BRIEF SUMMARY OF THE INVENTION

[0002] The present invention concerns the field of organic synthesis. It concerns, more particularly, a process for the selective reduction of carbonyl compounds, such as aldehydes, ketones, esters and lactones into the corresponding alcohols, using silanes as reducing agents, preferably polymethylhydrosiloxane (PMHS), in the presence of catalysts which comprise monomeric zinc compounds, complexed by basic ligands such as amines, polyamines, aminoalcohols, amine oxydes, amides, phosphoramides, etc.

BACKGROUND OF THE INVENTION

[0003] The selective reduction of carbonyl compounds to the corresponding alcohols in the course of which only the reaction of the C═O function is observed, is an important task in the field of organic chemistry. Until now, there were exclusively used hydride reducing agents, such as lithium aluminum hydride LiAlH ₄ , sodium borohydride NaBH ₄ , or sodium dihydroxybis(2-methoxyethoxy)aluminate (SDMA) of formula NaAlH ₂ (OCH ₂ CH ₂ OCH ₃ ) ₂ , the two latter reagents being of limited value for the reduction of esters and lactones. All the above-mentioned reagents are employed in stoichiometric amounts and show the disadvantage of releasing hydrogen in the course of the reaction or, when entering into contact with humidity, of leading to explosion risks and requiring the inertization of the reactors used. Furthermore, the use of these reagents is costly as they are required in stoichiometric amounts. Thus, there is a continuous search for other systems which are more economic and easier to use.

[0004] Several publications describe the use of silanes as reducing agents for carbonyl substrates, together with a metal catalyst. A preferred silane for this type of reductions is polymethylhydrosiloxane or PMHS, according to the general formula 1

[0005] U.S. Pat. No. 3,061,424 to Nitzsche and Wick describes the reduction of aldehydes and ketones with PMHS and a salt of mercury, iron, copper, titanium, nickel, zirconium, aluminum, zinc, lead, cadmium and, as the preferred embodiment, tin. This reductive system requires activation by a proton source, without which the reaction does not proceed. However, the system is not effective for the reduction of esters and lactones.

[0006] U.S. Pat. No. 5,220,020 to Buchwald et al. describes a method for the preparation of alcohols by the reduction of carbonyl compounds using a system composed of a silane reducing agent and a metal catalyst of formula M(L)(L ^I )(L ^II ) to M(L)(L ^I )(L ^II )(L ^III )(L ^IV )(L ^V ), in which M is a metal belonging to any of groups 3, 4, 5, or 6 of the periodical table, a lanthanide or an actinide, whereas (L ^I ) to (L ^V ) represent hydrogen, an alkyl group, an aryl group, a silyl group, a halogen atom, or a —OR, —SR or —NR(R′) group, R and R′ being hydrogen, an alkyl or an aryl group. Amongst the preferred catalysts, the cited patent mentions titane (IV) isopropylate or ethylate or trichlorotitane (IV) isopropylate. Such a system is said to be appropriate for the reduction of esters, lactones, amides or imines. More recently, Breedon and Lawrence (Synlett., 1994, 833) and Reding and Buchwald (J. Org. Chem., 1995, 60, 7884) have described a similar process, namely the use of non-activated titane tetraalkoxydes as catalysts for the reduction of esters by PMHS. The method described in those three mentioned references requires the use of large amounts, at least 25 mole % with respect to the substrate, of catalyst. Barr, Berk and Buchwald (J. Org. Chem., 1994, 59, 4323) have shown that the complex Cp ₂ TiCl ₂ , when reduced by butyllithium or ethylmagnesium bromide, could catalyze the reduction of esters into the corresponding alcohols with good yields, but this technique requires reagents which are expensive and difficult to use in a large scale, as is the case in industrial organic synthesis.

[0007] As closest prior art, there should be cited the international application WO 96/12694 of the applicant, describing the reduction of aldehydes, ketones, esters and lactones by a reductive system composed of silanes and a metal hydride, leading to the corresponding alcohols with good yields. This systems requires only very low amounts of catalyst, i.e. the metal hydride, in the order of 1 mol % with respect to the substrate. The hydride is formed by the reaction of a salt of the respective metal with an appropriate reducing agent, preferably NaBH ₄ . Besides zinc salts, cobalt, manganese and iron salts are used as precursors for the generation of metal hydrides. According to another preferred embodiment, PMHS is used as silane reducing agent.

DETAILED DESCRIPTION OF THE INVENTION

[0008] We have now successfully developped a process for the reduction of carbonyl compounds with silanes, catalyzed by metal derivatives which are not hydrides and which, in consequence, do not require the use of a reducing agent like, for example, NaBH ₄ .

[0009] The object of the invention is a process for the preparation of alcohols by reduction of the carbonyl function in substrates belonging to the class of aldehydes, ketones, esters or lactones, which substrates may contain unsaturated functions other than the carbonyl group, wherein

[0010] a) said carbonyl substrate is reacted with an effective amount of a silane, preferably PMHS, in the presence of catalytic amounts of an active zinc compound which is monomeric and not a hydride, to form a siloxane,

[0011] b) the thus-obtained siloxane is hydrolyzed with a basic agent to form an alcohol, and

[0012] c) the resulting alcohol is separated and purified, if necessary.

[0013] Another object of the invention is a reductive system comprising

[0014] a) a silane, preferably PMHS, and

[0015] b) an active zinc compound which is monomeric and not a hydride.

[0016] The present invention is based on the surprising fact that the use of a monomeric species of zinc considerably enhances the reactivity of a reductive system for carbonyl compounds comprising a silane and a zinc compound. Thus, reductive systems comprising a zinc salt and a silane, as described in U.S. Pat. No. 3,061,424 to Nitzsche and Wick which has been cited beforehand, are by far less reactive than the system according to the present application. In particular, the system as described in the prior art is not capable of reducing esters and lactones, in contrast to the reductive system of the present invention.

[0017] On the other hand, although the above-cited document WO 96/12694 of the applicant shows that it is possible to enhance the reactivity of a silane for the reduction of carbonyl substrates by adding zinc salts or complexes, the latter require the activation by a reducing agent. As reducing agent, compounds like NaBH ₄ , LiAlH ₄ , lithium or aluminum alkyls or Grignard compounds were used to generate a highly reactive species, namely a hydride.

[0018] The present invention, however, uses zinc compounds such as salts or complexes which do not require the activation by a reducing agent and which, when employed in stoichiometric amounts and together with a silane, catalyze the reduction of all sorts of carbonyl compounds.

[0019] The chemistry of zinc is in general characterized by the tendency of the metal to reach a coordination number higher than 2 which is a consequence of its valence state +2. The zinc can reach the higher coordination number it desires to attain by oligo- or polymerization, after which in general a tetra- or hexacoordination is observed. For those reasons, zinc salts or complexes are in most cases oligo- or polymeric, and as examples, there are mentioned here zinc carboxylates and halides.

[0020] However, an electronically unsaturated class of compounds are dialkyl- and diaryl zinc compounds. They are not capable of reaching a higher coordination number than 2 by oligo- or polymerization because alkyl and aryl groups cannot act as bridging ligands. Dialkyl- and diaryl zinc compounds are therefore monomeric, and they show a linear structure.

[0021] We have established that all the above-mentioned compounds show either no activity or a very low activity when used for the reduction of carbonyl compounds. However, these poly- or oligomeric species as well as dialkyl- or diaryl zinc compounds, when treated with an appropriate complexing agent which is capable of generating a monomeric active species, become highly effective catalysts for the reduction of aldehydes, ketones, esters and lactones by a silane.

[0022] According to the invention, there can be used an oligo- or polymeric precursor compound or a dialkyl- or diaryl zinc compound, which is converted into an active salt or complex by treatment with an appropriate complexing agent. Moreover, we have found that there can also be used known monomeric complexes or salts which turned out to be active in the process of the invention, but whose activity has passed completely unnoticed until now.

[0023] As the precursor compound, practically any known compound of zinc according to the general formula ZnX ₂ can be used. In this formula, X stands for any anion. Preferred anions X are defined below.

[0024] The active catalyst of the invention can be described by the general formula ZnX ₂ L _n . The catalyst can be obtained in situ, in the reaction medium, or be prepared separately from a zinc compound such as, for example, a salt or complex of general formula ZnX ₂ , mentioned above. In the formula ZnX ₂ of the precursor compound and ZnX ₂ L _n of the active catalyst, X is preferably any anion selected from the group consisting of carboxylates, β-diketonates, enolates, amides, silylamides, halides, carbonates and cyanides and organic groups such as alkyl, cycloalkyl, alkoxy, aryl, aryloxy, alkoxyalkyl, alkoxyaryl, aralkoxy, aralcoyl and alkylaryl groups. Amongst this group, one will preferably use a zinc carboxylate of formula Zn(RCO ₂ ) ₂ like, for example, the acetate, propionate, butyrate, isobutyrate, isovalerate, diethylacetate, benzoate, 2-ethylhexanoate, stearate or naphthenate; a zinc alkoxyde of formula Zn(OR) ₂ , wherein R is an alkyl group from C ₁ to C ₂₀ , preferably from C ₁ to C ₅ such as, for example, the methoxyde, ethoxyde, isopropoxyde, tert-butoxyde, tert-pentoxyde, or the 8-hydroxyquinolinate; a zinc β-diketonate like, for example, the acetylacetonate, substituted or unsubstituted, or the tropolonate; a compound of the type alkylzinc, arylzinc, alkyl(alkoxy)zinc or aryl(alkoxy)zinc comprising from 1 to 20 carbon atoms, preferably from 1 to 5 carbon atoms or a derivative thereof such as, for example, dimethylzinc, diethylzinc, dipropylzinc, dibutylzinc, diphenylzinc, methyl(methoxy)zinc or methyl(phenoxy)zinc, or a derivative of the type halide(alkyl)zinc.

[0025] In the formula ZnX ₂ L _n , n is an integer from 1 to 6. The ligands L can be identical or different and be selected from the group consisting of amines, polyamines, imines, polyimines, aminoalcools, amines oxydes, phosphoramides and amides.

[0026] The amine may be a primary, secondary, or tertiary aliphatic, alicyclic or aromatic amine comprising from 2 to 30 carbon atoms. Non-limiting examples include aniline, triethylamine, tributylamine, N,N-dimethylaniline, morpholine, piperidine, pyridine, picolines, lutidines, 4-tertiobutylpyridine, dimethylaminopyridine, quinoline and N-methylmorpholine.

[0027] The polyamines may comprise from 2 to 6 primary, secondary or tertiary amine groups, and from 2 to 30 carbon atoms such as, for example, ethylenediamine, 1,2- and 1,3-propylenediamine, 1,2-, 1,3- and 1,4-butanediamine, hexamethylenediamine, N,N-dimethylethylenediamine, diethylenetriamine, dipropylenetriamine, triethylenetetramine, tetramethylethylenediamine, N,N-dimethylpropylenediamine, N,N,N′-trimethylethylenediamine, N,N,N′,N′-tetramethyl-1,3-propanediamine, hexamethylenetetramine, diazabicyclononane, sparteine, orthophenantroline, 2,2′-bipyridine and neocuproine.

[0028] The aminoalcohols may comprise one or several primary, secondary or tertiary amine functions together with one or several primary, secondary or tertiary alcohol functions like in, for example, ethanolamine, diethanolamine, triethanolamine, dimethylaminoethanol, diethylaminoethanol, dimethylaminomethanol, diethylaminomethanol, 2-aminobutanol, ephedrine, prolinol, valinol, cinchonidine, quinine and quinidine.

[0029] As ligands belonging to the family of imines or diimines and capable of activating zinc derivatives or compounds in the context of the present invention, one can cite, as non-limiting examples, the compound families according to formulae [I] to [V] below, in which the groups R ₁ to R ₆ each represent a hydrogen atom or an alkyl, cycloalkyl, alkoxy, aryl, aryloxy, alkoxyalkyl, alkoxyaryl, aralkoxy, aralcoyl, alkylaryl or aralkyl goup comprising from 1 to 20 carbon atoms. 2

[0030] Other ligands capable of activating zinc compounds and derivatives yet include amides like, for example, dimethylformamide, dimethylacetamide or N-methyl-pyrrolidone, phosphoramides such as, for example, hexamethylphosphortriamide, phosphine oxides like, for example, triphenylphosphine oxide, tributyl- or trioctylphosphine oxide, amine oxides like, for example, pyridine N-oxyde, 4-picoline-N-oxyde, N-methyl-morpholine N-oxyde and sulfoxydes like, for example, dimethyl- or diphenylsulfoxyde.

[0031] The invention also concerns monomeric zinc complexes which turned out to be active in the process of the invention. A preferred class of compounds are monomeric zinc carboxylates. This class of molecules is not described in the chemical literature, with the exception of the compound Zn(O ₂ CCH ₃ ) ₂ (pyridine) ₂ , see J. Am. Chem. Soc. 119, 7030, (1997).

[0032] As preferred compounds amongst these complexes, there are cited here [Zn(benzoate) ₂ (Me ₂ NCH ₂ CH ₂ OH) ₂ ], [Zn(diethylacetate) ₂ (2,2′-bipyridyl)], [Zn(diethylacetate) ₂ (1,2-diaminopropane) ₂ ] and [Zn(benzoate) ₂ (TMEDA)](TMEDA=tetramethylethylenediamine). The preparation and characterization of these compounds is described below.

[0033] A great number of silanes can be used in the process according to the present invention. Such silanes are known to a person skilled in the art, and they will be chosen according to their capacity to effectively reduce carbonyl substrates in the process according to the present invention. As non-limiting examples, there can be cited trialkylsilanes, dialkylsilanes or trialkoxysilanes. More specific examples include dimethylsilane, diethylsilane, trimethoxysilane and triethoxysilane. There will preferably be used PMHS due to its effectiveness, availability and price.

[0034] The procees according to the present invention is lined out in the following reaction schemes, which apply to the particular and preferred case of employing PMHS as reducing agent.

[0035] Reduction of aldehydes (R ₁ =alkyl, aryl; R ₂ =H) and ketones (R ₁ , R ₂ =alkyl, aryl) 3

[0036] Reduction of esters and lactones (R ₁ , R ₂ =alkyl, aryl) 4

[0037] The concentration of the catalyst ZnX ₂ L _n , given in mole % with respect to the substrate, is generally from 0.1 to 10%, preferably from 1 to 5%.

[0038] There will typically be consumed 2 mole equivalents of PMHS per ester or lactone function, and one equivalent for the reduction of aldehydes and ketones. For practical reasons, there will preferably be used a slight excess of PMHS with respect to these stoichiometric amounts, in general of the order of 10 to 40% excess, based on the stoichiometric quantity. The reduction reaction according to the invention also takes place when the silane is used in sub-stoichiometric amounts, but this results in a decrease in conversion. According to the invention, therefore, the term “effective amount” means an amount of silane sufficient to induce reduction of the substrate.

[0039] The alcohol which is obtained as reaction product can be obtained by hydrolysis of the formed polysilylether. This hydrolysis may be carried out by adding to the reaction mixture an aqueous or alcoholic solution of a basic agent such as, for example, sodium or potassium hydroxide, lime or sodium or potassium carbonate. The ratio of the base with respect to the PMHS used will be from about 1 to 2 mole equivalents. After complete hydrolysis, there will in general be observed the formation of two phases. The desired alcohol is found in the organic phase and can be obtained by evaporation of the solvent which may be present. The obtained residue may be distilled for further purification.

[0040] The reduction can be carried without a solvent or in a solvent such as, for example, an ether (e.g. methyltert-butylether, diisopropylether, dibutylether, tert-amyl-methylether, tetrahydrofurane or dioxane), an aliphatic hydrocarbon (e.g. heptane, petroleum ether, octane, or cyclohexane) or an aromatic hydrocarbon (e.g. benzene, toluene, xylene or mesitylene), or mixture thereof.

[0041] As laid out above, the reduction according to the invention is applicable to various carbonyl compounds which may contain unsaturated functionalities other than the carbonyl group such as, for example, olefin, acetylene, nitrile or nitro groups which will not be affected by the reduction reaction.

[0042] As non-limiting examples for aldehyde substrates, there can be cited butanal, pentanal, heptanal, octanal, decanal, dodecanal, linear or branched. Other aldehydes which are unsaturated and which can be selectively reduced into the corresponding unsaturated alcohols include acroleine, methacroleine, prenal, citral, retinal, campholene aldehyde, cinnamic aldehyde, hexylcinnamic aldehyde, formylpinane and nopal. Aromatic aldehydes like, for example, benzaldehyde, cuminic aldehyde, vanilline, salicylaldehyde or heliotropine are also easily reduced to the corresponding alcohols.

[0043] As non-limiting examples for saturated and unsaturated ketones which can be reduced into the corresponding alcohols by silanes according to the invention, there can be cited hexan-2-one, octan-2-one, nonan-4-one, dodecan-2-one, methylvinylketone, mesityl oxide, acetophenone, cyclopentanone, cyclododecanone, cyclohexen-1-en-3-one, isophorone, oxophorone, carvone, camphor, beta-ionone, geranylacetone and 2-pentylcyclopenten-2-one.

[0044] As non-limiting examples for saturated and unsaturated esters or lactones which can be reduced into the corresponding alcohols by silanes according to the invention, there can be cited acetates, propionates, butyrates, isobutyrates, benzoates, acrylates and crotonates, cinnamates, cis-3-hexenoates, sorbates, salicylates, 10-undecylenates, oleates, linoleates, any ester of natural fatty acids and mixtures thereof. All the above-cited esters may, for example, be alkyl or aryl esters, preferably methyl esters. Other non-limitative examples include lactones, such as ε-caprolactone, decalactone, dodecalactone, diketene and sclareolide.

[0045] A remarkable property of the catalysts according to the invention is that they allow the reduction of natural triglycerides of fatty acids, like those which form the vegetable and animal oils. In the course of the reaction of a mixed triglyceride derived from distinct fatty acids, there can be obtained simultaneously saturated and unsaturated natural alcohols without any modification of the position or of the stereochemistry of the olefinic double bonds. This is of particular value for olefinic bonds showing a cis-configuration. 5

[0046] In the above Scheme (3), the substituents R ₁ , R ₂ and R ₃ are hydrocarbon groups which can be identical or different and which can contain from 1 to 20 carbon atoms. In the case where these groups contain one or more olefinc groups of a defined stereochemistry (which, in general, will be cis), the corresponding alcohol obtained after reduction according to the invention will have the same stereochemistry. Thus, oils rich in linoleic and/or linolenic acid, like linseed oil, will be transformed into mixtures rich in linoleyl and/or linolenyl alcohol. Conventional hydrogenation of these vegetable oils is generally carried out at high pressures and temperatures, in contrast with the present invention. Furthermore, because there are used in these conventional hydrogenations the methyl esters of the respective acids obtained by transesterification of the oils with methanol, there is in most cases observed a modification of the stereo-chemistry of the precursor fatty esters in the course of the transesterification and the hydrogenation reaction.

[0047] Amongst the triglycerides which can be reduced by the process according to the invention, there can be cited, as non-limiting examples, trioleine, peanut oil, soya oil, olive oil, colza oil, sesame oil, grape-seed oil, linseed oil, cacao butter, palm oil, palm-kernel oil, cotton oil, copra oil, coconut oil, and pork, beef, mutton and chicken fat.

[0048] Other oils and fats which are found in nature and which are not triglycerides, but esters of unsaturated fatty acids and monovalent unsaturated alcohols, like jojoba oil and sperm oil, can also be reduced according to the present invention, without any modification of the position or of the stereochemistry of the double bonds present in the ester molecule.

[0049] The reaction temperature can vary within a wide range of values, and will in general be in the range of from −50° C. to 250° C. The temperature chosen will depend on the reactivity of the substrate and can be adjusted accordingly without difficulty. More generally, the reaction will be carried out at a temperature within the range of from 50 to 110° C.

[0050] The invention will now be illustrated in greater detail in the following examples in which the temperatures are indicated in degrees centigrade, the yields in mole %, the chemical shift δ of the NMR data in ppm, relative to tetramethylsilane as internal reference, and the abbreviations have the usual meaning in the art.

[0051] Embodiments of the Invention