Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
  • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C67/00—Preparation of carboxylic acid esters
  • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
  • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
  • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
  • C07D213/46—Oxygen atoms
  • C07D213/48—Aldehydo radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/09—Geometrical isomers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• the present invention relates to a process for the diastereoselective preparation of olefins by the Horner-Wadsworth-Emmons reaction consisting in reacting at low temperature a phosphonate on a carbonyl derivative in the presence of a base in an appropriate solvent.
• the reaction involved is as follows:
• the carbonyl compound (B) may be an aldehyde or a ketone, with the condition that R has priority over Rio according to the rules of Cahn Ingold and Prelog. The latter are described for example in the book entitled “Advanced Organic Chemistry” Reactions, Mechanisms, and Structure, third edition, Jerry March, John Wiley & sons, 1985, the content of pages 96 to 112 of which is incorporated by reference. It is known from Tetrahedron Letters, Vol. 24, No.
• this crown ether has the disadvantage of being expensive, toxic and harmful to the environment. There was a need to find another way to improve the diastereoselectivity of the olefin obtained without using this crown ether.
• the subject of the present invention is a process for the diastereoselective preparation of olefins (C) by the Horner-Wadsworth-Emmons reaction consisting in reacting at low temperature a phosphonate (A) on a carbonyl derivative (B) in the presence a base in an appropriate solvent,
• Y represents an electron-withdrawing group known to those skilled in the art and chosen so as not to disturb the Homer-Wadsworth-Emmons reaction.
• these groups there may be mentioned in particular: -CO 2 R
• R 6 , R taken independently may be the same or different and represent: - a saturated or unsaturated, linear or aliphatic radical branched, having from 1 to 24 carbon atoms optionally substituted by heteroatoms; - a saturated, unsaturated or aromatic, monocyclic or polycyclic cycloaliphatic radical having from 4 to 24 carbon atoms optionally substituted by heteroatoms; - a saturated or unsaturated, linear or branched aliphatic radical, carrying a cyclic substituent optionally substituted by heteroatoms in the aliphatic part and / or the cyclic part;
• Rio, R and R 'taken independently may be the same or different and represent: - a hydrogen atom; a saturated or unsaturated, linear or branched aliphatic radical having from 1 to 24 carbon atoms optionally substituted by heteroatoms;
• R ⁇ , R 7 , R and R ' can also be taken together to form a saturated, unsaturated or aromatic ring optionally comprising heteroatoms;
• R 8 represents a radical chosen from:
• R 9 represents a radical chosen from:
• - a saturated, unsaturated or aromatic, monocyclic or polycyclic cycloaliphatic radical having from 4 to 24 carbon atoms optionally substituted by heteroatoms; the heteroatoms may also be present in the cyclic part; - a saturated or unsaturated, linear or branched aliphatic radical, carrying a cyclic substituent optionally substituted by heteroatoms in the aliphatic part and / or the cyclic part; with the condition that R has priority over Rio according to the rules of Cahn Ingold and Prelog,
• n is an integer between 0 and 10;
• Ri, R 2 , R 3 , R 4 may be the same or different, and represent a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms;
• R 5 represents a hydrogen atom, an alkyl or cycloalkyl radical having up to 12 carbon atoms, a phenyl radical or a radical of formula -C m H 2m - ⁇ , or
• a tris- (polyoxaalkyl) -amine sequestering agent of formula (I) is used in which:
• Ri, R 2 , R 3 , Ri may be the same or different, and represent a hydrogen atom or a methyl radical; n is an integer between 0 and 3;
• R 5 represents a hydrogen atom, an alkyl radical having from 1 to 4 carbon atoms.
• a tris- (polyoxaalkyl) -amine sequestering agent of formula (I) is used in which: Ri, R 2 , R 3 , R 4 represent a hydrogen atom; n is 1;
• R 5 represents a methyl radical.
• the tris- (polyoxaalkyl) -amine sequestering agent of formula (I) can be used in an amount which varies from 0.05 to 10 equivalents per 1 equivalent of phosphonate, one equivalent of aldehyde and one equivalent of base.
• the amount of tris- (polyoxaalkyl) -amine sequestering agent of formula (I) used is from 0.1 to 5 equivalents per 1 equivalent of phosphonate, one equivalent of aldehyde and one equivalent of base.
• the amount of tris- (polyoxaalkyl) -amine sequestering agent of formula (I) used is 1 equivalent for 1 equivalent of phosphonate, one equivalent of aldehyde and one equivalent of base, the whole being put in solution in a solvent.
• the phosphonate used for the reaction can be chosen from the phosphonates of formula (A): in which,
• Y represents CO 2 R, with R represents a hydrogen atom, an alkyl radical having from 1 to 12 linear, branched or cyclic, saturated or unsaturated carbon atoms, R e and R 7 represent a radical -CH 2 CF 3 , and R 8 represents a hydrogen atom.
• R represents a hydrogen atom, an alkyl radical having from 1 to 12 linear, branched or cyclic, saturated or unsaturated carbon atoms
• R e and R 7 represent a radical -CH 2 CF 3
• R 8 represents a hydrogen atom.
• a phosphonate of formula (A) is used in which:
• Y represents a CO 2 R radical, and R represents a methyl radical
• R 6 and R 7 represent a radical -CH 2 CF 3 ; and R 8 represents a hydrogen atom.
• the carbonyl derivative (B) used for the reaction can be an aldehyde or a ketone.
• the substituents R 9 and Rio are of course chosen so as not to disturb the Homer-Wadsworth-Emmons reaction.
• a condition according to the rule of Cahn, Ingold and Prélog was imposed, so as to define the selectivity of the olefin (C).
• the rule of Cahn Ingold and Prélog is described for example in the book entitled "Advanced Organic Chemistry” Reactions, Mechanisms, and Structure, third edition, Jerry March, John Wiley & sons, 1985 whose content of pages 96 to 112 is incorporated by reference.
• the carbonyl derivative (B) is preferably chosen from aldehydes, which corresponds to Rio representing a hydrogen atom.
• the aldehydes used can be, depending on the nature of the radical R 9 , aliphatic, and optionally include ethylenic unsaturations, or they can be aromatic. In the case where the aldehydes used are aromatic, they can comprise possible substitutions by electron-donating or electron-withdrawing groups.
• the electron donor group mention may be made of C1-C6 alkyl and C1- alkoxy groups.
• electron withdrawing group is understood to mean a group as defined by HC BROWN in the book entitled “Advanced Organic Chemistry” Reactions, Mechanisms, and Structure, third edition, Jerry March, John Wiley & sons, 1985, the contents of pages 243 and 244 are incorporated by reference. Mention may in particular be made, as representative of the electron-withdrawing groups:
• aromatic aldehyde is used.
• aliphatic aldehydes mention may be made of cyclohexane carboxaldehyde (R 9 is a cyclohexyl radical) or an aliphatic aldehyde in which R 9 is nC 7 H ⁇ s. It is preferred to use the aliphatic aldehyde in which R 9 is a cyclohexyl radical.
• aromatic aldehydes there may be mentioned benzaldehyde (R represents a phenyl radical), or an aldehyde characterized in that the radical R 9 used is aromatic and optionally comprises one or more substitutions by alkoxy groups having from 1 to 6 carbon atoms or halogen atoms. Mention may also be made, by way of example, of the aldehydes listed in the table VIL
• aromatic aldehyde can include heteroatoms in the aromatic ring.
• the aromatic aldehyde can also include substitutions by CF 3 groups.
• the base is chosen from: - amides of the MNR “R” 'type with M an alkali metal such as lithium, sodium or potassium, and R ", R'” being chosen from alkyl radicals or radicals of the type alkylsilane, such as the potassium salt of hexamethyldisilazane (KHMDS),
• alkali or alkaline earth hydroxides such as LiOH, NaOH, KOH, CsOH, Mg (OH) 2 , Ca (OH) 2 , Ba (OH) 2 ,
• organic bases such as l, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), l, l, 3,3-tetramethylguanidine (TMG), or l, 4-diazabicyclo [2.2 .2] octane (DABCO) in combination with alkali or alkaline earth halides.
• DBU 8-diazabicyclo [5.4.0] undec-7-ene
• TMG 3,3-tetramethylguanidine
• DABCO 4-diazabicyclo [2.2 .2] octane
• the potassium salt of hexamethyldisilazane (KHMDS) or potassium tert-butoxide (tBuOK) is used.
• the solvent used is an organic solvent.
• a polar solvent is used.
• an ethereal solvent such as THF or mefhylterbutylether (MTBE) is used.
• the amount of solvent used is generally between 0.1 and 20 ml per mmol of phosphonate.
• the improvement in the selectivity of the reaction in the presence of the sequestering agent of the invention is observed whatever the temperature. It is thus possible to implement the method of the invention at a temperature of 0 ° C. However, it is preferred to carry out the process of the invention at a temperature less than or equal to -20 ° C, and even more preferably at a temperature less than or equal to -50 ° C. As an indication, the reaction is generally carried out at a temperature above -100 ° C.
• Example 1 Demonstration of the Effect of the TDA-1 Sequestering Agent and Comparison with the 18-crown- ⁇ at -78 ° C
• the phosphonate used corresponds to a phosphonate of formula (A) in which:
• Y represents a CO R radical with R representing a methyl radical, R 6 and R 7 represent a -CH 2 CF 3 radical; and R 8 represents a hydrogen atom.
• the carbonyl compound (B) used is benzaldehyde.
• the base used is potassium hexamethyldisilazane (KHMDS) dissolved in toluene at 0.5M.
• KHMDS potassium hexamethyldisilazane
• the solvent used is THF.
• TDA-1 The sequestering agent of the invention used, called TDA-1, corresponds to a tris- (polyoxaalkyl) -amine sequestering agent of formula (I) in which:
• Ri, R 2 , R 3 , R 4 represent a hydrogen atom; n is 1;
• R 5 represents a methyl radical
• the mixture is analyzed by gas chromatography using a Narian Star 3400CX device.
• the column used is a DB1 125-1034 from J&W Scientific (length: 30 m, internal diameter: 0.53 mm and film thickness of 3 ⁇ m).
• the initial temperature of the column is 100 ° C and the temperature rise of 7 ° C per minute. Under these conditions, the retention times of the various compounds are as follows:
• the Z and E isomers are defined in the reaction scheme boxed on the previous page. In the present case, the role of the additive is to improve the selectivity for the Z isomer.
• TDA-1 sequestering agent of the invention
• Example 2 Evaluation of the conditions of Example 1 (THF, KHMDS, TDA-1, -78 ° C) with cyclohexanecarboxaldehyde
• Example 2 the procedure of Example 1 is repeated and the nature of the aldehyde used is varied. Benzaldehyde is replaced by cyclohexanecarboxaldehyde (R 9 represents a cyclohexyl radical). The temperature is maintained for approximately 4 hours at -78 ° C. before allowing the system to return to ambient temperature overnight. The reaction medium is then treated by the addition of a saturated solution of ammonium chloride and extracted with toluene.
• R 9 represents a cyclohexyl radical
• Example 1 the mixture is analyzed by gas chromatography using a Varian Star 3400CX device.
• the column used is a DB1 125-1034 from J&W Scientific (length: 30 m, internal diameter: 0.53 mm and film thickness of 3 ⁇ m).
• the initial temperature of the column is 100 ° C and the temperature rise of 7 ° C per minute.
• the retention times (Î R ) of the various compounds are as follows:
• Example 3 Effect of the concentration under the conditions of Example 1 (THF, KHMDS TDA-1, -78 ° C benzaldehyde)
• Example 1 The procedure of Example 1 is repeated with TDA-1 and several tests are carried out by reducing the amount of THF used.
• the tests are carried out with respectively 20 ml of THF (volume of Example 1), 4 ml of THF, 2 ml of THF and without THF. This corresponds to phosphonate concentrations of 0.05M, 0.15M, 0.21M and 0.41M.
• Table IV The results obtained are shown in Table IV below.
• the toluene in the KHMDS solution is the reaction solvent.
• the transformation is much slower and much less selective.
• Example 4 Use of potassium tert-butoxide as a base under the conditions of Example 1 (THF, TDA-1, -78 ° C)
• the temperature is maintained for approximately 4 hours at -78 ° C. before allowing the system to return to ambient temperature overnight.
• the reaction medium is then treated by the addition of a saturated solution of ammonium chloride and extracted with toluene. The results will be collated in the table below.
• Example 5 Effect of the concentration under the conditions of Example 4 (Benzaldehyde HF, tBuOK, TDA-1, -78 ° C)
• Example 4 The procedure of Example 4 is repeated with benzaldehyde and several tests are carried out by reducing the amount of THF used. The tests are carried out with 20 ml of THF respectively (volume of Example 4), 4 ml of THF, 2 ml of THF and 1 ml of THF. This corresponds to phosphonate concentrations of 0.05M, 0.21M, 0.37M and 0.60M. The results obtained are shown in Table VI below.
• the medium is allowed to rise to ambient temperature overnight before treatment.
• MTBE methyl tert-butyl ether

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