2H); 31 P ⁇ +77.90 NMR (1 s).
  • Example 6. 2c is prepared according to 1 (A) or (B). 1 H NMR ⁇ 1.29 (d, 3H) 5 0.90-1.93 (1 m, 3H) 5
  • Example 7. 2d is prepared according to 1 (A) or (B). 1 H NMR ⁇ 0.50-1.70 (1 m, 3H), 1.23 (d, 3H), 2.62 (d, 3H) 5 4.25 (m 5 H), 4.55 and 4.64 (2d, 2H), 4.89 (d, IH) 7.13-7.63 (m, 14H); NMR 31 P ⁇ + 68.90 (m).
  • Example 8. 2da is prepared according to 1 (B). 1 H NMR ⁇ 0.50-1.80 (1 m, 3H), 1.25 (d, 3H), 2.64 (d,
  • Example 10 2ec is prepared according to 1 (B). 1 H NMR ⁇ 0.60-1.70 (1 m, 3H), 0.83 (s, 9H) 5 1.18 (d,
  • Example 11 2ed is prepared according to 1 (B). 1 H NMR ⁇ 0.70-1.73 (1 m, 3H), 1.26 (d, 3H) 5 1.40 (s,
  • Example 12. 2e is prepared according to 1 (A) or (B). 1 H NMR ⁇ 0.62-1.67 (1 m, 3H), 1.26 (d, 3H),
  • Example 15.2e is prepared according to 1 (B). 1 H NMR ⁇ 0.20-1.32 (1 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).
  • Example 16. 2f is prepared according to 1 (B). 1 H NMR ⁇ 0.81-1.80 (1 m, 3H), 1.22 (d, 3H), 2.19 (s, 6H), 2.74 (d, 3H), 3.39 and 3.89 (2d, 2H) 3. 4.21 (m, 1H) 4.74 (d, 1H), 7.28 (m, 6H), 7.45 (m, 5H), 7.59 (m, 2H), 7.76 (m, 1H); NMR 31 P ⁇ + 70.41 (m).
  • Example 17 2fm is prepared according to 1 (B).
  • Example 18 Example 18
  • 2g is prepared according to 1 (B) - 1 H NMR ⁇ 0.33-1.38 (1 m, 3H), 0.71 (d, 3H) 3 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); NMR 31 P ⁇ + 55.14 (m).
  • Example 19 is prepared according to 1 (B).
  • Example 20. 2hn is prepared according to 1 (B). 1 H NMR ⁇ 1.17 (d, 3H), 1.24 and 1.44 (2s 3 6H), 0.40- 1.70 (1 s, 3H), 2.92 (d, 3H) 3 3.74 and 4.10 (2d, 2H), 3.84 (m, 1H), 4.42 (d, 1H), 7.01 (m, 2H), 7.19 (m, 3H) 3 7.40-7.58 (m, 8H) 3 7.74 (m, 1H); NMR 31 P ⁇ + 71.37 (m).
  • Example 21. 2i is prepared from 1 using 1.2 eq. TMSCH 2 Li or by MeLi action (2.2 eq.) followed by an excess of TMSCI.
  • Example 22. 2j is prepared from 1 using 2.2 eq. TMSCH 2 Li followed by an excess of parafbraldehyde or from 2i by the action of sec-BuLi (2.2 eq.) followed by an excess of paraformaldehyde.
  • Example 23.2k is prepared from 1 by the action of MeLi (2.2 eq.) followeded by an excess of paraformaldehyde.
  • Example 24. 2m is prepared from the anion of (S) -PAMP-BH 3 and 1. 1 H NMR ⁇ 0.05-
  • Y OMe: A raminophosphine-borane 2 in MeOH (or MeOHZCH 2 Cl 2 ) at room temperature, is added with stirring (A) BF 3 etherate or BF 3 in MeOH ( ⁇ 1 eq.) Or (B ) anhydrous FH 2 SO 4 ( ⁇ 1 eq.). Following the disappearance of 95-98% of the starting material (followed by TLC), the mixture is filtered on a bed of silica gel and then concentrated. The residue is extracted with a water / CH 2 Cl 2 mixture, and the organic phase is dried SUrNa 2 SO 4 and then concentrated. The residue is purified on silica gel and / or crystallized to provide compound 3 in 85-95% yield. HPLC analysis of 3a and 3b showed> 99% ee.
  • Y Cl: A raminophosphine-borane 2 diluted in an aprotic solvent (such as toluene, CH 2 Cl 2 , THF) at 0 ° C, a solution of HCl in an aprotic solvent is added with stirring. After 1 hour, the ephedrine hydrochloride was removed by filtration on a fine porosity frit, and the filtrate concentrated to yield the borophosphine borane as a thick oil in 90-95% yield.
  • an aprotic solvent such as toluene, CH 2 Cl 2 , THF
  • Example 26 The enantiomer of 3a is prepared from the enantiomer of 2a.
  • Example 27.3b is prepared according to 2 (A) or (B). 1 H NMR ⁇ 0.66-1.87 (I m, 3H), 3.79 (d, 3H), 7.25-7.80 (m, 10H), 8.39 (d, 1H), 8.60 (s, 1H), 31 P ⁇ +105.99 NMR. (m).
  • Example 28. 3c is prepared according to 2 (B). 1 H NMR ⁇ 0.45-1.85 (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).
  • Example 29. 3d is prepared according to 2 (B). 1 H NMR ⁇ 0.45-1.80 (m, 3H), 5.55 (m, 2H) 5 7.38-
  • Example 30. 3e is prepared according to 2 (B). 1 H NMR ⁇ 0.42-1.77 (1 m, 3H), 1.37 (s, 9H), 3.81 (d5 3H), 7.19 (m, IH), 7.40-7.66 (m, 7H), 7.80 (ddd, IH) 7.93 (dd, 1H); 31 P ⁇ +110.33 NMR (m).
  • Example 31. 3'a is prepared in CH 2 Cl 2 according to protocol 2 with 1 ⁇ C1 in toluene.
  • Example 32 .ab is prepared in toluene according to protocol 2 with HCl in toluene.
  • General Protocol 3 Synthesis of phosphine-boranes 4
  • Example 33. 4a is prepared according to 3 (A) or (B) from 3a or from 3'a.
  • Example 34 The enantiomer of 4a is prepared from the enantiomer of 3a.
  • Example 35. 4b is prepared according to 3 (A) or (B). 1 H NMR ⁇ 0.71-1.95 (1 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); 31 P ⁇ +2.66 NMR (m).
  • Example 36 The enantiomer of 4b is prepared from the enantiomer of 3b.
  • Example 37. 4c is prepared according to 3 (A) or (B).
  • Example 38. 4d is prepared according to 3 (A) or (B).
  • Example 39. 4e is prepared according to 3 (B). 1 H NMR ⁇ 0.45-1.68 (m, 3H) 5 1.89 (d5 3H), 2.19 (t, IH) 5 4.40 (dd 5 IH) 5 4.71 (dd, IH) 5 7.39-7.67 (m, 9H); NMR 31 P ⁇ + 10.70 (m).
  • Example 40. 4f is prepared according to 3 (A). 1 H NMR ⁇ 0.67-2.05 (m, 6H) 5 4.13, 4.54, 4.57 and 4.67 (4m, 8H) 5 6.81-7.01 (m, 6H), 7.31-7.48 (m, 12H) 5 7.59 (1 s, 2H ); 31 P ⁇ +8.82 NMR (1 s).
  • General Protocol 4 Functionalization in alpha of alkylphosphine-boranes; Synthesis of phosphine boranes 5-13
  • the reaction mixture is left for 1 hour at this temperature, then: anhydrous CuCl 2 (1.05 eq) or (RTT) SiCl 2 (0.5 eq) is added at -30 to -40 ° C; or an electrophile (0.5-1.2 eq.) at -20 to 0 ° C.
  • the reaction mixture is cooled to room temperature. Water (or acidulated water until neutral pH is reached) is added, then the mixture is concentrated and the residue is extracted with CH 2 Cl 2 , dried over Na 2 SO 4 and then concentrated.
  • the residue is filtered on a bed of silica gel eluting with AcOEt.
  • the pure product 5-13 is obtained with a yield of 65-90% after purification on a silica gel and / or crystallization.
  • Example 41. 5a is prepared according to 4 (A) or (B) from 4a.
  • Example 42. 5b is prepared according to 4 (A) or (B) from 4b.
  • Example 44. 6a is prepared according to 4 (A) or (B) from 4a.
  • Example 46. 8a is prepared according to 4 (A) or (B) from 4a and paraformaldehyde. 1 H NMR ⁇ 0.40-1.72 (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); 31 P ⁇ +8.13 NMR (m).
  • Example 47. 9a is prepared according to 4 (A) or (B) from 4a and Ph 2 PCl. In this case, after 12 hours at room temperature, BH 3 -Me 2 S (1 eq) is added at 0 ° C to the reaction mixture. After 1 hour, water is added and the mixture is concentrated.
  • Example 48. 9ab is prepared according to 4 (C) from 4ab, Ph 2 PCl and BH 3 -Me 2 S as described for 9a. The pure product is obtained with a yield of 75% after purification on a silica gel eluting with toluene.
  • Example 49. 10ab is prepared according to 4 (C) from 4ab and 3ab. 31 P ⁇ +13.61 NMR (m).
  • Example 50. llaf is prepared according to 4 (A) or (B) from 4a and 3 equivalents of TMSCl.
  • 11a is prepared from llaf by heating at 50 ° C for 1 hour a solution of 11a in MeOH in the presence of silica gel.
  • Example 52. 12a is prepared according to 4 (A) or (B) from 4e.
  • Example 53. 13a is prepared according to 4 (A) from 3d.
  • Example 55 Similarly as before, (R) -o- (methylphenylphosphino) phenol (4'a) (108 mg, 0.5 mmol) yields (R) -o- (methylphenylphosphino-borane) phenol (4a) (109 mg) ) with 95% yield under the action of BH 3 -THF (1.1 eq.).
  • the 1 H and 31 P NMR spectra are identical to those of the product prepared according to Protocol 3.
  • Example 56.2aa is prepared according to 6 (B) from 2a and iodomethane. NMR spectra
  • Example 57. 2ab is prepared according to 6 (B) from 2a and isopropyl iodide.
  • the 1 H and 31 P NMR spectra are identical to those of the product prepared from 1 and
  • Example 58.3aa is prepared according to 6 (B) from 3a and iodomethane. NMR spectra
  • Example 59 The enantiomer of 3aa is prepared from the enantiomer of 3a.
  • Example 60.3ab is prepared according to 6 (B) from 3a and isopropyl iodide.
  • Example 61.3an is prepared according to 6 (A) from 3a and Moscher acid (R) -chloride.
  • Example 62.3bd is prepared according to 6 (A) from 3b and triflic anhydride (Tf 2 O) in ether.
  • Example 63.4aa is prepared according to 6 (A) or (B) from 4a and iodomethane. The 1 H and 31 P NMR spectra are in accordance with those of the literature.
  • Example 65.4ad is prepared according to 6 (A) from 4a and triflic anhydride (Tf 2 O).
  • Example 66.4al is prepared according to 6 (A) from 4a and COF 6 in DMF. 1 H NMR ⁇
  • Example 67. 4an is prepared according to 6 (A) from 4a and Mosher acid (R) -chloride. 1 H NMR ⁇ 0.25-1.50 (1 m, 3H), 1.71 (d, 3H), 3.37 (q, 3H), 7.23-7.45 (m, 12H), 7.61 (m, 1H), 7.99 (ddd, 1H). ; NMR 19 ⁇ -70.91 (s); NMR 31 P ⁇ + 12.91 (m).
  • Example 68. 4at is prepared according to 6 (B) from 4a and 2,4,6-tris (bromomethyl) mesitylene.
  • Example 69. 4av is prepared according to 6 (B) from ethyl 4a and bromo (dimethylacetate).
  • Example 70.4ea is prepared according to 6 (A) from 4e and iodomethane.
  • Example 71.4e is prepared according to 6 (A) from 4e and mesyl chloride. 1 H NMR ⁇ 0.15-1.65 (m, 3H), 1.92 (d, 3H), 2.75 (s, 3H), 5.13 and 5.35 (2d, 2H), 7.42-7.75 (m, 9H).
  • Example 72.5aa is prepared according to 6 (B) from 5a and iodomethane. NMR spectra
  • Example 73.5a is prepared according to 6 (B) from 5a and 9- (chloromethyl) anthracene.
  • Example 74.5ak is prepared according to 6 (A) from 5a and (PhO) 2 P (O) Cl.
  • Example 75 5abe is prepared according to 6 (B) from 5a and 3-bromocyclohexene.
  • Phosphine-borane 4-12 leads to the corresponding phosphine 4'-12 '(followed by TLC) after 2-12 hours of reflux in Et 2 NH under an inert atmosphere. After concentration and purification under an inert atmosphere of the residue on a silica gel and / or crystallization, the phosphine is obtained in a yield of 85-95% (Table 3).
  • Example 76. 4'ac is prepared according to protocol 7 from 4ac. 1 H NMR ⁇ 1.27 (s, 9H),
  • Example 77 4'ak is prepared according to the procedure 7 from 4ak 1 H NMR ⁇ 1.54 (d, 3H),
  • Example 78. 4'ao is prepared according to protocol 7 from 4ao.
  • Example 79. 4'ap is prepared according to protocol 7 from 4ap. 1 H NMR ⁇ 1.58 (d, 6H),
  • Example 80 4'aq is prepared according to protocol 7 from 4aq. 1 H NMR ⁇ 1.59 (d, 6H),
  • Example 81. 4 f dc is prepared according to the procedure 7 from 4dc. 1 H NMR ⁇ 1.07 and 1.10 (2d, 6H), 1.13 (s, 9H), 4.48 (sep, 1H), 6.70-6.86 (m, 4H), 7.04-7.14 (m, 2H), 7.24-7.38 (m). 7H);
  • Example 82.4'dy is prepared according to protocol 7 from 4dy. 1 H NMR ⁇ 0.93 and 1.11 (2d,
  • Example 83. 4'fb is prepared according to protocol 7 from 4fb. 1 H NMR ⁇ 0.71 and 1.19 (2d,
  • Example 84.4 f fbd is prepared according to the procedure 7 from 4fbd. 1 H NMR ⁇ 0.36 and 0.90
  • Example 85 DiPMP (5'a) is prepared according to protocol 7 from 5a. In this case, an addition compound with a molecule of Et 2 NH precipitates.
  • 1 H NMR (DMSOd 6) S 1.00 (t, 6H) 5 1.83 and 2.18 (2m, 4H) 5 2.53 (q 5 4H) 5 6.79 (m, 6H) 5 7.14 (m, 2H) 5 7.21-7.39 (m , 1OH); 31 P NMR (DMSO-d ⁇ ) ⁇ -21.17 (s).
  • the free diphosphine is obtained quantitatively after catch of Et 2 NH with a weakly acid such Amberlite ® IRC-50 resin H 5 in MeOH.
  • SMS-PiP (5'ab) is prepared according to protocol 7 from 5ab.
  • SMS-Piv (5'ac) is prepared according to protocol 7 from 5ac. 1 H NMR ⁇ 1.25
  • Example 88. 5'af is prepared according to protocol 7 from 5af.
  • Example 89. 5'ag is prepared according to protocol 7 from 5ag. 1 H NMR ⁇ 0.28 (s, 18H),
  • Example 90. 5'ah is prepared according to protocol 7 from 5ah. 1 H NMR ⁇ 1.83 and 2.08
  • Example 91. 5'aj is prepared according to protocol 7 from 5aj. 1 H NMR ⁇ 1.42 (s, 18H),
  • Example-92.5 f ap is prepared according to protocol 7 from 5ap.
  • Example 93. 5'bb is prepared according to protocol 7 from 5bb.
  • Example 94. 5'bc is prepared according to protocol 7 from 5bc. 1 H NMR ⁇ 1.48 (1 s, 18H),
  • Example 95 5'az is prepared according to protocol 7 from 5az. 1 H NMR ⁇ 2.06 and 2.34 (2m, 5 4H), 6.75 (m, 4H), 6.94-7.42 (m, 24H); 31 P ⁇ -22.53 (s) NMR.
  • Example 96. 5'abc is prepared according to protocol 7 from 5abc. 1 H NMR ⁇ 0.85 and 0.87
  • Example 97. 5'abf is prepared according to protocol 7 from 5abf. 1 H NMR ⁇ 1.08-2.46 (m, 0 * 24H), 4.20 (m, 2H), 6.73-6.83 (m, 4H), 7.02 (m, 2H), 7.17-7.40 (m, 12H); NMR 31 P ⁇ -19.28
  • Example 98. 5'abb is prepared according to protocol 7 from 5abb. 1 H NMR ⁇ 1.16-1.34 (m, 24H), 1.89 and 2.31 (2m, 4H), 4.49 and 4.76 (2SEP, 4H), 6.49 (m, 2H), 6.79-6.89 (m, 4H), 7.22-7.38 (m, 10H); 31 P NMR ⁇ -21.43 (s).
  • Example 99. Abbb is prepared according to protocol 7 from 5abbb. 1 H NMR ⁇ 1.10 (d,
  • Example 100. 5'e is prepared according to protocol 7 from 5ae. 1 H NMR ⁇ 1.88 (m, 4H), 2.38 (s, 6H), 6.98 (m, 2H), 7.06-7.35 (m, 20H), 7.76 (m, 4H); 31 P NMR ⁇ -24.72 (s).
  • Example 101. 5'acb is prepared according to protocol 7 from 5acb. 1 H NMR ⁇ 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); NMR 31 P ⁇ -
  • Example 102. 5'akb is prepared according to protocol 7 from 5akb. 1H NMR 1.86-2.22
  • Example 103. 5'abd is prepared according to protocol 7 from 5abd. 1 H NMR ⁇ 0.67 and
  • Example 104 5'abh is prepared according to protocol 7 from 5abh. 1 H NMR ⁇ 1.36 (s,
  • Example 105. 5'ay is prepared according to protocol 7 from 5ay. 1 H NMR ⁇ 1.33 (s, 18H), 2.02 and 2.19 (2m, 4H), 4.27 and 4.35 (2d, 4H), 6.70 (1 s, 2H), 6.80 (m, 2H), 6.98 (m, 2H). 7.09 (m, 2H), 7.31 (m, 12H); 31 P NMR ⁇ -24.44 (s).
  • Example 106.ab is prepared according to protocol 7 from 7ab.
  • Example 107. 12'aa is prepared according to protocol 7 from 12aa. 1 H NMR ⁇ 2.09 (m, 4H), 3.29 (s, 6H), 4.53 and 4.75 (2d, 4H), 7.16-7.47 (m, 18H); 31 P NMR ⁇ -24.77 (s). Examples of modifications of the phosphorus atom P * (see also the products prepared according to protocol 5) Example 108. Preparation of the salt DiPAMP-2HBF 4 ( 5f aa-2HBF 4 )
  • DiPAMP indicator [(cod) Ru (OTf) 2 ] 2 A 20 20 16 95 28.3

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EP06778624A 2005-06-20 2006-06-20 Neue p-chirale funktionalisierte arylphosphine und derivate, ihre herstellung und ihre verwendung zur asymmetrischen katalyse Withdrawn EP1899358A2 (de)

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FR0506226A FR2887253A1 (fr) 2005-06-20 2005-06-20 Nouvelles arylphosphines p chirales ortho-fonctionnalisees et derives: leur preparation et utilisation en catalyse asymetrique
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WO2017009205A1 (de) 2015-07-10 2017-01-19 Basf Se Verfahren zur hydroformylierung von 2-substituierten butadienen und zur herstellung von folgeprodukten davon, speziell von ambrox
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