FR2749847A1 - CHIRAL ORGANOBORANES - Google Patents

Abstract

Chiral organoboranes of general formulae (I) and (II), wherein each of R1 and R2, which are the same or different, is a hydrogen atom or an alkyl or cycloalkyl radical, or R1 and R2, taken together, are a saturated divalent hydrocarbon grouping; X1 is a hydrogen atom; and X2 is a hydrogen or halogen atom; are disclosed. Methods for preparing such compounds, and the use thereof, particularly as an asymmetrical reducing agent, are also disclosed.

Description

The invention relates to chiral organoboranes, processes for their preparation and their use in particular as an asymmetric reducing agent.

dans lesquelles soit R1 et R2 représentent, indépendamment, un atome d'hydrogène ou un radical allyle ou cycloalkyle, soit R1 et R2 représentent ensemble un groupement hydrocarboné divalent saturé;
X1 représente un atome d'halogène ; et
X2 représente un atome d'hydrogène ou d'halogène.A subject of the invention is therefore compounds of general formulas I and II

in which either R1 and R2 independently represent a hydrogen atom or an allyl or cycloalkyl radical, or R1 and R2 together represent a divalent saturated hydrocarbon group;
X1 represents a halogen atom; and
X2 represents a hydrogen or halogen atom.

In the definitions indicated above, the expression halogen represents a fluorine, chlorine, bromine or iodine atom, preferably fluorine, chlorine, and bromine.

The expression allyl preferably represents an allyl radical having from 1 to 6 carbon atoms, linear or branched, and in particular an allyl radical having from 1 to 4 carbon atoms such as the methyl, ethyl, propyl, isopropyl, butyl radicals , isobutyl, sec-butyl and tert-butyl.

The saturated cycloalkyl radicals can be chosen from radicals having from 3 to 7 carbon atoms such as the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl radicals, optionally substituted by a lower alkyl group.

The expression saturated divalent hydrocarbon group comprises from 6 to 8 carbon atoms and can be represented by a bicyclo group [5,1,1], [4,1,2], [3,1,3], [ 4.1.1], [3.1.2], [3.1.1] or [2.1.2], and preferably of the type [3.1.3].

avec un composé hydrogéné insaturé approprié, pour obtenir un composé de formule IV

dans lequel R1 et R2 sont tels que définis ci-dessus, produit de formule IV que l'on fait réagir avec un organolithien de formule R'Li dans laquelle R' représente un groupe organique, pour obtenir le composé de formule I.A subject of the invention is also a process for preparing the compounds of general formula I as defined above, characterized in that a compound of general formula III is reacted

with a suitable unsaturated hydrogenated compound, to obtain a compound of formula IV

in which R1 and R2 are as defined above, product of formula IV which is reacted with an organolithian of formula R'Li in which R 'represents an organic group, to obtain the compound of formula I.

The expression suitable unsaturated hydrogenated compound represents a hydrocarbon compound comprising one or two double bond (s),
The expression organic group represents an allyl or aryl radical, and preferably an allyl radical such as tert-butyl.

Thus, the reaction of a cycloalkyldiene comprising from 6 to 8 carbon atoms with the compound of formula III, makes it possible to obtain a compound of formula I in which R1 and
R2 together represent a divalent saturated hydrocarbon group of 6 to 8 atoms respectively. Likewise, the production of an allyl and / or cycloalkyl radical on the boron atom of the compound of formula I is obtained by reacting the corresponding alkene and / or cycloalkene (s) respectively, with the compound of formula III. This means that a compound of formula I in which R1 represents an acyl radical and R2 a cycloalltyl, is obtained by reacting the compound of formula III with an achene having the same number of carbon atoms as the desired allyl radical and a cycloalkene having the same number of carbon atoms as the desired cycloalkyl radical. Of course, R1 and R2 can represent the same radical.

The invention also relates to a process for the preparation of the compounds of general formula II as defined above. The process for preparing a compound of formula II in which Xl has the meaning indicated above and X2 represents hydrogen, is characterized in that a compound of general formula III as defined above is reacted , with one mole of a hydrogen halide of formula HX1, in which X1 has the meaning indicated above. The process for the preparation of a compound of formula II in which X1 has the meaning indicated above and X2 represents a halogen, is characterized in that a compound of general formula III as defined above is reacted, with one mole of a hydrogen halide HX1 and one mole of the hydrogen halide HX2. Of course, X1 and X2 can represent the same halogen atom.

The starting compound III is known; it can be prepared by hydroboration of 2-myrtényl 1,3-dithiane with diborane or by a complex of diborane with a Lewis acid (patent EP 61408).

The compounds of formulas I and II can thus be prepared in optically active form, from compound III in optically active form.

The compounds of the present invention are useful as an asymmetric reducing agent. A subject of the invention is therefore also the use of the compounds of formula I and II for asymmetric reductions. Preferably, the compounds of the present invention are used for the stereospecific reduction of ketone or imine function (s). The stereospecific reduction of ketone or imine consists in reacting the ketone or imine with an enantiomer of a compound of general formula I or 11.

The following examples are presented to illustrate the invention and should in no way be considered as limiting the scope of the invention.

Example 1
Preparation of compound (-) - II in which X1 = X2 = C1
In a 100 ml flask under a nitrogen atmosphere, 3 g (11 mmol) of the compound (-) - III are suspended in 60 ml of anhydrous ethyl ether. The suspension is cooled in a cooling bath to -600 ° C. and 5.6 ml (25 mmol) of 4.5N hydrochloric ether are introduced quickly. The bath is removed, then the temperature is maintained at -10 ° C. for 2.5 hours. The product precipitates in the form of a white powder. The solvent is removed in vacuo. The overall yield is 83.7%, calculated on the basis of 2-myrtenyl-1,3-dithiane borane.

The white solid is collected in 20 ml of anhydrous tetrahydrofuran and used as such in the reductions.

représente

Example 2
Preparation of the compound of formula I, in which

represented

37 g of the compound (-) - III are poured into 140 ml of anhydrous tetrahydrofuran. The temperature is brought back to 0 ° C. and 20 ml of cyclooctadiene in 20 ml of tetrahydrofuran are added over 30 minutes. The reaction mixture is then brought to reflux overnight. After cooling to -70 + 5 ° C., 81 ml of a 1.7M solution of t-butyllithium in pentane are added over 45 minutes. The reaction mixture is maintained at -70 IT 50 C for two additional hours, then the various solvents are removed, under reduced pressure and at ambient temperature, as well as the excess of cyclooctadiene. The residue obtained is taken up with 100 ml of MTBE. After two hours of stirring at room temperature then decantation at -20 "C, the liquid phase is separated. The white solid residue is washed with 100 ml of heptane at room temperature which are then removed by filtration. After a final additional washing at room temperature with 100 ml of MTBE and drying under reduced pressure, 45.9 g of white crystals are obtained (yield 86.4%) These crystals are stored at 40 ° C. under argon and protected from light.

1 g (3,15 mmol) du composé 1 solubilisé dans 10 ml de tétrahydrofuranne anhydre sont ajoutés, à 0 OC sous atmosphère d'azote, à une solution de 3,7 g (11 mmol) du composé (-)-II tel qu'obtenu à l'exemple 1, solubilisé dans 20 ml de tétrahydrofuranne anhydre. La solution est agitée pendant 48 heures à 250 C. Le solvant est ensuite éliminé sous pression réduite. Le résidu est repris dans 60 mi d'éther éthylique et 2,6 g (25 mmol) de diéthanolamine sont ajoutés. L'insoluble est éliminé par filtration et le filtrat est concentré à sec.Example 3
Use of compound II obtained in Example 1, for the reduction below:

1 g (3.15 mmol) of compound 1 dissolved in 10 ml of anhydrous tetrahydrofuran are added, at 0 ° C. under a nitrogen atmosphere, to a solution of 3.7 g (11 mmol) of compound (-) - II such as obtained in Example 1, dissolved in 20 ml of anhydrous tetrahydrofuran. The solution is stirred for 48 hours at 250 C. The solvent is then removed under reduced pressure. The residue is taken up in 60 ml of ethyl ether and 2.6 g (25 mmol) of diethanolamine are added. The insoluble material is removed by filtration and the filtrate is concentrated to dryness.

The residue represents 0.6 g of compound 2 of enantiomeric composition 75% (+): 25% (-).

Example 4
Use of compound I obtained in Example 2, for the reduction 1-> 2 as defined above
10 g of compound I as obtained above are dissolved in 45 ml of anhydrous tetrahydrofuran under an inert atmosphere. The reaction mixture is then thermostatically controlled at a temperature of approximately -78 "C, and 0.5 equivalent of compound I diluted in 10 ml of tetrahydrofuran is added over 30 minutes. The reaction is allowed to continue for approximately 2 hours. -780 C. The excess borohydride is neutralized with alcohol The reaction mixture is dried under vacuum The residue obtained is redissolved in 25 ml of ethyl ether and the organic phase is washed with water until 'at neutral pH.

After dehydration with sodium sulfate, filtration and drying under vacuum, 8.9 g of a mixture are recovered which are separated by chromatography on a silica column. The ratio of the enantiomers of compound 2 is 96% (+): 4% (-).

représente

préparé in Site, pour la réduction 1 - > 2 telle que définie ci-dessus.Example 5
Use of the compound of formula I, in which

represented

prepared in Site, for reduction 1 -> 2 as defined above.

a) Preparation of compound (+) 2: 214.2 g of (-) myrtenyl dithiane dissolved in THF (1280 ml), are added to 9-bora bicyclo [3,3,1] nonane. After dissolution, the reaction mixture is heated at reflux overnight, to complete the reaction, then cooled to -800 C.

Then, tertiary butyl lithium is added in less than an hour, keeping the temperature between -60 and -80 C.

Compound 1 (100 g) is then added in fractions in less than 15 minutes. The mixture is kept for two hours at -600 C. At this precise moment, the compound 1 is completely transformed.

After a treatment as in the previous example, the compound (+) 2 is crystallized from hexane (530 ml), to give 52.1 g with a composition 98.2% (-) / 1.8% ( +).

b) Preparation of compound (-) 2:
39.5 g of compound (+) III are dissolved in THF (240 ml). The solution is cooled to 0 ° C. and incorporated into a solution of 1.5 cyclo octadiene (15.9 g) in THF (45 ml).

The resulting solution is heated at reflux overnight, then treated as above with tBuLi to reduce the compound 1 (21 g) and give, after usual treatment, the compound (-) 2 (10 g - ee 100% ).

Claims (9)

1. The compounds of general formula I and II

 in which either R1 and R2 independently represent a hydrogen atom or an allyl or cycloalkyl radical, or R1 and R2 together represent a divalent saturated hydrocarbon group; X1 represents a halogen atom; and X2 represents a hydrogen or halogen atom. 2. The compounds of general formula I as defined in claim 1, characterized in that R1 and R2, independently, a hydrogen atom or a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl radical, tert-butyl, or a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl radical, optionally substituted by a lower aikyl group. 3. The compounds of general formula I as defined in claims 1 in which R1 and R2 together represent a divalent saturated hydrocarbon group containing 8 carbon atoms, and preferably a group such as

 represented

  4. The compounds of general formula II as defined in one of claims 1 or 4, in which X1 and X2 represent a halogen atom and preferably a chlorine atom. 5. Method for preparing the products of general formula I as defined in one of claims 1 to 2, characterized in that a compound of general formula III is reacted

 with a suitable unsaturated hydrogenated compound, to obtain a compound of formula IV

 in which R1 and R2 are as defined above, product of formula IV which is reacted with an organolithian of formula R'Li in which R 'represents an organic group, to obtain the compound of formula I. 6. Method for preparing the products of general formula II as defined in claim 1, in which X1 has the meaning indicated in claim 1 and X2 represents hydrogen, characterized in that a compound of formula is reacted General III as defined in claim 4, with one mole of a hydrogen halide of formula HX1 in which X1 has the meaning indicated above. 7. Process for the preparation of products of general formula II as defined in claim 1, in which X1 has the meaning indicated in claim 1 and X2 represents a halogen, characterized in that a compound of general formula is reacted III as defined in claim 4, with one mole of a hydrogen halide of formula HX1 in which X1 has the meaning indicated above and one mole of a hydrogen halide HX2 in which X2 has the meaning indicated above. 8. Use of the products of formula I or II as defined in any one of claims 1 to 4, as an asymmetric reducing agent, and in particular for the asymmetric reduction of ketones or imines. 9. Use according to claim 8, wherein the ketone is the compound of formula 1