Preparation of manganous enolates and its applications
This application is a request for U.S. examination filed under 35 USC 371 of International application No. PCT/FR92/000877 filed on Sep. 21, 1992. 
     The invention relates to a novel method of preparing manganous enolates and to its applications. 
     The utility of enolates in general is well recognized, particularly since the work by FLEMING et al. (&#34;Synthesis&#34; 1976, 736, and &#34;Chem. Soc. Rev.&#34; 1981, 10, 83); these compounds are used especially as intermediates in different chemical reactions. They make it possible, for example, to obtain various esters, ketones or aldehydes which are useful in perfumery or as starting materials for the production of drugs or pesticides. Particularly valuable enolates, namely manganous enolates, form the subject of a French patent application published under no. 2 639 939. According to said document, manganous enolates are prepared by reacting mixed organomanganous compounds with ketones. 
     The advantages of Mn enolates include, for example, that of avoiding the polyalkylation or polyalkarylation of the ketone when these enolates are reacted with alkyl or alkaryl halides; by contrast, alkali metal and alkaline earth metal enolates, in particular lithium enolates, lead to a greater or lesser degree of polyalkylation or polyalkarylation. On the other hand, certain organomanganous compounds, particularly amides prepared by the method referred to above, give relatively inadequate yields in some of their applications, such as esterification or silylation reactions. 
     The present invention provides an improvement which, while retaining the advantage of avoiding polyalkylation or polyalkarylation, makes it possible substantially to increase the yield of reactions where organomanganous compounds were somewhat deficient. 
     The method according to the invention for the preparation of manganous enolates comprises treating an alkali metal or alkaline earth metal enolate with a manganous compound in a solvent for the Mn enolate to be prepared. 
     As alkali metal and alkaline earth metal enolates and their preparation are known, it is not necessary to describe them in detail here, suffice it to say that they are usually compounds of Na, K, Li, Ca or Mg, especially Li. Their preparation consists in reacting a corresponding organometallic compound with an organic compound carrying at least one carbonyl, particularly a ketone. The reaction is carried out in a solvent, generally at between -78° C. and +100° C., room temperature being suitable in many cases. 
     The reaction according to the invention, which constitutes a transmetalation, can be represented as follows: ##STR1## M&#39; being a monovalent metal, M&#34; being a divalent metal and it being possible for X and Y, which are identical or different, to be non-oxidizing anions or amino groups. MnX 2  can be replaced with YMnX. Manganous halides, especially MnCl 2 , are suitable as MnX 2 . 
     Lithium enolates, where M&#39; is Li, are particularly suitable. 
     In general, depending on the nature of the compounds involved, the temperature of the reaction medium is adjusted so as not to affect the stability of the reactants and so as to obtain the desired product in a reasonable period of time, for example in 0.3 to 3 hours. The preferred temperatures range between about -78° and +100° C. and in particular from 10° C. to 50° C.; one of the advantages of the method is that room temperature is suitable in many cases, it being possible for the reaction to be completed in about 0.5 to 2 hours at temperatures of 15° to 30° C. 
     The molar ratios of the reactants according to reaction (1) or (2) indicated above are usually stoichiometric, but it can be useful to employ an excess of manganous salt MnX 2  of, for example, 0 to 100% relative to stoichiometry, i.e. 1 to 2 mol per mol of enolate, but a deficiency thereof for reaction (3). 
     The method of the invention can be carried out with various concentrations of the reactants in the solvent used; the preferred concentrations range between about 0.1 and 2 mol or, preferably, between 0.2 and 0.8 mol of the compound carrying the carbonyl group per liter of solvent. 
     Ethers, especially diethyl ether, pyran, 1,2-dimethoxyethane and particularly tetrahydrofuran, may be mentioned among the principal solvents which can be used; it is also possible to employ dimethyl sulfoxide or sulfolane, other solvents being within the scope of those skilled in the art. It is sometimes possible to improve the solubility of the manganous salt MnX 2  in the solvent by the addition of an alkali metal salt, in particular an Li salt, as is practiced in the art. 
     The method of the invention is applicable to alkali metal and alkaline earth metal enolates derived from numerous ketones. Linear aliphatic ketones such as 
     CH 3  (CH 2 ) n  --CO--(CH 2 ) m  CH 3 , 
     in which the numbers n and m, which are identical or different, are 0 to 17, are suitable among the corresponding monoketones. Furthermore, in one or each of their chains (CH 2 ) n  and (CH 2 ) m , there can be a double or triple bond and/or an alkyl or aryl substituent. Similar ketones carry a secondary or tertiary group, i.e. ##STR2## in place of one or both of the terminal CH 3  groups. It is also possible to use enolates of ketones in which one or both of the chains CH 3  (CH 2 ) n  or CH 3  (CH 2 ) m  are replaced with a phenyl, tolyl, xylyl, naphthyl, cyclopentyl, cyclohexyl or cyclohexenyl ring which can carry one or more alkyl substituents. The starting ketones can carry functional groups (halogens, alkoxy, thioalkoxy, etc.). 
     By way of non-limiting examples, the invention can be carried out starting from enolates corresponding to ketones like diethyl ketone, dipropyl ketone, diisopropyl ketone, ethyl propyl ketone, ethyl hexyl ketone, ethyl cyclohexyl ketone, ethyl phenyl ketone, butylcyclopentanone, methylcyclohexanone, hexyl heptyl ketone, butyl dodecyl ketone, acetophenone, etc. 
     The foregoing statements regarding the ketones define the nature of the groups R 1  and R 2  in reactions (1) and (2) illustrated above. Thus, while R 2  can be H, R 1  and R 2 , which are identical or different, can consist of C 1  to C 20 , preferably C 1  to C 12 , alkyl, alkenyl or alkynyl chains which can comprise aryl substituents, or cycloalkyls, in particular cyclopentyl or cyclohexyl, which can carry one or more C 1  to C 12  alkyl substituents; aryl rings, in particular phenyl or naphthyl, which can optionally carry 1 to 3 C 1  to C 12  substituents, are suitable; phenyl, tolyl, xylyl, mesityl, mono-, di- or tri-ethylphenyl, dipropylphenyl, etc. thus form valuable enolates. 
     In the manganous compound MnX 2 , X can be a halogen or a non-oxidizing anion of a compound of S, P, B, C or Si, an oxy- or thia-hydrocarbon group, an amino group, etc. Thus, for example, X is Cl, Br or I, CF 3  --SO 2 , R&#39;COO, BF 4 , --OR&#39; or --SR&#39; (R&#39; being an alkyl or aryl) --NR&#39; 2  or --NR&#39;R&#34;, R&#39; and R&#34; being hydrocarbon groups, mainly C 1  to C 12  alkyl groups and/or C 6  to C 10  aryl groups. 
     The manganese enolate formed can be recovered from the reaction medium by evaporation of the solvent in the absence of air and moisture, or by any other known means, and can then be converted to the desired derivative. However, in the majority of common applications, this enolate can easily be treated in situ, in its original solvent, with the optional addition of another solvent and/or modification of the temperature, before a new appropriate reactant is introduced. The product can thus be acylated, silylated, alkylated, halogenated, hydroxyalkylated, etc., in its reaction medium, by the addition of an acid anhydride or chloride, a trialkylsilyl halide, an allyl or alkyl halide, a halogen or an aidehyde, followed by water, etc. As the manganese is eliminated during such reactions, the final products are esters of the enols in question, β-diketones, silylated derivatives or the corresponding alkylated, allylated or halogenated ketones, etc. The starting ketone can likewise be aldolized. 
    
    
     EXAMPLE 1 
     Preparation of a manganous enolate corresponding to dipropyl ketone and its application to the α-benzylation thereof 
     The starting material is the corresponding lithium enolate: ##STR3## obtained by reacting Li diisopropylamide, i.e.: ##STR4## with dipropyl ketone: ##STR5## at room temperature. A. - 125 mmol of MnCl 2  in the form of its double salt MnCl 2  ·2LiCl, in 200 ml of THF, are added to a solution of 100 mmol of Li enolate in 150 ml of tetrahydrofuran (THF). The mixture is stirred for 1 hour at 20° C., resulting in transmetalation: ##STR6## 125 mmol of benzyl bromide, PhCH 2  Br, and 75 ml of dimethyl sulfoxide (DMSO) are added dropwise to the solution obtained. After stirring for 1 hour at 20° C., the formation of dipropyl ketone benzylated in the α-position to the ketone functional group is observed with a yield of 94% relative to the starting heptanone. ##STR7## No polybenzylation takes place. B. - The starting material is the same Li enolate as in A but, instead of carrying out a transmetalation, the benzyl halide is reacted immediately by stirring 100 mmol of the Li enolate in 150 ml of THF with 125 mmol of PhCH 2  Br and 75 ml of DMSO for 1 hour at 20° C. The following reaction takes place: ##STR8## but the benzylated ketone is thus obtained with a yield of only 68% (compared with 94% in A) and is accompanied by polybenzylated products formed at a rate of 23%, these products being of the type ##STR9## It can thus be seen that the conversion of the Li enolate to the Mn enolate has brought marked advantages. 
     EXAMPLE 2 
     Preparation of a manganous enolate and its silylation 
     A. - One experiment consisted in starting from an Mn enolate prepared not by the direct reaction of an organo-Mn compound with cyclohexanone but by transmetalation from the lithium enolate in a manner similar to A of Example 1: ##STR10## Silylation, performed as under B (see below), is then carried out with a yield of 77%. 
     B. - In another experiment, an enolate is prepared by the reaction of 100 mmol of phenylmanganese N-methyl-N-phenylamide: ##STR11## with 100 mmol of cyclohexanone in 200 ml of THF at 20° C. for 1 hour: ##STR12## 100 mmol of trimethylchlorosilane, ClSiMe 3 , are added to the resulting solution at 20° C. and the mixture is stirred for 30 minutes to produce the following reaction: ##STR13## 1-Trimethylsilyloxycyclohexene is obtained with a yield of 59%, compared with 77% for procedure A. 
     EXAMPLE 3 
     Preparations analogous to those of Example 2 are carried out starting from 3-methylcyclohexanone instead of cyclohexanone. The procedure in B is the same, starting from ##STR14## but the procedure in A is transmetalation of the lithium enolate to the manganous enolate. Silylation is then carried out with yields of 
     79% for A 
     and 67% for B. 
     EXAMPLE 4 
     Experiments similar to those of Examples 2 and 3 are performed starting from nonanone: ##STR15## The yields of silylated compound: ##STR16## are as follows in this case: for A - 78% 
     for B - traces. 
     The advantage of transmetalation to give the manganous enolate appears to be particularly marked for the products derived from ketones possessing a methyl in the α-position to the carbonyl. 
     EXAMPLES 5 to 7 
     The technique of Example 1, A and B, was applied to the preparation of an Mn enolate from cyclohexanone, 2-methylcyclohexanone and 3-methylcyclohexanone. Each of these Mn enolates was then alkylated with benzyl bromide, C 6  H 5  CH 2  Br, by comparison with the same alkylation applied to the corresponding lithium enolate. The Table below gives the % yields of the benzylated ketone obtained and the % polybenzylation. 
     
         ______________________________________                                    
     Meth-                       Yield % poly-                            
Ex.  od      Starting ketone                                              
                         Enolate of                                       
                                 %     alkylation                         
______________________________________                                    
5    A       cyclohexanone                                                
                         Mn by   88     0                                 
                         trans-                                           
                         metalation                                       
5    B          &#34;        Li      55    32                                 
6    A       2-methylcyclo-                                               
                         Mn by   85     0                                 
             hexanone    trans-                                           
                         metalation                                       
6    B       2-methylcyclo-                                               
                         Li      65    25                                 
             hexanone                                                     
7    A       3-methylcyclo-                                               
                         Mn by   79     0                                 
             hexanone    trans-                                           
                         metalation                                       
7    B       3-methylcyclo-                                               
                         Li      37    47                                 
             hexanone                                                     
______________________________________                                    
 
    
     Compared with those of Example 1, these results show that the yield is improved by the invention, both for the linear starting ketones and for the cyclic ketones, the same applying to polyalkylation. This is completely suppressed in the method according to the invention, whereas it takes on substantial proportions in the prior art, as moreover indicated by H. HOUSE in Organic Syntheses Cell. vol. VI, 1988, 121, and by H. HOUSE et al. in J. Org. Chem. 1971, 36, 2361. 
     EXAMPLE 8 
     Application to the aldolization of a ketone 
     Transmetalation of the lithium enolate derived from pentanone was used to prepare the manganous enolate in a manner analogous to that of Example 1-A: ##STR17## 100 mmol of benzaldehyde, C 6  H 5  CHO, were mixed in 1 minute at -78° C. with 200 ml of THF containing 100 mmol of the above compound. This was followed by reaction with water: ##STR18## 
     EXAMPLE 9 
     Application of the invention to the aldolization of a ketone 
     50 mmol (5.1 ml) of benzaldehyde are added at -78° C. to the manganous enolate of diethyl ketone, prepared by the procedure described above. After stirring for 10 seconds at -78° C., the reaction medium is hydroIyzed by the dropwise addition of a saturated solution of (NH 4 ) 2  SO 4 . After decantation, filtration on hyflo-supercel and evaporation of the solvents under vacuum, 5-phenyl-5-hydroxy-4-methylpentan-3-one is isolated by low pressure liquid chromatography on 15 μm silica gel using cyclohexane/ethyl acetate (90/10) as the eluent. Yield=72%. Erythro/threo=61/39. 
     EXAMPLE 10 
     Preparation of a manganous enolate of an ester 
     50 mmol of BuLi/hexane are added at -30° C. to a solution of 50 mmol (5.05 g) of diisopropylamine in 60 ml of THF. The reaction medium is stirred at room temperature for 30 minutes, after which 40 mmol (4.08 g) of ethyl propionate are added dropwise over 15 minutes at -78° C. Stirring is maintained for 15 minutes at this temperature and a solution of 50 mmol (10.55 g) of the complex MnCl 4  Li 2  in 80 ml of THF is then added dropwise over 10 minutes. The reaction medium is stirred at room temperature for 30 minutes (orange coloration). 
     EXAMPLE 11 
     Aldolization of an ester 
     50 mmol (5.10 ml) of benzaldehyde are added at -78° C. to the manganous enolate of ethyl propionate, prepared as indicated above. After stirring for 10 seconds at -78° C., the reaction medium is hydrolyzed by the dropwise addition of a saturated solution of (NH 4 ) 2  SO 4 . After decantation, filtration on hyflo-supercel and evaporation of the solvents under vacuum, ethyl 3-phenyl-3-hydroxy-2-methylpropionate is isolated by low pressure liquid chromatography on 15 μm silica gel using cyclohexane/ethyle acetate (90/10) as the eluent. Yield=72%. Erythro/threo=61/39.