FENG XIANGDONG (CN)
LANDERT HEIDI (CH)
PUGIN BENOIT (CH)
FENG XIANGDONG (CN)
LANDERT HEIDI (CH)
| WO2006003195A1 | 2006-01-12 |
Claims
1. Process for preparing compounds of the formulae I and II, or a mixture of these enantiomers,
R'i is Ci-C 4 -alkyl and n is 0, 1 or 2;
Ri is d-Cs-alkyl, C 2 -C 8 -alken-1 -yl, -CH 2 -OR or -CH 2 -NR 5 R 6 ; the two radicals R 2 are identical or different and are each hydrogen or a monovalent radical of an electrophilic organic compound; sec-phos is a secondary phosphino group;
R is d-Cs-alkyl and
R 5 and Re are each d-Cβ-alkyl or R 5 and Re together form tetramethylene, pentamethylene or 3-oxa-1 ,5-pentylene; which comprises the steps: a) reaction of a compound of the formula III or IV
R'i and Ri are as defined above, with at least equivalent amounts of an aliphatic Li sec-amide or a halogen-Mg sec-amide to form a compound of the formula V or Vl,
C) reaction of a compound of the formula VII or VIII with one or two equivalents of alkyllithium or alkyl-MgXi to form compounds of the formulae IX, X, Xl and XII,
d) (d1 ) reaction of a compound of the formula IX, X, Xl or XII with at least equivalent amounts of water or an electrophilic organic compound to introduce the two monovalent radicals R2 and form the compounds of the formulae I and II, or
(d2) reaction of a compound of the formula IX or X with at least equivalent amounts of water or an electrophilic organic compound to introduce a monovalent radical R2, renewed reaction of the compound obtained with one equivalent of alkyllithium or alkyl-MgXi and subsequent reaction of the metallated compound with water or an electrophilic organic compound to introduce a monovalent radical R2 which is different from the monovalent radical R2 introduced first.
2. Process according to Claim 1 , characterized in that, in the formulae I and II, n is 0 and Ri is Ci-C 4 -alkyl or C 2 -C 4 -alk-1 ,2-en-1 -yl and preferably ethyl or vinyl.
3. Process according to Claim 1 , characterized in that the secondary phosphino group corresponds to the formula -PRsR 4 where R3 and R 4 are each, independently of one another, a hydrocarbon radical which has from 1 to 18 carbon atoms and is unsubstituted or substituted by Ci-C 6 -alkyl, trifluoromethyl, Ci-C 6 -alkoxy, trifluoro- methoxy, (Ci-C 4 -alkyl) 2 amino, (CeHs) 3 Si, (Ci-Ci2-alkyl) 3 Si and/or contains hetero- atoms O.
4. Process according to Claim 1 , characterized in that a radical R2 of an electrophilic organic compound is derived from reactive reagents which are attached with replacement of a metal bound to the cyclopentadienyl ring and are, if appropriate, dehvatized after attachment.
5. Process according to Claim 1 , characterized in that the radicals R2 are selected from the group consisting Of -CO 2 H, -C(O)-OR x , -C(O)-R x , -CH=O, -CH(OH)-R x , -C(OH)R x R 3 , -CH 2 OH, -CH 2 NH 2 , Ci-Ci 8 -alkyl, (Ci-C 8 -alkyl) 3 Si-, and R x S-, where R x is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl having from
1 to 12 and preferably from 1 to 8 carbon atoms and R a independently has one of the meanings of R x or R x and R a together form a cycloaliphatic ring having from 3 to 8 ring atoms.
6. Compounds of the formulae XIII and XIV
R'i is Ci-C 4 -alkyl and n is 0, 1 or 2;
Ri is d-Cs-alkyl, C 2 -C 8 -alken-1 -yl, -CH 2 -OR or -CH 2 -NR 5 R 6 ;
R 8 is hydrogen or a secondary phosphino group sec-phos; and a Br atom in one Cp ring can be replaced by a radical R 2 and R 2 is as defined in
Claim 1.
7. Enantiomeric compounds of the formulae XV and XVI or a mixture of these enantiomers,
R'i is Ci-C 4 -alkyl and n is 0, 1 or 2;
Ri is d-Cs-alkyl, C 2 -C 8 -alken-1 -yl, -CH 2 -OR or -CH 2 -NR 5 R 6 ; sec-phos is a secondary phosphino group;
R is d-Cs-alkyl;
R 5 and R 6 are each Ci-C 6 -alkyl or R 5 and R 6 together form tetramethylene, penta- methylene or 3-oxa-1 ,5-pentylene;
Rg and Rio are each hydrogen;
Rg is hydrogen and Rio is a monovalent radical of an electrophilic organic compound; Rg and R10 are each a monovalent radical of an electrophilic organic compound and are different from one another; or R 9 and R10 are identical and are each Ci-Cis-alkyl, C 3 -C 8 -CyClOaI kyl, C 3 -C 8 -cycloalkyl-Ci-C 4 -alkyl, C 6 -Ci 4 -aryl, C 7 -Ci 8 -aralkyl, -Si(CrCi 8 - alkyl) 3 , triphenylsilyl, -C(O)-Rn, -SH, -SRi 2 , -C(OH)Ri 3 Ri 4 , -B(OH) 2 , -S(O) 2 (OH) or -P(O)(OH) 2 , or salts, esters and amides of the acid groups -CO 2 H, -S(O) 2 (OH) or -P(O)(OH) 2 ; and
Rii, Ri2, Ri3, and Ri 4 are each Ci-Ci 2 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-Ci-C 4 - alkyl, C 6 -Ci 4 -aryl, C 7 -Ci 6 -aralkyl.
8. Complexes of metals selected from the group of transition metals, preferably TM- VIII metals, with one of the compounds of the formulae XIII, XIV, XV and XVI as ligand.
9. Process for preparing chiral organic compounds by asymmetric addition of hydrogen onto a carbon-carbon or carbon-heteroatom double bond in prochiral organic compounds in the presence of a catalyst, which is characterized in that the addition reaction is carried out in the presence of catalytic amounts of at least one metal complex according to Claim 8.
10. Use of metal complexes according to Claim 8 as homogeneous catalysts for the preparation of chiral organic compounds, preferably for the asymmetric addition of hydrogen onto a carbon-carbon or carbon-heteroatom double bond in prochiral organic compounds. |
Diphosphines and metal complexes
The present invention relates to ferrocenes which are substituted in the 1 ,1 ',2,2' positions of the cyclopentadienyl rings (Cp rings) and bear secondary phosphino groups in the 3,3' positions of the Cp rings, a process for preparing them, complexes of transition metals (for example TM-VIII metals) with these ferrocenes as ligands and the use of the metal complexes in the homogeneous, stereoselective synthesis of organic compounds.
Chiral ligands have proven to be extraordinarily important auxiliaries for catalysts in homogeneous stereoselective catalysis. The effectiveness of such catalysts is frequently found to be specific for particular substrates. To be able to achieve optimization for particular substrates, it is therefore necessary to have a sufficiently large number of chiral ligands available. There is therefore a continuing need for further efficient chiral ligands which are simple to prepare and give good results in stereoselective catalytic reactions. Ligands whose properties can be matched to and optimized for particular catalytic problems are of particular interest. Ligands which can be built up in a modular fashion are particularly suitable for this purpose. Modular construction of diphosphine ligands has hitherto been directed first and foremost at the ability to vary the phosphino radicals in a simple manner and if possible in the last stage. There are only very few known examples of ligands whose modularity is not based on variation of the phosphino radicals but on the variation of radicals by means of which the ligand framework and thus the coordination sphere of these ligands can be configured and influenced geometrically and electronically.
WO 2006/003196 A1 describes ferrocenediphosphines of the Mandyphos (trivial name) type which correspond to the known variation of phosphino radicals:
where R is, for example, methyl or phenyl, in which the phosphino radicals can be introduced and modified in the last stage by means of a previously introduced further substituent R' in the α position relative to the sec-phosphino group. The substitution pattern Me2NCH(R)-/sec-phosphino/R' in the Cp rings is also prescribed here.
There has hitherto not been any method by means of which a modular construction can be achieved in the ferrocene framework in the synthesis either in respect of secondary phosphino groups or a further substituent. It has now surprisingly been found that these opportunities are opened up by ferrocenediphosphines which have the substitution pattern sec-phosphino/substituent/substituent in the Cp rings. The ferrocenediphosphines, some of which are novel, can be obtained by lithiation of 1 ,1 '- substituent-2,2'-bromoferrocenes in the α position relative to the bromine atoms, stereoselective introduction of the secondary phosphino groups, subsequent lithiation of the bromine atoms and reaction with electrophilic organic compounds, which surprisingly leads to introduction of second substituents which are themselves bulky between existing (steric hindrance) substituents in the 1 and 3 positions.
The invention firstly provides a process for preparing compounds of the formulae I and II, or a mixture of these enantiomers,
R'i is Ci-C 4 -alkyl and n is 0, 1 or 2;
Ri is d-Cs-alkyl, C 2 -C 8 -alken-1 -yl, -CH 2 -OR or -CH 2 -NR 5 R 6 ; the two radicals R 2 are identical or different and are each hydrogen or a monovalent radical of an electrophilic organic compound; sec-phos is a secondary phosphino group;
R is d-Cs-alkyl and
R 5 and Re are each d-Cβ-alkyl or R 5 and Re together form tetramethylene, pentamethylene or 3-oxa-1 ,5-pentylene; which comprises the steps: a) reaction of a compound of the formula III or IV
R'i and Ri are as defined above, with at least equivalent amounts of an aliphatic Li sec-amide or a halogen-Mg sec-amide to form a compound of the formula V or Vl,
- A -
C) reaction of a compound of the formula VII or VIII with one or two equivalents of alkyllithium or alkyl-MgXi to form compounds of the formulae IX, X, Xl and XII,
An alkyl radical R'i can be, for example, methyl, ethyl, n- or i-propyl, n- or i-butyl, with
preference being given to methyl, n is preferably 0 (and R'i is thus a hydrogen atom).
An alkyl radical Ri can be, for example, Ci-C 4 -alkyl and in particular methyl, ethyl, n- or i-propyl, n- or i-butyl, pentyl, hexyl, heptyl or octyl, with preference being given to methyl and in particular ethyl. An alken-1 -yl radical Ri can be, for example, C 2 -Cs-alk- 1 ,2-en-1 -yl and preferably C 2 -C 4 -alk-1 ,2-en-1-yl, for example vinyl, 1-propenyl, but- 1 ,2-en-1 -yl, pentenyl or hexenyl, with particular preference being given to vinyl. R in the group -CH 2 -OR is preferably Ci-C 4 -alkyl, for example methyl, ethyl, propyl or butyl, with preference being given to methyl. R 5 and Re are preferably Ci-C 4 -alkyl such as methyl, ethyl, propyl and butyl, with particular preference being given to methyl.
In a preferred embodiment, Ri is methyl, ethyl or vinyl.
In a preferred embodiment, n in the formulae I and Il is 0 and Ri in the formulae I and Il is Ci-C 4 -alkyl or C 2 -C 4 -alk-1 ,2-en-1-yl and preferably ethyl or vinyl.
The secondary phosphino group sec-phos can contain two identical or two different hydrocarbon radicals. The secondary phosphino group preferably contains two identical hydrocarbon radicals.
The hydrocarbon radicals can be unsubstituted or substituted and/or contain hetero- atoms selected from the group consisting of O, S, -N= or N(Ci-C 4 -alkyl). They can contain from 1 to 22, preferably from 1 to 12 and particularly preferably from 1 to 10, carbon atoms. A preferred sec-phosphino group is one in which the phosphino group contains two identical or different radicals selected from the group consisting of linear or branched Ci-Ci2-alkyl; unsubstituted or Ci-Cβ-alkyl- or d-Cβ-alkoxy-substituted C 5 -Ci2-cycloalkyl or C 5 -Ci2-cycloalkyl-CH 2 -; phenyl, naphthyl, furyl or benzyl; and d-Cβ-alkyl-, trifluoromethyl-, d-Cβ-alkoxy-, thfluoromethoxy-, (CeHs) 3 Si-, (C1-C12- alkyl) 3 Si- or sec-amino-substituted phenyl or benzyl.
Examples of alkyl substituents on P, which preferably contain from 1 to 6 carbon
atoms, are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl and the isomers of pentyl and hexyl. Examples of unsubstituted or alkyl-substituted cycloalkyl sub- stituents on P are cyclopentyl, cyclohexyl, methylcyclohexyl and ethylcyclohexyl and dimethylcyclohexyl. Examples of alkyl- and alkoxy-substituted phenyl and benzyl substituents on P are methylphenyl, dimethylphenyl, trimethylphenyl, ethylphenyl, methylbenzyl, methoxyphenyl, dimethoxyphenyl, trimethoxyphenyl, trifluoromethyl- phenyl, bistrifluoromethylphenyl, tristrifluoromethylphenyl, trifluoromethoxyphenyl, bistrifluoromethoxyphenyl and 3,5-dimethyl-4-methoxyphenyl.
Preferred secondary phosphino groups are ones in which the identical radicals are selected from the group consisting of d-Cβ-alkyl, cyclopentyl or cyclohexyl which may be unsubstituted or substituted by from 1 to 3 Ci-C 4 -alkyl or Ci-C 4 -alkoxy groups, benzyl and in particular phenyl which are unsubstituted or substituted by from 1 to 3 CrC 4 -alkyl, Ci-C 4 -alkoxy, Ci-C 4 -fluoroalkyl or Ci-C 4 -fluoroalkoxy groups.
The secondary phosphino group preferably corresponds to the formula -PR3R4, where R 3 and R 4 are each, independently of one another, a hydrocarbon radical which has from 1 to 18 carbon atoms and is unsubstituted or substituted by CrCβ- alkyl, trifluoromethyl, d-Cβ-alkoxy, trifluoromethoxy, (Ci-C 4 -alkyl) 2 amino, (CeHs) 3 Si, (Ci-Ci2-alkyl) 3 Si and/or contains heteroatoms O.
R 3 and R 4 are preferably identical radicals selected from the group consisting of linear or branched Ci-Cβ-alkyl, cyclopentyl or cyclohexyl which may be unsubstituted or substituted by from one to three Ci-C 4 -alkyl or Ci-C 4 -alkoxy groups, furyl, benzyl which may be unsubstituted or substituted by from one to three Ci-C 4 -alkyl or CrC 4 - alkoxy groups and in particular phenyl which may be unsubstituted or substituted by from one to three CrC 4 -alkyl, Ci-C 4 -alkoxy, Ci-C 4 -fluoroalkyl or Ci-C 4 -fluoroalkoxy groups .
R3 and R 4 are particularly preferably identical radicals selected from the group consisting of Ci-Cβ-alkyl, cyclopentyl, cyclohexyl, furyl and phenyl which may be unsubstituted or substituted by from one to three Ci-C 4 -alkyl, Ci-C 4 -alkoxy and/or
Ci-C 4 -fluoroalkyl groups.
The secondary phosphino group can be cyclic sec-phosphino, for example a group of one of the formulae
which are unsubstituted or substituted by one or more Ci-Cs-alkyl, C 4 -C 8 -cycloalkyl, d-Cβ-alkoxy, Ci-C 4 -alkoxy-Ci-C 4 -alkyl, phenyl, Ci-C 4 -alkyl or CrC 4 -alkoxyphenyl, benzyl, Ci-C 4 -alkylbenzyl or CrC 4 -alkoxybenzyl, benzyloxy, Ci-C 4 -alkylbenzyloxy or Ci-C 4 -alkoxybenzyloxy or Ci-C 4 -alkylidenedioxyl groups.
The substituents can be present in one or both α positions relative to the P atom in order to introduce chiral carbon atoms. The substituents in one or both α positions are preferably Ci-C 4 -alkyl or benzyl, for example methyl, ethyl, n- or i-propyl, benzyl or -CH 2 -O-Ci-C 4 -alkyl or -CH 2 -O-C 6 -Ci 0 -aryl.
Substituents in the β,γ positions can be, for example, CrC 4 -alkyl, Ci-C 4 -alkoxy, benzyloxy or -0-CH 2 -O-, -O-CH(Ci-C 4 -alkyl)-O- and -O-C(Ci-C 4 -alkyl) 2 -O-. Some examples are methyl, ethyl, methoxy, ethoxy, -O-CH(methyl)-O- and -O-C(methyl) 2 - O-.
Depending on the type of substitution and number of substituents, the cyclic phosphino radicals can be C-chiral, P-chiral or C- and P-chiral.
An aliphatic 5- or 6-membered ring or benzene can be fused onto two adjacent carbon atoms in the radicals of the above formulae.
The cyclic secondary phosphino group can, for example, correspond to one of the
formulae (only one of the possible diastereomers shown),
where the radicals R' and R" are each Ci-C 4 -alkyl, for example methyl, ethyl, n- or i-propyl, benzyl or -CH 2 -O-Ci-C 4 -alkyl or -Chb-O-Ce-Cio-aryl, and R' and R" are identical or different.
In the compounds of the formulae I and II, sec-phos is preferably acyclic sec- phosphino selected from the group consisting of -P(Ci-C6-alkyl) 2 , -P(C 5 -Cs-CyCIo- alkyl) 2 , -P(C 7 -C 8 -bicycloalkyl)2, -P(C 5 -C 8 -cycloalkyl)2, -P(o-furyl) 2> -P(C 6 Hs) 2 , -P[2-(Ci- C6-alkyl)C 6 H 4 ] 2j -P[3-(Ci-C 6 -alkyl)C 6 H 4 ] 2j -P[4-(Ci-C 6 -alkyl)C 6 H 4 ] 2j -P[2-(Ci-C 6 - alkoxy)C 6 H 4 ] 2 , -P[3-(Ci-C 6 -alkoxy)C 6 H 4 ] 2 , -P[4-(Ci-C 6 -alkoxy)C 6 H 4 ] 2 , -P[2-(trifluoro- methyl)C 6 H 4 ] 2 , -P[3-(trifluoromethyl)C 6 H 4 ] 2 , -P[4-(Thfluoromethyl)C 6 H 4 ] 2 , -P[3,5- bis(thfluoromethyl)C 6 H 3 ] 2 , -P[3,5-bis(Ci-C6-alkyl) 2 C 6 H3] 2 , -P[3,5-bis-(Ci-C 6 - alkoxy) 2 C 6 H 3 ] 2 and -P[3,5-bis(Ci-C6-alkyl) 2 -4-(Ci-C6-alkoxy)C 6 H 2 ] 2 , or cyclic phosphino selected from the group consisting of
and
which is unsubstituted or substituted by one or more Ci-C 4 -alkyl, CrC 4 -alkoxy, Ci-C 4 -alkoxy-Ci-C 2 -alkyl, phenyl, benzyl, benzyloxy or Ci-C 4 -alkylidenedioxyl groups.
Some specific examples are -P(CH 3 ) 2 , -P(i-C3H 7 ) 2 , -P(n-C 4 H 9 ) 2 , -P(i-C 4 H 9 ) 2 , -P(t-C 4 H 9 )2, -P(C 5 H 9 ), -P(C 6 Hn) 2 , -P(norbornyl) 2 , -P(o-furyl) 2> -P(C 6 H 5 ) 2 , P[2-(methyl)C 6 H 4 ] 2 , P[3-(methyl)C 6 H 4 ] 2 , -P[4-(methyl)C 6 H 4 ] 2 , -P[2-(methoxy)C 6 H 4 ] 2 , -P[3-(methoxy)C 6 H 4 ] 2 , -P[4-(methoxy)C 6 H 4 ] 2 , -P[3-(trifluoromethyl)C 6 H 4 ] 2 , -P[4-(trifluoromethyl)C 6 H 4 ] 2 , -P[3,5-bis(trifluoromethyl)C 6 H3] 2 , -P[3,5- bis(methyl) 2 C 6 H 3 ] 2 , -P[3,5-bis(methoxy) 2 C 6 H 3 ] 2 and -P[3,5-bis(methyl) 2 -4-(me- thoxy)C 6 H 2 ] 2 and groups of the formulae
where
R' is methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, methoxymethyl, ethoxy- methyl or benzyloxymethyl and R" has one of the meanings of R'.
For the purposes of the invention, a radical of an electrophilic compound is any reactive reagent which can replace a metal bound to the cyclopentadienyl ring, if appropriate using catalysts and with monovalent radicals R 2 being able to be formed only in a subsequent step after addition of the reagent (for example hydrolysis). Many such reagents are known in organometallic chemistry and have been described for metallated aromatic hydrocarbons; see, for example, V. Snieckus, Chem. Rev., 90
(1990) 879-933; Manfred Schlosser (Editor), Organometalics in Synthesis, A. Manual, second edition, John Wiley & Sons, LTD, (2002); Organolithiums: Selectivity for Synthesis (Tetrahedron Organic Chemistry Series ) Chapter 6 & 7, Pergamon Press (2002) and Kagan, H. B., et al., J. Org. Chem., 62 (1997), 6733-45, (examples of the introduction of a selection of possible electrophilic compounds on metallated ferrocenes).
Preferably R2 is an electrophilic organic compound derived from reactive reagents which are attached with replacement of a metal bound to the cyclopentadienyl ring and are, if appropriate, dehvatized after attachment.
Examples of reactive electrophilic compounds for forming radicals R2 are: halogens (CI2, Br 2 , I 2 ), interhalogens (Cl-Br, Cl-I) and aliphatic, perhalogenated hydrocarbons (CI3C-CCI3 or BrF 2 C-CF 2 Br, N-fluorobis(phenyl)sulfonylamine) for introducing F, Cl, Br or I; CO 2 for introducing the carboxyl group -CO 2 H; chlorocarbonates or bromocarbonates [CI-C(O)-OR x ] or carbonates [R x O-C(O)-ORχ] for introducing a carboxylate group, where R x is a hydrocarbon radical (alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl) which has from 1 to 18, preferably from 1 to 12 and particularly preferably from 1 to 8, carbon atoms and is unsubstituted or substituted by inert substituents such as di(Ci-C8-alkyl) 2 N-, -C(O)- Od-Cs-alkyl or -Od-Cs-alkyl (inert substituents include reactive groups such as Cl, Br or I when groups which are more reactive toward a metal or a metal group in compounds of the formulae V, Vl and IX to XII, for example-CHO, are simultaneously present or when Cl and Br, Cl and I or Br and I are simultaneously present in a preferably aromatic hydrocarbon radical); di(Ci-C 4 -alkyl)formamides, for example dimethylformamide or diethylformamide, for introducing the -CH(O) group; di(Ci-C 4 -alkyl)carboxamides for introducing a -C(O)-R x group; aldehydes which may be substituted in the group R x for introducing a -CH(OH)-R x group or paraformaldehyde for introducing the -CH 2 OH group; symmetrical or unsymmetrical ketones which may be substituted in the group R x or
Ra for introducing a -C(OH)R x R 3 group, where R a independently has one of the meanings of R x or R x and R a together form a cycloaliphatic ring having from 3 to 8 ring atoms; epoxides for introducing a -C-C-OH group in which the carbon atoms may be substituted by H or R; an Eschenmoser salt of the formula (CH3)2N + =CH 2 -I " for introducing the CH 2 -N(CHs) 2 group; imines R x -CH=N-R 3 for introducing the -CH(R)-NHR 3 group, where R 3 independently has one of the meanings of R x or R x and R 3 together form a cycloaliphatic ring having from 3 to 8 ring atoms; imines R x -C(R b )=N-R 3 for introducing the -C(R x )(R b )-NH R 3 group, where R 3 independently has one of the meanings of R x or R x and R 3 together form a cycloaliphatic ring having from 3 to 8 ring atoms, Rb independently has one of the meanings of R x or R x and Rb together form a cycloaliphatic ring having from 3 to 8 ring atoms; hydrocarbon and heterohydrocarbon monohalides, in particular chlorides, bromides and iodides, for introducing hydrocarbon and heterohydrocarbon radicals (for example Ci-Ciβ-alkyI, C 6 -Ci 4 -aryl, C 7 -Ci 4 -aralkyl); halogenated hydrocarbons and halogenated heterohydrocarbons having halogen atoms of differing reactivities, in particular combinations of chlorine with bromine or iodine, bromine with iodine or two bromine or iodine atoms, for introducing hydrocarbon and heterohydrocarbon radicals (for example Ci-Ci 8 -alkyl, C 6 -Ci 4 -aryl, C 7 -Ci 4 -aralkyl); alkenyl halides, in particular chlorides, bromides and iodides, for introducing alkenyl groups such as allyl and vinyl; tri(Ci-Cs-alkyl)silyl halides (chlorides, bromides) for introducing the tri(Ci-Cs-alkyl)-Si- group; di(sec-amino)phosphine monohalides (chlorides, bromides) for introducing di(sec- amino)phosphino groups such as di(dimethylamino)phosphino, di(diethyl- amino)phosphino, N,N-diethylcyclohexylenediaminophosphino; phosphoric ester monohalides (chlorides, bromides) for introducing phosphonic ester groups such as (CH 3 O) 2 (O)P-, (C 2 H 5 O)(O)P-, (cyclohexylO) 2 (O)P-, (ethylene-
dioxyl )(O)P-; phosphorous ester monohalides (chlorides, bromides) for introducing phosphorous ester groups such as (CH 3 O) 2 P-, (02H 5 O)P-, (cyclohexylO^P-, (ethylenedioxyl)P-; sulphuryl chloride for introducing sulphonic acid groups or sulphonic ester groups; sulphuric ester monohalides for introducing sulphonic acid groups such as
(CH 3 O)(O)S-, (C 2 H 5 O)(O)S- and (cyclohexylO)(O)S-; organic disulphides R-SS-R for introducing the -SR group; sulphur (S 8 ) for introducing the -SH group;
B(OCi-C 4 -alkyl) 3 for introducing boronic acid groups, and substituted or unsubstituted ferrocenyl monohalides (chlorides, bromides, iodides).
Preferred radicals R 2 are -CO 2 H, -C(O)-OR x , -C(O)-R x , -CH=O, -CH(OH)-R x , -C(OH)R x R 3 , -CH 2 OH, -CH 2 NH 2 , Ci-Ci 8 -alkyl, (Ci-C 8 -alkyl) 3 Si- and R x S-, where R x is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl having from 1 to 12 and preferably from 1 to 8 carbon atoms and R a independently has one of the meanings of R x or R x and R a together form a cycloaliphatic ring having from 3 to 8 ring atoms.
For the purposes of the invention, at least equivalent amounts means the use of 1 equivalent or a small excess of up to 1.2 equivalents of Li-alkyl, a magnesium Grignard compound, an electrophilic organic compound or sec-phos-Xi per =CH group, per =CBr group or =CM group in the cyclopentadienyl ring. At least equivalent amounts of Li sec-amide, halogen-Mg sec-amide means 1 equivalent per =CH group or an excess of up to 3 equivalents. However, it is also possible to use excesses greater than 1 , 2 or 3 equivalents.
In process step a), the ferrocene framework is metallated regioselectively in the ortho position relative to the bromine atom in both cyclopentadienyl rings, with metal amides being sufficient to replace the acidic H atom in the ortho position relative to the bromine atom. It is possible to use, for example, from 1 to 3 equivalents of an aliphatic Li sec-amide or an XiMg sec-amide per CH group in the cyclopentadienyl ring of the ferrocene.
Aliphatic Li sec-amide or XiMg sec-amide can be derived from secondary amines containing from 2 to 18, preferably from 2 to 12 and particularly preferably from 2 to 10, carbon atoms. The aliphatic radicals bound to the N atom can be alkyl, cycloalkyl or cycloalkylalkyl, or N-heterocyclic rings having from 4 to 12 and preferably from 5 to 7 carbon atoms can be present. Examples of radicals bound to the N atom are methyl, ethyl, n- and i-propyl, n-butyl, pentyl, hexyl, cyclopentyl, cyclohexyl and cyclo- hexylmethyl. Examples of N-heterocyclic rings are pyrrolidine, pipehdine, morpholine, N-methylpiperazine, 2,2,6,6-tetramethylpiperidine and azanorbornane. In a preferred embodiment, the amides correspond to the formulae Li-N(C3-C 4 -alkyl) 2 or X 2 Mg- N(C3-C 4 -alkyl) 2 , where alkyl is in particular i-propyl. In another preferred embodiment, the amides correspond to Li(2,2,6,6-tetramethylpipehdine).
The reaction of process step a) can be carried out in the solvents described below and under reaction conditions for the preparation of compounds of the formulae IX, X, Xl and XII. The compounds of the formulae V and Vl are generally not isolated but instead the reaction mixture obtained is preferably used in the subsequent step b).
The compounds of the formulae III and IV can be prepared as follows: a) Ri = alkyl or alkenyl
Dimethylamine can be eliminated from known compounds of the formula (see P.
Knochel et al., Tetrahedron: Asymmetry, 10 (1999), pages 1839-1842)
b) Ri = -CH 2 -OR or -CH 2 -NR 5 R 6
Compounds of the formula III or Vl in which Ri is a -CH 2 -NR 5 R 6 group can be obtained, for example, by substitution of a ferrocene which is brominated in both Cp rings and has quaternized chiral sec-amino radicals bound via CH 2 in the α position of the Cp rings by -HNR 5 R 6 . The chirality of the sec-amino radicals ensures a high stereoselectivity in the metallation of the ferrocenes which are substituted in this way and are firstly formed and then reacted with a brominating agent. Examples of such CH 2 -bonded sec-amino radicals are radicals of the formulae
R 8 is Ci-C 4 -alkyl, phenyl, (Ci-C 4 -alkyl) 2 NCH 2 -, (Ci-C 4 -alkyl) 2 NCH 2 CH 2 -, CrC 4 - alkoxymethyl or Ci-C 4 -alkoxyethyl. R 8 is particularly preferably methoxymethyl or dimethylaminomethyl. Quaternization is advantageously carried out using alkyl halides (alkyl iodides), for example methyl iodide.
Compounds of the formula III or Vl in which Ri is -CH 2 -OR can be obtained by firstly acoxylating 1-(R 5 R 6 NCH 2 )-2-bromoferrocenes prepared as described above by means of carboxylic anhydrides, for example acetic anhydride, to form 1 -(acyloxy- CH 2 )-2-bromoferrocene (for example 1 -acetyloxy-CH 2 -2-bromoferrocene) and then reacting these intermediates with alcohols in the presence of bases or with alkali metal alkoxides to give 1 -(RO-CH 2 )-2-bromoferrocene.
1 ,1 '-Dimethyl-2,2'dibromoferrocenes can be obtained by means of hydrogenolytic cleavage in the presence of catalysts. An amine or ether cleavage of 1 -(R 5 R 6 NCH 2 )- 2-bromoferrocenes or 1 -(RO-CH 2 )-2-bromoferrocenes or ester cleavage of 1-(acy- loxy-CH 2 )-2-bromoferrocene by means of strong acids and subsequent modification of cleavage products formed with, for example, -CH 2 OH or -CH 2 -halide in a manner known per se likewise leads to compounds of the formula III or Vl.
The reaction of process step b) is carried out using at least equivalent amounts or an excess of up to 1.5 equivalents per =CM group which reacts in the cyclopentadienyl ring of a compound of the formula sec-phos-Xi. However, it is also possible to use a significant excess of up to 3 equivalents. In process step b), sec-phos radicals are introduced by reaction with compounds of the formula sec-phos-Xi with replacement Of M.
The reaction is advantageously carried out at low temperatures, for example from 30 to -100 0 C, preferably from 0 to -80 0 C. The reaction is advantageously carried out under an inert protective gas, for example a noble gas such as argon or nitrogen. After addition of the reactive electrophilic compound, the reaction mixture is advantageously allowed to warm to room temperature or is heated to elevated temperatures, for example up to 100°C and preferably up to 50 0 C, and stirred for some time under these conditions in order to complete the reaction.
The reaction is advantageously carried out in the presence of inert solvents. Such solvents can be used either alone or as a combination of at least two solvents. Examples of solvents are aliphatic, cycloaliphatic and aromatic hydrocarbons and also open-chain or cyclic ethers. Specific examples are petroleum ether, pentane, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, diethyl ether, dibutyl ether, tert-butyl methyl ether, ethylene glycol dimethyl or diethyl ether, tetrahydrofuran and dioxane.
The compounds of the formulae VII and VIII can be isolated by known methods (extraction, distillation, crystallization, chromatographic methods) and, if appropriate, purified in a manner known per se.
The metallation of ferrocenes as per process step c) is a known reaction which has been described, for example, by T. Hayashi et al., Bull. Chem. Soc. Jpn. 53 (1980), pages 1138 to 1151 , or in Jonathan Clayden Organolithiums: Selectivity for Synthesis (Tetrahedron Organic Chemistry Series), Pergamon Press (2002). The
alkyl in the alkyllithium can contain, for example, from 1 to 4 carbon atoms. Use is frequently made of methyllithium and butyllithium. Magnesium Grignard compounds are preferably compounds of the formula (Ci-C 4 -alkyl)MgX 0 , where Xo is Cl, Br or I.
The reaction is advantageously carried out at low temperatures, for example from 20 to -100 0 C, preferably from 0 to -80 0 C. The reaction time is from about 1 to 20 hours. The reaction is advantageously carried out under an inert protective gas, for example nitrogen or a noble gas such as argon.
The reaction can be carried out in the presence of inert solvents as are also used in process step b).
The compounds of the formulae IX, X, Xl and XII are advantageously used in the subsequent step d) without prior isolation. In process step d1 ), a radical R2 or two identical radicals R2 of electrophilic compounds are introduced with replacement of M or one or two hydrogen atoms are introduced by hydrolysis of =CH-M groups by means of water. Examples of various electrophilic compounds have been given above. Process step d2) makes it possible to obtain novel compounds of the formulae I and Il in which one R2 is a hydrogen atom and the other is a radical of an electrophilic organic compound or in which the two radicals R2 are different (i.e. not identical) radicals of electrophilic organic compounds. At least equivalent amounts means the use of from 1 to 1.2 equivalents of a reactive electrophilic compound per =CM group which reacts. However, it is also possible to use a significant excess of up to 2.5 equivalents. Water can also be used in larger excesses of, for example, up to 10 equivalents.
The reaction is advantageously carried out at low temperatures, for example from 20 to -100°C, preferably from 0 to -8O 0 C. The reaction is advantageously carried out under an inert protective gas, for example a noble gas such as argon or nitrogen. After addition of the reactive electrophilic compound, the reaction mixture is advantageously allowed to warm to room temperature or is heated to elevated temperatures, for example up to 100 0 C and preferably up to 50°C, and stirred for
some time under these conditions to complete the reaction.
The reaction can be carried out in the presence of inert solvents as are also used in process step b).
Isolation of the compounds of the formulae I and Il can be effected by methods known per se, for example extraction, filtration, precipitation and crystallization. After isolation, the compounds can be purified, for example by recrystallization or by chromatographic methods. The compounds of the formulae I and Il are obtained in good total yields and high optical purities.
The invention further provides compounds of the formulae XIII and XIV which are valuable precursors and intermediates for the preparation of compounds of the formulae I and II:
R'i is Ci-C 4 -alkyl and n is 0, 1 or 2;
Ri is d-Cs-alkyl, C 2 -C 8 -alken-1 -yl, -CH 2 -OR or -CH 2 -NR 5 Re;
Rs is a secondary phosphino group sec-phos; and a Br atom in one Cp ring can be replaced by a radical R 2 and R 2 is as defined above.
Compounds of the formulae XIII and XIV can also be used as described below as ligands for metal complexes as catalysts for asymmetric syntheses.
The compounds of the formulae I and Il are obtained in good total yields and high chemical and optical purities by means of the process of the invention. The great
flexibility for the introduction of secondary phosphino groups and radicals of electro- philic organic compounds represents a particular advantage of the process, since it makes economical production-line syntheses in which different radicals R2 can be attached after introduction of a defined secondary phosphino group possible. The synthesis of an intermediate then allows many substituted ferrocene ligands having various subsitutents R2 to be synthesized and made available. Functional groups in substituents R2 can also be modified or derivatized in a manner known per se using known methods. Thus, OH groups can be etherified or esterified, amino groups can be alkylated or amidated and acid groups can be converted into salts, esters or amides.
The process of the invention also makes it possible to obtain novel ferrocene- diphosphines which cannot be prepared by processes according to WO 2006/003196 A1. These diphosphines are valuable ligands for metal complexes which can be used as catalysts in asymmetric syntheses.
The invention further provides enantiomeric compounds of the formulae XV and XVI or a mixture of these enantiomers,
where
R'i is Ci-C 4 -alkyl and n is 0, 1 or 2;
Ri is d-Cs-alkyl, C 2 -C 8 -alken-1 -yl, -CH 2 -OR or -CH 2 -NR 5 R 6 ; sec-phos is a secondary phosphino group;
R is d-Cs-alkyl;
R 5 and Re are each d-Cβ-alkyl or R 5 and Re together form tetramethylene, penta- methylene or 3-oxa-1 ,5-pentylene;
Rg and R10 are each hydrogen;
Rg is hydrogen and R10 is a monovalent radical of an electrophilic organic compound; Rg and R10 are each a monovalent radical of an electrophilic organic compound and are different from one another; or Rg and R10 are identical and are each Ci-Cis-alkyl, C 3 -C 8 -CyClOaI kyl, C 3 -C 8 -cycloalkyl-Ci-C 4 -alkyl, C 6 -Ci 4 -aryl, C 7 -Ci 8 -aralkyl, -Si(CrCi 8 - alkyl) 3 , triphenylsilyl, -C(O)-Rn, -SH, -SRi 2 , -C(OH)Ri 3 Ri 4 , -B(OH) 2 , -S(O) 2 (OH) or -P(O)(OH) 2 , or salts, esters and amides of the acid groups -CO 2 H, -S(O) 2 (OH) or -P(O)(OH) 2 ; and
Rii, Ri2, Ri3, and Ri 4 are each Ci-Ci 2 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-Ci-C 4 - alkyl, C 6 -Ci 4 -aryl, C 7 -Ci 6 -aralkyl.
When R'i, Ri, R, R 5 , R 6 , Rg and R10 are monovalent radicals of electrophilic organic compounds, the embodiments and preferences described above apply.
Al kyl groups Rg and R10 preferably contain 1 -12, more preferably 1 -8 and particularly preferably from 1 to 4, carbon atoms. The alkyl is preferably linear. Some examples are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl and octadecyl. Particular preference is given to methyl, ethyl, n-propyl and n-butyl.
Cycloalkyl groups Rg and Rio are preferably C 4 -C6-cycloalkyl. Examples are cyclo- propyl, cyclobutyl, cyclopentyl and cyclohexyl.
Cycloalkylalkyl groups Rg and Ri 0 are preferably C 4 -C 6 -cycloal kyl methyl, for example cyclopentylmethyl and cyclohexylmethyl.
Aryl groups Rg and Ri 0 can be, for example, phenyl or naphthyl.
Aralkyl groups Rg and Rio can be, for example, benzyl, phenylethyl or naphthylmethyl.
Rg and Rio can be substituted by Ci-C 4 -alkyl in cyclic radicals cycloalkyl, aryl and aryl in aralkyl.
SiIyI radicals R 9 and Ri 0 are preferably -Si(Ci-C 8 -alkyl) 3 and particularly preferably -Si(Ci-C 4 -alkyl) 3 . Trimethylsilyl is very particularly preferred.
Alkyl groups Rn, R12, R13, and Ri 4 preferably contain 1 -8, more preferably 1 -6 and particularly preferably 1-4, carbon atoms. The alkyl is preferably linear. Some examples are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and dodecyl. Particular preference is given to methyl, ethyl, n-propyl and n-butyl.
Cycloalkyl groups Rn, R12, R13 and Ri 4 can be, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Cycloalkylalkyl groups Rn, R12, R13 and Ri 4 can be, for example, cyclopentylmethyl and cyclohexyl methyl.
Aryl groups Rn, R12, R13 and Ri 4 can be naphthyl and in particular phenyl.
Aralkyl groups Rn, R12, R13 and Ri 4 can be naphthylmethyl and in particular phenyl- methyl or phenylethyl.
Salts, esters and amides of the acid groups -CO2H, -S(O)OH 2 or -P(O)OH 2 are, for example, alkali metal and alkaline earth metal salts (Li, Na, K, Mg and Ca), CrC 4 - alkyl, C 4 -C 6 -cycloalkyl, C 4 -C 6 -cycloalkylmethyl, phenyl and benzyl esters and unsubstituted amides, N-Ci-C 4 -alkyl-substituted amides and N,N-di(CrC 4 -alkyl)- substituted amides.
The compounds of the formulae I, II, XIII, XIV, XV and XVI according to the invention are ligands for complexes of transition metals, preferably selected from the group consisting of TM-VIII metals, in particular from the group consisting of Ru, Rh and Ir, which are excellent catalysts or catalyst precursors for asymmetric syntheses, for example the asymmetric hydrogenation of prochiral, unsaturated, organic compounds. If prochiral unsaturated organic compounds are used, a very high excess of optical isomers can be induced in the synthesis of organic compounds and a high chemical
conversion can be achieved in short reaction times. The enantioselectivity and catalyst activities which can be achieved are excellent. Furthermore, such ligands can also be used in other asymmetric addition or cyclization reactions. The results which can be achieved can depend on the type of prochiral substrate.
The invention further provides complexes of metals selected from the group of transition metals, for example TM-VIII metals, with one of the compounds of the formulae XIV, XV and XVI as ligand.
Possible metals are, for example, Cu, Ag, Au, Ni, Co, Rh, Pd, Ir, Ru and Pt. Preferred metals are rhodium and iridium and also ruthenium, platinum and palladium.
Particularly preferred metals are ruthenium, rhodium and iridium.
The metal complexes can, depending on the oxidation number and coordination number of the metal atoms, contain further ligands and/or anions. The complexes can also be cationic metal complexes. Such analogous metal complexes and their preparation are widely described in the literature.
The metal complexes can, for example, correspond to the general formulae XVII and XVIII,
AiMel_ r (XVII), (AiMeL r ) (z+) (E " ) z (XVIII),
where Ai is one of the compounds of the formulae XIII, XIV, XV and XVI,
L represents identical or different monodentate, anionic or non-ionic ligands or L represents identical or different bidentate, anionic or non-ionic ligands; r is 2, 3 or 4 when L is a monodentate ligand or r is 1 or 2 when L is a bidentate ligand; z is 1 , 2 or 3;
Me is a metal selected from the group consisting of Rh, Ir and Ru; with the metal having the oxidation state 0, 1 , 2, 3 or 4;
E " is the anion of an oxo acid or complex acid; and
the anionic ligands balance the charge of the oxidation state 1 , 2, 3 or 4 of the metal.
The preferences and embodiments described above apply to the compounds of the formulae XIV, XV and XVI.
Monodentate non-ionic ligands can, for example, be selected from the group consisting of olefins (for example ethylene, propylene), solvating solvents (nitriles, linear or cyclic ethers, unalkylated or N-alkylated amides and lactams, amines, phosphines, alcohols, carboxylic esters, sulphonic esters), nitrogen monoxide and carbon monoxide.
Suitable polydentate anionic ligands are, for example, allyls (allyl, 2-methallyl) or deprotonated 1 ,3-diketo compounds such as acetylacetonate.
Monodentate anionic ligands can, for example, be selected from the group consisting of halide (F, Cl, Br, I), pseudohalide (cyanide, cyanate, isocyanate) and anions of carboxylic acids, sulphonic acids and phosphonic acids (carbonate, formate, acetate, propionate, methylsulphonate, thfluoromethylsulphonate, phenylsulphonate, tosylate).
Bidentate non-ionic ligands can, for example, be selected from the group consisting of linear or cyclic diolefins (for example hexadiene, cyclooctadiene, norbornadiene), dinitriles (malononitrile), unalkylated or N-alkylated carboxylic diamides, diamines, diphosphines, diols, dicarboxylic diesters and disulphonic diesters.
Bidentate anionic ligands can, for example, be selected from the group consisting of anions of dicarboxylic acids, disulphonic acids and diphosphonic acids (for example oxalic acid, malonic acid, succinic acid, maleic acid, methylenedisulphonic acid and methylenediphosphonic acid).
Preferred metal complexes also include those in which E is -Cl " , -Br " , -I " , CIO 4 " , CF 3 SO 3 " , CH 3 SO 3 " , HSO 4 " , (CF 3 SO 2 ) 2 N " , (CF 3 SO 2 ) 3 C " , tetraarylborates such as
B(phenyl) 4 " , B[bis(3,5-trifluoromethyl)phenyl] 4 ~ , B[bis(3,5-dimethyl)phenyl] 4 " , B(C 6 Fs) 4 " and B(4-methylphenyl) 4 " , BF 4 " , PF 6 " , SbCI 6 " , AsF 6 " or SbF 6 " .
Particularly preferred metal complexes which are particularly suitable for hydrogenations correspond to the formulae XIX and XX,
[A 1 Me 2 YiZ] (XIX), [A 1 Me 2 Yi] + E 1 " (XX),
where
A 1 is one of the compounds of the formulae XIII, XIV, XV and XVI;
Me 2 is rhodium or iridium;
Y 1 represents two olefins or a diene;
Z is Cl, Br or I; and
E 1 " is the anion of an oxo acid or complex acid.
The embodiments and preferences described above apply to the compounds of the formulae XIII, XIV, XV and XVI.
An olefin Y 1 can be a C 2 -C 12 -, preferably C 2 -C 6 - and particularly preferably C 2 -C 4 - olefin. Examples are propene, 1 -butene and in particular ethylene. The diene can contain from 5 to 12 and preferably from 5 to 8 carbon atoms and can be an open- chain, cyclic or polycyclic diene. The two olefin groups of the diene are preferably connected by one or two CH 2 groups. Examples are 1 ,4-pentadiene, cyclopentadiene, 1 ,5-hexadiene, 1 ,4-cyclohexadiene, 1 ,4- or 1 ,5-heptadiene, 1 ,4- or 1 ,5-cyclo- heptadiene, 1 ,4- or 1 ,5-octadiene, 1 ,4- or 1 ,5-cyclooctadiene and norbornadiene. Y preferably represents two ethylenes or is 1 ,5-hexadiene, 1 ,5-cyclooctadiene or norbornadiene.
In the formula XIX, Z is preferably Cl or Br. Examples of E 1 are BF 4 " , CIO 4 " , CF3SO3 " , CH 3 SO 3 " , HSO 4 " , B(phenyl) 4 " , B[bis(3,5-trifluoromethyl)phenyl] 4 " , PF 6 " , SbCI 6 " , AsF 6 " and SbF 6 " .
The metal complexes of the invention are prepared by methods known from the
literature (see also US-A-5,371 ,256, US-A-5,446,844, US-A-5,583,241 and E. Jacobsen, A. Pfaltz, H. Yamamoto (Eds.), Comprehensive Asymmetric Catalysis I to III, Springer Verlag, Berlin, 1999, and references cited therein).
The metal complexes of the invention are homogenous catalysts, or catalyst precursors which can be activated under the reaction conditions, which can be used for asymmetric addition reactions onto prochiral, unsaturated, organic compounds.
The metal complexes can be used, for example, for the asymmetric hydrogenation (addition of hydrogen) of prochiral compounds having carbon-carbon or carbon- heteroatom double bonds. Such hydrogenations using soluble homogeneous metal complexes are described, for example, in Pure and Appl. Chem., Vol. 68, No. 1 , pages 131-138 (1996). Preferred unsaturated compounds to be hydrogenated contain the groups C=C, C=N and/or C=O. According to the invention, metal complexes of ruthenium, rhodium and iridium are preferably used for the hydrogenation.
The invention further provides for the use of the metal complexes of the invention as homogeneous catalysts for the preparation of chiral organic compounds, preferably for the asymmetric addition of hydrogen onto a carbon-carbon or carbon-heteroatom double bond in prochiral organic compounds.
A further aspect of the invention is a process for preparing chiral organic compounds by asymmetric addition of hydrogen onto a carbon-carbon or carbon-heteroatom double bond in prochiral organic compounds in the presence of a catalyst, which is characterized in that the addition reaction is carried out in the presence of catalytic amounts of at least one metal complex according to the invention.
Preferred prochiral, unsaturated compounds to be hydrogenated can contain one or more, identical or different groups C=C, C=N and/or C=O in open-chain or cyclic organic compounds, with the groups C=C, C=N and/or C=O being able to be part of a ring system or exocyclic groups. The prochiral unsaturated compounds can be
alkenes, cycloalkenes, heterocycloalkenes and also open-chain or cyclic ketones, α,β-di ketones, α- or β-ketocarboxylic acids or their α,β-ketoacetals or -ketoketals, ethylenically unsaturated, organic monocarboxylic or polycarboxylic acids and their salts, esters and amides, ketimines and kethydrazones.
Some examples of unsaturated organic compounds are acetophenone, 4-methoxy- acetophenone, 4-thfluoromethylacetophenone, 4-nitroacetophenone, 2-chloroaceto- phenone, corresponding unsubstituted or N-substituted acetophenonebenzylimines, unsubstituted or substituted benzocyclohexanone or benzocyclopentanone and corresponding imines, imines from the group consisting of unsubstituted or substituted tetrahydroquinoline, tetrahydropyridine and dihydropyrrole, and unsaturated carboxylic acids, esters, amides and salts, for example α- and if appropriate β-sub- stituted acrylic acids or crotonic acids. Preferred carboxylic acids are those of the formula
Roi-CH=C(R 02 )-C(O)OH
and also their salts, esters and amides, where R01 is d-Cβ-alkyl, Cs-Cs-cycloalkyl which may be unsubstituted or be substituted by from 1 to 4 d-Cβ-alkyl, Ci-Cβ- alkoxy, Ci-C6-alkoxy-CrC 4 -alkoxy groups or Cβ-Cio-aryl and preferably phenyl which may be unsubstituted or substituted by from 1 to 4 Ci-C 6 -alkyl, Ci-C 6 -alkoxy, CrC 6 - alkoxy-Ci-C 4 -alkoxy groups and R02 is linear or branched Ci-C 6 -alkyl (for example isopropyl), cyclopentyl, cyclohexyl or phenyl which may be unsubstituted or substituted as defined above or protected amino (for example acetylamino).
The process of the invention can be carried out at low or elevated temperatures, for example temperatures of from -20 to 150 0 C, preferably from -10 to 100 0 C, and particularly preferably from 10 to 8O 0 C. The optical yields are generally better at a relatively low temperature than at higher temperatures.
The process of the invention can be carried out at atmospheric pressure or super- atmospheric pressure. The pressure can be, for example, from 10 5 to 2x10 7 Pa (pascal). Hydrogenations can be carried out at atmospheric pressure or at super-
atmospheric pressure.
Catalysts are preferably used in amounts of from 0.0001 to 10 mol%, particularly preferably from 0.001 to 10 mol% and very particularly preferably from 0.01 to 5 mol%, based on the compound to be hydrogenated.
The preparation of the ligands and catalysts and also the hydrogenation can be carried out without a solvent or in the presence of an inert solvent, with one solvent or mixtures of solvents being able to be used. Suitable solvents are, for example, aliphatic, cycloaliphatic and aromatic hydrocarbons (pentane, hexane, petroleum ether, cyclohexane, methylcyclohexane, benzene, toluene, xylene), aliphatic halogenated hydrocarbons (methylene chloride, chloroform, dichloroethane and tetrachloroethane), nithles (acetonitrile, propionitrile, benzonitrile), ethers (diethyl ether, dibutyl ether, t-butyl methyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, dioxane, diethylene glycol monomethyl or monoethyl ether), ketones (acetone, methyl isobutyl ketone), carboxylic esters and lactones (ethyl or methyl acetate, valerolactone), N-substituted lactams (N-methylpyrrolidone), carboxamides (dimethylamide, dimethylformamide), acyclic ureas (dimethylimidazoline) and sulphoxides and sulphones (dimethyl sulphoxide, dimethyl sulphone, tetramethylene sulphoxide, tetramethylene sulphone) and alcohols (methanol, ethanol, propanol, butanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether) and water. The solvents can be used either alone or as a mixture of at least two solvents.
The reaction can be carried out in the presence of cocatalysts, for example quaternary ammonium halides (tetrabutylammonium iodide) and/or in the presence of protic acids, for example mineral acids (see, for example, US-A-5,371 ,256, US-A- 5,446,844 and US-A-5,583,241 and EP-A-O 691 949). The presence of fluorinated alcohols such as 1 ,1 ,1-trifluoroethanol can likewise promote the catalytic reaction.
The metal complexes used as catalysts can be added as separately prepared
isolated compounds or else can be formed in situ prior to the reaction and then mixed with the substrate to be hydrogenated. It can be advantageous to add additional ligand in the reaction using isolated metal complexes or use an excess of the ligand in the in-situ preparation. The excess can be, for example, from 1 to 6 mol and preferably from 1 to 2 mol, based on the metal compound used for the preparation.
The process of the invention is generally carried out by placing the catalyst in a reaction vessel and then adding the substrate, if appropriate reaction auxiliaries and the compound to be added on and subsequently starting the reaction. Gaseous compounds to be added on, for example hydrogen or ammonia, are preferably introduced under pressure. The process can be carried out continuously or batchwise in various types of reactor.
The chiral, organic compounds prepared according to the invention are active substances or intermediates for the preparation of such substances, in particular in the preparation of flavours and fragrances, pharmaceuticals and agrochemicals.
The following examples illustrate the invention.
Starting materials and abbreviations 1 ,1 '-Bis[(dimethylamino)eth-1 -yl]-2,2'-dibromoferrocene of the formula
10 (1999) 1839-42. The compound will hereinafter be referred to as V1.
The reactions are carried out under inert gas (argon).
The reactions and yields are not optimized.
Abbreviations: TMP = 2,2,6,6-tetramethylpiperidine; TBME= tert-butyl methyl ether;
DMF: N,N-dimethylformamide, THF = tetrahydrofuran, EA = ethyl acetate, TO =
toluene, MeOH = methanol, EtOH = ethanol, Me = methyl, Et = ethyl, i-Pr = i-propyl, nbd = norbornadiene, DABCO = 1 ,4-diazabicyclo[2.2.2]octane; Cy = cyclohexyl, Hep = heptane, Ph = phenyl, MOD = 3,5-dimethyl-4-methoxyphen1 -yl, n-BuLi = n-butyl- lithium, eq. = equivalents.
A) Preparation of precursors
Example A1 : Preparation of 1 ,1 '-divinyl-2,2'-dibromoferrocene of the formula A1
5.01 g (10.3 mmol) of the compound V1 in 100 ml of acetic anhydride are stirred at 120 0 C for 16 hours and subsequently at 130 0 C for 8 hours. After cooling, the red- brown reaction mixture is extracted with 50 ml of water, 10 ml of saturated, aqueous sodium chloride solution and 50 ml of toluene. The organic phase is washed with water and NaCI solution, the collected aqueous phases are extracted once more with toluene and the organic phases are then dried over sodium sulphate. The organic phase is subsequently freed of the solvent under reduced pressure on a rotary evaporator. The crude product can, if required, be purified by chromatography on a short column (silica gel 60; eluent = TBME). After the purification, the title compound A1 is obtained as a red-brown oil in a yield of 95%.
1 H-NMR (C 6 D 6 , 300 MHz) characteristic signals: 6.57-6.45 (m, 2H), 5.36-5.29 (m, 2H), 5.20-5.14 (m, 2H), 4.18 (m, 2H), 4.03 (m, 2H), 3.75 (m, 2H).
Example A2: Preparation of 1 ,1 '-diethyl-2,2'-dibromoferrocene of the formula A2
6.71 g (16.9 mmol) of the compound A1 are stirred in 30 ml of THF in the presence of
0.67 g of Rh/C (5%, Engelhard, Code 4806) in a hydrogen atmosphere (atmospheric pressure). After uptake of hydrogen has ceased, the catalyst is filtered off and rinsed with a little THF. After distilling off the solvent, the product is purified by chromatography (silica gel 60; eluent = Hep). The title compound A2 is obtained as a red-brown oil in a yield of 89%.
1 H-NMR (C 6 D 6 , 300 MHz) characteristic signals: 4.12 (m, 2H), 3.72 (m, 2H), 3.67 (t, 2H), 3.39-3.20 (m, 4 H), 1.05 (t, 6H).
B) Preparation of 1 ,1 '-disubstituted 2,2'-dibromo-3,3'-di-sec-phosphinoferrocenes
Example B1 : Preparation of the compound having the formula B1
Preparation of the Li-TMP solution: 51 ml (85.7 mmol) of n-BuLi (1.6M in hexane) are added dropwise to a solution of 14.59 ml (85.7 mmol) of TMP in 70 ml of THF at 0 0 C while stirring. This solution is added dropwise to a solution of 6.53 g (16.3 mmol) of the compound A2 in 50 ml of THF which is stirred at -70 0 C. The resulting orange- brown solution is stirred at from -30 0 C to -35°C for 3 hours. It is then cooled to -78°C and 28.8 g (85.7 mmol) of bis(3,5-dimethyl-4-methoxyphen-1 -yl)chlorophosphine are added dropwise at such a rate that the temperature does not rise above -60 0 C. The mixture is subsequently stirred at from -30°C to -35°C for another 1 hour before 50 ml of water are added. The reaction mixture is extracted with TBME/water. The organic phases are collected, washed with aqueous 10% strength ammonium chloride solution and NaCI solution and then dried over sodium sulphate. The solvent is distilled off under reduced pressure on a rotary evaporator and the crude product is purified by chromatography (silica gel 60; eluent = firstly TO, then TO/EA 50:1 ). The title compound B1 is obtained as an orange solid in a yield of 77%. 1 H-NMR (C 6 D 6 , 300 MHz) characteristic signals: 7.33 (s, 2H), 7.31 (s, 2H), 7.21 (s, 2H), 7.18 (2H), 4.62 (d, 2H), 3.72 (d, 2H), 3.30 (s, 6H), 3.24 (s, 6H), 2.79-2.66 (m, 2H), 2.54-2.40 (m, 2H), 2.06 (s, 12H), 2.04 (s, 12H), 1.37 (t, 6H). 31 P-NMR (C 6 D 6 ,
121 MHz): -20.8 (S).
Example B2: Preparation of the compound having the formula B2
Preparation of the Li-TMP solution: 11.5 ml (18.8 mmol) of n-BuLi (1.6M in hexane) are added dropwise to a solution of 3.42 ml (20.1 mmol) of TMP in 20 ml of THF at 0 0 C while stirring. This solution is added dropwise to a solution of 2.68 g (6.7 mmol) of the compound A2 in 20 ml of THF which is stirred at -70 0 C. The resulting orange- brown solution is stirred at from -30 0 C to -35°C for 3 hours. It is then cooled to -78°C and 3.72 ml (20.1 mmol) of diphenylphosphine chloride are added dropwise at such a rate that the temperature does not rise above -60 0 C. The mixture is subsequently stirred at -30°C to -35°C for another 3 hours before 50 ml of water are added. The reaction mixture is extracted with TBME/water. The organic phases are collected, washed with aqueous 10% strength ammonium chloride solution and NaCI solution and dried over sodium sulphate. The solvent is distilled off under reduced pressure on a rotary evaporator and the crude product is purified by chromatography (silica gel 60; eluent = firstly Hep, then Hep/TO 100:1 to 1 :1 ). The title compound B2 is obtained as a yellow solid in a yield of 52%.
1 H-NMR (C 6 D 6 , 300 MHz) characteristic signals: 7.36-6.85 (diverse m, 20H), 4.48 (d, 2H), 3.20 (d, 2H), 2.68-2.55 (m, 2H), 2.45-2.32 (m, 2H), 1.24 (t, 6H). 31 P-NMR (C 6 D 6 , 121 MHz): -19.3 (S).
C) Preparation of 1 ,1 '-disubstituted 2,2'-disubstituted -3,3'-di-sec-phosphinoferrocenes Example C1 : Preparation of the compound having the formula C1
6.1 ml (9.7 mmol) of n-BuLi (1.6M in hexane) are added dropwise to 3.25 g (3.24 mmol) of the compound B1 in 50 ml of TBME at O 0 C while stirring. 13.65 ml (162.1 mmol) of dimethyl carbonate are added to the resulting red solution over a period of 30 seconds, the cooling is removed and the reaction mixture is stirred overnight at room temperature. The reaction mixture is extracted with water and TBME. The organic phases are collected and dried over sodium sulphate. After distilling off the solvent under reduced pressure on a rotary evaporator, the crude product is purified by chromatography (silica gel 60: eluent = Hep/EA 5:1 ). The title compound C1 is obtained as an orange solid in a yield of 65%. The product can also be purified by recrystallization from MeOH.
1 H-NMR (C 6 D 6 , 300 MHz) characteristic signals: 7.30 (s, 2H), 7.27 (s, 2H), 7.25 (s, 2H), 7.22 (s, 2H), 4.85 (d, 2H), 3.87 (m, 2H), 3.41 (s, 6H), 3.35 (s, 6H), 3.25 (s, 6H), 3.13-3.00 (m, 2H), 2.89-2.75 (m, 2H), 2.08 (s, 12H), 2.06 (s, 12H), 1.40 (t, 6H). 31 P-NMR (C 6 D 6 , 121 MHz): -17.0 (s)
Example C2: Preparation of the compound having the formula C2
10 ml (16.5 mmol) of n-BuLi (1.6M in hexane) are added dropwise to 5.5 g (5,5 mmol) of the compound B1 in 80 ml of TBME at 0 0 C while stirring. 3 ml (39 mmol) of DMF are added to the resulting red solution, the cooling is removed and the reaction mixture is stirred overnight at room temperature. The reaction mixture is extracted with water and EA. The organic phases are collected and dried over sodium sulphate. After distilling off the solvent under reduced pressure on a rotary evaporator, the crude product
obtained is purified by chromatography (silica gel 60; eluent = TO/EA 20:1 ). The title compound C2 is obtained as a red solid in a yield of 82%.
1 H-NMR (C 6 D 6 , 300 MHz) characteristic signals: 10, 40 (d, 2H), 7.32 (s, 2H), 7.30 (s, 2H), 7.14 (s, 2H), 7.11 (s, 2H), 4.77 (d, 2H), 3.91 (m, 2H), 3.32 (s, 6H), 3.22 (s, 6H), 2.95-2.82 (m, 2H), 2.66-2.30 (m, 2H), 2.06 (s, 12H), 2.03 (s, 12H), 1.23 (t, 6H). 31 P-NMR (C 6 D 6 , 121 MHz): -23.7 (s).
Example C3: Preparation of the compound having the formula C3
400 mg of lithium aluminium hydride are added to a solution of 3.06 g (3.4 mmol) of the compound C1 in 25 ml of THF while stirring. After stirring for 2 hours, 2 ml of water are slowly added dropwise and the mixture is admixed with 50 ml of TBME and sodium sulphate. The suspension is filtered, the solid residue is washed with TBME, the solvent is distilled off under reduced pressure on a rotary evaporator and the crude product obtained is purified by chromatography (silica gel 60; eluent = TO/EA 50:1 to 5:1 ). The title compound C3 is obtained as a yellow-orange solid in a yield of 88%. 1 H-NMR (C 6 D 6 , 300 MHz) characteristic signals: 7.43 (s, 2H), 7.40 (s, 2H), 7.24 (s, 2H), 7.22 (s, 2H), 4.78-4.70 (m, 2H), 4.43 (d, 2H), 4.30-4.33 (m, 2H), 3.76 (d, 2H), 3.31 (s, 6H), 3.22 (s, 6H), 2.44 (q, 4H), 2.08 (s, 12H), 2.03 (s, 12H), 1.30 (t, 6H). 31 P-NMR (C 6 D 6 , 121 MHz): -24.1 (s).
As an alternative, the compound C3 can also be prepared by reaction of the dilithiated compound B1 with paraformaldehyde.
Example C4: Preparation of the compound having the formula C4
95 mg (0.105 mmol) of the compound C2 are stirred in 2 ml of THF in the presence of 0.104 ml (1.06 mmol) of isopropylisocyanate and a catalytic amount of DABCO at 100 0 C in a glass pressure ampoule for 7.5 hours. After distilling off the solvent, the crude product is purified by chromatography (silica gel 60; eluent = TO/EA 5:1 ). The title compound C4 is obtained as an orange solid in a yield of 85%. 1 H-NMR (C 6 D 6 , 300 MHz) characteristic signals: 7.49 (s, 2H), 7.49 (s, 2H), (the further phenyl protons are covered by toluene signals), 3.30 (s, 6H), 3.26 (s, 6H), 2.53 (q, 4H), 2.10 (s, 12H), 2.04 (s, 12H), 1.23 (t, 6H), 0.89-0.78 (broad signal, 12H). 31 P-NMR (C 6 D 6 , 121 MHz): -24.2 (s).
Example C5: Preparation of the compound having the formula C5
3.9 ml (6.3 mmol) of n-BuLi (1.6M in hexane) are added dropwise to 2.08 g (2.09 mmol) of the compound B1 in 20 ml of TBME at 0 0 C while stirring. 1.6 ml (12.5 mmol) of trimethylchlorosilane are added to the resulting red solution, the cooling is removed and the reaction mixture is stirred overnight at room temperature. The reaction mixture is extracted with water and TBME. The organic phases are collected and dried over sodium sulphate. After distilling off the solvent under reduced pressure on a rotary evaporator, the crude product obtained is purified by chromatography (silica gel 60; eluent = Hep/EA 10:1 ). The title compound C5 is obtained as an orange solid in a yield of 76%. The product can also be purified by
recrystallization from ethanol.
1 H-NMR (C 6 D 6 , 300 MHz) characteristic signals: 7.99 (s, 2H), 7.97 (s, 2H), ca. 7.16 (signal covered by benzene peak), 7.14 (s, 2H), 4.31 (d, 2H), 4.23 (d, 2H), 3.37 (s, 6H), 3.30 (s, 6H), 2.60-2.40 (m, 4H), 2.27 (s, 12H), 2.12 (s, 12H), 1.18 (t, 6H), 0.21 (s, 18H). 31 P-NMR (C 6 D 6 , 121 MHz): -21.1 (s).
Example C6: Preparation of the compound having the formula C6
(C6)
1.06 ml (1.71 mmol) of n-BuLi (1.6M in hexane) are added dropwise to 1.48 g (1.48 mmol) of the compound B1 in 30 ml of TBME at 0 0 C while stirring. 0.3 ml (2.37 mmol) of trimethylchlorosilane is added to the resulting red suspension, the cooling is removed and the reaction mixture is stirred overnight at room temperature. The reaction mixture is extracted with water and TBME. The organic phases are collected and dried over sodium sulphate. The solvent is removed under reduced pressure on a rotary evaporator. The title compound C6 (1.51 g, orange, solid foam) is used without purification in Example C7. 31 P-NMR (C 6 D 6 , 121 MHz): -18.9 (s), -20.1 (S).
Example C7: Preparation of the compound having the formula C7
(C7)
2.7 ml (1.71 mmol) of n-BuLi (1.6M in hexane) are added dropwise to the crude product C6 in 15 ml of TBME at 0 0 C while stirring. 0.7 ml (8.9 mmol) of N,N-dimethyl-
formannide is then added, the cooling is removed and the reaction mixture is then stirred overnight at room temperature. The reaction mixture is extracted with water and TBME. The organic phases are collected and dried over sodium sulphate. After distilling off the solvent under reduced pressure on a rotary evaporator, the crude product obtained is purified by chromatography (silica gel 60; eluent = Hep/EA 5:1 ). The title compound C7 is obtained as a red-orange solid in a yield of 42% (based on compound B1 ).
1 H-NMR (C 6 D 6 , 300 MHz) characteristic signals: 10, 43 (d, 2H), 7.40-7.34 (multiple signals, 4H), 7.15-7.08 (multiple signals, 4H), 4.83 (d, 1 H), 4.72 (d, 1 H), 3.95 (m, 1 H), 3.88 (m, 1 H), 3.32 (s, 3H), 3.31 (s, 3H), 3.28 (s, 3H), 3.21 (s, 3H), 2.90-2.40 (2 m, 4H), 2.07-2.04 (24H), 1.33 (t, 3H), 1.24 (t, 3H), 0.41 (s, 9H). 31 P-NMR (C 6 D 6 , 121 MHz): -19.9 (S), -23.1 (s).
Example C8: Preparation of the compound having the formula C8
120 mg of lithium aluminium hydride are added to a solution of 0.53 g (0.57 mmol) of the compound C7 in 5 ml of THF while stirring. After stirring overnight, 1 ml of water is slowly added dropwise and the mixture is admixed with 20 ml of TBME and sodium sulphate. The suspension is filtered, the solid residue is washed with TBME, the solvent is distilled off under reduced pressure on a rotary evaporator and the crude product obtained is purified by chromatography (silica gel 60; eluent = Hep/EA 25:1 ). The title compound is obtained as a yellow-orange solid in a yield of 69%. 1 H-NMR (C 6 D 6 , 300 MHz) characteristic signals: 7.51 (s, 1 H), 7.49 (s, 1 H), 7.47 (s, 1 H), 7.44 (s, 1 H), 7.24 (s, 1 H), 7.22 (s, 1 H), 7.13 (s, 1 H), 7.11 (s, 1 H), 4.72-4.65 (m, 1 H), 4.55 (d, 1 H), 4.48 (d, 1 H), 4.47-4.38 (m, 1 H), 3.96 (m, 1 H), 3.78 (m, 1 H), 3.33 (s, 3H), 3.31 (s, 3H), 3.29 (s, 3H), 3.20 (s, 3H), 2.71 (q, 2H), 2.45 (m, 2H), 2.12 (s, 6H),
2.11 (S, 6H), 2.08 (s, 6H), 2.03 (s, 6H), 1.36 (t, 3H), 1.23 (t, 3H), 0.38 (s, 9H). 31 P-NMR (C 6 D 6 , 121 MHz): -19.3 (s), -23.7 (s).
Example C9: Preparation of the compound having the formula C9
4.0 mmol of hydroxylamine (hydroxylammonium chloride in ethanol set free using sodium ethoxide and NaCI filtered off) in 2 ml of ethanol are added to 0.6 g (0.67 mmol) of the compound C2 in 7 ml of ethanol at 0 0 C while stirring. After addition of 2 ml of THF, the cooling is removed and the reaction mixture is stirred overnight at 50 0 C. A red solution is obtained. The solvents are distilled off under reduced pressure on a rotary evaporator. The title compound C9 is used further without purification.
1 H-NMR (C 6 D 6 , 300 MHz) characteristic signals: 8.60 (d, 2H), 7.34 (s, 2H), 7.31 (s, 2H), 7.13 (s, 2H), 7.11 (s, 2H), 4.82 (d, 2H), 3.78 (m, 2H), 3.31 (s, 6H), 3.22 (s, 6H), 3.0-2.74 (m, 4H), 2.05 (s, 12H), 2.01 (s, 12H), 1.45 (t, 6H). 31 P-NMR (C 6 D 6 , 121 MHz): -22.9 (S).
Example C10: Preparation of the compound having the formula C10
The compound C9 is taken up in 10 ml of THF and 100 mg of LiAIH 4 are added in 6 portions. After stirring at 50 0 C for 3 hours, the reaction mixture is slowly admixed with 3 ml of water. After addition of 40 ml of TBME and sodium sulphate, the suspension is filtered, the solid residue is washed with TBME, the solvent is distilled off under reduced pressure on a rotary evaporator and the crude product obtained is purified
by chromatography (silica gel 60; eluent = ethanol).
1 H-NMR (C 6 D 6 , 300 MHz) characteristic signals: 7.41 (s, 2H), 7.39 (s, 2H), 7.24 (s, 2H), 7.21 (s, 2H), 4.49 (d, 2H), 4.0-3.9 (m, 2H), 3.72 (m, 2H), 3.5-3.4 (m2,H), 3.31 (s, 6H), 3.25 (s, 6H), 2.54-2.23 (m, 4H), 2.08 (s, 12H), 2.03 (s, 12H), 1.30 (t, 6H). 31 P-NMR (C 6 D 6 , 121 MHz): -24.1 (s).
Example C11 : Preparation of the compound having the formula C11
)
2.5 ml (5 mmol) of phenylmagnesium chloride (2 molar solution in THF) are added dropwise to a solution of 1.5 g (1.67 mmol) of the compound C2 in 15 ml of THF at -78°C. The mixture is stirred at this temperature for another 1 hour, the cooling bath is then removed, the temperature is allowed to rise to room temperature and the mixture is stirred for another 1 hour. The reaction mixture is admixed with 20 ml of water and 10 ml of saturated aqueous ammonium chloride solution and extracted with TBME. The organic phase is dried over sodium sulphate and the solvent is distilled off on a rotary evaporator. A 1 H-NMR of the solid yellow-orange residue shows that the reaction of the Grignard with the aldehyde has occurred with very high stereoselectivity. After recrystallization from EtOH, the desired product is obtained as a yellow, crystalline product in a yield of 83%. According to a crystal structure analysis, the two newly formed stereogenic centres have the (S) configuration. 1 H-NMR (C 6 D 6 , 300 MHz) characteristic signals: 7.59 (s, 2H), 7.56 (s, 2H), 7.48 (s, 2H), 7.45 (s, 2H), 6.97-6.75 (m), 6.28 (d, 2H), 6.02-5.92 (m, 2H), 4.56 (s, 2H), 3.97 (s, 2H), 3.29 (s, 6H), 3.24 (s, 6H), 2.6-2.1 (m, 4H), 2.06 (s, 12H), 1.94 (s, 12H), 1.01 (t, 6H). 31 P-NMR (C 6 D 6 , 121 MHz): -24.0 (s).
Example C12: Preparation of the compound having the formula C12
66.2 mg (0.0733 mmol) of the diol compound C8 in 1 ml of acetic anhydride are converted into the corresponding diacetate by stirring at 100 0 C for 3 hours. The acetic acid formed and the excess of acetic anhydride are subsequently distilled off under reduced pressure. 1 ml of a 33% solution of dimethylamine in ethanol is then added to the resulting yellow, solid diacetate and the reaction mixture is stirred at 85°C for 20 hours. After cooling, a yellow-orange suspension is formed. This is admixed with water, the solid material is filtered off, washed with water and finally dissolved in ethyl acetate. This solution is dried over sodium sulphate and the solvent is distilled off on a rotary evaporator. The product is obtained as an orange solid in virtually quantitative yield.
1 H-NMR (C 6 D 6 , 300 MHz) characteristic signals: 7.56 (s, 2H), 7.53 (s, 2H), 7.22 (s, 2H), 7.19 (s, 2H), 4.31 (d, 2H), 3.87 (d, 2H), 3.80-3.74 (m), 3.27 (s, 6H), 3.24 (s, 6H), 2.82-2.42 (m, 4H), 2.13 (s, 12H), 2.03 (s, 12H), 2.00 (s, 12H), 1.40 (t, 6H). 31 P-NMR (C 6 D 6 , 121 MHz): -24.6 (S).
Example C13: Preparation of the compound having the formula C13
2.83 ml (4.53 mmol) of n-BuLi (1.6M in hexane) are added dropwise to 1.51 g (1.51 mmol) of the compound B1 in 20 ml of TBME at 0 0 C while stirring. The mixture is stirred for a further 1 hour and 32 g of dry ice are then added and the mixture is stirred until no more gas evolution can be observed. The temperature is then allowed
to rise to room temperature and the mixture is stirred overnight. The reaction mixture is admixed with water and the pH is brought to about 12 by addition of 2N NaOH. After extraction with TBME, the aqueous phase is made neutral by means of 2N HCI and the product is extracted with TBME. After drying over sodium sulphate, the solvent is distilled off under reduced pressure on a rotary evaporator. This gives 1 .37 g of orange, solid product (yield: 97%) which can, if required, be recrystallized from toluene/ethyl acetate (94:6).
1 H-NMR (CDCI 3 , 300 MHz) characteristic signals: 6.81 (m, 2H), 6.78 (s, 2H), 6.77 (s, 2H), 6.74 (s, 2H), 4.54 (m, 2H), 3.74 (s, 6H), 3.66 (s, 6H), 3.41 (m, 2H), 2.7-2.25 (m, 4H), 2.19 (s, 12H), 2.09 (s, 12H), 1 .07 (t, 6H). 31 P-NMR (C 6 D 6 , 121 MHz): -19.3 (s).
Example C14: Preparation of the compound having the formula C14
1 .85 ml (2.95 mmol) of n-BuLi (1 .6M in hexane) are added dropwise to 0.76 g (0.98 mmol) of the compound B2 in 7.5 ml of TBME at 0 0 C while stirring. 3.5 g of dry ice are added to the resulting red solution and the reaction mixture is stirred overnight at room temperature. The reaction mixture is extracted with aqueous 0.4N HCI and TBME. The organic phases are collected and dried over sodium sulphate. After distilling off the solvent under reduced pressure on a rotary evaporator, the crude product obtained is purified by chromatography (silica gel 60; eluent = methylene chlohde/MeOH 5:1 ). The title compound C1 1 is obtained as an orange solid. 1 H-NMR (CD 3 OD, 300 MHz) characteristic signals: 7.33-7.07 (various m, 20H), 4.44 (d, 2H), 3.15 (m, 2H), 2.87-2.72 (m, 2H), 2.52-2.33 (m, 2H), 1 .07 (t, 6H). 31 P-NMR (CD 3 OD, 121 MHz): -19 (S).
Example C15: Preparation of the compound having the formula C15
0.49 ml (0.78 mmol) of n-BuLi (1.6M in hexane) is added dropwise to 200 mg (0.26 mmol) of the compound D2 in 4 ml of TBME at 0 0 C while stirring. 0.2 ml (2.6 mmol) of acetone is added to the resulting red solution, the cooling is removed and the reaction mixture is stirred overnight at room temperature. The reaction mixture is extracted with water and TBME. The organic phases are collected and dried over sodium sulphate. After distilling off the solvent under reduced pressure on a rotary evaporator, the crude product obtained is purified by chromatography (silica gel 60: eluent = Hep/EA, firstly 4:1 , then 2:1 ). The orange title compound C12 is obtained as a virtually solid oil.
1 H-NMR (CD 3 OD, 300 MHz) characteristic signals: 4.52 (d, 2H), 3.33-3.24 (m, 4H), 3.22 (m, 2H), 1.85 (d, 6H), 1.48 (s, 6H), 1.29 (t, 6H). 31 P-NMR (CD 3 OD, 121 MHz): -17.7 (s).
D) Preparation of metal complexes
Example D1 :
Preparation of the rhodium complex having the formula D1
BR 1 (D1 )
5.1 mg (0.0136 mmol) of [Rh(nbd) 2 ]BF 4 and 13.5 mg (0.015 mmol) of compound C3 as described in Example C3 are weighed into a Schlenk vessel provided with a
magnetic stirrer and the air is displaced by means of vacuum and argon. Addition of 0.8 ml of degassed methanol while stirring gives an orange solution of the metal complex (catalyst solution). 31 P-NMR: (121 MHz, CD 3 OD, δ/ppm): 27.0 (s), 25.7 (s).
E) Use examples
Examples E1 -E17: Hydrogenation of various substrates
The hydrogenations are carried out in 1.2 ml vials. Stirring is effected by intensive shaking.
Solutions having a volume of about 0.5 ml and the compositions shown in Table 1 are prepared in the 1.2 ml vials under a nitrogen atmosphere in a glove box. The catalysts are prepared "in situ" by mixing 1 equivalent of the metal precursor with 1.3 equivalents of ligand in dichloroethane and subsequently distilling off the dichloro- ethane under reduced pressure. The substrate is dissolved in the hydrogenation solvent and added as a solution to the catalyst. These vials are fixed in a pressure- rated, heatable vessel, the vessel is closed, the desired temperature is set, the nitrogen atmosphere in the vessel is replaced by hydrogen under the desired pressure and the hydrogenation is started by switching on the shaker.
Hvdroqenation conditions
Table 1 : Summary of the hydrogenation results
1) Substrate concentration; 2) Molar ratio of substrate to catalyst 3) Metal precursor: Rh+ = [Rh(nbd) 2 ]BF 4 ; Rh+TFA = [Rh(nbd)CF 3 COO] 2 ; RhCI = [Rh(nbd)CI] 2 ; Ru = [RuCI 2 (P- cymene)] 2 . 4) Reaction is performed in a 15ml vial with magnetic stirrer. The molar ratio between metal and ligand is 1 to 1.1. The total volume of the solution is 3 ml.
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