WO2016202894A1 - Procédé de conversion d'un alcool en halogénure - Google Patents

Procédé de conversion d'un alcool en halogénure Download PDF

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WO2016202894A1
WO2016202894A1 PCT/EP2016/063815 EP2016063815W WO2016202894A1 WO 2016202894 A1 WO2016202894 A1 WO 2016202894A1 EP 2016063815 W EP2016063815 W EP 2016063815W WO 2016202894 A1 WO2016202894 A1 WO 2016202894A1
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optionally substituted
alcohol
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chloride
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Peter Helmut HUY
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Universitaet des Saarlandes
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
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    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
    • C07C209/06—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms
    • C07C209/08—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms with formation of amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
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    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
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    • C07C247/08—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated
    • C07C247/10—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated and containing rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
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    • 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
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

  • the present invention relates to a method of converting an alcohol into a corresponding halide. Further, the present invention relates to a method of converting an alcohol into a corresponding substitution product, wherein this method comprises as a step thereof the method of converting an alcohol into a corresponding halide.
  • the method of Dubey et al. uses a pre-formed complex of ⁇ , ⁇ -dimethylformamide and pivaloyl chloride for converting alcohols in to the corresponding chlorides (see A. Dubey, A. K. Upadhyay, P. Kumar, Tetrahedron Letters 2010, 51, 744-746).
  • the alcohols are treated with a pre- formed complex of ⁇ , ⁇ -dimethylformamide and pivaloyl chloride.
  • a method published by Kimura et al. (see. Y. Kimura, D. Matsuura, T. Hanawa, Y. Kobayashi, Tetrahedron Letters 2012, 53, 1116-1118) relates to a preparation method for the Vilsmeier reagent and related imidoyl chlorides.
  • the Vilsmeier reagent is used for the transformation of alcohols into chlorides.
  • the present invention relates to a method of converting an alcohol into a corresponding halide, the method comprising:
  • the aromatic carboxylic acid halide is an aromatic carboxylic acid chloride or an aromatic carboxylic acid bromide.
  • the aromatic carboxylic acid halide is an optionally substituted benzoic acid halide.
  • the N- substituted formamide is an N-monosubstituted formamide or an ⁇ , ⁇ -disubstituted formamide.
  • the alcohol is a primary, secondary or tertiary alcohol.
  • the alcohol is an optionally substituted alkyl alcohol.
  • the alcohol is an optionally substituted allylic alcohol.
  • the alcohol is an optionally substituted propargylic alcohol.
  • the alcohol is an optionally substituted benzylic alcohol.
  • the alcohol is an optionally substituted a-hydroxy carboxylic acid ester.
  • the alcohol is an optically active alcohol.
  • the conversion of the alcohol into the corresponding halide is carried out in a solvent. In other embodiments the conversion of the alcohol into the corresponding halide is carried out under solvent-free conditions.
  • the present invention also relates to a method of converting an alcohol into a corresponding substitution product, the method comprising:
  • steps (a) and (b) are performed in a one-pot procedure without isolation of the halide.
  • the nucleophile is selected from the group consisting of C nucleophiles, N nucleophiles, O nucleophiles, and S nucleophiles.
  • the present invention relates to a method of converting an alcohol into a corresponding halide, the method comprising:
  • aromatic carboxylic acid halide refers to a compound having a halogenocarbonyl group linked to an aromatic nucleus, such as, for example, a benzene or a naphthalene nucleus.
  • optionally substituted aromatic carboxylic acid halide in general encompasses an optionally substituted aromatic carboxylic acid fluoride, an optionally substituted aromatic carboxylic acid chloride, an optionally substituted aromatic carboxylic acid bromide, and an optionally substituted aromatic carboxylic acid iodide.
  • optionally substituted as used in context with the aromatic carboxylic acid halide indicates that the aromatic carboxylic acid halide may be unsubstituted or substituted.
  • the optionally substituted aromatic carboxylic acid halide is an optionally substituted aromatic carboxylic acid chloride or an optionally substituted aromatic carboxylic acid bromide.
  • the optionally substituted aromatic carboxylic acid halide is an optionally substituted aromatic carboxylic acid chloride.
  • the present inventor has found a method of converting an alcohol into a corresponding halide which has a broad scope and is applicable to a great variety of alcohols.
  • the inventor has found out that by using an optionally substituted aromatic carboxylic acid halide and an N- substituted formamide alcohol substrates having a great structural variety can be converted into the corresponding halide.
  • this reaction in general provides the halogenated product in satisfactory to high yield and selectivity.
  • an ester formed as a byproduct from the alcohol used as starting material in a reaction with the aromatic carboxylic acid halide is in general formed in low to minimum amounts only.
  • the method disclosed herein further tolerates a large variety of functional groups present in the starting materials.
  • the method of converting an alcohol into a corresponding halide allows for an ecologically beneficial synthesis of chlorinated compounds since the amount of waste products can be kept low compared to known methods. In this respect, it is in general sufficient to employ the N-substituted formamide in catalytic amounts.
  • the method of the invention can be performed under solvent-free conditions.
  • the method of converting an alcohol into a corresponding halide is easily scalable. Hence, the conversions described herein can be up-scaled, and the methods described herein can be applied in syntheses on larger scale.
  • the presence of the N-substituted formamide in the conversion of an alcohol into a corresponding halide described herein is required in order to perform such conversion successfully.
  • the N-substituted formamide is absent, as shown by numerous examples the alcohol directly reacts with the aromatic carboxylic acid halide to form an ester, and only low to minimum amounts of the desired conversion product in which the hydroxyl group of the alcohol is replaced by the halogen atom are obtained. Without wishing to be bound by any theory, it can be therefore assumed that the N-substituted formamide catalyzes the desired conversion of the alcohol into the corresponding halide.
  • the methods of converting an alcohol into a corresponding halide comprise reacting the alcohol with an optionally substituted aromatic carboxylic acid halide in the presence of an N-substituted formamide to replace a hydroxyl group of the alcohol by a halogen atom.
  • the aromatic carboxylic acid halide is reacted with the alcohol in the presence of the N-substituted formamide to give the corresponding halide.
  • the alcohol may be contacted with the aromatic carboxylic acid halide.
  • the alcohol may be contacted with the aromatic carboxylic acid halide in the presence of the N-substituted formamide.
  • a conversion of the alcohol to the corresponding halide employing a preformed halogenation reagent such as, for example, a pre-formed complex obtained from a formamide and a carboxylic acid halide, or a pre-formed Vilsmeier reagent, may be avoided.
  • a preformed halogenation reagent such as, for example, a pre-formed complex obtained from a formamide and a carboxylic acid halide, or a pre-formed Vilsmeier reagent, may be avoided.
  • pre-formed halogenation reagent in particular denotes a halogenation reagent, which is pre-formed by reacting a formamide with a carboxylic acid halide prior to contacting the obtained reagent with the alcohol to be converted.
  • the optionally substituted aromatic carboxylic acid halide is an optionally substituted benzoic acid halide.
  • optionally substituted benzoic acid halide encompasses an optionally substituted benzoic acid fluoride, an optionally substituted benzoic acid chloride, an optionally substituted benzoic acid bromide and an optionally substituted benzoic acid iodide.
  • optionally substituted denotes that the benzoic acid halide may be unsubstituted or may be substituted with one or more substituents independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl optionally substituted alkoxy, optionally substituted alkanoyloxy, optionally substituted alkylamino, optionally substituted alkanoylamino, optionally substituted alkanoyl, carboxyl, optionally substituted alkoxycarbonyl, carbamoyl, optionally substituted N-alkylcarbamoyl, optionally substituted ⁇ , ⁇ -dialkylcarbamoyl, optionally substituted thioalkoxy, optionally substituted alkyl
  • halogen are a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • optionally substituted aryl may refer to an aromatic hydrocarbon radical having six to ten ring atoms, and includes fused and non-fused aryl rings.
  • the aromatic hydrocarbon radical has six ring atoms, i.e. preferably the aromatic hydrocarbon radical is a phenyl radical.
  • the aryl group may be unsubstituted or substituted.
  • Substituents of the aryl group may be, for example, H, halogen, N0 2 , CN, NMe 2 , OMe, and the like.
  • the term "optionally substituted heteroaryl” may refer to aromatic radicals containing from five to ten skeletal ring atoms, preferably from five to seven skeletal ring atoms, more preferably five or six skeletal ring atoms, where one or more of the ring atoms is a heteroatom independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon and selenium, preferably selected from oxygen, nitrogen and sulfur, but not limited to these atoms.
  • heteroaryl may include heteroaryl radicals having one or two heteroatoms.
  • Heteroaryl may also include fused and non-fused heteroaryls having from five to ten skeletal ring atoms.
  • the heteroaryl group may be unsubstituted or substituted. Substituents of the heteroaryl group may be, for example, H, halogen, N0 2 , CN, NMe 2 , OMe, and the like.
  • the term “optionally substituted alkyl” may refer to a linear or branched C1-C10, preferably to a linear or branched C1-C6, more preferably to a linear or branched C1-C4, most preferably to a linear or branched C1-C3 saturated hydrocarbon radical.
  • alkyl group examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and the like.
  • the alkyl group may be unsubstituted or substituted.
  • Substituents of the alkyl group may be, for example, H, halogen, N0 2 , CN, NMe 2 , OMe, and the like.
  • optionally substituted alkenyl may refer to a linear or branched C2-C10, preferably to a linear or branched C2-C6, more preferably to a linear or branched C2-C4, most preferably to a linear or branched C2-C3 radical having one or more carbon-carbon double bond(s).
  • the group may be either in the cis or trans and E or Z, respectively, configuration about the double bond(s), and should be understood to include both isomers.
  • the alkenyl group may be unsubstituted or substituted.
  • Substituents of the alkenyl group may be, for example, H, halogen, N0 2 , CN, NMe 2 , OMe, and the like.
  • alkynyl may refer to a linear or branched C2-C10, preferably to a linear or branched C2-C6, more preferably to a linear or branched C2-C4, most preferably to a linear or branched C2-C3 hydrocarbon radical having one or more carbon-carbon triple bond(s).
  • Non-limiting examples include ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like.
  • the alkynyl group may be unsubstituted or substituted.
  • Substituents of the alkynyl group may be, for example, H, halogen, N0 2 , CN, NMe 2 , OMe, and the like.
  • the term "optionally substituted alkoxy" may refer to an alkyl ether radical, O-alkyl, wherein the alkyl group is a linear or branched C1-C10, preferably a linear or branched C1-C6, more preferably a linear or branched C1-C4, most preferably a linear or branched C1-C3 saturated hydrocarbon radical.
  • Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.
  • the alkoxy group may be unsubstituted or substituted.
  • Substituents of the alkoxy group may be, for example, H, halogen, N0 2 , CN, NMe 2 , OMe, and the like.
  • alkanoyloxy may refer to an alkanoyloxy group -0(CO)Alk, wherein the alkyl portion Alk of the alkanoyloxy group is a linear or branched C1-C10, preferably a linear or branched C1-C6, more preferably a linear or branched C1-C4, most preferably a linear or branched C1-C3 saturated hydrocarbon radical.
  • the alkanoyloxy group may be unsubstituted or substituted.
  • Substituents of the alkanoyloxy group may be, for example, H, halogen, N0 2 , CN, NMe 2 , OMe, and the like.
  • the term "optionally substituted alkylamino" may refer to a monoalkylamino group, i.e. an amino group in which one hydrogen atom is replaced by an alkyl group, group or a dialkylamino group, i.e. an amino group in which two hydrogen atoms are replaced by an alkyl group.
  • the alkyl group of both a monoalkylamino group and a dialkylamino group may be a linear or branched C1-C10, preferably a linear or branched C1-C6, more preferably a linear or branched C1-C4, most preferably a linear or branched C1-C3 saturated hydrocarbon radical.
  • a dialkylamino group the two alkyl groups may be selected independently from each other. Examples for a monoalkylamino group are methylamino, ethylamino, n-propylamino, iso-propylamino, and the like.
  • Examples for a dialkylamino group are dimethylamino, diethylamino, di-n-propylamino, di-iso-propylamino, and the like.
  • the alkylamino group may be unsubstituted or substituted.
  • Substituents of the monoalkylamino and the dialkylamino group may be, for example, H, halogen, N0 2 , CN, NMe 2 , OMe, and the like.
  • alkanoylamino may refer to a group -NH(CO)Alk, wherein the alkyl portion Alk of the alkanoylamino group is a linear or branched C1-C10, preferably a linear or branched C1-C6, more preferably a linear or branched C1-C4, most preferably a linear or branched C1-C3 saturated hydrocarbon radical.
  • the alkanoylamino group may be unsubstituted or substituted.
  • Substituents of the alkanoylamino group may be, for example, H, halogen, N0 2 , CN, NMe 2 , OMe, and the like.
  • the term "optionally substituted alkanoyi” may refer to a group -(CO)Alk, wherein the alkyl portion Alk of the alkanoyi group is a linear or branched C1-C10, preferably a linear or branched C1-C6, more preferably a linear or branched C1-C4, most preferably a linear or branched C1-C3 saturated hydrocarbon radical.
  • the alkanoyi group may be unsubstituted or substituted.
  • Substituents of the alkanoyi group may be, for example, H, halogen, N0 2 , CN, NMe 2 , OMe, and the like.
  • the term "optionally substituted alkoxycarbonyl” may refer to an alkoxycarbonyl group -(CO)OAIk, wherein the alkyl portion Alk of the alkoxycarbonyl group is a linear or branched C1-C10, preferably a linear or branched C1-C6, more preferably a linear or branched Cl- C4, most preferably a linear or branched C1-C3 saturated hydrocarbon radical.
  • the alkoxycarbonyl group may be unsubstituted or substituted.
  • Substituents of the alkoxycarbonyl group may be, for example, H, halogen, N0 2 , CN, NMe 2 , OMe, and the like.
  • N-alkylcarbamoyl may refer to an N-alkylcarbamoyl group -(CO)NHAIk, wherein the alkyl portion Alk of the N-alkylcarbamoyl group group is a linear or branched Cl-ClO, preferably a linear or branched C1-C6, more preferably a linear or branched C1-C4, most preferably a linear or branched C1-C3 saturated hydrocarbon radical.
  • the N-alkylcarbamoyl group may be unsubstituted or substituted.
  • Substituents of the N-alkylcarbamoyl group may be, for example, H, halogen, N0 2 , CN, NMe 2 , OMe, and the like.
  • the term "optionally substituted ⁇ , ⁇ -dialkylcarbamoyl” may refer to an N,N- dialkylcarbamoyl group -(CO)N(Alk) 2 , wherein the alkyl portions Alk of the N,N-dialkylcarbamoyl group group are a linear or branched Cl-ClO, preferably a linear or branched C1-C6, more preferably a linear or branched C1-C4, most preferably a linear or branched C1-C3 saturated hydrocarbon radical.
  • the two alkyl portions Alk of (Alk) 2 may be the same or may be selected independently from each other.
  • the ⁇ , ⁇ -dialkylcarbamoyl group may be unsubstituted or substituted.
  • Substituents of the ⁇ , ⁇ -dialkylcarbamoyl group group may be, for example, H, halogen, N0 2 , CN, NMe 2 , OMe, and the like.
  • thioalkoxy may refer to an alkyl thioether radical, S-alkyl, wherein the alkyl group is a linear or branched Cl-ClO, preferably a linear or branched C1-C6, more preferably a linear or branched C1-C4, most preferably a linear or branched C1-C3 saturated hydrocarbon radical.
  • thioalkoxy groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, and the like.
  • the thioalkoxy group may be unsubstituted or substituted.
  • Substituents of the thioalkoxy group may be, for example, H, halogen, N0 2 , CN, NMe 2 , OMe, and the like.
  • alkylsulfonyl may refer to an alkylsulfonyl group -(S0 2 )Alk, wherein the alkyl portion Alk of the alkylsulfonyl group is a linear or branched Cl-ClO, preferably a linear or branched C1-C6, more preferably a linear or branched Cl- C4, most preferably a linear or branched C1-C3 saturated hydrocarbon radical.
  • the alkylsulfonyl group may be unsubstituted or substituted.
  • Substituents of the alkylsulfonyl group may be, for example, H, halogen, N0 2 , CN, NMe 2 , OMe, and the like.
  • the term "optionally substituted alkylsulfoxyl” may refer to an alkylsulfoxyl group -(SO)Alk, wherein the alkyl portion Alk of the alkylsulfoxyl group is a linear or branched Cl-ClO, preferably a linear or branched C1-C6, more preferably a linear or branched C1-C4, most preferably a linear or branched C1-C3 saturated hydrocarbon radical.
  • the alkylsulfoxyl group may be unsubstituted or substituted.
  • Substituents of the alkylsulfoxyl group may be, for example, H, halogen, N0 2 , CN, NMe 2 , OMe, and the like.
  • the definitions of the substituents provided in this paragraph may be also applied to the following specific embodiments which make reference to an optionally substituted benzoic acid halide. In particular, these definitions may be applied to the radical of the specific embodiments set forth in the following which make reference to an optionally substituted benzoic acid halide having formula (I).
  • substituents may be applied to an "optionally substituted naphtalene carboxylic acid halide", an “optionally substituted 1-naphthalene carboxylic acid halide” or an “optionally substituted 2-naphthalene carboxylic acid halide” as set forth herein further below.
  • the optionally substituted benzoic acid halide has the formula (I):
  • R is each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl optionally substituted alkoxy, optionally substituted alkanoyloxy, optionally substituted alkylamino, optionally substituted alkanoylamino, optionally substituted alkanoyl, carboxyl, optionally substituted alkoxycarbonyl, carbamoyl, optionally substituted N-alkylcarbamoyl, optionally substituted N,N-dialkylcarbamoyl, optionally substituted thioalkoxy, optionally substituted alkylsulfonyl, and optionally substituted alkylsulfoxyl;
  • n is an integer of from 0 to 5, preferably of from 0 to 3, more preferably of from 0 to 2 and most preferably of from 0 to 1;
  • X is a halogen atom, preferably a chlorine atom or a bromine atom, more preferably a chlorine atom.
  • X of formula (I) is a chlorine atom
  • the hydroxyl group of the alcohol is replaced by a chlorine atom.
  • X is a bromine atom
  • the hydroxyl group of the alcohol is replaced by a bromine atom.
  • the radical R is each independently selected from the group consisting of hydrogen, halogen, nitro, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkanoyloxy, optionally substituted alkylamino, optionally substituted alkanoylamino; wherein n is an integer of from 0 to 5, preferably of from 0 to 3, more preferably of from 0 to 2 and most preferably of from 0 to 1;
  • X is a halogen atom, preferably a chlorine atom or a bromine atom, more preferably a chlorine atom.
  • the radical is each independently selected from the group consisting of hydrogen, halogen, nitro, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted alkylamino;
  • n is an integer from 0 to 5, preferably of from 0 to 3, more preferably of from 0 to 2 and most preferably of from 0 to 1;
  • X is a halogen atom, preferably a chlorine atom or a bromine atom, more preferably a chlorine atom.
  • the radical R is each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, nitro, methyl, methoxy, and ⁇ , ⁇ -dimethyl amino;
  • n is an integer from 0 to 5, preferably of from 0 to 3, more preferably of from 0 to 2 and most preferably of from 0 to 1;
  • X is a halogen atom, preferably a chlorine atom or a bromine atom, more preferably a chlorine atom.
  • n 1 or 2.
  • R may be each the same.
  • X is a chlorine atom. Accordingly, in some preferred embodiments the compound of formula (I) represents an optionally substituted benzoyl chloride.
  • the compound of formula (I) is selected from the group consisting of:
  • the N-substituted formamide may be selected from the group consisting of N-methylformamide, ⁇ , ⁇ -dimethylformamide, N- formylpyrrolidine, and any combination thereof.
  • the compound of formula (I) is selected from the group consisting of
  • the N-substituted formamide may be selected from the group consisting of N-methylformamide, ⁇ , ⁇ -dimethylformamide, N- formylpyrrolidine, and any combination thereof.
  • the compound of formula (I) is selected from the group consisting of t and any combination thereof.
  • the N-substituted formamide may be selected from the group consisting of N-methylformamide, N,N- dimethylformamide, N-formylpyrrolidine, and any combination thereof.
  • the compound of formula (I) is This compound is 2- fluorobenzoyl chloride and, in particular, it has been found that this compound is useful in the conversion of optically active, i.e. enantioenriched, chiral alpha-hydroxyesters to the corresponding chlorides.
  • optically active i.e. enantioenriched, chiral alpha-hydroxyesters
  • the corresponding a- chlorohydroxyesters are obtained in a particularly high enantiomeric purity.
  • the N-substituted formamide may be selected from the group consisting of N-methylformamide, ⁇ , ⁇ -dimethylformamide, N- formylpyrrolidine, and any combination thereof.
  • the compound of formula (I) is .
  • This compound is 4- methoxybenzoyl chloride and provides excellent yields of the chlorinated product in case that the alcohol to be converted into the corresponding chloride is an aliphatic alcohol.
  • the N-substituted formamide may be selected from the group consisting of N-methylformamide, ⁇ , ⁇ -dimethylformamide, N- formylpyrrolidine, and any combination thereof.
  • the compound of formula (I) is .
  • This compound is benzoyl chloride and provides excellent yield and selectivity for the chlorinated product in the methods of converting an alcohol into a corresponding chloride with a great variety of alcohols.
  • benzoyl chloride is readily available and minimizes the weight amount of waste since benzoyl chloride does not bear any further substituents.
  • benzoyl chloride is rather stable towards hydrolysis, and therefore the methods of converting an alcohol into the corresponding chloride described herein may be performed without special measures for excluding moisture, such as, for example, moisture from air, from the process in case that benzoyl chloride is used.
  • the N-substituted formamide may be selected from the group consisting of N-methylformamide, N,N- dimethylformamide, N-formylpyrrolidine, and any combination thereof.
  • the compound of formula (I) is j n j s compound is benzoyl bromide and may be used in case that the hydroxyl group of the alcohol is replaced by a bromine atom.
  • the N-substituted formamide may be selected from the group consisting of N-methylformamide, N,N- dimethylformamide, N-formylpyrrolidine, and any combination thereof.
  • the optionally substituted benzoic acid halide has the formula (II):
  • substituted benzoic acid halide is selected from the group consisting of
  • the optionally substituted benzoic acid halide is .
  • This compound is isopthaloyl chloride and provides particularly high yields in the conversion of an alcohol into the corresponding chloride in case that it is employed in substoichiometric amounts.
  • the N-substituted formamide may be selected from the group consisting of N-methylformamide, N,N- dimethylformamide, N-formylpyrrolidine, and any combination thereof.
  • the aromatic carboxylic acid halide is an optionally substituted naphthalene carboxylic acid halide.
  • optionally substituted naphthalene carboxylic acid halide encompasses an optionally substituted naphthalene carboxylic acid fluoride, an optionally substituted naphthalene carboxylic acid chloride, an optionally substituted naphthalene carboxylic acid bromide and an optionally substituted naphthalene carboxylic acid iodide.
  • the optionally substituted naphthalene carboxylic acid halide may be an optionally substituted naphthalene carboxylic acid chloride or an optionally substituted naphthalene carboxylic acid bromide.
  • the optionally substituted naphthalene carboxylic acid halide is an optionally substituted 1-naphthalene carboxylic acid halide.
  • the optionally substituted 1- naphthalene carboxylic acid halide may be an optionally substituted 1-naphthalene carboxylic acid chloride or an optionally substituted 1-naphthalene carboxylic acid bromide.
  • the optionally substituted naphthalene carboxylic acid halide is an optionally substituted 2- naphthalene carboxylic acid halide.
  • the optionally substituted 2-naphthalene carboxylic acid halide may be an optionally substituted 2-naphthalene carboxylic acid chloride or an optionally substituted 2-naphthalene carboxylic acid bromide.
  • the naphthalene carboxylic acid halide may be unsubstituted or may carry 1, 2, 3, 4, 5, 6, or 7 of the aforementioned substituents. More preferably, the naphthalene carboxylic acid halide is unsubstituted or carries 1, 2, or 3 of these substituents.
  • substituents of the naphthalene carboxylic acid are H, CH 3 , halogen, N0 2 , CN, NMe 2 , OMe, and the like.
  • N-substituted formamide as used with regard to any one of the methods for converting an alcohol into the corresponding halide described herein denotes a compound which has the formula (III):
  • Rl and R2 are not both hydrogen. In this respect, at most one out of Rl and R2 may be hydrogen.
  • the N-substituted formamide employed in the methods disclosed herein is an N- monosubstituted formamide or an ⁇ , ⁇ -disubstituted formamide.
  • N-monosubstituted formamide one of Rl and R2 is hydrogen, and the other of Rl and R2 is not hydrogen.
  • Rl and R2 are not hydrogen and may be the same or different from each other.
  • N-substituted formamide has the formula (III):
  • Rl and R2 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted aralkyl.
  • Rl and R2 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted aralkyl.
  • the possible meaning of some substituents disclosed above and below for Rl and R2 within the context of an N-substituted formamide having the formula (III) is defined in the following.
  • the term "optionally substituted alkyl” may refer to a linear or branched C1-C6, preferably to a linear or branched C1-C4, more preferably to a linear or branched C1-C3, most preferably to a linear or branched C1-C2 saturated hydrocarbon radical.
  • alkyl group examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and the like.
  • the alkyl group may be unsubstituted or substituted.
  • Substituents of the alkyl group may be, for example, H, halogen, N0 2 , CN, NMe 2 , OMe, and the like.
  • cycloalkyl may refer to a saturated hydrocarbon ring containing from three to ten ring carbon atoms, preferably from four to seven ring carbon atoms, and more preferbly five or six ring carbon atoms.
  • the cycloalkyl group may be unsubstituted or substituted.
  • Substituents of the cycloalkyl group may be, for example, H, halogen, a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n- butyl, sec-butyl, tert-butyl, and the like, N0 2 , CN, NMe 2 , OMe, and the like.
  • optionally substituted aryl may refer to an aromatic hydrocarbon radical having six to ten ring atoms, and includes fused and non-fused aryl rings.
  • aryl may be a phenyl or naphthyl radical.
  • aryl is a phenyl radical.
  • the aryl group may be unsubstituted or substituted.
  • Substituents of the aryl group may be, for example, H, halogen, a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n- butyl, sec-butyl, tert-butyl, and the like, N0 2 , CN, NMe 2 , OMe, and the like.
  • a non-limiting example for an optionally substituted aryl group is an optionally substituted phenyl group.
  • phenyl when used herein whithin the context of formula (III) may denote an unsubstituted or substituted phenyl group.
  • Substituents of the phenyl group may be, for example, H, halogen, a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso- propyl, n-butyl, sec-butyl, tert-butyl, and the like, N0 2 , CN, NMe 2 , OMe, and the like.
  • heteroaryl may refer to aromatic radicals containing from five to ten skeletal ring atoms, preferably from five to seven skeletal ring atoms, more preferably five or six skeletal ring atoms, where one or more of the ring atoms is a heteroatom independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon and selenium, preferably selected from oxygen, nitrogen and sulfur, but not limited to these atoms.
  • heteroaryl may include heteroaryl radicals having one or two heteroatoms.
  • Heteroaryl may also include fused and non-fused heteroaryls having from five to ten skeletal ring atoms.
  • the heteroaryl group may be unsubstituted or substituted.
  • Substituents of the heteroaryl group may be, for example, H, halogen, a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso- propyl, n-butyl, sec-butyl, tert-butyl, and the like, N0 2 , CN, NMe 2 , OMe, and the like.
  • alkyl portion Alk is a linear or branched C1-C6, preferably a linear or branched C1-C4, more preferably a linear or branched Cl- C3, most preferably a linear or branched C1-C2 saturated hydrocarbon radical.
  • alkyl portion Alk include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, and the like.
  • the aryl portion Ar of the aralkyl group may be an aromatic hydrocarbon radical having six to ten ring atoms, and includes fused and non-fused aryl rings.
  • the aryl portion may be a phenyl or naphthyl radical.
  • the aryl portion Ar is a phenyl radical.
  • Non- limiting examples for the aralkyl group are benzyl, phenylethyl, phenyl-n-propyl, and the like.
  • the aralkyl group may be unsusbtituted or substituted.
  • Substituents of the aralkyl group may be, for example, H, halogen, a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, and the like, N0 2 , CN, NMe 2 , OMe, and the like.
  • the substituents may be attached to the alkyl portion and/or the aryl portion of the aralkyl group. Preferably, the substituents are attached to the aryl portion, and the alkyl portion is unsubstituted.
  • an optionally substituted aralkyl group is an optionally substituted benzyl group.
  • the term "optionally substituted benzyl” may denote an unsubstituted or substituted benzyl group.
  • Substituents of the benzyl group may be, for example, H, halogen, a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, and the like, N0 2 , CN, NMe 2 , OMe, and the like.
  • the substituents may be attached to the phenyl portion and/or the CH 2 portion of the benzyl group.
  • the phenyl portion of the benzyl group is substituted and the CH 2 portion of the benzyl group is unsubstituted.
  • the N-substituted formamide has the formula (III), wherein l and R2 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted aralkyl.
  • the N-substituted formamide has the formula (III), wherein Rl and R2 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted phenyl and optionally substituted benzyl. In some embodiments the N-substituted formamide has the formula (III), wherein Rl and R2 are the same.
  • the N-substituted formamide has the formula (III), wherein Rl and R2 are each independently selected from the group consisting of hydrogen and optionally substituted alkyl.
  • Rl may be hydrogen and R2 may be optionally substituted alkyl.
  • R2 may be, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl or tert- butyl.
  • both Rl and R2 may be optionally substituted alkyl.
  • one or both of Rl and R2 may be, for example, methyl, ethyl, n-propyl or n-butyl.
  • the N-substituted formamide has the formula (III), wherein Rl is selected from the group consisting of hydrogen and optionally substituted alkyl; and wherein R2 is selected from the group consisting of optionally substituted phenyl and optionally substituted benzyl.
  • the N-substituted formamide has the formula (III), wherein Rl is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl and n-butyl; and wherein R2 is selected from the group consisting of optionally substituted phenyl and optionally substituted benzyl.
  • Rl is selected from the group consisting of hydrogen, methyl or ethyl. More preferably, Rl is hydrogen or methyl.
  • the N-substituted formamide has the formula (III), wherein Rl and R2 are both optionally substituted benzyl.
  • the N-substituted formamide has the formula (III), wherein Rl and R2 are each optionally substituted alkyl; and wherein Rl and R2 are joined together to form a three- to eight-membered ring.
  • Said ring may optionally comprise 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, silicon, phosphorus, and any combination thereof.
  • the optional heteroatoms are selected from the group consisting of nitrogen, oxygen, sulfur, and any combination thereof.
  • Rl and R2 are joined together to form a four- to seven- membered ring, more preferably to form a five- or six-membered ring.
  • N-substituted formamide is selected from the group consisting of
  • N-substituted formamides have been found out to provide high yields in the methods of converting an alcohol into a corresponding halide with a particularly high selectivity for the halogenated product.
  • N-substituted formamide is selected from , O O
  • the N-substituted formamide is .
  • this compound N-formyl pyrrolidine may be used as the N-substituted formamide in case that benzoyl chloride, 4-methoxybenzoyl chloride and 2-fluoro benzoyl chloride, respectively, is used as the aromatic carboxylic acid halide. It has been found that N-formylpyrrolidine exhibits a high catalytic activity in the methods of converting an alcohol into the corresponding halide described herein and therefore allows for particularly low catalyst loadings compared to other N-substituted formamides without compromising yield and selectivity for the halogenated product.
  • N-formyl pyrrolidine is particularly preferred in case that the alcohol to be converted into the corresponding halide is an optically active alcohol, i.e. an enantioenriched chiral alcohol.
  • the corresponding halides can be obtained in a particularly high enantiomeric urity.
  • the N-substituted formamide is .
  • ⁇ , ⁇ -dimethyl formamide may be used as the N-substituted formamide in case that benzoyl chloride is used as the aromatic carboxylic acid halide.
  • ⁇ , ⁇ -dimethylformamide is readily available and provides high yield and selectivity for the halogenated product when employed in the methods of converting an alcohol into a corresponding halide described herein.
  • ⁇ , ⁇ -dimethyl formamide can be used in catalytic amounts. However, it is also possible to use excess ⁇ , ⁇ -dimethyl formamide as solvent in the methods of converting an alcohol to a corresponding halide described herein.
  • N-substituted formamide is H X NHMe .
  • this compound N-methyl formamide may be used as the N-substituted formamide in case that benzoyl chloride is used as the aromatic carboxylic acid halide.
  • N-methyl formamide also provides high yield and selectivity for the halogenated product when employed in the methods for converting an alcohol into the corresponding halide described herein.
  • N-methyl formamide is the N-substituted formamide having the lowest molecular mass and is therefore particularly useful in case that the conversion of an alcohol into the corresponding halide is performed in a large scale. In this context, due to the low molecular mass in a large scale synthesis the weight amount of waste can be efficiently lowered.
  • the alcohol employed in the methods of converting an alcohol into a corresponding halide described herein is not particularly limited, and virtually any alcohol can be used. As shown in the Examples, a great variety of structurally different alcohols can be converted into the corresponding halides using the methods disclosed herein.
  • an alcohol is regarded as a compound in which a hydroxyl group is bound to a saturated carbon atom.
  • a compound in which a hydroxyl group is bonded to an unsaturated carbon atom, such as an aromatic or an olefinic carbon atom is in general not regarded as an alcohol.
  • phenol or an enol is not regarded as an alcohol.
  • the alcohol is a primary, a secondary or a tertiary alcohol.
  • the alcohol has the formula (IV):
  • R3, R4 and R5 are each independently selected from the group consisting of hydrogen, deuterium, carboxylic acid ester, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkenyl, optionally substituted alkynyl, optionally substituted heteroalkynyl, optionally substituted cycloalkynyl, optionally substituted heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted aralkenyl, optionally substituted heteroaralkenyl, optionally substituted aralkinyl, and optionally substituted heteroaralkinyl.
  • optionally substituted alkyl may refer to a linear or branched C1-C30, preferably to a linear or branched C1-C20, more preferably to a linear or branched C1-C15, still more, preferably to a linear or branched C1-C10, and most preferably to a linear or branched C1-C5 saturated hydrocarbon radical.
  • alkyl group examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, decyl, dodecyl, and the like.
  • the alkyl group may be unsubstituted or substituted.
  • Substituents of the alkyl group may be, for example, H, halogen, a nitrogen containing group such as, for example, N0 2 , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond and the like.
  • a nitrogen containing group such as, for example, N0 2 , CN
  • a protected or substituted amino group such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like
  • a protected or substituted hydroxyl group such as, for
  • optionally substituted heteroalkyl may refer to a linear or branched saturated hydrocarbon-containing radical comprising 1 to 30, preferably 1 to 20, more preferably 1 to 15, still more preferably 1 to 10 and most preferably 1 to 5 chain atoms, wherein one or more of the chain atoms is a heteroatom independently selected from oxygen, nitrogen, sulfur, selenium, phosphorus and silicon, but not limited to these atoms.
  • a non-limiting example for heteroalkyl may be an oligoethyleneglycol radical.
  • the heteroalkyi group may be unsubstuted or substituted.
  • Substituents of the heteroalkyi group may be, for example, H, halogen, a nitrogen containing group, such as, for example, N0 2 , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond and the like.
  • a nitrogen containing group such as, for example, N0 2 , CN
  • a protected or substituted amino group such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like
  • a protected or substituted hydroxyl group such as
  • cycloalkyi may refer to a saturated hydrocarbon ring having from three to fifteen ring carbon atoms, preferably from four to ten ring carbon atoms, more pfererably from five to seven ring carbon atoms, and most preferably five or six ring carbon atoms.
  • the cycloalkyi group may be unsubstituted or substituted.
  • Substituents of the cycloalkyi group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl and the like, a nitrogen containing group, such as, for example, N0 2 , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond and the like.
  • heterocycloalkyl may refer to a cyclic hydrocarbon radical having from three to fifteen ring atoms, preferably from four to ten ring atoms, more pfererably from five to seven ring atoms, and most preferably five or six ring atoms, wherein one or more of the ring atoms is a heteroatom independently selected from oxygen, nitrogen, sulfur, selenium, phosphorus and silicon, but not limited to these atoms.
  • the heterocycloalkyl group may be unsubstituted or substituted.
  • Substituents of the heterocycloalkyl group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n- butyl, sec-butyl, tert-butyl and the like, a nitrogen containing group, such as, for example, N0 2 , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond and the like.
  • optionally substituted alkenyl may refer to a linear or branched C2-C30, preferably to a linear or branched C2-C20, more preferably to a linear or branched C2-C15, still more preferably to a linear or branched C2-C10, most preferably to a linear or branched C2-C5 radical having one or more carbon-carbon double bond(s).
  • the group may be either in the cis or trans configuration about the double bond(s), and should be understood to include both isomers.
  • the alkenyl group may be unsubstituted or substituted.
  • Substituents of the alkenyl group may be, for example, H, halogen, a nitrogen containing group, such as, for example, N0 2 , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon triple bond and the like.
  • a nitrogen containing group such as, for example, N0 2 , CN
  • a protected or substituted amino group such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like
  • a protected or substituted hydroxyl group such as, for example, an ether group, in particular such as
  • optionally substituted heteroalkenyl may refer to a linear or branched hydrocarbon-containing radical comprising 1 to 30, preferably 1 to 20, more preferably 1 to 15, still more preferably 1 to 10 and most preferably 1 to 5 chain atoms, wherein one or more of the chain atoms is a heteroatom independently selected from oxygen, nitrogen, sulfur, selenium, phosphorus and silicon, but not limited to these atoms, and wherein the radical has one or more carbon-carbon double bond.
  • the group may be either in the cis or trans configuration about the double bond(s), and should be understood to include both isomers.
  • the heteroalkenyl group may be unsubstituted or substituted.
  • Substituents of the heteroalkenyl group may be, for example, H, halogen, a nitrogen containing group, such as, for example, N0 2 , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon- carbon triple bond and the like.
  • a nitrogen containing group such as, for example, N0 2 , CN
  • a protected or substituted amino group such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like
  • a protected or substituted hydroxyl group such as, for example, an ether group, in particular such
  • cycloalkenyl may refer to an olefinic unsaturated hydrocarbon ring having from three to fifteen ring carbon atoms, preferably from four to ten ring carbon atoms, more pfererably from five to seven ring carbon atoms, and most preferably five or six ring carbon atoms, wherein the hydrocarbon ring has one or more carbon- carbon double bond.
  • the cycloalkenyl group may be unsubstituted or substituted.
  • Substituents of the cycloalkenyl group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl and the like, a nitrogen containing group, such as, for example, N0 2 , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond and the like
  • heterocycloalkenyl may refer to an olefinic unsaturated cyclic radical having from three to fifteen ring atoms, preferably from four to ten ring atoms, more pfererably from five to seven ring atoms, and most preferably five or six ring atoms, wherein one or more of the ring atoms is a heteroatom independently selected from oxygen, nitrogen, sulfur, selenium, phosphorus and silicon, but not limited to these atoms, and wherein the ring has one or more carbon-carbon double bond(s).
  • the heterocycloalkenyl group may be unsubstituted or substituted.
  • Substituents of the heterocycloalkenyl group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n- butyl, sec-butyl, tert-butyl and the like, a nitrogen containing group, such as, for example, N0 2 , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, and the
  • alkynyl may refer to a linear or branched C2-C30, preferably to a linear or branched C2-C20, more preferably to a linear or branched C2-C15, still more preferably to a linear or branched C2-C10, most preferably to a linear or branched C2-C5 radical having one or more carbon-carbon triple bond(s).
  • Non-limiting examples include ethynyl, 1-propynyl, 1-butynyl, 1,3-butadiynyl and the like.
  • the alkynyl group may be unsubstituted or substituted.
  • Substituents of the alkynyl group may be, for example, H, halogen, a nitrogen containing group, such as, for example, N0 2 , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, and the like.
  • a nitrogen containing group such as, for example, N0 2 , CN
  • a protected or substituted amino group such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like
  • a protected or substituted hydroxyl group such as, for example, an ether group, in particular
  • optionally substituted heteroalkynyl may refer to a linear or branched hydrocarbon-containing radical comprising 1 to 30, preferably 1 to 20, more preferably 1 to 15, still more preferably 1 to 10 and most preferably 1 to 5 chain atoms, wherein one or more of the chain atoms is a heteroatom independently selected from oxygen, nitrogen, sulfur, selenium, phosphorus and silicon, but not limited to these atoms, and wherein the radical has one or more carbon-carbon triple bond(s).
  • the heteroalkynyl group may be unsubstituted or substituted.
  • Substituents of the heteroalkynyl group may be, for example, H, halogen, a nitrogen containing group, such as, for example, N0 2 , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond and the like.
  • a nitrogen containing group such as, for example, N0 2 , CN
  • a protected or substituted amino group such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like
  • a protected or substituted hydroxyl group such as, for example, an ether group, in particular
  • cycloalkynyl may refer to an acetylenic unsaturated hydrocarbon ring having from eight to fifteen ring carbon atoms, preferably from ten to fifteen ring carbon atoms, wherein the hydrocarbon ring has one or more carbon-carbon triple bond.
  • the cycloalkynyl group may be unsubstituted or substituted.
  • Substituents of the cycloalkynyl group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl and the like, a nitrogen containing group, such as, for example, N0 2 , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, and
  • heterocycloalkynyl may refer to an acetylenic unsaturated cyclic radical having from eight to fifteen ring atoms, preferably from ten to fifteen ring atoms, wherein one or more of the ring atoms is a heteroatom independently selected from oxygen, nitrogen, sulfur, selenium, phosphorus and silicon, but not limited to these atoms, and wherein the ring has one or more carbon-carbon triple bond(s).
  • the heterocycloalkynyl group may be unsubstituted or substituted.
  • Substituents of the heterocycloalkynyl group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n- butyl, sec-butyl, tert-butyl and the like, a nitrogen containing group, such as, for example, N0 2 , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, and
  • aryl may refer to an aromatic hydrocarbon radical having six to ten ring atoms, and includes fused and non-fused aryl rings.
  • the aryl group may be a phenyl or naphthyl radical.
  • the aryl group is a phenyl radical.
  • the aryl group may be unsubstituted or substituted.
  • Substituents of the aryl group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl and the like, a nitrogen containing group, such as, for example, N0 2 , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, and the like.
  • heteroaryl may refer to aromatic radicals containing from five to ten skeletal ring atoms, preferably from five to seven skeletal ring atoms, more preferably five or six skeletal ring atoms, where one or more of the ring atoms is a heteroatom independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon and selenium, but not limited to these atoms.
  • Heteroaryl may also include fused and non-fused heteroaryls having from five to ten skeletal ring atoms. As denoted by the term “optionally substituted", the heteroaryl group may be unsubstituted or substituted.
  • Substituents of the heteroaryl group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl and the like, a nitrogen containing group, such as, for example, N0 2 , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, and the like.
  • optionally substituted aralkyl may refer to a group -Alk-Ar, wherein the alkyl portion Alk is a linear or branched C1-C10, preferably a linear or branched C1-C6, more preferably a linear or branched Cl- C4, still more preferably a linear or branched C1-C3, most preferably a linear or branched C1-C2 saturated hydrocarbon radical.
  • alkyl portion include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like.
  • the aryl portion Ar of the aralkyl group may be an aromatic hydrocarbon radical having six to ten ring atoms, and includes fused and non-fused aryl rings.
  • the aryl portion may be a phenyl or naphthyl radical.
  • the aryl portion is a phenyl radical.
  • Non-limiting examples for the aralkyl group are benzyl, phenylethyl, phenyl-n-propyl, and the like.
  • the aralkyl group may be unsubstituted or substituted.
  • Substituents of the aralkyl group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl and the like, a nitrogen containing group, such as, for example, N0 2 , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, and the like.
  • the substituents may be attached to the alkyl portion and/or the aryl portion of the aralkyl group.
  • the term "optionally substituted heteroaralkyl” may refer to a group - Alk-HAr, wherein the alkyl portion Alk is a linear or branched C1-C10, preferably a linear or branched C1-C6, more preferably a linear or branched C1-C4, still more preferably a linear or branched C1-C3, most preferably a linear or branched C1-C2 saturated hydrocarbon radical.
  • alkyl portion examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, pentyl, hexyl, and the like.
  • the heteroaryl portion HAr of the heteroaralkyl group may refer to aromatic radicals containing from five to ten skeletal ring atoms, preferably from five to seven skeletal ring atoms, more preferably five or six skeletal ring atoms, where one or more of the ring atoms is a heteroatom indenpendently selected from oxygen, nitrogen, sulfur, phosphorus, silicon and selenium, but not limited to these atoms.
  • the heteroaryl portion may also include fused and non-fused heteroaryls having from five to ten skeletal ring atoms.
  • the heteroaralkyl group may be unsubstituted or substituted.
  • Substituents of the heteroaralkyl group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec- butyl, tert-butyl and the like, a nitrogen containing group, such as, for example, N0 2 , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, and the like.
  • the substituents may be attached to the alkyl portion and/or the heteroaryl portion of the heteroaralkyl group.
  • the term "optionally substituted aralkenyl” may refer to a group -Alkenyl-Ar, wherein the alkenyl portion Alkenyl is a linear or branched C2-C10, preferably to a linear or branched C2-C6, more preferably to a linear or branched C2-C4, most preferably to a linear or branched C2-C3 radical having one or more carbon- carbon double bond(s).
  • the group may be either in the cis or trans configuration about the double bond(s), and should be understood to include both isomers.
  • alkenyl portion examples include, but are not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like.
  • the aryl portion Ar of the aralkyl group may be an aromatic hydrocarbon radical having six to ten ring atoms, and includes fused and non-fused aryl rings.
  • the aryl portion may be a phenyl or naphthyl radical.
  • the aryl portion is a phenyl radical.
  • the aralkenyl group may be unsubstituted or substituted.
  • Substituents of the aralkenyl group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert- butyl and the like, a nitrogen containing group, such as, for example, N0 2 , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, and the like
  • the substituents may be attached to the alkenyl portion and/or the aryl portion of the aralkenyl group.
  • the term "optionally substituted heteroaralkenyl” may refer to a group -Alkenyl-HAr, wherein the alkenyl portion Alkenyl is a linear or branched C2-C10, preferably to a linear or branched C2-C6, more preferably to a linear or branched C2-C4, most preferably to a linear or branched C2-C3 radical having one or more carbon- carbon double bonds.
  • the group may be either in the cis or trans configuration about the double bond(s), and should be understood to include both isomers.
  • alkenyl portion examples include, but are not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like.
  • the heteroaryl portion HAr of the heteroaralkenyl group may refer to aromatic radicals containing from five to ten skeletal ring atoms, preferably from five to seven skeletal ring atoms, more preferably five or six skeletal ring atoms, where one or more of the ring atoms is a heteroatom indenpendently selected from oxygen, nitrogen, sulfur, phosphorus, silicon and selenium, but not limited to these atoms.
  • the heteroaryl portion may also include fused and non-fused heteroaryls having from five to ten skeletal ring atoms.
  • the heteroaralkenyl group may be unsusbtituted or substituted.
  • Substituents of the heteroaralkenyl group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl and the like, a nitrogen containing group, such as, for example, N0 2 , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, and the like
  • the substituents may be attached to the alkenyl portion and/or the heteroaryl portion of the heteroaralkenyl group.
  • the term "optionally substituted aralkynyl” may refer to a group - Alkynyl-Ar, wherein the alkynyl portion Alkynyl is a linear or branched C2-C10, preferably to a linear or branched C2-C6, more preferably to a linear or branched C2-C4, most preferably to a linear or branched C2-C3 radical having one or more carbon-carbon triple bond(s).
  • alkynyl portion examples include, but are not limited to ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • the aryl portion Ar of the aralkynyl group may be an aromatic hydrocarbon radical having six to ten ring atoms, and includes fused and non-fused aryl rings.
  • the aryl portion may be a phenyl or naphthyl radical.
  • the aryl portion is a phenyl radical.
  • the aralkynyl group may be unsubstituted or substituted.
  • Substituents of the aralkynyl group may be, for example, H, halogen, a linear or branched C1-C6, a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl and the like, a nitrogen containing group, such as, for example, N0 2 , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, and the like.
  • the substituents may be attached to the alkynyl portion and/or the aryl portion of the aralkynyl group.
  • the term "optionally substituted heteroaralkynyl” may refer to a group -Alkynyl-HAr, wherein the alkynyl portion Alkynyl is a linear or branched C2-C10, preferably to a linear or branched C2-C6, more preferably to a linear or branched C2-C4, most preferably to a linear or branched C2-C3 radical having one or more carbon-carbon triple bond(s).
  • alkynyl portion examples include, but are not limited to ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • the heteroaryl portion HAr of the heteroaralkynyl group may refer to aromatic radicals containing from five to ten skeletal ring atoms, preferably from five to seven skeletal ring atoms, more preferably five or six skeletal ring atoms, where one or more of the ring atoms is a heteroatom independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon and selenium, but not limited to these atoms.
  • the heteroaryl portion may also include fused and non-fused heteroaryls having from five to ten skeletal ring atoms.
  • the heteroaralkynyl group may be unsubstituted or substituted.
  • Substituents of the heteroaralkynyl group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert- butyl and the like, a nitrogen containing group, such as, for example, N0 2 , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, and the
  • the alcohol has the formula (IV), wherein R3, R4 and R5 are each independently selected from the group consisting of hydrogen, carboxylic acid ester, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted aralkyl.
  • the optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroalkenyl, optionally substituted heterocycloalkenyl, optionally substituted heteroalkynyl, optionally substituted heterocycloalkynyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkinyl may comprise one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, sulfur, selenium, phosphorus, silicon, and any combination thereof.
  • the one or more heteroatoms are selected from the group consisting of nitrogen, oxygen, sulfur, and any combination thereof.
  • the alcohol has the formula (IV), wherein one of R3, R4 and R5 is hydrogen.
  • the two other radicals out of R3, R4 and R5, respectively, may be, in particular, independently selected from the radicals disclosed herein above with regard to formula (IV) and are each not hydrogen.
  • the alcohols of these embodiments are therefore secondary alcohols.
  • the alcohol has the formula (IV), wherein two of R3, R4 and R5 are hydrogen.
  • the one other radical out of R3, R4 and R5, respectively, may be, in particular, selected from the radicals disclosed herein above with regard to formula (IV) and is not hydrogen.
  • the alcohols of these embodiments are therefore primary alcohols.
  • the alcohol has the formula (IV), wherein one of 3, R4 and R5 is selected from the group consisting of methyl, ethyl and propyl.
  • "Propyl” may be n-propyl or iso-propyl.
  • the one of R3, R4 and R5 is methyl.
  • the two other radicals out of R3, R4 and R5, respectively may be, in particular, selected from the radicals disclosed herein above with regard to formula (IV) and are not hydrogen.
  • the alcohols of these embodiments are therefore tertiary alcohols.
  • the alcohol has the formula (IV), wherein two of R3, R4 and R5 are selected from the group consisting of methyl, ethyl and propyl.
  • "Propyl” may be n-propyl or iso-propyl.
  • two of R3, R4 and R5 are methyl.
  • the one other radical out of R3, R4 and R5, respectively, may be, in particular, selected from the radicals disclosed herein above with regard to formula (IV) and is not hydrogen.
  • the alcohols of these embodiments are therefore secondary alcohols.
  • the alcohol has the formula (IV), wherein one of R3, R4 and R5 is methyl or ethyl and one of R3, R4 and R5 is hydrogen.
  • the one other radical out of R3, R4 and R5, respectively, may be, in particular, selected from the radicals disclosed herein above with regard to formula (IV) and is not hydrogen.
  • the alcohols of these embodiments are thereforesecondary alcohols.
  • the alcohol is an optionally substituted alkyl alcohol.
  • An alkyl alcohol can be also regarded as an aliphatic alcohol, i.e. an alcohol, wherein the hydroxyl group is bonded to a saturated carbon atom.
  • the alkyl alcohol may be a linear or branched C2-C20 alkyl alcohol, prepferably a linear or branched C2-C15 alkyl alcohol, more preferably a linear or branched C2 to CIO alkyl alcohol and most preferably a linear or branched C2-C4 alkyl alcohol.
  • the alkyl alcohol may be unsubstituted or substituted.
  • Substituents of the alkyl alcohol may be, for example, H, halogen, a nitrogen containing group, such as, for example, N0 2 , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, a group comprising an aryl group or a heteroaryl group, and the like. Since the alkyl alcohol may be substituted with a group containing a carbon-carbon double bond, the alkyl alcohol may be a homoallylic alcohol. In
  • m is an integer of from 0 to 18, preferably of from 2 to 16, more preferably of from 4 to 14, even more preferably of from 6 to 12, and most preferably of from 8 to 10.
  • the alcohol is an optionally substituted allylic alcohol.
  • the allylic alcohol may be unsubstituted or substituted.
  • Substituents of the allylic alcohol may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert- butyl, pentyl, hexyl, and the like, a nitrogen containing group, such as, for example, N0 2 , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a
  • the alcohol is an optionally substituted propargylic alcohol.
  • the propargylic alcohol may be unsubstituted or substituted.
  • Substituents of the propargylic alcohol may be, for example, H, halogen, a linear or branched C1-C6, preferably C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like, a nitrogen containing group, such as, for example, N0 2 , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as
  • the alcohol is an optionally substituted benzylic alcohol.
  • a benzylic alcohol as referred to herein comprises the basic structure .
  • the benzylic alcohol may be unsubstituted or substituted.
  • Substituents of the benzylic alcohol may be, for example, H, halogen, a carboxylic acid ester, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like, a nitrogen containing group, such as, for example, N0 2 , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe 2 and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond,
  • the alcohol is an optionally substituted a-hydroxy carboxylic acid ester.
  • the a-hydroxy carboxylic acid ester may be unsubstituted substituted or substituted.
  • Substituents of the ⁇ -hydroxy carboxylic acid ester may be, for example, H, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, a group containing an aryl group such as, for example, a phenyl group or a phenyl group substituted with a hydrogen, a group containing a heteroaryl group, and the like.
  • a linear or branched C1-C6 preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-prop
  • the part of the carboxylic acid ester group which formally derives from the alcohol may be, for example, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso- propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, a group containing an aryl group such as, for example, a benzyl group, a group containing a heteroaryl group, and the like.
  • the optionally substituted a-hydroxy carboxylic acid ester is selected from the
  • the alcohol is an optically active alcohol.
  • An optically active alcohol as referred to herein may also be denoted as a chiral alcohol, i.e. an alcohol having a stereogenic center.
  • the "term optically active alcohol” denotes an enantioenriched chiral alcohol.
  • enantioenriched is to be understood that in a sample of the alcohol one enantiomer, i.e. the major enantiomer, is present in a major amount, while the other enantiomer, i.e. the minor enantiomer, is present in a minor amount.
  • the ratio of enantiomers deviates from a racemic sample in which both enantiomers are present in a 50:50 ratio.
  • the major enantiomer is present in an amount of more than 50 %, and the minor enantiomer is present in an amount of less than 50 %, each based on 100 % of both enantiomers.
  • the major amount may be present in the sample in 60 %, 70 %, 80 %, 90 % or even 95 % based on 100 % of both enantiomers.
  • the ratio of the major enantiomer to the minor enantiomer in other words the enantiomeric ratio, is 60:40, 70:30, 80:20, 90:10 and 95:5.
  • the enantiomeric ratio of the alcohol employed is substantially maintained in the obtained corresponding halide.
  • an enantioenriched alcohol having a high enantiomeric purity is used as starting material, such high enantiomeric purity is advantageously also found in the corresponding halide obtained as product.
  • the methods of converting an alcohol into the corresponding halide disclosed herein permit to synthesize halides having a high enantiomeric purity.
  • particularly good enantiomeric purities of the corresponding halide are achieved in case that N-formylpyrrolidine is used as the N-substituted formamide.
  • 2-fluorobenzoyl chloride provides a particularly high enantiomeric purity of the corresponding chlorides.
  • the optically active alcohol is enantioenriched 1-phenyl ethanol.
  • the optically active alcohol is enantioenriched 4-phenyl-2-butanol. In an embodiment the optically active alcohol is enantioenriched ethyl 2-hydroxypropanoate. In an embodiment the optically active alcohol is enantioenriched benzyl 2-hydroxypropanoate. In an embodiment the optically active alcohol is enantioenriched methyl 2-hydroxy-2-phenylethanoate.
  • the enantiomer present in major amount in the enantioenriched alcohol may be the ( ) enantiomer or the (S) enantiomer.
  • the N- substituted formamide may be used in catalytic amounts, substoichiometric amounts, stoichiometric amounts and overstoichiometric amounts.
  • catalytic substoichiometric
  • stoichiometric stoichiometric
  • overstoichiometric are used to denote the molar ratio of the N-substituted formamide to the hydroxyl groups of the alcohol to be converted into the corresponding halide.
  • the molar ratio of the N-substituted formamide to the hydroxyl groups is 1:1.
  • the molar ratio of the N-substituted formamide to the hydroxyl groups is less than 1, such as, e.g. 0.8, 0.5, 0.2 or 0.1.
  • the molar ratio of the N-substituted formamide to the hydroxyl groups is, for example, 1.1.
  • the N-substituted formamide is used in an amount of from 0,05 to 120 mol-%, preferably of from 0.1 to 80 mol-%, more preferably of from 0.5 to 70 mol-%, even more preferably of from 0.8 to 60 mol-%, still more preferably of from 1 to 50 mol-%, still more preferably of from 3 to 40 mol-%, still more preferably of from 5 to 30 mol-% and most preferably of from 10 to 20 mol-% based on 100 mol-% of the hydroxyl groups to be converted into the corresponding halide.
  • the N-substituted formamide may be used in an amount of from 1 to 40 mol-%, 5 to 60 mol-%, 5 to 20 mol-%, 10 to 20 mol-% and 20 to 60 mol-% based on 100 mol-% of the hydroxyl groups to be converted into the corresponding halide.
  • the term "mol-%" denotes the amount of the N-substituted formamide relative to a reference value of 100 mol-% of the hydroxyl groups to be converted into the corresponding halide.
  • the amount of the N-substituted formamide means that in case that 100 mmol of the hydroxyl groups are present, the amount of the N-substituted formamide is 20 mmol.
  • the amount of the N-substituted formamide may be expressed as the molar ratio of the N-substituted formamide to the hydroxyl groups to be converted into the corresponding halide.
  • the N-substituted formamide may be used in a molar ratio of the N-substituted formamide to the hydroxyl groups to be converted into the corresponding halide of from 0.0005 to 1.2, preferably of from 0.001 to 0.8, more preferably of from 0.005 to 0.7, even more preferably of from 0.008 to 0.6, still more preferably of from 0.01 to 0.5, still more preferably of from 0.03 to 0.4, still more preferably of from 0.05 to 0.3 and most preferably of from 0.1 to 0.2.
  • the N-substituted formamide may be used in a molar ratio of the N-substituted formamide to the hydroxyl groups to be converted into the corresponding halide of from 0.01 to 0.4, 0.05 to 0.6, 0.05 to 0.2, 0.1 to 0.2 and 0.2 to 0.6.
  • catalytic or substoichiometric amounts of the N-substituted formamide are in general sufficient to perform the methods of converting an alcohol into the corresponding halide described herein.
  • the minimum amount of the N-substituted formamide required for carrying out the methods described herein can be readily determined by a person skilled in the art using routine experimentation.
  • the conversion of the alcohol into the corresponding halide is carried out in a solvent.
  • the solvent is selected from the group consisting of N,N- dimethylformamide, dioxane, dichloromethane, tetrahydrofuran, acetone, diethylether, 1,2- dichloroethane, acetonitrile, chloroform, 1,2-dimethoxyethane, methyl-ieri-butyl ether, ethyl acetate, cyclohexane, toluene, and 2-methyl tetrahydrofuran, and any combination thereof.
  • the solvent in case that ⁇ , ⁇ -dimethylformamide is used as the solvent, it also acts as a catalyst for the conversion.
  • the solvent is selected from the group consisting of N,N- dimethylformamide, dioxane, dichloromethane, tetrahydrofuran, acetone, 2- Methyltetrahydrofurane, diethylether, 1,2-dichloroethane, methyl-ieri-butyl ether, acetonitrile, chloroform, and 1,2-dimethoxyethane, and any combination thereof. It has been found that in these solvents the conversion of the alcohol into the corresponding halide results in a high yield and selectivity for the halogenated product.
  • the solvent is selected from the group consisting of dioxane, methyl-ieri-butyl ether, acetone, and any combination thereof. Accordingly, in a preferred embodiment the solvent is dioxane. It has been found that by using dioxane as the solvent a particularly high selectivity for the halogenated product is achieved.
  • the solvent is methyl-terf-butyl ether.
  • Methyl-tert-butyl ether is an ecologically beneficial solvent and provides a high selectivity for the halogenated product. Furthermore, methyl-tert-butyl ether allows for a high enantiomeric purity in case that an optically active, enantioenriched alcohol is used as substrate for the conversion.
  • the solvent is acetone.
  • acetone is a solvent which is particularly environmentally beneficial and is therefore preferred from an ecological point of view.
  • the conversion of the alcohol into the corresponding halide can be carried out under solvent-free conditions.
  • solvent-free conditions is particularly preferred from the viewpoint of reducing waste and performing the methods of converting an alcohol into the corresponding halide as an economically as well as ecologically beneficial process.
  • solvent-free conditions does not exclude that the reaction is performed in the presence of an N-substituted formamide which may be also used as a solvent, such as, for example, N,N-dimethylformamide.
  • the N-substituted formamide is preferably used in substoichiometric or catalytic amounts. Also preferably, under solvent-free conditions the molar ratio of the N-substituted formamide to the hydroxyl groups of the alcohol to be converted into the corresponding halide is not more than 1.2:1.
  • the alcohol to be converted optionally a solvent, the N-substituted formamide and the optionally substituted aromatic carboxylic acid halide are added to a reaction vessel, and the resulting mixture is reacted for an appropriate time at an appropriate temperature.
  • the acohol, the N- substituted formamide and the optionally substituted aromatic carboxylic acid halide may be added contemporaneously.
  • Appropriate conditions for the temperature and the time can be readily selected by a person skilled in the art.
  • the reaction mixture is stirred during the conversion of the alcohol into the halide.
  • a step of pre-forming a halogenation reagent may be avoided, as the aromatic carboxylic acid and the alcohol react with each other in the presence of the N-substituted formamide to convert the alcohol into the corresponding halide. Accordingly, in some embodiments the methods may be performed without employing a pre-formed halogenation reagent such as, for example, a reagent pre-formed from an N- substituted formamide and a carboxylic acid halide, and/or a Vilsmeier reagent.
  • a pre-formed halogenation reagent such as, for example, a reagent pre-formed from an N- substituted formamide and a carboxylic acid halide, and/or a Vilsmeier reagent.
  • the temperature at which the methods of converting an alcohol into the corresponding halide described herein are performed is not particularly limited.
  • the conversion of the alcohol into the corresponding halide is carried out at a temperature of from 0°C to 120°C, preferably of from 2°C to 100°C, more preferably of from 5°C to 80°C, even more preferably of from 10°C to 60°C, still more preferably of from 15°C to 40 °C, and most preferably of from 20°C to 25°C.
  • the reaction time is not particularly limited.
  • the conversion of the alcohol into the corresponding halide is carried out for a time of from 0.5 hours to 48 hours, preferably of from 1 hour to 24 hours, more preferably of from 2 hours to 20 hours, and most preferably of from 5 hours to 12 hours.
  • the corresponding halide obtained from the alcohol by any one of the methods described herein may be isolated from the reaction mixture. Any suitable isolation technique may be used. As an example, the isolation may comprise work-up of the reaction mixture and/or purification of the corresponding halide. For example, the work-up may be carried out as aqueous work-up. Purification of the corresponding halide may be carried out using chromatography or distillation.
  • the methods of converting an alcohol into a corresponding halide described herein may comprise that an alcohol is reacted with an optionally substituted aromatic carboxylic acid chloride in presence of an N-substituted formamide and a bromide salt.
  • the inventor has found that when reacting an alcohol with an optionally substituted aromatic carboxylic acid chloride in the presence of an N-substituted formamide and in the presence of a bromide salt, the alcohol can be efficiently converted into the corresponding bromide by replacing the hydroxyl group of the alcohol by a bromine atom.
  • the present invention also relates to a method of converting an alcohol into a corresponding halide, the method comprising:
  • any alcohol described herein in the context of the methods of converting an alcohol into the corresponding halide may be used.
  • the alcohol is an optionally substituted benzylic alcohol.
  • the alcohol is an optionally substituted alkyl alcohol.
  • any optionally substituted carboxylic acid chloride described herein in the context of converting an alcohol into the corresponding halide in presence of an N-substituted formamide may be used.
  • benzoyl chloride is used as the carboxylic acid chloride.
  • I n some embodiments 2,6-dichlorobenzoyl chloride is used as the aromatic carboxylic acid chloride.
  • I n general, any N-substituted formamide described herein in the context of the methods of converting an alcohol into the corresponding halide may be used.
  • N- formylpyrrolidine, ⁇ , ⁇ -dimethylformamide and/or N-methyl formamide is used as the N- substituted formamide.
  • N-formylpyrrolidine is used.
  • the bromide salt used in these embodiments is not particularly limited.
  • an alkali metal bromide salt is used.
  • the alkali metal bromide salt may be, for example, selected from the group consisting of lithium bromide, sodium bromide, potassium bromide and any combination thereof.
  • sodium bromide may be used as the bromide salt.
  • the methods of converting an alcohol into a corresponding halide described herein may comprise that an alcohol is reacted with an optionally substituted aromatic carboxylic acid chloride in presence of an N-substituted formamide and an iodide salt.
  • the inventor has found that when reacting an alcohol with an optionally substituted aromatic carboxylic acid chloride in the presence of an N-substituted formamide and in the presence of an iodide salt, the alcohol can be efficiently converted into the corresponding iodide by replacing the hydroxyl group of the alcohol by an iodine atom.
  • the present invention also relates to a method of converting an alcohol into a corresponding halide, the method comprising:
  • any alcohol described herein in the context of the methods of converting an alcohol into the corresponding halide may be used.
  • the alcohol is an optionally substituted benzylic alcohol.
  • the alcohol is an optionally substituted alkyl alcohol.
  • any optionally substituted carboxylic acid chloride described herein in the context of converting an alcohol into the corresponding halide in presence of an N-substituted formamide may be used.
  • benzoyl chloride is used as the carboxylic acid chloride.
  • 2,6-dichlorobenzoyl chloride is used as the aromatic carboxylic acid chloride.
  • any N-substituted formamide described herein in the context of the methods of converting an alcohol into the corresponding halide may be used.
  • N-formylpyrrolidine, ⁇ , ⁇ -dimethylformamide and/or N-methyl formamide is used as the N-substituted formamide.
  • N-formylpyrrolidine is used.
  • the iodide salt used in these embodiments is not particularly limited. For example, in some embodiments an alkali metal iodide salt is used.
  • the alkali metal iodide salt may be, for example, selected from the group consisting of lithium iodide, sodium iodide, potassium iodide and any combination thereof.
  • lithium iodide may be used as the iodide salt.
  • the present invention also relates to a halide obtainable or being obtained from an alcohol by any one of the methods of converting an alcohol into a corresponding halide disclosed herein.
  • the present invention further relates to a method of converting an alcohol into a corresponding substitution product, the method comprising:
  • step (a) of the method of converting an alcohol into a corresponding substitution product the alcohol is converted into the corresponding halide in accordance with any one the methods described herein above.
  • step (b) the corresponding halide is then reacted with a nucleophile.
  • step (b) the halide undergoes a nucleophilic substitution reaction with the nucleophile which converts the halide into the corresponding nucleophilic substitution product.
  • step (a) and before step (b) the corresponding halide may be isolated from the reaction mixture.
  • steps (a) and (b) are performed in a one-pot procedure without isolation of the halide.
  • the halide obtained in step (a) is not isolated from the reaction mixture, and in step (b) the nucleophile is combined directly with the reaction mixture obtained in step (a), which comprises the halide.
  • the halide is preferably added to the same reaction vessel in which the conversion of step (a) is performed.
  • steps (a) and (b) in a one-pot procedure saves an isolation step, which may include work-up of the reaction mixture and/or purification of the halide, and is thus advantageous from an economical and ecological point of view.
  • the nucleophile is selected from the group consisting of C nucleophiles, N nucleophiles, O nucleophiles, and S nucleophiles.
  • the C nucleophile is a cyanide or an enolate.
  • the C nucleophile is a cyanide or an enolate.
  • CN denotes the cyanide ion.
  • the N nucleophile is selected from the group consisting of an amine, an amide
  • N nucleophile may be selected from the group consisting of /
  • N 3 ⁇ denotes the azide ion.
  • the O nucleophile is a compound having a hydroxyl group or a deprotonated hydroxyl group.
  • the compound having a hydroxyl group may be an alcohol.
  • the compound having a deprotonated hydroxyl group may be, for example, an alcoholate.
  • the O-nucleophile may be also an
  • aromatic hydroxyl compound such as, for example, or a deprotonated aromatic hydroxyl compound.
  • the S nucleophile is a thiol or a thiolate.
  • the S nucleophile is In some embodiments of the method of converting an alcohol into a corresponding substitution
  • step (a) the alcohol reacted in step (a) and the nucleophile reacted in step (b) are:
  • step (a) the alcohol reacted in step (a) and the nucleophile reacted in step (b) are
  • step (a) of the methods of converting an alcohol into a corresponding substitution product any solvent or solvent mixture as described herein above with regard to the methods of converting an alcohol into the corresponding halide may be used.
  • step (a) is performed using dioxane as solvent.
  • dioxane can be used in case that steps (a) and (b) are performed in a one-pot procedure without isolation of the halide. Accordingly, dioxane may be also used as solvent in step (b).
  • a further solvent in step (b) such as, for example, acetonitrile or methanol.
  • step (b) may be performed using a mixture of dioxane and acetonitrile.
  • step (b) may be performed using a mixture of dioxane and methanol.
  • step (a) is performed using benzoyl chloride as the aromatic carboxylic acid halide as the N-substituted formamide.
  • N-formyl pyrrolidine can be employed in catalytic amounts and allows for particularly low catalyst loadings compared to other N- substituted formamides described herein.
  • benzoyl chloride provides good results with a great variety of alcohols, is readily available and minimizes the amount of waste since it does not bear any further substituents.
  • Step (b) of any one of the methods of converting an alcohol into a corresponding substitution product described herein may be performed in the presence of a base.
  • a base in step (b) has turned out to be particularly useful in case that the nucleophile comprises a protic functional group which can be deprotonated by a base.
  • deprotonation of the nucleophile increases nucleophilicity and therefore reactivity in step (b) of the methods of converting an alcohol into a corresponding substitution product.
  • Suitable bases which can be used in step (b) of the methods described herein are, for example, alkali carbonates or tertiary amines, such as triethyl amine. Accordingly, in an embodiment the base may be potassium carbonate.
  • step (b) of the methods of converting an alcohol into the corresponding substitution product described herein is performed is not particularly limited.
  • a suitable reaction temperature can be appropriately selected by a person skilled in the art.
  • step (b) is performed at a temperature of from 0°C to 120°C, preferably of from 2°C to 100°C, more preferably of from 5°C to 80°C, even more preferably of from 10°C to 60°C, still more preferably of from 15°C to 40 °C, and most preferably of from 20°C to 25°C.
  • the reaction time of step (b) is not particularly limited and can be appropriately selected by a skilled person.
  • step (b) is carried out for a time of from 0.5 hours to 48 hours, preferably of from 1 hour to 24 hours, more preferably of from 2 hours to 20 hours, and most preferably of from 2 hours to 12 hours.
  • the present invention also relates to a substitution product obtainable or being obtained from an alcohol by any one of the methods of converting an alcohol into a corresponding substitution product disclosed herein.
  • KMn0 4 3 g KMn0 4 and 20 g K 2 C0 3 in 300 mL water
  • GC Gas chromatography
  • a GC-2010 from Shimadzu with a CP-Chirasil-DX CB column (length 25 m, diameter 0.25 mm, 0.25 ⁇ layer thickness) from Agilent Technologies and nitrogen as carrier gas.
  • Compounds were either detected by an FID or a GCMS-QP2010 Plus mass detector from Shimadzu.
  • High pressure liquid chromatography (HPLC) was conducted on a D-7000 machine from Merck-Hitachi with a Chiracel OD-H column of Daicel Industries (length 250 mm, diameter 4.6 mm). Visualisation was realized by a diode array UV detector (wavelength 190-300 nm).
  • a 4 mL glas vial with a stir bar was charged successively with the alcohol 1 (1.0 equiv, 0.2-1 mmol) and the catalyst, in particular the N-substituted formamide, either in pure form or as a 1 N solution in the solvent (In order to improve the accuracy of the determination of the catalyst loading for instance from DMF and FPyr were prepared 1 N stock solutions in the solvent and added via an Eppendorf pipette to the reaction vessel) and the mixture was diluted with the solvent to the desired concentration.
  • the acid chloride was added via an Eppendorf pipette (Due to the high viscosity of for instance some starting materials 1 the amount of 1, the catalyst and reagent was additionally checked by weighing (in the reaction vial). at ambient temperature and the reaction mixture was stirred for the time period t at the reaction temperature T.
  • the crude product was dried either at 50 mbar for 2 min (chlorides 2 ⁇ 8 C-atoms), for 5 min (chlorides 2 9-10 C-atoms) or 2 min at 20 mbar (chlorides 2 >10 C-atoms). Finally, the crude product was dissolved with an exactly weight amount of naphthalene or dodecane (20-50 mg) in CDCI 3 (ca. 0.5 mL) and ca. 50 ⁇ were transferred to an NM - tube and diluted with 0.5 mL of CDCI 3 .
  • the mixture was taken up with a 20 mL syringe, the phases were separated and the organic phase was washed with further NaHC0 3 -solution (1 x 2 mL) remaining in the syringe (In order to avoid leaking the needle of the syringe was sealed with a rubber plug during mixing of the phases).
  • the organic phase was dried over MgS0 4 , concentrated and dried under reduced pressure at the rotatory evaporator.
  • the crude product was dried either at 50 mbar for 2 min (chlorides 2 ⁇ 8 C-atoms), for 5 min (chlorides 2 9-10 C-atoms) or 2 min at 20 mbar (chlorides 2 >10 C-atoms).
  • the conversion and ratio of the chloride 2 to the ester 3 were determined by 1 H-NM (ca. 5 mg of the crude product) (Residual dioxane (50-100 mol%) was separated automatically by the chromatographic purification from the volatile chlorides 2).
  • the crude product was purified by column chromatography on silica gel (ultra pure, ratio 8-40:1 referred to the weight of the crude product, amount of Si0 2 dependent on the separation difficulty) (Small amounts of silica gel are utmost important to avoid significant decomposition of the chlorides 2. In particular chlorides 2 bearing electronrich ⁇ -systems in a-position are sensitive to decomposition.
  • H-Nu H-NR 2 , H-NHR, H-OAr, HSR, H-CH(C0 2 R) 2
  • silica gel masses of crude product/Si0 2 1:2-1:2.5
  • DCM ca. 5 mL
  • amines were adsorbed on silica gel (mass of crude product/Si0 2 1:2-1:2.5) through dissolution in DCM (ca. 5 mL), addition of silica gel and concentration.
  • the silica gel column had to be prepared with the same eluent mixture without NEt 3 in prior.
  • the mass of raw materials implies the mass of starting materials, catalysts and solvents (except of water) and therefore gives a more exact picture of the amount of waste formed (environmental impact) of a given process. Ideally, the E-factor of a process is 0 (no waste is generated).
  • NCS (1.5 equiv), SMe 2 (2.0 equiv),
  • the present method uses inexpensive benzoyl chloride, while literature protocols require more expensive reagents such as oxalyl chloride (entries 8, 10 and 11), pivaloyl chloride (entry 9) and TMSCI (2 equiv, entries 2, 3). Additionally, the catalysts of the present method show significantly lower molecular weights ( ⁇ 100 g/mol) than those of reported ones (> 200 g/mol, entries 8, 10, 11) and are commercial available. Beside DMSO (entry 2) DMF is also one of the cheapest catalysts, as it is a commonly used organic solvent.
  • An additional advantage of the present method is the excellent transfer of enantiopurity from chiral non racemic alcohols of type 1 to the corresponding chlorides 2 under inversion as exemplified with phenylethanol S-l 3 (Table 5, entry 2).
  • the chlorination protocol of Lambert oxalyl chloride in the presence of a cyclopropenone catalyst
  • n 1 , 2, 3,
  • benzyl alcohol li was chosen as model substrate as illustrated in Scheme 2 due to its high reactivity (as a primary benzylic alcohol) and simple 1 H-NM spectra (and of thereof derived products), which allowed a more accurate determination of the yields through NMR-standard than with more complex substrates.
  • FPyr l-Formylpyrollidine
  • FPip 1-Formylpiperidine
  • BnF Benzylformamide
  • iBuF fe/t-Butylformamide
  • MF Methylformamide
  • BnMF Benzylmethylformamide
  • DBuF Di-n- butylformamide
  • DBnF Dibenzylformamide
  • PMPMF ( ⁇ ara-MethoxyjDhenyl) methylformamide
  • MPF Methyl ⁇ henylformamide
  • DPF Di ⁇ henylformamide
  • NMP / ⁇ /-Methyl]Dyrrolidinone
  • F Formamide.
  • Entries 1-15 According to General Procedure I (see chapter 2.1.1) phenylethanol S-l 3 (36.3 ⁇ , 24.0 mg, 0.30 mmol, 1.0 equiv, er > 99:1 according to chiral HPLC) was allowed to react with benzoyl chloride (63.9 ⁇ , 52.8 mg, 0.45 mmol, 1.5 equiv) in the presence of the FPyr (5.9 mg, 6.1 mg, 0.06 mmol, 0.2 equiv) in the solvent (150 ⁇ , 2 M, see Table 18) for 24 h at the temperature T (see Table 18).
  • the enantiomeric ratio of the product 2 3 correlates with the solvent polarity inversed proportional (entries 1-11).
  • the er of 2 3 increased from DMF as solvent (entry 15) 75:25 in the order acetone, DCM, THF, dioxane, EtOAc, MTBE and Et 2 0 to 94:6.
  • Less polar solvents such as toluene and cyclohexane again lead to diminished ratios of enantiomers (89:11 and 92:8, respectively).
  • reaction mixture was transferred to a one necked flask (25 mL) and under vigorous stirring nPen (10 mL) was added dropwise, whereby a solid precipitated (OPPh 3 ).
  • nPen 10 mL
  • OPPh 3 a solid precipitated
  • the mixture was stirred vigorously for 10 min in order to coagulate the precipitated phosphine oxide and filtered through a plug of wool.
  • Both, the 4 mL reaction vial and the 25 mL flask were washed with nPen (2 x 2 mL), the collected filtrates were concentrated under reduced pressure and dried at 50 mbar for 2 min.
  • thionyl chloride (96 ⁇ , 1.20 mmol, 1.2 equiv) was added dropwise by means of a syringe (S0 2 - and HCI-evolution), the mixture was stirred 15 min at 0 °C and for the time period t at ambient temperature.
  • Table 21, entry 1 An exactly weighed amount of the NMR-standard (dodecane) was directly added to the reaction mixture.
  • reaction control via 1 H-NMR revealed full conversion (A small aliquot of the reaction suspension (ca. 100 ⁇ ) was concentrated under reduced pressure, diluted with CDCI 3 (600 ⁇ ) and filtered through a small plug of wool). Thereby isophthalic acid started to precipitate after 2 h of stirring.
  • reaction mixture was cooled in an ice bath and saturated, aqueous Na 2 C0 3 solution (80 mL) was added dropwise accompanied by a week C0 2 evolution.
  • the mixture was transferred to a 500 mL extraction funnel, the reaction flask was rinsed with MTBE and H 2 0 (2 x 20 mL/20 mL) and water (120 mL) was added to improve phase separation (pH of the aq. phase ca. 7).
  • the reaction mixture was dissolved in MTBE (200 mL, 1 mL/1 mmol of 1 5 ) cooled in an ice bath and 60 mL of saturated, aqueous Na 2 C0 3 -solution were added dropwise within 5 min.
  • the mixture was transferred to a 500 mL extraction funnel and diluted with water (140 mL, ratio total volume of aq. phase to amount of starting material 1 5 1 mL/1 mmol) to dissolve precipitated NaOBz.
  • Entry 1 According to general procedure III (chapter 2.1.3) £-3,7-dimethyl-2,6-octadien-l-ol (geraniol E-l 4 , 89 mL, 77.90 g, 500 mmol, l.O equiv) and FPyr (4.9 mL; 5.11 g, 50.0 mmol, 10 mol%) were dissolved in MTBE (250 mL, 2 M) in a 1 L one necked flask with a strong stir bar.
  • MTBE 250 mL, 2 M
  • reaction solution was cooled in an ice bath and benzoyl chloride (59 mL, 71.70 g, 505 mmol, 1.01 equiv) was added dropwise via a dropping funnel within 45 min. After further 30 min of stirring the cooling bath was removed and the reaction solution was allowed to stir overnight (14 h). Then the resulting pale yellow reaction suspension was concentrated under reduced pressure (190 mL of MTBE were reisolated and utilized for the work up) and dried at 150 mbar for 10 min. 1 H-NMR of a small aliquot of the reaction mixture (ca. 10 mg) showed 97% conversion. After 2 h of further stirring at ambient temperature reaction control through 1 H-NMR indicated full conversion.
  • reaction mixture was diluted with MTBE (250 mL, MTBE/amount of starting material 1 0.5 mL/1 mmol), cooled to 0 °C and saturated, aqueous Na 2 C0 3 -solution (150 mL, 0.3 mL/1 mmol of 1) was added dropwise within 15 min, whereby a weak C0 2 -evolution occured.
  • the heterogeneous mixture was transferred to a 1 L extraction funnel and the reaction flask was rinsed with water (2 x 100 mL, 0.4 mL/1 mmol).
  • reaction mixture was diluted with MTBE (250 mL, MTBE/amount of starting material 1 0.5 mL/1 mmol), cooled to 0 °C and saturated, aqueous Na 2 C0 3 -solution (150 mL, 0.3 mL/1 mmol of 1) was added dropwise within 15 min, whereby a weak C0 2 -evolution occured.
  • the heterogeneous mixture was transferred to a 1 L extraction funnel and the reaction flask was rinsed with water (2 x 100 mL, 0.4 mL/1 mmol).
  • reaction suspension was stirred for further 12 h at 40 °C.
  • Monitoring by 1 H-NMR showed 90% conversion after 6 h of stirring at room temperature and > 96% after 11.5 h.
  • Cinnamyl chloride 2 i4 was isolated in 94% yield with DMF in catalytic quantities (entry 1), while without any catalyst only small traces of this chloride were observed (9% according to N MR- standard, entry 2). However, also the regioisomeric starting material 6-li 4 gave the linear chloride 2 i4 in an S w 2 ' -substitution in 62% yield with 20 mol% FPyr (entry 3).
  • the white reaction suspension was next subjected to distillation at 1 atm through a Claisen distillation bridge with a 20 cm water cooler to yield allyl chloride 2 16 as a colorless liquid with bp. of 41-42 °C (12.45 g, 162.3 mmol, 82%).
  • the distillation apparatus was equipped with a KOH-drying tube and the collecting flask was cooled in an ice bath.
  • the oil bath temperature had to be raised from 90 to 180 °C.
  • reaction solution was stirred for further 15 min at 0 °C, the cooling bath was removed, the dropping funnel was replaced by an internal thermometer with quick-fit and the reaction mixture was allowed to stir at ambient temperature. After 2 h the internal temperature had raised to 50 °C. Thus the reaction mixture was cooled for 5 min in an ice bath to decrease the internal temperature to 20 °C accompanied by precipitation of benzoic acid. As reaction control indicated 72% conversion only ( 1 H-NMR) the reaction suspension was allowed to stir overnight (13 h), whereupon 1 H-NMR proved full consumption of the starting material li 8 and a regioisomeric ratio of 83:17.

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Abstract

La présente invention concerne un procédé de conversion d'un alcool en un halogénure correspondant. Ce procédé comprend la réaction de l'alcool avec un halogénure d'acide carboxylique aromatique éventuellement substitué en présence d'un formamide N-substitué pour remplacer un groupe hydroxyle de l'alcool par un atome d'halogène. La présente invention concerne également un procédé de conversion d'un alcool en un produit de substitution correspondant. Le second procédé comprend : (a) l'exécution du procédé de l'invention de conversion d'un alcool en l'halogénure correspondant ; et (b) la réaction de l'halogénure correspondant avec un agent nucléophile pour convertir l'halogénure en le produit de substitution nucléophile.
PCT/EP2016/063815 2015-06-17 2016-06-16 Procédé de conversion d'un alcool en halogénure Ceased WO2016202894A1 (fr)

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CN106831362A (zh) * 2017-01-25 2017-06-13 山东凯盛新材料股份有限公司 2‑丙氧基氯乙烷的生产方法
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CN107056589A (zh) * 2017-01-25 2017-08-18 山东凯盛新材料股份有限公司 2‑丙氧基氯乙烷的制备工艺
CN107857695A (zh) * 2017-11-30 2018-03-30 山东凯盛新材料股份有限公司 提高生产2‑丙氧基氯乙烷收率的装置和方法
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CN110655446A (zh) * 2019-10-22 2020-01-07 邹平铭兴化工有限公司 氯代异丁烷的化学合成方法
CN111138293A (zh) * 2020-01-10 2020-05-12 蚌埠丰原医药科技发展有限公司 一种用微通道反应器合成富马酸伊布利特中间体的方法
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FR3125043A1 (fr) * 2021-07-09 2023-01-13 Snf Sa Procédé d’obtention de sel alcalin de (méth)allyl sulfonate biosourcé

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