Process for preparing amides from esters

Abstract

The invention relates to a method for preparing an amide of formula (I-1) or a diamide of formula (I-2), wherein the variables are as defined in the claims and the description, by reacting an ester with an aromatic or heteroaromatic amine in the presence of an alkali-containing metal base and a Lewis acid; wherein the reaction is carried out under substantially anhydrous conditions. # imgabs0 #

Description

[0001] The present invention relates to a process for preparing an amide of formula (I-1) or a diamide of formula (I-2) as defined below derived from an aromatic or heteroaromatic amine by reacting an ester with an aromatic or heteroaromatic amine in the presence of an alkali metal base and a Lewis acid; wherein the reaction is carried out under substantially anhydrous conditions. Background Art

[0002] Amide functional groups are commonly found in organisms, drugs, agricultural chemicals and natural products. Therefore, efficient amide synthesis routes are very important. Aromatic amides are of great concern, especially as drugs and pesticides and as precursors of such active ingredients. To cite just a few examples, fungicides boscalid, fluxapyroxad or bixafen are prominent representatives. They are usually synthesized by combining corresponding acyl chlorides and amines with stoichiometric amounts of bases (such as triethylamine) to form corresponding amide bonds in these target molecules in sufficiently high yields (see, for example, Green Chemistry [green chemistry], 2021, 23, 8169-8180). Acid chlorides are usually formed by corresponding acids and chlorinating agents (such as thionyl chloride), and the acid is usually made by hydrolysis of esters (esters are more common synthetic intermediates than corresponding acids). The disadvantages of this route to generate amides are the three steps usually required - ester hydrolysis, acyl chloride formation, amidation -, the use of chlorinating agents and the amount of waste formed. Other established routes to amide formation involve reacting the corresponding acid with an amine using an activating agent such as HATU or EDC. The disadvantages of this route are similar to those mentioned above - the need for two steps and the formation of stoichiometric amounts of waste byproducts.

[0003] Therefore, a route to synthesize amides via direct reaction of esters with amines is desirable, without the use of halogenating agents or other stoichiometric activators, and with fewer steps. In addition, efficient amidation routes starting from (hetero)aromatic amines are particularly desirable, which remain challenging in view of their weaker nucleophilicity compared to aliphatic amines. As mentioned above, (hetero)aromatic amide moieties are widely present in many drugs and pesticides.

[0004] In the last few years, several synthetic methods have been proposed for the preparation of amides via the direct reaction of esters with (aromatic) amines.

[0005] H. Moromoto et al. describe the La(OTf)3 (OTf=CF3SO3)-catalyzed amidation of esters with different amines in Organic Letters, 2014, 16, 2018-2021. For aromatic amines, a catalyst loading of 2-5 mol-% of the lanthanum catalyst is required. In addition, the amidation is only carried out with very electron-rich and activated aromatic amines (such as 4-methoxyaniline). Therefore, this route is only feasible for a limited range of substrates. In addition, lanthanum catalysts are expensive, and given that lanthanum is a rare earth metal, their production involves polluting and dangerous processes.

[0006] BDMkhonazi et al. describe the amidation of esters with different amines catalyzed by Lewis acids (e.g., FeCl3, FeBr3, AlCl3, BiCl3) in Molecules [molecules], 2020, 25, 1040-1048. For aromatic amines, a catalyst loading of 15 mol% of FeCl3 is required, and the amidation with aromatic amines can only be carried out when ethyl 2-pyridine-carboxylate is used as the ester (the 2-pyridyl group is crucial for the activation of the catalyst). Therefore, this route is also only feasible for a limited range of substrates.

[0007] TBHalima et al. describe in Angewandte Chemie, International Edition [Applied Chemistry International Edition], 2018, 57, 12925-12929 the direct amidation of esters with aromatic amines by using a combination of Ni(COD)2 (COD=1,5-cyclooctadiene) and N-heterocyclic carbene IPr (1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) as catalysts. The best results were reported at a loading of 10 mol % of Ni complex and 20 mol % of N-heterocyclic carbene. The system is suitable for a variety of anilines. The disadvantage of this system is the use of relatively large amounts of sensitive and expensive Ni(COD)2 and N-heterocyclic carbene (NHC) ligands.

[0008] W. Nicholson et al. describe in Angewandte Chemie, International Edition [Applied Chemistry International Edition] 2021, 60, 21686-21874 the direct amidation of esters with aromatic amines using ball milling in the presence of an alkoxide base such as KOtBu (potassium tert-butoxide) as a medium. This system is applicable to a variety of different anilines. Unfortunately, high yields can only be obtained when a stoichiometric amount of the alkoxide base is used. In addition, ball milling equipment is not generally available, and the technology is not currently applicable to organic synthesis on an industrial scale.

[0009] R. Zhang et al., Green Chemistry, 2021, 23, 3972-3982, describe the solvent-free direct amidation of esters with aromatic amines using an alkoxide base such as NaOtBu (sodium tert-butoxide) as a medium. This system is applicable to a variety of different electron-rich and electron-poor anilines. Unfortunately, high yields can only be obtained when a stoichiometric amount of the alkoxide base is used.

[0010] Z.Fu et al., Journal of Organic Chemistry, 2021, 86, 2339-2358, describe the direct amidation of esters with aromatic amines by using a manganese (I) pincer complex containing an N-heterocyclic carbene (NHC) ligand as a catalyst and an alkoxide base as a co-catalyst. The best results were reported at a loading of 1 mol% of the Mn complex and 20 mol% of the alkoxide base NaOtBu (sodium tert-butoxide). The system is applicable to a variety of different anilines. The disadvantage of this system is the use of a relatively large amount of 20 mol% of the alkoxide base and the complex Mn catalyst whose production requires a multi-step synthesis.

[0011] It is an object of the present invention to provide a process for the synthesis of amides from esters and aromatic or heteroaromatic amines which is suitable for a broad substrate range and uses a simple and economical catalyst system which also works at low catalyst loadings.

[0012] These objects are achieved by using a Lewis acid catalyst in combination with an alkali metal base under substantially anhydrous conditions. Summary of the invention

[0013] Therefore, the present invention relates to a method for preparing a

[0014] (I-1) or a diamide having formula (I-2)

[0015]

[0016] in

[0017] R 1 is selected from the group consisting of: hydrogen, unsubstituted or carrying m groups R a C1-C 30 -alkyl, unsubstituted or with m groups R a C1-C 30 -haloalkyl, unsubstituted or with m groups R a C2-C 30 -alkenyl, unsubstituted or with m groups R a C2-C30 -haloalkenyl, unsubstituted or with m groups R a C2-C 30 -alkynyl, unsubstituted or with m groups R a C2-C 30 -haloalkynyl, unsubstituted or with m groups R b C3-C 30 - cycloalkyl, unsubstituted or with m groups R b C6-C 22 - aryl and unsubstituted or with m groups R b a 3- to 30-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from N, O, S, SO and SO2 as ring members;

[0018] R 2 is unsubstituted or carries m groups R b C6-C 22 -aryl, or a 5- to 30-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members, wherein the heteroaromatic ring is unsubstituted or carries m radicals R b ;

[0019] R 3 is selected from the group consisting of: hydrogen, unsubstituted or carrying m groups R a C1-C 30 -alkyl, unsubstituted or with m groups R a C1-C 30 -haloalkyl, unsubstituted or with m groups R a C2-C 30 -alkenyl, unsubstituted or with m groups R a C2-C 30 -haloalkenyl, unsubstituted or with m groups R a C2-C 30 -alkynyl, unsubstituted or with m groups R a C2-C 30 -haloalkynyl, unsubstituted or with m groups R b C3-C 30 - cycloalkyl, unsubstituted or with m groups R b C6-C 22 - aryl and unsubstituted or with m groups R b a 3- to 30-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from N, O, S, SO and SO2 as ring members;

[0020] or

[0021] R 3 Formed with the aromatic or heteroaromatic ring R 2 a saturated or unsaturated 2-, 3- or 4-membered linking group of a carbon or nitrogen ring atom of ; wherein the linking group may contain 1 or 2 heteroatoms or heteroatom groups selected from N, O, S, SO and SO2; wherein the linking group may carry 1, 2 or 3 groups selected from the group consisting of halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy;

[0022] A is a divalent aliphatic, aliphatic-alicyclic, alicyclic, aromatic, aromatic-aliphatic or heterocyclic moiety;

[0023] Each R a independently selected from the group consisting of cyano, nitro, hydroxy, C1-C4-alkoxy, C1-C4-haloalkoxy, C(=O)R c , amino, C1-C4-alkylamino, di-(C1-C4-alkyl)-amino, C3-C 20 - cycloalkyl, unsubstituted or with m groups R d C6-C 22 - aryl and unsubstituted or with m groups R d a 3- to 20-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from N, O, S, SO and SO2 as ring members;

[0024] Each R b independently selected from the group consisting of halogen, cyano, nitro, hydroxy, C1-C4-alkoxy, C1-C4-haloalkoxy, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)-amino, NR e R f 、C(=O)NR e R f 、C1-C 20 -alkyl, C1-C 20 -haloalkyl, C2-C 20 -alkenyl, C2-C 20 -haloalkenyl, C2-C 20 -Alkynyl, C2-C 20 -haloalkynyl, C3-C 20 - cycloalkyl, unsubstituted or with m groups R d C6-C 22 - aryl and unsubstituted or with m groups Rd a 3- to 20-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from N, O, S, SO and SO2 as ring members;

[0025] Each R c are independently selected from the group consisting of: C1-C4-alkyl, C1-C4-haloalkyl, e R f C1-C4-alkyl, C1-C4-alkoxy and C1-C4-haloalkoxy;

[0026] Each R d independently selected from the group consisting of halogen, cyano, hydroxy, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy;

[0027] Each R e independently selected from the group consisting of: hydrogen and C1-C4-alkyl;

[0028] Each R f independently selected from the group consisting of: -C(=O)-phenyl and phenyl which is unsubstituted or substituted by 1, 2 or 3 groups selected from the group consisting of halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy;

[0029] Each m is independently 1, 2, 3, 4 or 5;

[0030] The method comprises making an ester compound (II) having formula (II-1) or (II-2)

[0031]

[0032] in

[0033] R 1 and A are as defined above; and

[0034] R 4 Selected from the group consisting of: C1-C 30 -alkyl, C6-C 14 -Aryl and C6-C 14 -Aryl-C1-C4-alkyl;

[0035] With an amine having formula (III)

[0036]

[0037] Where R 2 and R 3As defined above,

[0038] reacting in the presence of an alkali metal base and a Lewis acid;

[0039] wherein the reaction is carried out under anhydrous conditions, wherein the water content in the reaction mixture is at most 0.15% by weight relative to the total weight of the reaction mixture. DETAILED DESCRIPTION

[0040] definition

[0041] In this specification, when defining the variable R in the formula presented x When using a radical, the term radical is used interchangeably with the term group or substituent.

[0042] The term "halogen" denotes in each case fluorine, chlorine, bromine or iodine.

[0043] The term "alkyl" refers to a group having, for example, 1 to 30 ("C1-C 30 -alkyl") carbon atoms, or 1 to 20 ("C1-C 20 -alkyl") carbon atoms, or 1 to 10 ("C1-C 10 A saturated straight-chain or branched aliphatic non-cyclic hydrocarbon radical having 1 to 6 (“C1-C6-alkyl”) carbon atoms, or 1 to 4 (“C1-C4-alkyl”) or 1 to 3 (“C1-C3-alkyl”) or 1 or 2 (“C1-C2-alkyl”) carbon atoms. C1-C2-alkyl is methyl or ethyl. Examples of C1-C3-alkyl, in addition to those mentioned for C1-C2-alkyl, are propyl and isopropyl. Examples of C1-C4-alkyl, in addition to those mentioned for C1-C3-alkyl, are butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl) or 1,1-dimethylethyl (tert-butyl). In addition to those mentioned for C1-C4-alkyl, C1-C2-alkyl is methyl or ethyl. Examples of C6-alkyl are also pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl. In addition to those mentioned for C1-C6-alkyl, 10Examples of C1-C2-alkyl groups are also heptyl, octyl, 2-ethylhexyl, nonyl, decyl and positional isomers thereof. 10 -alkyl, in addition to those mentioned above, C1-C 20 Examples of -alkyl groups are also n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, n-eicosyl and positional isomers thereof. 20 -alkyl, in addition to those mentioned above, C1-C 30 Examples of -alkyl are also n-heneicosyl, n-docosyl, n-tricosyl, n-tetracosyl, n-pentacosyl, n-hexacosyl, n-octacosyl, n-nonacosyl, n-triacontyl and positional isomers thereof.

[0044] The term "haloalkyl" (also expressed as "partially or fully halogenated alkyl") refers to a alkyl radical having, for example, 1 to 30 ("C1-C 30 -haloalkyl") carbon atoms, or 1 to 20 ("C1-C 20 -haloalkyl") carbon atoms, or 1 to 10 ("C1-C 10The term "C1-C2-haloalkyl" refers to a saturated straight-chain or branched aliphatic non-cyclic hydrocarbon radical having 1 to 2 carbon atoms ("C1-C6-haloalkyl") or 1 to 4 ("C1-C4-haloalkyl") or 1 or 2 ("C1-C2-haloalkyl") carbon atoms, wherein some or all of the hydrogen atoms in these radicals are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and / or bromine. "C1-C2-haloalkyl" refers to an alkyl radical having 1 or 2 carbon atoms (as mentioned above), wherein some or all of the hydrogen atoms in these radicals are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and / or bromine. . “C1-C3-haloalkyl” refers to straight-chain or branched alkyl groups having 1 to 3 carbon atoms (as mentioned above), wherein some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and / or bromine. “C1-C4-haloalkyl” refers to straight-chain or branched alkyl groups having 1 to 4 carbon atoms (as mentioned above), wherein some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and / or bromine. “C1-C6-haloalkyl” refers to straight-chain or branched alkyl groups having 1 to 6 carbon atoms (as mentioned above), Wherein some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and / or bromine.Examples of C1-C2-haloalkyl are chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl. Examples of C1-C3-haloalkyl, in addition to those mentioned for C1-C2-haloalkyl, are 1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 1,1-difluoropropyl, 2,2-difluoropropyl, 1,2-difluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, heptafluoropropyl, 1,1,1-trifluoroprop-2-yl, 1,1,1,3,3,3-hexafluoroprop-2-yl, heptafluoroprop-2-yl, 3-chloropropyl, etc. Examples of C1-C4-haloalkyl, in addition to those mentioned for C1-C3-haloalkyl, are 4-chlorobutyl, etc.

[0045] Strictly speaking, the term "alkenyl" refers to a group having, for example, 2 to 30 ("C2-C 30 -alkenyl") carbon atoms, or 2 to 20 ("C2-C 20 -alkenyl") carbon atoms, or 2 to 10 ("C2-C 10A monounsaturated (i.e. containing one C-C double bond) straight-chain or branched aliphatic non-cyclic hydrocarbon radical having, for example, 4 to 30 ("C-C6-alkenyl") carbon atoms, or 2 to 6 ("C2-C6-alkenyl") or 2 to 4 ("C2-C4-alkenyl") carbon atoms, wherein the C-C double bond may be in any position. However, as used in the present invention, the term also encompasses "alkapolyenyl", i.e., alkylpolyenyl radicals having, for example, 4 to 30 ("C4-C 30 -alkylpolyenyl") carbon atoms or 4 to 20 ("C4-C 20 -alkylpolyenyl") carbon atoms or 4 to 10 ("C4-C 10-alkylpolyenyl") carbon atoms, and two or more conjugated or isolated but not cumulative CC double bonds, straight or branched aliphatic non-cyclic hydrocarbon radicals. C2-alkenyl is ethenyl / vinyl. Examples of C2-C3-alkenyl in the strict sense (only 1 CC double bond) are ethenyl, 1-propenyl, 2-propenyl or 1-methylethenyl. Examples of C2-C4-alkenyl in the strict sense (only 1 CC double bond) are ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl and 2-methyl-2-propenyl.Examples of C2-C6-alkenyl in the strict sense (only one CC double bond) are ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl- 3-Butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl C2-C6-alkenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, 1-ethyl-2-methyl-2-propenyl, etc. In addition to the examples mentioned for C2-C6-alkenyl, C2-C6-alkenyl in the strict sense is C2-C6-alkenyl. 10Examples of alkenyl (only one C-C double bond) are also 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl and positional isomers thereof. 10 In addition to the examples mentioned for -alkenyl, in the strict sense, C2-C 20 Examples of alkenyl (only one C-C double bond) are also 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 1-tridecenyl, 2-tridecenyl, 3-tridecenyl, 4-tridecenyl, 5-tridecenyl, 6-tri ...6-tridecenyl, 6-tridecenyl, 6-tridecenyl, 6-tridecenyl, 6-tridecenyl, 6-tridecenyl, 6-tridecenyl, 6-tridecenyl, 6-tridecenyl -tetradecenyl, 2-tetradecenyl, 3-tetradecenyl, 4-tetradecenyl, 5-tetradecenyl, 6-tetradecenyl, 7-tetradecenyl, 1-pentadecenyl, 2-pentadecenyl, 3-pentadecenyl, 4-pentadecenyl, 5-pentadecenyl, 6-pentadecenyl, 7-pentadecenyl, 1-hexadecenyl, 2-hexadecenyl, 3-hexadecenyl, 4-hexadecenyl, 5-hexadecenyl, 6-deceneyl, Hexadecenyl, 7-hexadecenyl, 8-hexadecenyl, 1-heptadecenyl, 2-heptadecenyl, 3-heptadecenyl, 4-heptadecenyl, 5-heptadecenyl, 6-heptadecenyl, 7-heptadecenyl, 8-heptadecenyl, 1-octadecenyl, 2-octadecenyl, 3-octadecenyl, 4-octadecenyl, 5-octadecenyl, 6-octadecenyl, 7-octadecenyl, 8-octadecenyl, 9-octadecenyl The invention also includes but is not limited to the following: 1-nonadecenyl, 2-nonadecenyl, 3-nonadecenyl, 4-nonadecenyl, 5-nonadecenyl, 6-nonadecenyl, 7-nonadecenyl, 8-nonadecenyl, 9-nonadecenyl, 1-eicosenyl, 2-eicosenyl, 3-eicosenyl, 4-eicosenyl, 5-eicosenyl, 6-eicosenyl, 7-eicosenyl, 8-eicosenyl, 9-eicosenyl and positional isomers thereof.

[0046] Examples of alkylpolyenyl groups are buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, penta-1,3-dien-1-yl, penta-1,3-dien-2-yl, penta-1,3-dien-3-yl, penta-1,3-dien-4-yl, penta-1,3-dien-5-yl, penta-1,4-dien-1-yl, penta-1,4-dien-2-yl, penta-1,4-dien-3-yl, and the like.

[0047] As used herein, the term "haloalkenyl" (which may also be expressed as "alkenyl substituted by halogen") refers to a halogenated alkenyl having 2 to 30 ("C2-C 30 -haloalkenyl") or 2 to 20 ("C2-C 20 -haloalkenyl") or 2 to 4 ("C2-C4-haloalkenyl") or 2 to 3 ("C2-C3-haloalkenyl") carbon atoms and one or more double bonds in any position (provided that they are not cumulative), unsaturated straight-chain or branched aliphatic non-cyclic hydrocarbon radicals, wherein some or all of the hydrogen atoms in these radicals are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and bromine, for example vinyl chloride, chloroallyl, etc.

[0048] As used herein, the term "alkynyl" refers to a moiety having, for example, 2 to 30 ("C2-C 30 -alkynyl") carbon atoms, or 2 to 20 ("C2-C 20 -alkynyl") carbon atoms, or 2 to 10 ("C2-C 10 alkynyl) or ("C2-C6-alkynyl") or 2 to 4 ("C2-C4-alkynyl") carbon atoms and a triple bond in any position. Examples of C2-C3-alkynyl are ethynyl, 1-propynyl or 2-propynyl. Examples of C2-C4-alkynyl are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3- Examples of C2-C6-alkynyl groups are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl. alkynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1-pentynyl, 3-methyl-4-pentynyl, 4-methyl 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl, and the like.

[0049] As used herein, the term "haloalkynyl" (which may also be expressed as "alkynyl substituted by halogen") refers to a halogen-substituted alkynyl having 2 to 30 ("C2-C30 -haloalkynyl") or 2 to 20 ("C2-C 20 -haloalkynyl”) or 2 to 4 (“C2-C4-haloalkynyl”) or 2 to 3 (“C2-C3-haloalkynyl”) carbon atoms and a triple bond in any position, wherein some or all of the hydrogen atoms in these radicals are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and bromine.

[0050] The term "cycloalkyl" refers to a group having typically 3 to 30 ("C3-C 30 -cycloalkyl"), or 3 to 20 ("C3-C 20 -cycloalkyl"), or 3 to 10 ("C3-C 10 -cycloalkyl"), or 3 to 8 ("C3-C8-cycloalkyl") or 3 to 6 ("C3-C6-cycloalkyl") carbon atoms (of course without heteroatoms) as ring members; i.e. monocyclic, bicyclic or polycyclic saturated hydrocarbon radicals whose all ring members are carbon atoms. Examples of monocyclic cycloalkyl radicals having 3 to 4 carbon atoms include cyclopropyl and cyclobutyl. Examples of monocyclic cycloalkyl radicals having 3 to 5 carbon atoms include cyclopropyl, cyclobutyl and cyclopentyl. Examples of monocyclic cycloalkyl radicals having 3 to 6 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of monocyclic cycloalkyl radicals having 3 to 8 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Examples of monocyclic cycloalkyl radicals having 3 to 10 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl.

[0051] The bicyclic or polycyclic saturated hydrocarbon group usually has 4 to 30 (“polycyclic C4-C 30 -cycloalkyl"), or 4 to 20 ("polycyclic C4-C 20 -cycloalkyl"), or 6 to 20 ("polycyclic C6-C 20-cycloalkyl") carbon atoms (of course no heteroatoms) as ring members; that is, all ring members are carbon atoms. Bicyclic and polycyclic groups may be fused, bridged or spiro rings. Examples of bicyclic fused saturated groups having 6 to 10 carbon atoms include bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.3.0]octyl (1,2,3,3a,4,5,6,6a-octahydropentalenyl), bicyclo[4.2.0]octyl, bicyclo[4.3.0]nonyl (2,3,3a,4,5,6,7,7a-octahydro-1H-indene), bicyclo[4.4.0]decyl (decahydronaphthyl) and the like. Examples of bridged bicyclic fused saturated groups having 7 to 10 carbon atoms include bicyclo[2.2.1]heptyl, bicyclo[3.1.1] Examples of bicyclic spiro saturated groups are spiro[2.2]pentyl, spiro[2.4]heptyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[5.5]undecyl, etc. Examples of saturated polycyclic groups include 2,3,4,4a,4b,5,6,7,8,8a,9,9a-dodecahydro- 1H-fluorenyl, 1,2,3,4,4a,5,6,7,8,8a,9,9a,10,10a-tetradecahydroanthracenyl, 1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a-tetradecahydrophenanthrenyl, 2,3,3a,4,5,6,6a,7,8,9,9a,9b-dodecahydro-1H-phenanthrenyl, adamantyl and the like.

[0052] Preferably, the cycloalkyl group is monocyclic.

[0053] C3-C6-cycloalkyl-C1-C 10 -Alkyl is a C1-C 10 -alkyl, in which one hydrogen atom is replaced by a C3-C6-cycloalkyl as defined above. Examples are cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, 1-cyclobutylethyl, 2-cyclobutylethyl, 1-cyclopentylethyl, 2-cyclopentylethyl, 1-cyclohexylethyl, 2-cyclohexylethyl, 1-cyclopropylpropyl, 2-cyclopropylpropyl, 3-cyclopropylpropyl, 1-cyclobutylpropyl, 2-cyclobutylpropyl, 3-cyclobutylpropyl, 1-cyclopentylpropyl, 2-cyclopentylpropyl, 3-cyclopentylpropyl, 1-cyclohexylpropyl, 2-cyclohexylpropyl, 3-cyclohexylpropyl, 1-cyclohexylpropyl, 2-cyclohexylpropyl, 3-cyclohexylpropyl, 1-cyclohexylpropyl, 2-cyclohexylpropyl, 3-cyclohexylpropyl, 1-cyclohexylbutyl, 2-cyclohexylbutyl, 3-cyclohexylbutyl, 4-cyclohexylbutyl, etc.

[0054] "Alkoxy" is an alkyl group as defined above attached to the rest of the molecule via an oxygen atom; for example a C1-C4-alkyl group attached to the rest of the molecule via an oxygen atom ("C1-C4-alkoxy"). "C1-C2-alkoxy" is a C1-C2-alkyl group as defined above attached via an oxygen atom. "C1-C3-alkoxy" is a C1-C3-alkyl group as defined above attached via an oxygen atom. C1-C2-alkoxy is methoxy or ethoxy. C1-C3-alkoxy is additionally, for example, n-propoxy and 1-methylethoxy (isopropoxy). C1-C4-alkoxy is additionally, for example, butoxy, 1-methylpropoxy (sec-butoxy), 2-methylpropoxy (isobutoxy) or 1,1-dimethylethoxy (tert-butoxy).

[0055] As used herein, the term "haloalkoxy" denotes in each case a straight-chain or branched alkoxy radical as defined above having 1 to 4 carbon atoms (=C1-C4-haloalkoxy), wherein the hydrogen atoms of this radical are partially or completely replaced by halogen atoms, in particular fluorine atoms (in this case, the radical is also referred to as fluorinated alkoxy). C1-C2-haloalkoxy is, for example, OCH2F, OCHF2, OCF3, OCH2Cl, OCHCl2, OCCl3, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy or OC2F5. C1-C3-haloalkoxy is additionally, for example, 2-fluoropropoxy, 3-fluoropropoxy, 2,2-difluoropropoxy, 2,3-difluoropropoxy, 2-chloropropoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 2-bromopropoxy, 3-bromopropoxy, 3,3,3-trifluoropropoxy, 3,3,3-trichloropropoxy, OCH2-C2F5, OCF2-C2F5, 1-(CH2F)-2-fluoroethoxy, 1-(CH2Cl)-2-chloroethoxy or 1-(CH2Br)-2-bromoethoxy. C1-C4-haloalkoxy is additionally, for example, 4-fluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy or nonafluorobutoxy.

[0056] The amino group is -NH2.

[0057] The term "C1-C4-alkylamino" denotes the group C1-C4-alkyl-N(H)-. Examples are methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, sec-butylamino, isobutylamino and tert-butylamino.

[0058] The term "di-(C1-C4-alkyl)-amino" means the group (C1-C4-alkyl)2N-. Examples are dimethylamino, diethylamino, ethylmethylamino, dipropylamino, diisopropylamino, methylpropylamino, methylisopropylamino, ethylpropylamino, ethylisopropylamino, n-butyl-methylamino, n-butyl-ethylamino, n-butyl-propylamino, di-n-butylamino, 2-butyl-methylamino, 2-butyl-ethylamino, 2-butyl-propylamino, isobutyl-methylamino, ethyl-isobutylamino, isobutyl-propylamino, tert-butyl-methylamino, tert-butyl-ethylamino, tert-butyl-propylamino, and the like.

[0059] "Aryl" is a monocyclic, bicyclic or polycyclic carbocyclic (i.e., without heteroatoms as ring members) aromatic group. An example of a monocyclic aromatic group is phenyl. In a bicyclic aryl ring, the two aromatic rings are fused, i.e., they share two ortho C atoms as ring members. An example of a bicyclic aromatic group is naphthyl. In a polycyclic aryl ring, three or more rings are fused. Examples of polycyclic aryl groups are phenanthrenyl, anthracenyl, naphthacene, 1H-benzo[a]phenalenyl, pyrenyl, etc. However, for the purposes of the present invention, "aryl" also covers bicyclic or polycyclic groups in which not all rings are aromatic, as long as at least one ring is aromatic. In R 2 In the case of aryl, the point of attachment to N must be on the aromatic part. Examples are indanyl, indenyl, tetrahydronaphthyl, 6,7,8,9-tetrahydro-5H-benzo[7]cycloannulyl, fluorenyl, 9,10-dihydroanthracenyl, 9,10-dihydrophenanthrenyl, 1H-benzo[a]phenanthrenyl and the like, and also ring systems in which not all rings are fused but, for example, spiro or bridged, such as benzonorbornenyl. In particular, aryl has 6 to 40, in particular 6 to 30, more particularly 6 to 22, in particular 6 to 14 or 6 to 10 carbon atoms as ring members.

[0060] C6-C 14 -Aryl-C1-C4-alkyl is a C1-C4-alkyl radical as defined above in which one hydrogen atom is replaced by a C6-C4-alkyl radical as defined above. 14 -aryl replacement (i.e., attachment to the rest of the molecule via an alkyl group). Examples are benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 2-phenyl-2-propyl, naphth-1-yl-methyl, naphth-2-yl-methyl, 1-(naphth-1-yl)-ethyl, 1-(naphth-2-yl)-ethyl, 2-(naphth-1-yl)-ethyl, 2-(naphth-2-yl)-ethyl, and the like.

[0061] The rings referred to as heterocycles or heterocyclic radicals or heteroaromatic rings or heteroaryls contain as ring members one or more heteroatoms, i.e. atoms different from carbon. For the purposes of the present invention, these heteroatoms are N, O and S, where S can also be present as a heteroatom group, i.e. as SO or SO2. Thus, for the purposes of the present invention, the rings referred to as heterocycles or heterocyclic radicals or heteroaromatic rings or heteroaryls contain as ring members one or more heteroatoms and / or heteroatom groups selected from the group consisting of N, O, S, SO and SO2.

[0062] For the purposes of the present invention, a heterocycle or heterocyclyl is a saturated, partially unsaturated or fully unsaturated (including aromatic) heteromonocyclic, bicyclic or polycyclic ring (if the ring is aromatic, it is also referred to as a heteroaromatic ring or heteroaryl) containing one or more, in particular 1, 2, 3 or 4, heteroatoms or heteroatom groups independently selected from the group consisting of N, O, S, SO and SO2 as ring members.

[0063] Unsaturated rings contain at least one CC and / or CN and / or NN double bond. Maximum unsaturated rings contain as many conjugated CC and / or CN and / or NN double bonds as the ring size allows. Maximum unsaturated 5- or 6-membered heteromonocyclic rings are usually aromatic. Exceptions are maximum unsaturated 6-membered rings containing O, S, SO and / or SO2 as ring members, such as pyrans and thiopyrans, which are not aromatic. Partially unsaturated rings contain less than the maximum number of CC and / or CN and / or NN double bonds allowed by the ring size.

[0064] The heterocycle may be attached to the rest of the molecule via a carbon ring member or via a nitrogen ring member. Of course, the heterocycle contains at least one carbon ring atom. If the ring contains more than one O ring atom, these are not adjacent.

[0065] The heterocyclic ring is usually 3-30-membered, for example 3-20-membered, or 5-10-membered, or 5-6-membered. The heterocyclic ring may be monocyclic, bicyclic or polycyclic.

[0066] The heteromonocyclic ring is especially 3- to 8-membered. Examples of 3-, 4-, 5-, 6-, 7- or 8-membered saturated heteromonocyclic rings include: oxirane-2-yl, thiirane-2-yl, aziridine-1-yl, aziridine-2-yl, oxetane-2-yl, oxetane-3-yl, thiirane-2-yl, thiirane-3-yl, 1-oxothietane-2-yl, 1-oxothietane-3-yl, 1,1-dioxothietane-2-yl, 1,1-dioxothietane-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophene-2-yl, tetrahydrothiophene-3-yl, 1-oxotetrahydrothiophene-2-yl. yl, 1,1-dioxotetrahydrothiophen-2-yl, 1-oxotetrahydrothiophen-3-yl, 1,1-dioxotetrahydrothiophen-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrazolidin-1-yl, pyrazolidin-3-yl, pyrazolidin-4-yl, pyrazolidin-5-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin- 4-yl, oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl, oxazolidin-5-yl, isoxazolidin-2-yl, isoxazolidin-3-yl, isoxazolidin-4-yl, isoxazolidin-5-yl, thiazolin-2-yl, thiazolin-3-yl, thiazolin-4-yl, thiazolin-5-yl, isothiazol-2-yl, isothiazol-3-yl, isothiazol-4-yl, Oxazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazolidine-2-yl, 1,2,4-oxadiazolidine-3-yl, 1,2,4-oxadiazolidine-4-yl, 1,2,4-oxadiazolidine-5-yl, 1,2,4-thiadiazolidin-2-yl, 1,2,4-thiadiazolidin-3-yl, 1,2,4-thiadiazolidin-4-yl, 1, 2,4-thiadiazolidin-5-yl, 1,2,4-triazolidin-1-yl, 1,2,4-triazolidin-3-yl, 1,2,4-triazolidin-4-yl, 1,3,4-oxadiazolidin-2-yl, 1,3,4-oxadiazolidin-3-yl, 1,3,4-thiadiazolidin-2-yl, 1,3,4-thiadiazolidin-3-yl, 1,3,4-triazolidin- -1-yl, 1,3,4-triazolidin-2-yl, 1,3,4-triazolidin-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl, 1,4-dioxan-2-yl, piperidin-1-yl, piperidin-2-yl, piperidin-4-yl, piperidin-5-yl, piperidin-2-yl, piperidin-1-yl, piperidin-2-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperidin-5-yl, piperidin-2-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperidin-5-yl, piperidin pyrimidine-3-yl, piperidin-4-yl, hexahydropyridazin-1-yl, hexahydropyridazin-3-yl, hexahydropyridazin-4-yl, hexahydropyrimidin-1-yl, hexahydropyrimidin-2-yl, hexahydropyrimidin-4-yl, hexahydropyrimidin-5-yl, piperazin-1-yl, piperazin-2-yl, 1,3,5-hexahydrotriazine-1-yl, 1,3,5-hexahydrotriazine-2-yl, 1,2,4-Hexahydrotriazine-1-yl, 1,2,4-hexahydrotriazine-2-yl, 1,2,4-hexahydrotriazine-3-yl, 1,2,4-hexahydrotriazine-4-yl, 1,2,4-hexahydrotriazine-5-yl, 1,2,4-hexahydrotriazine-6-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, thiomorpholin-2-yl, thiomorpholin-3-yl, thiomorpholin-4-yl, 1-oxo Thiomorpholin-2-yl, 1-oxothiomorpholin-3-yl, 1-oxothiomorpholin-4-yl, 1,1-dioxothiomorpholin-2-yl, 1,1-dioxothiomorpholin-3-yl, 1,1-dioxothiomorpholin-4-yl, azepan-1-, -2-, -3- or -4-yl, oxepane-2-, -3-, -4- or -5-yl, hexahydro-1,3-diazepine, Hexahydro-1,4-diazepine Hexahydro-1,3-oxazepine Hexahydro-1,4-oxazepine

[0013] 1,2-dioxepinyl, 1,4-dioxepinyl, 1,6-dioxepinyl, 1,8-dioxepinyl, 1,6-dioxepinyl, 1,8-dioxepinyl, 1,9-dioxepinyl, 2,3-dioxepinyl, 2,4 ...

[0067] Examples of 3-, 4-, 5-, 6-, 7- or 8-membered partially saturated heteromonocyclic rings include: 2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl, 2,4-dihydrofuran-2-yl, 2,4-dihydrofuran-3-yl, 2,3-dihydrothiophen-2-yl, 2,3-dihydrothiophen-3-yl, 2,4-dihydrothiophen-2-yl, 2,4-dihydrothiophen-3-yl. Dihydrothiophen-3-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin-3-yl, 2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-yl, 2-isoxazolin-5-yl , 3-isothiazolin-5-yl, 4-isothiazolin-5-yl, 2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4-isothiazolin-3-yl, 2-isothiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4-yl, 2-isothiazolin-5-yl, 3-isothiazolin-5-yl, 4-isothiazolin-5-yl, 2,3 -dihydropyrazol-1-yl, 2,3-dihydropyrazol-2-yl, 2,3-dihydropyrazol-3-yl, 2,3-dihydropyrazol-4-yl, 2,3-dihydropyrazol-5-yl, 3,4-dihydropyrazol-1-yl, 3,4-dihydropyrazol-3-yl, 3,4-dihydropyrazol-4-yl, 3,4-dihydropyrazol-5-yl, 4,5-dihydropyrazol-1-yl, 4,5-dihydropyrazol-3-yl, 4,5-dihydropyrazol-4-yl, 4,5-dihydropyrazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-3-yl, 2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol- Oxazol-4-yl, 3,4-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 2-, 3-, 4-, 5- or 6-di- or tetrahydropyridinyl, 3-di- or tetrahydropyridazinyl, 4-di- or tetrahydropyridazinyl, 2-di- or tetrahydropyrimidinyl, 4-di- or tetrahydropyrimidinyl , 5-di- or tetrahydropyrimidinyl, di- or tetrahydropyrazinyl, 1,3,5-di- or tetrahydrotriazin-2-yl, 1,2,4-di- or tetrahydrotriazin-3-yl, 2,3,4,5-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl, 3,4,5,6-tetrahydro[2H]azepin-2-, - 3-, -4-, -5-, -6- or -7-yl, 2,3,4,7-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl, 2,3,6,7-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl, tetrahydrooxacycloheptatrienyl, such as 2,3,4,5-tetrahydro[1H]oxepin-2-, -3-, -4-, -5-, -6- or -7-yl, 2,3,4,7-tetrahydro[1H]oxepin-2-, -3-, -4-, -5-, -6- or -7-yl, 2,3,6,7-tetrahydro[1H]oxepin-2-, -3-, -4-, -5-, -6- or -7-yl, tetrahydro-1,3-diazepinyl, tetrahydro-1,4-diazepinyl, tetrahydro-1,3-oxazepinyl , tetrahydro-1,4-oxazepine, tetrahydro-1,3-dioxacycloheptatrienyl, tetrahydro-1,4-dioxacycloheptatrienyl, 1,2,3,4,5,6-hexahydroazocine, 2,3,4,5,6,7-hexahydroazocine, 1,2,3,4,5,8-hexahydroazocine, 1,2,3,4,7,8-hexahydroazocine, 1,2,3,4,5,6-hexahydro-[1,5]diazacyclotetraene, 1,2,3,4,7,8-hexahydro-[1,5]diazacyclotetraene, etc. ,

[0068] Examples of 3-, 4-, 5-, 6-, 7- or 8-membered maximally unsaturated (but nonaromatic) heteromonocyclic rings are pyran-2-yl, pyran-3-yl, pyran-4-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 1-oxothiopyran-2-yl, 1-oxothiopyran-3-yl, 1-oxothiopyran-4-yl, 1,1-dioxothiopyran-2-yl, 1,1-dioxothiopyran-3-yl, 1,1-dioxothiopyran-4-yl, 2H-oxazin-2-yl, 2H-oxazin-3-yl, 2H-oxazin-4-yl, 4H-oxazin-5-yl, 2H-oxazin-6-yl, 4H-oxazin-3-yl, 4H-oxazin-4-yl, 4H-oxazin-5-yl, 4H-oxazin-6-yl, 6H-oxazin-3-yl, 6H-oxazin-4-yl, 7H-oxazin-5-yl, 8H-oxazin-6-yl, 2H-1,3-oxazin-2-yl, 2H-1,3-oxazin-4-yl, 2H-1,3-oxazin-5-yl, 2H-1,3-oxazin-6-yl, 4H-1,3-oxazin-2-yl, 4H-1,3-oxazin-4-yl, oxazine-4-yl, 4H-1,3-oxazine-5-yl, 4H-1,3-oxazine-6-yl, 6H-1,3-oxazine-2-yl, 6H-1,3-oxazine-4-yl, 6H-1,3-oxazine-5-yl, 6H-1,3-oxazine-6-yl, 2H-1,4-oxazine-2-yl, 2H-1,4-oxazine-3-yl, 2H-1,4-oxazine-5-yl, 2H-1,4-oxazine-6-yl, 4H-1,4-oxazine-2-yl, 4H-1,4-oxazine-3-yl, 4H-1,4-oxazine 4-oxazine-5-yl, 4H-1,4-oxazine-6-yl, 6H-1,4-oxazine-2-yl, 6H-1,4-oxazine-3-yl, 6H-1,4-oxazine-5-yl, 6H-1,4-oxazine-6-yl, 1,4-dioxin-2-yl, 1,4-oxathiin-2-yl, 1H-azepine, 1H-[1,3]-diazepine, 1H-[1,4]-diazepine, [1,3]diazepine, [1,5]diazepine, [1,5]diazepine, etc.

[0069] The heteroaromatic monocyclic ring is in particular 5- or 6-membered. Examples of 5- or 6-membered monocyclic heteroaromatic rings are 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl. 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazole-3-yl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazole-3 ... -yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-oxopyridin-2-yl, 1-oxopyridinyl -3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazine-2-yl, 1,2,4-triazine-3-yl, 1,2,4-triazine-5-yl, 1,2,3,4-tetrazine-1-yl, 1,2,3,4-tetrazine-2-yl, 1,2,3,4-tetrazine-5-yl, and the like.

[0070] "Heterobicycle" or "heterobicyclyl" contains two rings, which have at least one common ring atom. At least one of the two rings contains a heteroatom or heteroatom group selected from the group consisting of N, O, S, SO and SO2 as a ring member. The term includes condensed / fused ring systems in which the two rings have two common adjacent ring atoms, as well as spiro systems in which the rings have only one common ring atom, and bridged systems with at least three common ring atoms. For the purposes of the present invention, heterobicycles include fully aromatic bicyclic ring systems; these are also referred to as heteroaromatic bicyclics or bicyclic heteroaryls or heterobiaryls. Heterobicycles are preferably 7-, 8-, 9-, 10- or 11-membered. Heteroaromatic bicyclics are preferably 9-, 10- or 11-membered. Fully heteroaromatic heterobicyclics are 9- or 10-membered.

[0071] Examples of fused systems:

[0072] Examples of 7-, 8-, 9-, 10- or 11-membered saturated heterobicyclic rings containing 1, 2 or 3 (or 4) heteroatoms or heteroatom groups selected from the group consisting of N, O, S, NO, SO and SO2 as ring members are:

[0073]

[0074]

[0075] Examples of 7-, 8-, 9-, 10- or 11-membered partially unsaturated heterobicyclic rings containing 1, 2 or 3 (or 4) heteroatoms or heteroatom groups selected from the group consisting of N, O, S, SO and SO2 as ring members are:

[0076]

[0077]

[0078] Examples of 7-, 8-, 9-, 10- or 11-membered maximally unsaturated (but not fully heteroaromatic) heterobicyclic rings containing as ring members 1, 2 or 3 (or 4) heteroatoms or heteroatom groups selected from the group consisting of N, O, S, SO and SO2 are:

[0079]

[0080]

[0081] Examples of 9- or 10-membered maximally unsaturated fully heteroaromatic heterobicyclic rings containing 1, 2 or 3 (or 4) heteroatoms or heteroatom groups selected from the group consisting of N, O, S, SO and SO2 as ring members are:

[0082]

[0083]

[0084] Examples of spiro-connected 7-, 8-, 9-, 10- or 11-membered heterobicyclic rings containing 1, 2 or 3 (or 4) heteroatoms or heteroatom groups selected from the group consisting of N, O, S, NO, SO and SO2 as ring members are

[0085]

[0086] Examples of bridged 7-, 8-, 9-, 10- or 11-membered heterobicyclic rings containing 1, 2 or 3 (or 4) heteroatoms or heteroatom groups selected from the group consisting of N, O, S, NO, SO and SO2 as ring members are

[0087]

[0088] wait.

[0089] In the above structures, # indicates the point of attachment to the rest of the molecule. The point of attachment is not limited to the rings shown, but can be on either of the two rings, and can be on a carbon or nitrogen ring atom. If the rings carry one or more substituents, these substituents can be bound to carbon and / or nitrogen ring atoms.

[0090] Polycyclic heterocycles (polyheterocyclyls) contain three or more rings, each ring having at least one ring atom in common with at least one of the other rings of the polycyclic system. The rings may be fused, spiro-connected or bridged; mixed systems (e.g. one ring spiro-connected to a fused system, or a bridged system fused to another ring) are also possible. Fully aromatic rings are not encompassed by such polycyclic heterocycles (polyheterocyclyls); these are called polycyclic heteroaromatic rings or heteropolyaryls.

[0091] If the heterocyclic / heteroaromatic ring is substituted, the substituents may be bonded to both carbon ring atoms and secondary nitrogen ring atoms.

[0092] If R 3 Formed with an aromatic or heteroaromatic ring R 2 A saturated or unsaturated 2-, 3- or 4-membered linking group of a carbon or nitrogen ring atom; wherein the linking group may contain 1 or 2 heteroatoms or heteroatom groups selected from N, O, S, SO and SO2, then this is in R 2 When it is a monocyclic ring, a bicyclic heterocyclic system is produced or in R 2 When it is bicyclic or polycyclic, it produces a polycyclic heterocyclic ring system, wherein the ring system produced contains NR 2 R 3 The nitrogen atom of R is a ring member and is bonded to CO via this nitrogen ring member. 3 Bind to R 2 The formation of (group NR 2 R 3 If the (hetero)aromatic ring R 2 Fused. If the linking group R 3 Bind to R 2 On another ring atom of , the resulting ring system is a bridged ring system. To name just a few of the ring systems NR 2 R 3 As an illustrative example, 2,3-dihydroindole-1-yl (R 2 is phenyl, R 3 Forming -CH2CH2- attached at the ortho position of the attachment point of the phenyl group to the N), 1,2,3,4-tetrahydroquinolin-1-yl (R 2 is phenyl, R 3Forming -CH2CH2CH2- attached to the ortho position of the attachment point of the phenyl group to the N), indol-1-yl (R 2 is phenyl, R 3 Forming -CH=CH- attached to the ortho position of the attachment point of the phenyl group to the N), 1,2-dihydroquinolin-1-yl (R 2 is phenyl, R 3 Forming -CH2CH=CH- attached to the ortho position of the attachment point of the phenyl group to the N), 1,2,3,4-tetrahydro-1,2-naphthyridin-1-yl (R 2 is phenyl, R 3 Forming -NHCH2CH2- attached at the ortho position of the attachment point of the phenyl group to the N), 1,2,3,4-tetrahydro-1,3-naphthyridin-1-yl (R 2 is phenyl, R 3 Forming -CH2NHCH2- attached at the ortho position of the attachment point of the phenyl group to the N), 1,2,3,4-tetrahydro-1,4-naphthyridin-1-yl (R 2 is phenyl, R 3 Forming -CH2CH2NH- attached at the ortho position of the attachment point of the phenyl group to the N), 1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl (R 2 is pyridin-3-yl, R 3 Forming -CH2CH2CH2- attached to the 2-position of the pyridine ring), 1,2,3,4-tetrahydro-1,8-naphthyridin-1-yl (R 2 is pyridin-2-yl, R 3 To form -CH2CH2CH2-) attached to the 3-position of the pyridine ring, etc.

[0093] A is a divalent aliphatic, alicyclic, aromatic, aromatic-aliphatic or heterocyclic moiety.

[0094] Divalent aliphatic groups are those that do not contain alicyclic, carboaromatic or heterocyclic structures. Examples are alkylene (alkanediyl), alkenylene (alkenediyl) and alkynylene (alkynediyl).

[0095] Divalent alicyclic groups contain one or more, for example one or two, alicyclic moieties; however, they do not contain carbon aromatic or heterocyclic structures. 2 R 3 or COOR 4 The bonding site of the group is located on the alicyclic group.

[0096] The divalent aliphatic-alicyclic group contains not only at least one divalent aliphatic group but also at least one divalent alicyclic group. 2 R 3 Group or two COOR4 One of the two bonding sites of the group is located on the aliphatic group and the other is located on the alicyclic group.

[0097] Divalent aromatic groups contain one or more, for example one or two, carbon aromatic groups; however, they do not contain alicyclic or heterocyclic structures. Aromatic groups may be substituted with aliphatic groups, but the two CONR 2 R 3 Group or two COOR 4 The two bonding sites of the group are located on the aromatic group.

[0098] Divalent aromatic-aliphatic (abbreviated: araliphatic) groups are divalent groups containing at least one aromatic part and at least one aliphatic part. More precisely, they contain at least one divalent aliphatic group and at least one divalent carbon aromatic group; the two CONR 2 R 3 Group or two COOR 4 One of the two bonding sites of the group is located on the aliphatic group and the other is located on the aromatic group.

[0099] Divalent heterocyclic groups contain one or more, for example one or two, heterocyclic groups; however, they do not contain alicyclic or pure carbon aromatic structures. The heterocyclic groups may be substituted with aliphatic groups, but the two CONR 2 R 3 Group or two COOR 4 The two bonding sites of the group are located on the heterocyclic group.

[0100] Carboaromatic means that the aromatic system consists only of carbon atoms, as in phenyl or naphthyl. Heterocyclic encompasses heteroaromatic.

[0101] Alkylene is a straight-chain or branched divalent alkanediyl. C1-C4-alkylene (=C1-C4-alkanediyl) is a straight-chain or branched divalent alkyl radical having 1 to 4 carbon atoms. Examples are -CH2-, -CH2CH2-, -CH(CH3)-, -CH2CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2-, -CH2CH2CH2CH2-, -CH(CH3)CH2CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-. C1-C8-alkylene (=C1-C8-alkanediyl) is a straight-chain or branched divalent alkyl radical having 1 to 8 carbon atoms. Examples are -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2-, -CH2CH2CH2CH2-, -CH(CH3)CH2CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8- and positional isomers thereof. Straight-chain C1-C8-alkylene is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -(CH2)5-, -(CH2)6-, -(CH2)7- or -(CH2)8-.

[0102] Alkenylene is a straight or branched divalent alkene diyl radical having one or more double bonds in any position (provided that they do not accumulate). C2-C8-alkylene (=C2-C8-alkene diyl) is a straight or branched divalent alkyl radical having 2 to 8 carbon atoms. Examples are -CH=CH-, -C(=CH2)-, -CH2-CH=CH-, -CH=CH-CH2-, -CH2-C(=CH2)-, -C(=CH2)-CH2-, CH2-CH=CH-CH2-, etc.

[0103] Cycloalkylene is a divalent cycloalkanediyl radical. C3-C6-cycloalkanediyl is a divalent cycloalkanediyl radical having 3 to 6 carbon atoms. Examples are cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, cyclobutane-1,3-diyl, cyclopentene-1,1-diyl, cyclopentene-1,2-diyl, cyclopentene-1,3-diyl, cyclohexane-1,1-diyl, cyclohexane-1,2-diyl, cyclohexane-1,3-diyl, cyclohexane-1,4-diyl.

[0104] Examples of (carbon) aromatic divalent groups are phenylene, naphthylene, etc. Phenylene is 1,2-phenylene (benzene-1,2-diyl), 1,3-phenylene (benzene-1,3-diyl) or 1,4-phenylene (benzene-1,4-diyl).

[0105] Amine (III) is aromatic. This means that NR 2 R 3 The nitrogen atom of the ring is directly attached to an aromatic or heteroaromatic ring. This also includes (bicyclic or polycyclic) ring systems which are only partially aromatic, since one of the rings of this ring system is not aromatic (as in NR 2 R 3 The above-mentioned 2,3-dihydroindole-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl, 1,2-dihydroquinolin-1-yl, 1,2,3,4-tetrahydro-1,2-, -1,3-, -1,4-, -1,5- or -1,8-naphthyridin-1-yl are formed); provided that (the group NR 2 R 3 The) N of the radical is directly bonded to the aromatic or heteroaromatic ring.

[0106] Alkoxide or alcohol is an anion RO - , where R is an alkyl radical. Examples of C1-C4-alkoxides are methoxide (=methoxide; R=CH3), ethoxide (=ethoxide; R=ethyl), propoxide (=propoxide; R=n-propyl), isopropoxide (=isopropoxide; R=isopropyl), n-butoxide (=n-butoxide; R=n-butyl), sec-butoxide (=sec-butoxide; R=sec-butyl), isobutoxide (=isobutoxide; R=isobutyl) or tert-butoxide (=tert-butoxide; R=tert-butyl). In addition to those mentioned for C1-C4-alkoxides, C1-C4-alkoxides may be present in any of the following groups: 10 Examples of -alkoxides are also n-pentanol, n-hexanol, n-heptanol, n-octanol, 2-ethylhexanol, n-nonanol, n-decanol, 2-propylheptanol and the other positional isomers thereof.

[0107] Lewis acids are electron pair acceptors. In general, they include compounds in which atoms do not have a noble gas configuration, for example atoms of a main group atom with an incomplete or unstable electron octet, such as boron or aluminum in B(CH3)3, B(OH)3, BF3 or AlCl3. In addition to the boron and aluminum compounds mentioned above, examples are also metal salts, which are not in the form of complexes in which the central metal has a stable noble gas configuration (since ligands such as water or counteranions (if this is bidentate or multidentate) often obtain a noble gas configuration; in the absence of such ligands or if such ligands are easily displaced (see the description of Lewis acid precursors below), metal salts are usually Lewis acids); or metal complexes of metals (ions) that do not have a noble gas configuration, for example transition metal complexes of metals with incompletely filled d-orbitals, such as Cr 3+ As used herein, the term "Lewis acid" also encompasses Lewis acid precursors, provided that these precursors are converted into the appropriate Lewis acid under the reaction conditions used for the amidation reaction of the present invention. Examples are metal carbonyl complexes such as Cr(CO)6, MnBr(CO)5 or Mn2(CO) 10 , which loses the CO ligand and / or dissociates under typical reaction conditions for amidation reactions, especially at elevated temperatures (e.g., the binuclear complex Mn2(CO) 10 The Lewis acid used in the amidation of the present invention is preferably a metal salt or a metal complex in which the metal does not have a noble gas configuration; and a Lewis acid precursor, which is converted into a suitable Lewis acid under the reaction conditions for the amidation reaction of the present invention and is in the form of a metal complex, especially a metal carbonyl complex.

[0108] Embodiments of the present invention (Ex)

[0109] General and preferred embodiments Ex are summarized in the following non-exhaustive list. Further preferred embodiments become apparent from the paragraphs following this list.

[0110] E.1. A method for preparing an amide of formula (I-1) or a diamide of formula (I-2)

[0111]

[0112] in

[0113] R 1 is selected from the group consisting of: hydrogen, unsubstituted or carrying m groups R a C1-C 30 -alkyl, unsubstituted or with m groups R a C1-C30 -haloalkyl, unsubstituted or with m groups R a C2-C 30 -alkenyl, unsubstituted or with m groups R a C2-C 30 -haloalkenyl, unsubstituted or with m groups R a C2-C 30 -alkynyl, unsubstituted or with m groups R a C2-C 30 -haloalkynyl, unsubstituted or with m groups R b C3-C 30 - cycloalkyl, unsubstituted or with m groups R b C6-C 22 - aryl and unsubstituted or with m groups R b a 3- to 30-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from N, O, S, SO and SO2 as ring members;

[0114] R 2 is unsubstituted or carries m groups R b C6-C 22 -aryl, or a 5- to 30-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members, wherein the heteroaromatic ring is unsubstituted or carries m radicals R b ;

[0115] R 3 is selected from the group consisting of: hydrogen, unsubstituted or carrying m groups R a C1-C 30 -alkyl, unsubstituted or with m groups R a C1-C 30 -haloalkyl, unsubstituted or with m groups R a C2-C 30 -alkenyl, unsubstituted or with m groups R a C2-C 30 -haloalkenyl, unsubstituted or with m groups R a C2-C 30 -alkynyl, unsubstituted or with m groups R a C2-C 30 -haloalkynyl, unsubstituted or with m groups R b C3-C 30 - cycloalkyl, unsubstituted or with m groups R b C6-C 22- aryl and unsubstituted or with m groups R b a 3- to 30-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from N, O, S, SO and SO2 as ring members;

[0116] or

[0117] R 3 Formed with the aromatic or heteroaromatic ring R 2 a saturated or unsaturated 2-, 3- or 4-membered linking group of a carbon or nitrogen ring atom of ; wherein the linking group may contain 1 or 2 heteroatoms or heteroatom groups selected from N, O, S, SO and SO2; wherein the linking group may carry 1, 2 or 3 groups selected from the group consisting of halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy;

[0118] A is a divalent aliphatic, alicyclic, aliphatic-alicyclic, aromatic, aromatic-aliphatic or heterocyclic moiety;

[0119] Each R a independently selected from the group consisting of cyano, nitro, hydroxy, C1-C4-alkoxy, C1-C4-haloalkoxy, C(=O)R c , amino, C1-C4-alkylamino, di-(C1-C4-alkyl)-amino, C3-C 20 - cycloalkyl, unsubstituted or with m groups R d C6-C 22 - aryl and unsubstituted or with m groups R d a 3- to 20-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from N, O, S, SO and SO2 as ring members;

[0120] Each R b independently selected from the group consisting of halogen, cyano, nitro, hydroxy, C1-C4-alkoxy, C1-C4-haloalkoxy, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)-amino, NR e R f 、C(=O)NR e R f 、C1-C 20 -alkyl, C1-C 20 -haloalkyl, C2-C 20 -alkenyl, C2-C 20 -haloalkenyl, C2-C 20 -Alkynyl, C2-C20 -haloalkynyl, C3-C 20 - cycloalkyl, unsubstituted or with m groups R d C6-C 22 - aryl and unsubstituted or with m groups R d a 3- to 20-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from N, O, S, SO and SO2 as ring members;

[0121] Each R c are independently selected from the group consisting of: C1-C4-alkyl, C1-C4-haloalkyl, e R f C1-C4-alkyl, C1-C4-alkoxy and C1-C4-haloalkoxy;

[0122] Each R d independently selected from the group consisting of halogen, cyano, hydroxy, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy;

[0123] Each R e independently selected from the group consisting of: hydrogen and C1-C4-alkyl;

[0124] Each R f independently selected from the group consisting of: -C(=O)-phenyl and phenyl which is unsubstituted or substituted by 1, 2 or 3 groups selected from the group consisting of halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy;

[0125] Each m is independently 1, 2, 3, 4 or 5;

[0126] The method comprises making an ester compound (II) having formula (II-1) or (II-2)

[0127]

[0128] in

[0129] R 1 and A are as defined above; and

[0130] R 4 Selected from the group consisting of: C1-C 30 -alkyl, C6-C 14 -Aryl and C6-C 14 -Aryl-C1-C4-alkyl;

[0131] With an amine having formula (III)

[0132]

[0133] Where R 2 and R 3 As defined above,

[0134] reacting in the presence of an alkali metal base and a Lewis acid;

[0135] wherein the reaction is carried out under anhydrous conditions, wherein the water content in the reaction mixture is at most 0.15% by weight relative to the total weight of the reaction mixture.

[0136] E.2. The method according to embodiment E.1, wherein R 1 Selected from the group consisting of: C1-C 20 -alkyl, with 1 or 2 groups R a C1-C4-alkyl, C2-C 20 -alkenyl, C2-C4-alkenyl with a phenyl ring, unsubstituted or with m groups R b C3-C6-cycloalkyl, unsubstituted or with m groups R b C6-C 10 - aryl and unsubstituted or with m groups R b a 5- to 10-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members;

[0137] in

[0138] Each R a are independently C1-C4-alkoxy, C1-C4-haloalkoxy, C(=O)R c or phenyl; and

[0139] Each R b independently halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and unsubstituted or with m groups R d A 5-membered or 6-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members; wherein each R d Independently selected from the group consisting of halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy.

[0140] E.3. The method according to embodiment E.2, wherein R 1 Selected from the group consisting of: C1-C 20-alkyl, C1-C4-alkyl with a phenyl ring, C2-C 20 -alkenyl, C2-C4-alkenyl with a phenyl ring, unsubstituted or with m groups R b C6-C 10 - aryl and unsubstituted or with m groups R b a 5- to 10-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members;

[0141] Each R b are independently halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy.

[0142] E.4. The method according to embodiment E.3, wherein R 1 Selected from the group consisting of: C1-C4-alkyl with a phenyl ring, C2-C 20 -alkenyl, C2-C4-alkenyl with a phenyl ring, unsubstituted or with m groups R b Phenyl and unsubstituted or with m groups R b a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N, O and S as ring members;

[0143] Each R b are independently halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and m is 1, 2 or 3.

[0144] E.5. The method according to embodiment E.4, wherein R 1 Selected from the group consisting of: C1-C2-alkyl with a phenyl ring, C2-C 20 -alkenyl, C2-alkenyl with a phenyl ring, unsubstituted or with m groups R b Phenyl and unsubstituted or with m groups R b A 5-membered or 6-membered heteroaromatic ring containing 1 or 2 nitrogen atoms as ring members;

[0145] Each R b are independently halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and m is 1, 2 or 3.

[0146] E.6. The method according to embodiment E.4, wherein R 1 is unsubstituted or carries m groups R b Phenyl, either unsubstituted or with m groups Rb a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N, O and S as ring members;

[0147] Each R b are independently halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and m is 1, 2 or 3.

[0148] E.7. The method according to embodiment E.6, wherein R 1 is unsubstituted or carries m groups R b Phenyl, either unsubstituted or with m groups R b A 5-membered or 6-membered heteroaromatic ring containing 1 or 2 nitrogen atoms as ring members;

[0149] Each R b are independently halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and m is 1, 2 or 3.

[0150] E.8. The method according to any one of embodiments E.5 or E.7, wherein R 1 is unsubstituted or carries m groups R b Phenyl, either unsubstituted or with m groups R b pyridyl; wherein each R b are independently halogen, cyano, C1-C4-alkyl and C1-C4-alkoxy; and m is 1, 2 or 3.

[0151] E.9. The method according to any one of the preceding embodiments, wherein R 2 Selected from the group consisting of: unsubstituted or with m groups R b C6-C 10 - aryl, and unsubstituted or carrying m groups R b a 5- to 10-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members;

[0152] in

[0153] Each R b independently selected from the group consisting of halogen, cyano, hydroxyl, nitro, C(=O)NR e R f , C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and unsubstituted or with m radicals R d Phenyl;

[0154] Each R d independently selected from the group consisting of halogen, C1-C4-alkyl and C1-C4-haloalkyl;

[0155] Each R e independently selected from the group consisting of: hydrogen and C1-C4-alkyl;

[0156] Each R f Independently selected from the group consisting of: -C(=O)-phenyl and phenyl which is unsubstituted or substituted by 1, 2 or 3 groups selected from the group consisting of halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy.

[0157] E.10. The method according to embodiment E.9, wherein R 2 Selected from the group consisting of: unsubstituted or with m groups R b C6-C 10 - aryl, and unsubstituted or carrying m groups R b a 5- to 10-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members;

[0158] Each R b Independently selected from the group consisting of halogen, cyano, nitro, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and phenyl; preferably selected from halogen, cyano, nitro, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and m is 1, 2 or 3.

[0159] E.11. The method according to embodiment E.10, wherein R 2 Selected from the group consisting of: unsubstituted or with m groups R b phenyl, and unsubstituted or with m groups R b A 6- to 10-membered heteroaromatic ring containing 1 or 2 nitrogen atoms as ring members;

[0160] Each R b independently selected from the group consisting of halogen, nitro, C1-C4-alkyl, C1-C4-alkoxy and phenyl; preferably selected from halogen, nitro, C1-C4-alkyl and C1-C4-alkoxy; and m is 1, 2 or 3.

[0161] E.12. The method according to any one of the preceding embodiments, wherein R 3 is hydrogen or C1-C4-alkyl, preferably hydrogen or methyl.

[0162] E.13. The method according to embodiment E.12, wherein R 3 It's hydrogen.

[0163] E.14. The method according to any one of embodiments E.1 to E.11, wherein R 3 Formed with the aromatic or heteroaromatic ring R 2 The connecting group of the carbon or nitrogen ring atom is -(CH2)2-, -(CH2)3--CH=CH-.

[0164] E.15. The method according to embodiment E.14, wherein R 3 Formed with the aromatic or heteroaromatic ring R 2 The linking group is -(CH2)2- of a carbon or nitrogen ring atom.

[0165] E.16. The method according to any one of the preceding embodiments, wherein the linking group R 3 Bind to R 2 The formation of (group NR 2 R 3 The point of attachment of the (hetero)aromatic ring R is adjacent to the ring atom of the (hetero)aromatic ring R. 2 Condensed.

[0166] E.17. The method according to any one of embodiments E.1 to E.11 and E.14 to E.16, wherein the part of -NR 2 R 3 Forming 2,3-dihydroindolin-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl or indol-1-yl.

[0167] E.18. The method according to embodiment E.17, wherein the part -NR 2 R 3 This forms a 2,3-dihydroindolin-1-yl group.

[0168] E.19. A method according to any one of the preceding embodiments, wherein A is C1-C8-alkanediyl, C2-C 8- Alkenediyl, C3-C6-cycloalkanediyl or phenylene.

[0169] E.20. The method according to embodiment E.19, wherein A is C1-C8-alkanediyl, preferably C1-C4-alkanediyl.

[0170] E.21. The method according to embodiment E.20, wherein A is -CH2-.

[0171] E.22. The method according to any one of the preceding embodiments, wherein R 4Selected from the group consisting of C1-C4-alkyl, phenyl and benzyl, preferably selected from C1-C4-alkyl and phenyl.

[0172] E.23. The method according to embodiment E.22, wherein R 4 It is C1-C4-alkyl.

[0173] E.24. The method according to embodiment E.23, wherein R 4 It is methyl or ethyl.

[0174] E.25. The method according to any of the preceding embodiments, wherein the compound of formula (II-1) and the compound of formula (III) are used in a molar ratio of 5:1 to 1:5.

[0175] E.26. The method according to embodiment E.25, wherein the compound of formula (II-1) and the compound of formula (III) are used in a molar ratio of 2:1 to 1:2.

[0176] E.27. The method according to embodiment E.26, wherein the compound of formula (II-1) and the compound of formula (III) are used in a molar ratio of 1.5:1 to 1:1.5.

[0177] E.28. The method according to embodiment E.27, wherein the compound of formula (II-1) and the compound of formula (III) are used in a molar ratio of about 1:1.

[0178] E.29. The method according to any of the preceding embodiments, wherein the compound of formula (II-2) and the compound of formula (III) are used in a molar ratio of 2.5:1 to 1:10.

[0179] E.30. The method according to embodiment E.29, wherein the compound of formula (II-2) and the compound of formula (III) are used in a molar ratio of 1:1 to 1:4.

[0180] E.31. The method according to embodiment E.30, wherein the compound of formula (II-2) and the compound of formula (III) are used in a molar ratio of 0.75:1 to 1:3.

[0181] E.32. The method according to embodiment E.31, wherein the compound of formula (II-2) and the compound of formula (III) are used in a molar ratio of about 1:2.

[0182] E.33. A method according to any of the preceding embodiments, wherein the Lewis acid is selected from halides, nitrates, metals of Groups 4, 6 to 10, 12, 13 and 15 of the Periodic Table of the Elements, having the formula R—COO - Carboxylates - where R is C1-C 10 -alkyl, C3-C6-cycloalkyl or C3-C6-cycloalkyl-C1-C 10 -alkyl (more precisely, wherein the anion has the formula R-COO - or, alternatively, a salt of a carboxylic acid having the formula RC(O)OH, wherein R is C1-C 10 -alkyl, C3-C6-cycloalkyl or C3-C6-cycloalkyl-C1-C 10 -alkyl), acetylacetonate, C1-C4-alkoxide or carbonyl complex.

[0183] E.34. The method according to embodiment E.33, wherein the Lewis acid is selected from halides, nitrates, of Ti, Zr, Hf, Cr, Mo, Mn, Fe, Co, Ni, Zn, Al, Sb or Bi, having the formula R—COO - Carboxylates - where R is C1-C 10 -alkyl, C3-C6-cycloalkyl or C3-C6-cycloalkyl-C1-C 10 -alkyl (more precisely, wherein the anion has the formula R-COO - or, alternatively, a salt of a carboxylic acid having the formula RC(O)OH, wherein R is C1-C 10 -alkyl, C3-C6-cycloalkyl or C3-C6-cycloalkyl-C1-C 10 -alkyl), acetylacetonate, C1-C4-alkoxide and carbonyl complex.

[0184] E.35. The method according to embodiment E.34, wherein the Lewis acid is selected from the group consisting of: a halide of Mn, Co, Zn or Bi, a nitrate, a nitrate having the formula R—COO - Carboxylates - where R is C1-C 10 -alkyl, C3-C6-cycloalkyl or C3-C6-cycloalkyl-C1-C 10 -alkyl (more precisely, wherein the anion has the formula R-COO - or, alternatively, a salt of a carboxylic acid having the formula RC(O)OH, wherein R is C1-C 10 -alkyl, C3-C6-cycloalkyl or C3-C6-cycloalkyl-C1-C 10 -alkyl), acetylacetonate, C1-C4-alkoxide and carbonyl complex.

[0185] E.36. The method according to embodiment E.35, wherein the Lewis acid is selected from the group consisting of: a halide of Mn, Co, Zn or Bi having the formula R—COO - Carboxylates - where R is C1-C4-alkyl or C3-C6-cycloalkyl-C1-C 10 -alkyl-- (more precisely, wherein the anion has the formula R-COO - or, alternatively, a salt of a carboxylic acid of the formula RC(O)OH, wherein R is C1-C4-alkyl or C3-C6-cycloalkyl-C1-C 10 -alkyl), acetylacetonates, C1-C4-alkoxides and carbonyl complexes,

[0186] The Lewis acid is preferably selected from the group consisting of: a halide of Mn, Co, Zn or Bi, a halogenated salt of Mn, Co, Zn or Bi having the formula R—COO - Carboxylates - where R is C1-C4-alkyl or C3-C6-cycloalkyl-C1-C 10 -alkyl (more precisely, wherein the anion has the formula R-COO - or, alternatively, a salt of a carboxylic acid of the formula RC(O)OH, wherein R is C1-C4-alkyl or C3-C6-cycloalkyl-C1-C 10 -alkyl), acetylacetonates of Mn, Co, Zn or Bi, C1-C4-alkoxides of Mn, Co, Zn or Bi and carbonyl complexes of Mn.

[0187] E.37. The method according to embodiment E.34, wherein the Lewis acid is selected from the group consisting of: MnCl2, MoCl3, CrCl3, BiCl 3、 SbCl3, ZnCl2, FeCl3, FeCl2, CoCl2, NiCl2, TiCl4, ZrCl4, HfCl4, MnBr2, Mn(NO3)2, Co(NO3)2, Mn(OAc)2, Mn(4-cyclohexylbutyric acid)2, Fe (OAc)3, Bi(OAc)3, Mn(AcAc)2, Mn(AcAc)3, Fe(AcAc)2, Fe(AcAc)3, Ni(AcAc)2, Bi(OiPr)3, Ti(OiPr)4, Al(OiPr)3, Mn2(CO) 10 , Mn(CO)5Br, Cr(CO)6, Fe(CO)4 and Co2(CO)8; wherein OAc means acetate, AcAc means acetylacetonate and OiPr means isopropoxide.

[0188] E.38. The method according to embodiment E.37, wherein the Lewis acid is selected from the group consisting of: MnCl2, MnBr2, BiCl3, CoCl2, ZnCl2, NiCl2, Mn(OAc)2, Mn(AcAc)2, Mn(AcAc)3, Mn(4-cyclohexylbutyric acid)2, Bi(OiPr)3, Mn(CO)5Br and Mn2(CO) 10 .

[0189] E.39. The method according to embodiment E.38, wherein the Lewis acid is selected from the group consisting of: MnCl2, MnBr2, BiCl3, CoCl2, ZnCl2, Mn(OAc)2, Mn(AcAc)2, Mn(AcAc)3, Mn(4-cyclohexylbutyric acid)2, Bi(OiPr)3, Mn(CO)5Br and Mn2(CO) 10 .

[0190] E.40. The method according to embodiment E.39, wherein the Lewis acid is selected from the group consisting of: MnCl2, MnBr2, BiCl3, CoCl2, ZnCl2, Mn(OAc)2, Mn(AcAc)2, Mn(AcAc)3, Bi(OiPr)3 and Mn2(CO) 10 .

[0191] E.41. The method according to embodiment E.40, wherein the Lewis acid is selected from the group consisting of: MnCl2, MnBr2, BiCl3, CoCl2, Mn(AcAc)3, Bi(OiPr)3 and Mn2(CO) 10 .

[0192] E.42. The method according to embodiment E.41, wherein the Lewis acid is selected from the group consisting of: MnCl2 and MnBr2.

[0193] E.43. The method according to any one of the preceding embodiments, wherein the Lewis acid is used in an amount of 0.00001 to 0.2 mol per mol of the compound (Il) or (III) not used in excess.

[0194] E.44. The method according to embodiment E.43, wherein the Lewis acid is used in an amount of 0.00001 to 0.1 mol per mol of the compound (Il) or (III) not used in excess.

[0195] E.45. The method according to embodiment E.44, wherein the Lewis acid is used in an amount of 0.0001 to 0.05 mol per mol of the compound (Il) or (III) not used in excess.

[0196] E.46. The method according to embodiment E.45, wherein the Lewis acid is used in an amount of 0.001 to 0.01 mol per mol of the compound (Il) or (III) not used in excess.

[0197] E.47. The method according to embodiment E.45, wherein the Lewis acid is used in an amount of 0.005 to 0.009 mol per mol of the compound (Il) or (III) not used in excess.

[0198] E.48. The method according to any of the preceding embodiments, wherein the alkali metal-containing base is selected from the group consisting of alkali metal alkoxides, amides, hydrides, borohydrides, and aluminides.

[0199] E.49. The method according to embodiment E.48, wherein the alkali metal base is selected from the group consisting of: alkali metal C1-C 10 -alkoxide, having the formula M + [N(R g )2] - Alkali metal amides, wherein M + is an alkali metal cation and R g is hydrogen, C1-C4-alkyl or Si(C1-C4-alkyl)2, and has the formula M + [BH(C1-C4-alkyl)3] - Alkali metal borohydride, where M + It is an alkali metal cation.

[0200] E.50. The method according to any one of the preceding embodiments, wherein the alkali metal base is used in an amount of 0.00001 to 0.1 mol per mol of the compound (II) or (III) not used in excess.

[0201] E.51. The method according to embodiment E.50, wherein the alkali metal base is used in an amount of 0.0001 to 0.05 mol per mol of the compound (II) or (III) not used in excess.

[0202] E.52. The method according to embodiment E.51, wherein the alkali metal base is used in an amount of 0.001 to 0.04 mol per mol of the compound (II) or (III) not used in excess.

[0203] E.53. The method according to embodiment E.52, wherein the alkali metal base is used in an amount of 0.01 to 0.04 mol per mol of the compound (II) or (III) not used in excess.

[0204] E.54. The method according to any one of the preceding embodiments, wherein the water content in the reaction mixture is at most 0.1% by weight relative to the total weight of the reaction mixture.

[0205] E.55. The method according to embodiment E.54, wherein the water content in the reaction mixture is less than 0.1% by weight relative to the total weight of the reaction mixture.

[0206] E.56. The method according to embodiment E.55, wherein the water content in the reaction mixture is less than 0.08% by weight relative to the total weight of the reaction mixture.

[0207] E.57. A method according to any one of the preceding embodiments, wherein the reaction is carried out while continuously removing the alcohol R formed during the reaction. 4 -OH.

[0208] E.58. The method according to any of the preceding embodiments, wherein the reaction is carried out at a temperature of 80°C to 180°C.

[0209] E.59. The method according to embodiment E.58, wherein the reaction is carried out at a temperature of 90°C to 160°C.

[0210] E.60. The method according to embodiment E.59, wherein the reaction is carried out at a temperature of 100°C to 160°C.

[0211] E.61. The method according to embodiment E.60, wherein the reaction is carried out at a temperature of 120°C to 160°C.

[0212] Schematically, the amidation reaction can be depicted as follows:

[0213]

[0214] In compounds (I-1) and (II-1), R 1 Preferably selected from the group consisting of: C1-C 20 -alkyl, with 1 or 2 groups R a C1-C4-alkyl, C2-C 20 -alkenyl, C2-C4-alkenyl with a phenyl ring, unsubstituted or with m groups R b C3-C6-cycloalkyl, unsubstituted or with m groups R b C6-C 10 - aryl and unsubstituted or with m groups R b a 5- to 10-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members;

[0215] in

[0216] Each R a are independently C1-C4-alkoxy, C1-C4-haloalkoxy, C(=O)R c or phenyl; and

[0217] Each R b independently halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and unsubstituted or with m groups R d A 5-membered or 6-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members; wherein each R d Independently selected from the group consisting of halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy.

[0218] More preferably, R 1 Selected from the group consisting of: C1-C 20 -alkyl, C1-C4-alkyl with a phenyl ring, C2-C 20 -alkenyl, C2-C4-alkenyl with a phenyl ring, unsubstituted or with m groups R b C6-C 10 - aryl and unsubstituted or with m groups R b a 5- to 10-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members;

[0219] Each R b are independently halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy.

[0220] Even more preferably, R 1 Selected from the group consisting of: C1-C4-alkyl with a phenyl ring, C2-C 20 -alkenyl, C2-C4-alkenyl with a phenyl ring, unsubstituted or with m groups R b Phenyl and unsubstituted or with m groups R b a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N, O and S as ring members;

[0221] Each R b are independently halogen, cyano, C1-C4-alkyl and C1-C4-alkoxy; and m is 1, 2 or 3.

[0222] Particularly preferably, R1 Selected from the group consisting of: C1-C2-alkyl with a phenyl ring, C2-C 20 -alkenyl, C2-alkenyl with a phenyl ring, unsubstituted or with m groups R b Phenyl and unsubstituted or with m groups R b a 5- or 6-membered heteroaromatic ring containing 1 or 2 nitrogen atoms as ring members (for example pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl or imidazolyl, in particular pyridyl or pyrazolyl);

[0223] Each R b are independently halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and m is 1, 2 or 3.

[0224] In particular, R 1 Selected from the group consisting of: C1-C2-alkyl with a phenyl ring, C2-C 20 -alkenyl, C2-alkenyl with a phenyl ring, unsubstituted or with m groups R b Phenyl and unsubstituted or with m groups R b The pyridyl group;

[0225] Each R b are independently halogen, cyano, C1-C4-alkyl and C1-C4-alkoxy; and m is 1, 2 or 3.

[0226] More specifically, R 1 is unsubstituted or carries m groups R b Phenyl, either unsubstituted or with m groups R b a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N, O and S as ring members;

[0227] Each R b are independently halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and m is 1, 2 or 3.

[0228] Even more specifically, R 1 is unsubstituted or carries m groups R b Phenyl, either unsubstituted or with m groups R b A 5-membered or 6-membered heteroaromatic ring containing 1 or 2 nitrogen atoms as ring members;

[0229] Each R bare independently halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and m is 1, 2 or 3.

[0230] Very specifically, R 1 is unsubstituted or carries m groups R b Phenyl, either unsubstituted or with m groups R b pyridyl; wherein each R b are independently halogen, cyano, C1-C4-alkyl and C1-C4-alkoxy; and m is 1, 2 or 3.

[0231] In compounds (I-1), (I-2) and (III), R 2 Preferably selected from the group consisting of: unsubstituted or carrying m radicals R b C6-C 10 - aryl, and unsubstituted or carrying m groups R b a 5- to 10-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members;

[0232] in

[0233] Each R b independently selected from the group consisting of halogen, cyano, hydroxyl, nitro, C(=O)NR e R f , C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and unsubstituted or with m radicals R d Phenyl;

[0234] Each R d independently selected from the group consisting of halogen, C1-C4-alkyl and C1-C4-haloalkyl;

[0235] Each R e independently selected from the group consisting of: hydrogen and C1-C4-alkyl;

[0236] Each R f Independently selected from the group consisting of: -C(=O)-phenyl and phenyl which is unsubstituted or substituted by 1, 2 or 3 groups selected from the group consisting of halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy.

[0237] More preferably, R 2 Selected from the group consisting of: unsubstituted or with m groups R b C6-C 10- aryl, and unsubstituted or carrying m groups R b A 5- to 10-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members; wherein each R b Independently selected from the group consisting of halogen, cyano, nitro, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and phenyl; preferably selected from halogen, cyano, nitro, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and m is 1, 2 or 3.

[0238] Even more preferably, R 2 Selected from the group consisting of: unsubstituted or with m groups R b phenyl, and unsubstituted or with m groups R b a 6- to 10-membered heteroaromatic ring containing 1 or 2, preferably 1, nitrogen atom as a ring member (e.g., pyridyl or quinolyl); wherein each R b independently selected from the group consisting of halogen, nitro, C1-C4-alkyl, C1-C4-alkoxy and phenyl; preferably halogen, nitro, C1-C4-alkyl and C1-C4-alkoxy; and m is 1, 2 or 3.

[0239] In compounds (I-1), (I-2) and (III), R 3 Preferred is hydrogen or C1-C4-alkyl, more preferably hydrogen or methyl, even more preferably hydrogen.

[0240] Alternatively, R 3 Formed with an aromatic or heteroaromatic ring R 2 A saturated or unsaturated 2-, 3- or 4-membered linking group of a carbon or nitrogen ring atom; wherein the linking group may contain 1 or 2 heteroatoms or heteroatom groups selected from N, O, S, SO and SO2. As explained above, this is in R 2 When it is a monocyclic ring, a bicyclic heterocyclic system is produced or in R 2 When it is bicyclic or polycyclic, it produces a polycyclic heterocyclic ring system, wherein the ring system produced contains NR 2 R 3 The nitrogen atom of R is a ring member and is bonded to CO via this nitrogen ring member. 3 Bind to R 2 The formation of (group NR 2 R 3 If the (hetero)aromatic ring R 2 Fused. If the linking group R 3 Bind to R 2If the moiety is on another ring atom of , the resulting ring system is a bridged ring system.

[0241] In an alternative preferred embodiment, R 3 Formed with an aromatic or heteroaromatic ring R 2 The linking group R is a carbon or nitrogen ring atom linking group -(CH2)2-, -(CH2)3- or -CH=CH-, preferably a linking group -(CH2)2-. 3 Bind to R 2 The formation of (group NR 2 R 3 The point of attachment of the (hetero)aromatic ring R is adjacent to the ring atom of the (hetero)aromatic ring R. 2 Condensed.

[0242] The resulting ring system -NR 2 R 3 Preferred is 2,3-dihydroindolin-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl or indol-1-yl and more preferred is 2,3-dihydroindolin-1-yl.

[0243] In compounds (I-2) and (II-2), A is preferably C1-C8-alkanediyl, C2-C 8- more preferably C1-C8-alkanediyl, even more preferably C1-C6-alkanediyl, particularly preferably C1-C4-alkanediyl, and in particular -CH2-.

[0244] Compound (II-2) is a non-activated ester.

[0245] R 4 It is preferably selected from the group consisting of C1-C4-alkyl, phenyl and benzyl; and more preferably C1-C4-alkyl or phenyl, even more preferably C1-C4-alkyl, and in particular methyl or ethyl.

[0246] In a specific embodiment, in compound (I-1)

[0247] R 1 is unsubstituted or carries m groups R b Phenyl, either unsubstituted or with m groups R b A 5-membered or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N, O and S as ring members; wherein each R b independently selected from the group consisting of halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and m is 1, 2 or 3;

[0248] R2 Selected from the group consisting of: unsubstituted or with m groups R b C6-C 10 - aryl, and unsubstituted or carrying m groups R b A 5- to 10-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members; wherein each R b is independently selected from the group consisting of halogen, cyano, nitro, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and m is 1, 2 or 3; and

[0249] R 3 is hydrogen or C1-C4-alkyl; or

[0250] -NR 2 R 3 It is 2,3-dihydroindolin-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl or indol-1-yl.

[0251] More specifically, in compound (I-1)

[0252] R 1 is unsubstituted or carries m groups R b Phenyl, either unsubstituted or with m groups R b A 5-membered or 6-membered heteroaromatic ring containing 1 or 2 nitrogen atoms as ring members; wherein each R b independently selected from the group consisting of halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and m is 1, 2 or 3;

[0253] R 2 Selected from the group consisting of: unsubstituted or with m groups R b C6-C 10 - aryl, and unsubstituted or carrying m groups R b A 5- to 10-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members; wherein each R b is independently selected from the group consisting of halogen, cyano, nitro, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and m is 1, 2 or 3; and

[0254] R 3 is hydrogen or C1-C4-alkyl; or

[0255] -NR 2 R 3It is 2,3-dihydroindolin-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl or indol-1-yl.

[0256] Even more particularly, in compound (I-1)

[0257] R 1 is unsubstituted or carries m groups R b Phenyl, either unsubstituted or with m groups R b pyridyl; wherein each R b are independently halogen, cyano, C1-C4-alkyl or C1-C4-alkoxy; and m is 1, 2 or 3;

[0258] R 2 Selected from the group consisting of: unsubstituted or with m groups R b C6-C 10 - aryl, and unsubstituted or carrying m groups R b A 5- to 10-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members; wherein each R b is independently selected from the group consisting of halogen, cyano, nitro, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and m is 1, 2 or 3; and

[0259] R 3 is hydrogen or C1-C4-alkyl; or

[0260] -NR 2 R 3 It is 2,3-dihydroindolin-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl or indol-1-yl.

[0261] Very particularly, in compound (I-1)

[0262] R 1 is unsubstituted or carries m groups R b Phenyl, either unsubstituted or with m groups R b pyridyl; wherein each R b are independently halogen, cyano, C1-C4-alkyl and C1-C4-alkoxy; and m is 1, 2 or 3;

[0263] R 2 Selected from the group consisting of: unsubstituted or with m groups R b phenyl, and unsubstituted or with m groups R b A 6- to 10-membered heteroaromatic ring containing 1 or 2 nitrogen atoms as ring members; wherein each R bis independently selected from the group consisting of halogen, nitro, C1-C4-alkyl and C1-C4-alkoxy; and m is 1, 2 or 3; and

[0264] R 3 is hydrogen; or

[0265] -NR 2 R 3 It is 2,3-dihydroindole-1-yl.

[0266] In particular, in compound (I-2)

[0267] A is C1-C6-alkanediyl;

[0268] R 2 Selected from the group consisting of: unsubstituted or with m groups R b C6-C 10 - aryl, and unsubstituted or carrying m groups R b A 5- to 10-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members; wherein each R b is independently selected from the group consisting of halogen, cyano, nitro, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and m is 1, 2 or 3; and

[0269] R 3 is hydrogen or C1-C4-alkyl; or

[0270] -NR 2 R 3 It is 2,3-dihydroindolin-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl or indol-1-yl.

[0271] More specifically, in compound (I-2)

[0272] A is -CH2-;

[0273] R 2 Selected from the group consisting of: unsubstituted or with m groups R b phenyl, and unsubstituted or with m groups R b A 6- to 10-membered heteroaromatic ring containing 1 or 2 nitrogen atoms as ring members; wherein each R b is independently selected from the group consisting of halogen, nitro, C1-C4-alkyl and C1-C4-alkoxy; and m is 1, 2 or 3; and

[0274] R 3 It's hydrogen.

[0275] In particular, in compound (II-1)

[0276] R 1 is unsubstituted or carries m groups R b Phenyl, either unsubstituted or with m groups R b A 5-membered or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N, O and S as ring members; wherein each R b is independently selected from the group consisting of halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and m is 1, 2 or 3; and

[0277] R 4 is C1-C4-alkyl, phenyl or benzyl; preferably C1-C4-alkyl or phenyl.

[0278] More specifically, in compound (II-1)

[0279] R 1 is unsubstituted or carries m groups R b Phenyl, either unsubstituted or with m groups R b A 5-membered or 6-membered heteroaromatic ring containing 1 or 2 nitrogen atoms as ring members; wherein each R b independently selected from the group consisting of halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and m is 1, 2 or 3;

[0280] and

[0281] R 4 is C1-C4-alkyl, phenyl or benzyl; preferably C1-C4-alkyl or phenyl.

[0282] Even more particularly, in compound (II-1)

[0283] R 1 is unsubstituted or carries m groups R b Phenyl, either unsubstituted or with m groups R b pyridyl; wherein each R b are independently halogen, cyano, C1-C4-alkyl and C1-C4-alkoxy; and m is 1, 2 or 3; and

[0284] R 4 is C1-C4-alkyl, phenyl or benzyl; preferably C1-C4-alkyl or phenyl.

[0285] Very particularly, in compound (II-1)

[0286] R 1 is unsubstituted or carries m groups R b Phenyl, either unsubstituted or with m groups R b pyridyl; wherein each R b are independently halogen, cyano, C1-C4-alkyl and C1-C4-alkoxy; and m is 1, 2 or 3; and

[0287] R 4 It is C1-C4-alkyl, preferably methyl or ethyl, in particular methyl.

[0288] In particular, in compound (II-2)

[0289] A is C1-C6-alkanediyl; and

[0290] R 4 is C1-C4-alkyl, phenyl or benzyl; preferably C1-C4-alkyl or phenyl.

[0291] More specifically, in compound (II-2)

[0292] A is -CH2-; and

[0293] R 4 It is C1-C4-alkyl, preferably methyl or ethyl, in particular methyl.

[0294] In particular, in compound (III)

[0295] R 2 Selected from the group consisting of: unsubstituted or with m groups R b C6-C 10 - aryl, and unsubstituted or carrying m groups R b A 5- to 10-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members; wherein each R b is independently selected from the group consisting of halogen, cyano, nitro, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and m is 1, 2 or 3; and

[0296] R 3 is hydrogen or C1-C4-alkyl; or

[0297] -NR 2 R 3 It is 2,3-dihydroindolin-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl or indol-1-yl.

[0298] More particularly, in compound (III)

[0299] R 2 Selected from the group consisting of: unsubstituted or with m groups R b phenyl, and unsubstituted or with m groups R b A 6- to 10-membered heteroaromatic ring containing 1 or 2 nitrogen atoms as ring members; wherein each R b is independently selected from the group consisting of halogen, nitro, C1-C4-alkyl and C1-C4-alkoxy; and m is 1, 2 or 3; and

[0300] R 3 is hydrogen; or

[0301] -NR 2 R 3 It is 2,3-dihydroindole-1-yl.

[0302] In another specific embodiment,

[0303] R 1 Selected from the group consisting of: C1-C2-alkyl with a phenyl ring, C2-C 20 -alkenyl, C2-alkenyl with a phenyl ring, unsubstituted or with m groups R b Phenyl and unsubstituted or with m groups R b A 5-membered or 6-membered heteroaromatic ring containing 1 or 2 nitrogen atoms as ring members;

[0304] in

[0305] Each R b are independently halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and

[0306] m is 1, 2, or 3;

[0307] R 2 Selected from the group consisting of: unsubstituted or with m groups R b phenyl, and unsubstituted or with m groups R b A 6- to 10-membered heteroaromatic ring containing 1 or 2 nitrogen atoms as ring members;

[0308] in

[0309] Each R b are independently selected from the group consisting of halogen, nitro, C1-C4-alkyl, C1-C4-alkoxy and phenyl; and

[0310] m is 1, 2, or 3;

[0311] R 3is hydrogen or C1-C4-alkyl;

[0312] or

[0313] -NR 2 R 3 represents 2,3-dihydroindolin-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl or indol-1-yl;

[0314] A is C1-C4-alkanediyl; and

[0315] R 4 is C1-C4-alkyl or phenyl;

[0316] More specifically,

[0317] R 1 Selected from the group consisting of: C1-C2-alkyl with a phenyl ring, C2-C 20 -alkenyl, C2-alkenyl with a phenyl ring, unsubstituted or with m groups R b Phenyl and unsubstituted or with m groups R b A 5-membered or 6-membered heteroaromatic ring containing 1 or 2 nitrogen atoms as ring members;

[0318] in

[0319] Each R b are independently halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and

[0320] m is 1, 2, or 3;

[0321] R 2 Selected from the group consisting of: unsubstituted or with m groups R b phenyl, pyridyl and quinolyl;

[0322] in

[0323] Each R b are independently selected from the group consisting of halogen, nitro, C1-C4-alkyl, C1-C4-alkoxy and phenyl; and

[0324] m is 1, 2, or 3;

[0325] R 3 It is hydrogen;

[0326] or

[0327] -NR 2 R 3 represents 2,3-dihydroindole-1-yl;

[0328] A is -CH2-; and

[0329] R 4 It is C1-C4-alkyl.

[0330] Compounds (II) and (III) are commercially available or can be prepared by standard methods of organic chemistry.

[0331] Preferably, the compound of formula (II-1) and the compound of formula (III) are used in a molar ratio of 5:1 to 1:5, more preferably 2:1 to 1:2, even more preferably 1.5:1 to 1:1.5 and in particular about 1:1.

[0332] The compound of formula (II-2) and the compound of formula (III) are preferably used in a molar ratio of 2.5:1 to 1:10, more preferably 1:1 to 1:4, even more preferably 0.75:1 to 1:3 and in particular about 1:2.

[0333] In this context, "about" is intended to include deviations from the ideal stoichiometry caused, for example, by weighing errors. Such errors are typically less than 10%, mostly less than 5% or even less than 2%.

[0334] Among compounds (I-1) and (I-2) and (II-1) and (II-2), preferred are (I-1) and (II-1).

[0335] Lewis acid is preferably a metal salt or a metal complex. Preferably, the metal salt or complex is a salt or complex of a metal of Groups 4, 6 to 10, 12, 13 and 15 of the Periodic Table of Elements. More preferably, the metal salt or complex is selected from halides, nitrates, metals of Groups 4, 6 to 10, 12, 13 and 15 of the Periodic Table of Elements, having the (anionic) formula R—COO - Carboxylates - where R is C1-C 10 -alkyl, C3-C6-cycloalkyl or C3-C6-cycloalkyl-C1-C 10 -alkyl, acetylacetonate, C1-C4-alkoxide or carbonyl complex.

[0336] The group numbers refer to the IUPAC nomenclature of 1985. Groups 4, 6 to 10, 12, 13 and 15 are thus Ti, Cr, Mn, Fe, Co, Ni, Zn, B and N. Within group N (group 15), only metals are meant, i.e. As, Sb, Bi. Within group B (group 13), boron is included, although it is a semimetal. However, within group 13, its metals are preferred, i.e. Al, Ga, In, Tl.

[0337] Suitable halides are fluoride, chloride, bromide and iodide, with chloride and bromide being preferred.

[0338] In the context of Lewis acids herein, the term "carboxylate" refers to the anion R-COO - , where R is an organic group; in this case C1-C 10 -alkyl, C3-C6-cycloalkyl or C3-C6-cycloalkyl-C1-C 10 -alkyl. However, the term "carboxylate" is also used to refer to the salts of these anions as a part of the whole. Thus, the carboxylates of the metals listed above are salts of the metals in which the anion has the formula R-COO - , wherein R is as defined above. Examples of suitable carboxylates are acetate, propionate, butyrate, isobutyrate, cyclohexylcarboxylate or 4-cyclohexylbutyrate (cyclohexyl-(CH2)3-C(O)O - ).

[0339] C1-C4-alkoxide is an anion RO - , wherein R is C1-C4-alkyl. However, the term "alkoxide" is also used to refer to the salts of these anions as a part of the whole. Thus, the C1-C4-alkoxides of the metals listed above are salts of the metals in which the anion has the formula RO - , R is C1-C4-alkyl. Examples of suitable alkoxy groups are methoxy (methanol; CH3-O - ), ethoxylate (ethanol; CH3CH2-O - ), n-propoxyl (n-propanol; CH3CH2CH2-O - ), isopropoxyl radical (isopropanol radical CH(CH3)2-O - ), n-butoxide (n-butanol), sec-butoxide (sec-butanol), isobutoxide (isobutanol) or tert-butoxide (tert-butanol).

[0340] Suitable carbonyl complexes are those of the above-mentioned transition metals of groups 4, 6 to 10 and 12. If the metal in the carbonyl complex has a noble gas configuration, the complex must be sufficiently unstable to allow dissociation under the reaction conditions (loss of CO and / or dissociation of the binuclear complex) to form fragments with Lewis acidity. Examples of suitable carbonyl complexes are Mn(CO)5Br, Cr(CO)6, Fe(CO)4 and the binuclear complex Mn2(CO) 10 and Co2(CO)8.

[0341] Even more preferably, the metal salt or complex is a salt or complex of a metal of Ti, Zr, Hf, Cr, Mo, Mn, Fe, Co, Ni, Zn, Al, Sb and Bi. Among the salts and complexes of the metals, halides, nitrates, nitrates, halides of Ti, Zr, Hf, Cr, Mo, Mn, Fe, Co, Ni, Zn, Al, Sb and Bi are preferred. - Carboxylates - where R is C1-C 10 -alkyl (more precisely, wherein the anion has the formula R-COO - or, alternatively, a salt of a carboxylic acid having the formula RC(O)OH, wherein R is C1-C 10 -alkyl), having the formula R-COO - carboxylates wherein R is a C3-C6-cycloalkyl group (more specifically, wherein the anion has the formula R-COO - or, alternatively, a salt of a carboxylic acid of the formula RC(O)OH, wherein R is a C3-C6-cycloalkyl group), of the formula R-COO - Carboxylates - where R is C3-C6-cycloalkyl-C1-C 10 -alkyl (more precisely, wherein the anion has the formula R-COO - or, alternatively, a salt of a carboxylic acid of the formula RC(O)OH, wherein R is a C3-C6-cycloalkyl-C1-C 10 -alkyl), acetylacetonate, C1-C4-alkoxide or carbonyl complex. More preferably MnCl2, MoCl3, CrCl3, BiCl 3、 SbCl3, ZnCl2, FeCl3, FeCl2, CoCl2, NiCl2, TiCl4, ZrCl4, HfCl4, MnBr2, Mn(NO3)2, Co(NO3)2, Mn(OAc)2, Mn(4-cyclohexylbutyric acid)2, Fe (OAc)3, Bi(OAc)3, Mn(AcAc)2, Mn(AcAc)3, Fe(AcAc)2, Fe(AcAc)3, Ni(AcAc)2, Bi(OiPr)3, Ti(OiPr)4, Al(OiPr)3, Mn2(CO) 10 , Mn(CO)5Br, Cr(CO)6, Fe(CO)4 and Co2(CO)8; wherein OAc means acetate, AcAc means acetylacetonate and OiPr means isopropoxide.

[0342] Particularly preferred are Lewis acids selected from the group consisting of: halides of Mn, Co, Zn or Bi having the formula R—COO -carboxylates wherein R is C1-C4-alkyl (more precisely, wherein the anion has the formula R-COO - or, alternatively, a salt of a carboxylic acid of the formula RC(O)OH, wherein R is C1-C4-alkyl), of the formula R-COO - Carboxylates - where R is C3-C6-cycloalkyl-C1-C 10 -alkyl (more precisely, wherein the anion has the formula R-COO - or, alternatively, a salt of a carboxylic acid of the formula RC(O)OH, wherein R is a C3-C6-cycloalkyl-C1-C 10 -alkyl), acetylacetonates, C1-C4-alkoxides and carbonyl complexes; in particular halides of Mn, Bi, Co, Zn or Ni having the formula R-COO - carboxylates wherein R is C1-C4-alkyl (more precisely, wherein the anion has the formula R-COO - or, alternatively, a salt of a carboxylic acid of the formula RC(O)OH, wherein R is C1-C4-alkyl), of the formula R-COO - Carboxylates - where R is C3-C6-cycloalkyl-C1-C 10 -alkyl (more precisely, carboxylates in which the anion has the formula R-COO- or, alternatively, salts of carboxylic acids of the formula RC(O)OH, in which R is C3-C6-cycloalkyl-C1-C10-alkyl), acetylacetonates and C1-C4-alkoxides; and carbonyl complexes of Mn; more particularly preferably Lewis acids selected from the group consisting of MnCl2, MnBr2, BiCl3, CoCl2, ZnCl2, NiCl2, Mn(OAc)2, Mn(AcAc)2, Mn(AcAc)3, Mn(4-cyclohexylbutyric acid)2, Bi(OiPr)3, Mn(CO)5Br and Mn2(CO) 10 .

[0343] Even more particularly preferred are Lewis acids selected from the group consisting of MnCl2, MnBr2, BiCl3, CoCl2, ZnCl2, Mn(OAc)2, Mn(AcAc)2, Mn(AcAc)3, Mn(4-cyclohexylbutyric acid)2, Bi(OiPr)3, Mn(CO)5Br and Mn2(CO) 10 .

[0344] In particular, the Lewis acid is selected from the group consisting of: MnCl2, MnBr2, BiCl3, CoCl2, ZnCl2, Mn(OAc)2, Mn(AcAc)2, Mn(AcAc)3, Bi(OiPr)3 and Mn2(CO) 10 ; and in particular selected from MnCl2 and MnBr2.

[0345] It is also possible to use mixtures of two or more Lewis acids.

[0346] Lewis acids are usually used in essentially anhydrous form; in the case of metal salts, this means essentially no water of crystallization. In this context, "essentially" means that some negligible amount of water may be present, i.e. at most 5% by weight, preferably at most 2% by weight and more preferably at most 1% by weight, e.g. at most 0.1% by weight, relative to the total weight of the Lewis acid (metal salt or complex).

[0347] Therefore, the reaction carried out under anhydrous conditions preferably means that the water content in the reaction mixture (including the water contained as water of crystallization) is at most 0.15% by weight relative to the total weight of the reaction mixture. The reaction medium is generally composed of starting materials (II) and (III), a Lewis acid, a base and optionally a solvent.

[0348] Lewis acids are either commercially available or can be prepared from suitable starting materials by known means, for example by anion exchange of commercially available salts.

[0349] Although the Lewis acid can in principle be used in a stoichiometric amount or even in excess (relative to the starting material), the method of the invention is advantageously also very suitable when using very low substoichiometric amounts of the Lewis acid. Therefore, the Lewis acid is preferably used in an amount of 0.00001 to 0.2 mol, more preferably 0.00001 to 0.1 mol, even more preferably 0.0001 to 0.05 mol, particularly preferably 0.001 to 0.01 mol, and in particular 0.005 to 0.009 mol per mol of the compound (Il) or (III) not used in excess. Alternatively stated, the Lewis acid is preferably used in an amount of 0.001 to 20 mol-%, more preferably 0.001 to 10 mol-%, even more preferably 0.01 to 5 mol-%, particularly preferably 0.1 to 1 mol-%, and in particular 0.5 to 0.9 mol-%, relative to the amount of the compound (Il) or (III) not used in excess (in mol; this amount corresponds to 100 mol-%).

[0350] The "non-excessive" compound (II) or (III) refers to the starting compound (II) and (III) which is not used in excess among the compounds (II) and (III). If the compound (II) or (III) is used in equimolar amounts, of course, there is no excess of (II) and (III) among the two compounds.

[0351] If compounds (II) or (III) are used in equimolar amounts, the amounts of Lewis acid given above naturally relate to either compound (II) or (III).

[0352] In the case of compound (II-2), the "equimolar amount" and "excess" amounts in this particular context take into account the two carboxylate groups that can react in the amidation reaction (carboxylate group in this context means carboxylate ester group). Thus, "equimolar" amounts of (II-2) and (III) in this case means 0.5 mol (II-2) / 1 mol (III); "excess" use of (II-2) in this case means >0.5 mol (II-2) / 1 mol (III), and "excess" use of (III) in this case means >2 mol (III) / 1 mol (II-2).

[0353] The alkali metal-containing base is preferably selected from the group consisting of alkali metal alkoxides, amides, hydrides, borohydrides and aluminides.

[0354] Suitable alkali metals are Li, Na, K, Rb and Cs, preferably Li, Na, K and Cs.

[0355] Alkoxide is an anion RO - , wherein R is an alkyl group, preferably C1-C 10 -alkyl. Alkali metal alkoxides are therefore salts RO - M + , where M + is an alkali metal cation. Suitable C1-C 10 An example of an alkoxide anion is methoxy (methanol; CH3-O - ), ethoxylate (ethanol; CH3CH2-O - ), n-propoxyl (n-propanol; CH3CH2CH2-O - ), isopropoxide (isopropanol CH(CH3)2-O - ), n-butoxide (n-butoxide), sec-butoxide (sec-butoxide), isobutoxide (isobutoxide), tert-butoxide (tert-butoxide), pentoxide, hexoxide, heptoxide, octoxide, 2-ethylhexoxide, nonoxide, decoxide, 2-propylheptoxide or other positional isomers thereof. Suitable alkali metal C1-C 10Examples of -alkoxides are LiOMe, NaOMe, KOMe, CsOMe, LiOEt, NaOEt, KOEt, CsOEt, LiOPr, NaOPr, KOPr, CsOPr, LiOiPr, NaOiPr, KOiPr, CsOiPr, LiOBu, NaOBu, KOBu, CsOBu, LiOtBu, NaOtBu, KOtBu, CsOtBu, LiO(2-ethylhexyl), NaO(2-ethylhexyl), KO(2-ethylhexyl), CsO(2-ethylhexyl), etc., wherein OMe is methoxide, OEt is ethoxide, OPr is n-propoxide, OiPr is isopropoxide, OBu is n-butoxide, OtBu is tert-butoxide and O(2-ethylhexyl) is 2-ethylhexoxide.

[0356] Suitable amines are those having the formula [N(R g )2] - anion, where R g is hydrogen, alkyl (usually C1-C4-alkyl) or Si(alkyl)2 (usually Si(C1-C4-alkyl)2). Generally speaking, the two R g Thus, an alkali metal amide is a compound having the formula M + [N(R g )2] - Salt, where M + is an alkali metal cation. Examples of suitable alkali metal amides are LiNH2, NaNH2, KNH2, CsNH2, LiN(CH3)2, NaN(CH3)2, KN(CH3)2, CsN(CH3)2, LiN(CH2CH3)2, NaN(CH2CH3)2, KN(CH2CH3)2, CsN(CH2CH3)2, LiN(Si(CH3)3)2, NaN(Si(CH3)3)2(NaHMDS), KN(Si(CH3)3)2(KHMDS), CsN(Si(CH3)3)2, and the like.

[0357] Alkali metal hydrides are compounds having the formula M + H - Salt, where M + is an alkali metal cation. Examples are LiH, NaH and KH.

[0358] Suitable alkali metal borohydrides are those having the formula M + [BH(alkyl)3] - (Usually M + [BH(C1-C4-alkyl)3] - ) wherein M +is an alkali metal cation. Examples are Li[BH(ethyl)3], Na[BH(ethyl)3], K[BH(ethyl)3], Li[BH(n-propyl)3], Na[BH(n-propyl)3], K[BH(n-propyl)3], Li[BH(isopropyl)3], Na[BH(n-propyl)3], K[BH(n-propyl)3], Li[BH(n-butyl)3], Na[BH(n-butyl)3], K[BH(n-butyl)3], Li[BH(2-butyl)3], Na[BH(2-butyl)3] (sodium tri-sec-butylborohydride), K[BH(2-butyl)3] (potassium tri-sec-butylborohydride), etc. Other suitable alkali metal borohydrides are those having the formula M + [BH4] - Salt, where M + is an alkali metal cation. A suitable example is LiBH4.

[0359] Suitable alkali metal aluminum hydrides are those having the formula M + [AlH(alkyl)3] - (Usually M + [AlH(C1-C4-alkyl)3] - ) wherein M + It is an alkali metal cation.

[0360] Preferably, the alkali metal base is selected from the group consisting of: alkali metal C1-C 10 -alkoxide, having the formula M + [N(R g )2] - Alkali metal amides - where M + is an alkali metal cation and R g is hydrogen, C1-C4-alkyl or Si(C1-C4-alkyl)2, and has the formula M + [BH(C1-C4-alkyl)3] - Alkali metal borohydride, where M + It is an alkali metal cation.

[0361] The alkali metal-containing base is more preferably selected from the group consisting of:

[0362] -C1-C of Na, K or Cs 10 - alkoxides, such as NaOMe, KOMe, NaOEt, KOEt, NaOPr, KOPr, NaOiPr, KOiPr, NaOtBu, KOtBu or CsO(2-ethylhexyl) (preferably Na, K or Cs C4-C 10 - alkoxides, such as NaOtBu, KOtBu or CsO(2-ethylhexyl));

[0363] -Li, Na or K amide M + [N(R g )2] - , where M + It's Li + 、Na + or K + And R g is hydrogen, C1-C4-alkyl or Si(C1-C4-alkyl)2, such as LiNH2, NaNH2, KNH2, LiNEt2(Et=ethyl), NaNEt2, KNEt2, NaHMDS or KHMDS; and

[0364] -Na or K borohydride M + [BH(C1-C4-alkyl)3] - , where M + Yes + or K + , such as sodium tri-sec-butylborohydride or potassium tri-sec-butylborohydride.

[0365] Me is methyl, Et is ethyl, Pr is n-propyl, iPr is isopropyl and tBu is tert-butyl.

[0366] Specifically, the alkali metal-containing base is selected from the group consisting of KOtBu, CsO(2-ethylhexyl), LiNH2, LiNEt2(Et=ethyl), NaHMDS, KHMDS, sodium tri-sec-butylborohydride and potassium tri-sec-butylborohydride.

[0367] It is also possible to use mixtures of two or more bases.

[0368] The alkali metal base is preferably used in an amount of 0.00001 to 0.1 mol, more preferably 0.0001 to 0.05 mol, even more preferably 0.001 to 0.04 mol, and particularly preferably 0.01 to 0.04 mol per mol of the compound (II) or (III) not used in excess. Alternatively, the alkali metal base is preferably used in an amount of 0.001 mol-% to 10 mol-%, more preferably 0.01 mol-% to 5 mol-%, even more preferably 0.1 mol-% to 4 mol-%, and particularly preferably 1 mol-% to 4 mol-% relative to the amount of the compound (II) or (III) not used in excess (in mol; this amount corresponds to 100 mol-%).

[0369] If compound (II) or (III) is used in equimolar amounts, the amounts of the alkali metal base given above naturally relate to either compound (II) or (III).

[0370] In the case of compound (II-2), the "equimolar amount" and "excess" amounts in this particular context take into account the two carboxylate groups (in this context meaning carboxylate groups) that can react in the amidation reaction. Thus, an "equimolar" amount of (II-2) and (III) in this case means 0.5 mol (II-2) / 1 mol (III); an "excess" use of (II-2) in this case means >0.5 mol (II-2) / 1 mol (III), and an "excess" use of (III) in this case means >2 mol (III) / 1 mol (II-2).

[0371] Preferably, the Lewis acid is selected from the group consisting of: halides of Mn, Co, Zn and Bi having the formula R—COO - carboxylates wherein R is C1-C4-alkyl (more precisely, wherein the anion has the formula R-COO - or, alternatively, a salt of a carboxylic acid of the formula RC(O)OH, wherein R is C1-C4-alkyl), of the formula R-COO - Carboxylates - where R is C3-C6-cycloalkyl-C1-C 10 -alkyl (more specifically, a carboxylate wherein the anion has the formula R-COO-, or alternatively a salt of a carboxylic acid of the formula RC(O)OH wherein R is C3-C6-cycloalkyl-C1-C 10 -alkyl), acetylacetonate, C1-C4-alkoxide or carbonyl complex; and containing an alkali metal base selected from the group consisting of: alkali metal C1-C 10 -alkoxide, having the formula M + [N(R g )2] - Alkali metal amides - where M + is an alkali metal cation and R g is hydrogen, C1-C4-alkyl or Si(C1-C4-alkyl)2, and has the formula M + [BH(C1-C4-alkyl)3] - Alkali metal borohydride - where M + It is an alkali metal cation.

[0372] More preferably, the Lewis acid is selected from the group consisting of: halides of Mn, Co, Zn and Bi having the formula R—COO - carboxylates wherein R is C1-C4-alkyl (more precisely, wherein the anion has the formula R-COO - or, alternatively, a salt of a carboxylic acid of the formula RC(O)OH, wherein R is C1-C4-alkyl), of the formula R-COO- Carboxylates - where R is C3-C6-cycloalkyl-C1-C 10 -alkyl (more specifically, a carboxylate wherein the anion has the formula R-COO-, or alternatively a salt of a carboxylic acid of the formula RC(O)OH wherein R is C3-C6-cycloalkyl-C1-C 10 -alkyl), acetylacetonate and C1-C4-alkoxide, and carbonyl complex of Mn; and containing an alkali metal base selected from the group consisting of: alkali metal C1-C 10 -alkoxide, having the formula M + [N(R g )2] - Alkali metal amides - where M + is an alkali metal cation and R g is hydrogen, C1-C4-alkyl or Si(C1-C4-alkyl)2, and has the formula M + [BH(C1-C4-alkyl)3] - Alkali metal borohydride, where M + It is an alkali metal cation.

[0373] Even more preferably, the Lewis acid is selected from the group consisting of: MnCl2, MnBr2, BiCl3, CoCl2, ZnCl2, Mn(OAc)2, Mn(AcAc)2, Mn(AcAc)3, Mn(4-cyclohexylbutyric acid)2, Bi(OiPr)3, Mn(CO)5Br and Mn2(CO) 10 , and the alkali metal base is selected from the group consisting of: alkali metal C1-C 10 -alkoxide, having the formula M + [N(R g )2] - Alkali metal amides, wherein M + is an alkali metal cation and R g is hydrogen, C1-C4-alkyl or Si(C1-C4-alkyl)2, and has the formula M + [BH(C1-C4-alkyl)3] - Alkali metal borohydride, where M + It is an alkali metal cation.

[0374] In particular, the Lewis acid is selected from the group consisting of: MnCl2, MnBr2, BiCl3, CoCl2, ZnCl2, Mn(OAc)2, Mn(AcAc)2, Mn(AcAc)3, Mn(4-cyclohexylbutyric acid)2, Bi(OiPr)3, Mn(CO)5Br and Mn2(CO) 10, and the alkali metal base is selected from the group consisting of KOtBu, CsO(2-ethylhexyl), LiNH2, LiNEt2(Et=ethyl), NaHMDS, KHMDS, sodium tri-sec-butylborohydride and potassium tri-sec-butylborohydride.

[0375] Preferably, the Lewis acid is used in an amount of 0.00001 to 0.1 mol and the alkali metal base is used in an amount of 0.00001 to 0.1 mol, in each case per mol of the compound (II) or (III) not used in excess.

[0376] More preferably, the Lewis acid is used in an amount of 0.0001 to 0.05 mol, and the alkali metal base is used in an amount of 0.0001 to 0.05 mol, in each case per mol of the compound (II) or (III) not used in excess.

[0377] Even more preferably, the Lewis acid is used in an amount of 0.001 to 0.01 mol and the alkali metal base is used in an amount of 0.001 to 0.04 mol, in each case per mol of the compound (II) or (III) not used in excess.

[0378] In particular, the Lewis acid is used in an amount of 0.005 to 0.009 mol, and the alkali metal base is used in an amount of 0.01 to 0.04 mol, in each case per mol of the compound (II) or (III) not used in excess.

[0379] Preferably,

[0380] - A Lewis acid selected from the group consisting of: halides of Mn, Co, Zn and Bi, wherein the anion has the formula R-COO - Carboxylates of - wherein R is C1-C4-alkyl and wherein the anion has the formula R-COO - Carboxylates - where R is C3-C6-cycloalkyl-C1-C 10 - alkyl, acetylacetonate, C1-C4-alkoxide or carbonyl complex;

[0381] - an alkali metal base selected from the group consisting of: an alkali metal C1-C 10 -alkoxide, having the formula M + [N(R g )2] - Alkali metal amides, wherein M + is an alkali metal cation and R g is hydrogen, C1-C4-alkyl or Si(C1-C4-alkyl)2, and has the formula M + [BH(C1-C4-alkyl)3] -Alkali metal borohydride, where M + It is an alkali metal cation;

[0382] - the Lewis acid is used in an amount of 0.00001 to 0.1 mol per mol of the compound (II) or (III) not used in excess, and

[0383] The alkali metal base is used in an amount of 0.00001 to 0.1 mol per mol of the compound (II) or (III) which is not used in excess.

[0384] More preferably,

[0385] - A Lewis acid selected from the group consisting of: halides of Mn, Co, Zn and Bi; wherein the anion has the formula R-COO - Carboxylates of - wherein R is C1-C4-alkyl and wherein the anion has the formula R-COO - Carboxylates - where R is C3-C6-cycloalkyl-C1-C 10 -alkyl; acetylacetonates and C1-C4-alkoxides; and carbonyl compounds of Mn;

[0386] - an alkali metal base selected from the group consisting of: an alkali metal C1-C 10 -alkoxide, having the formula M + [N(R g )2] - Alkali metal amides, wherein M + is an alkali metal cation and R g is hydrogen, C1-C4-alkyl or Si(C1-C4-alkyl)2, and has the formula M + [BH(C1-C4-alkyl)3] - Alkali metal borohydride, where M + It is an alkali metal cation;

[0387] - the Lewis acid is used in an amount of 0.0001 to 0.05 mol per mol of the compound (II) or (III) not used in excess, and

[0388] The alkali metal base is used in an amount of 0.0001 to 0.05 mol per mol of the compound (II) or (III) which is not used in excess.

[0389] Even more preferably,

[0390] - A Lewis acid selected from the group consisting of: MnCl2, MnBr2, BiCl3, CoCl2, ZnCl2, Mn(OAc)2, Mn(AcAc)2, Mn(AcAc)3, Mn(4-cyclohexylbutyric acid)2, Bi(OiPr)3, Mn(CO)5Br and Mn2(CO) 10 ;

[0391] - an alkali metal base selected from the group consisting of: an alkali metal C1-C 10 -alkoxide, having the formula M + [N(R g )2] - Alkali metal amides, wherein M + is an alkali metal cation and R g is hydrogen, C1-C4-alkyl or Si(C1-C4-alkyl)2, and has the formula M + [BH(C1-C4-alkyl)3] - Alkali metal borohydride, where M + It is an alkali metal cation;

[0392] - the Lewis acid is used in an amount of 0.001 to 0.01 mol per mol of the compound (II) or (III) not used in excess, and

[0393] The alkali metal base is used in an amount of 0.001 to 0.04 mol per mol of the compound (II) or (III) which is not used in excess.

[0394] Specifically,

[0395] - A Lewis acid selected from the group consisting of: MnCl2, MnBr2, BiCl3, CoCl2, ZnCl2, Mn(OAc)2, Mn(AcAc)2, Mn(AcAc)3, Mn(4-cyclohexylbutyric acid)2, Bi(OiPr)3, Mn(CO)5Br and Mn2(CO) 10 ;

[0396] - an alkali metal-containing base selected from the group consisting of KOtBu, CsO(2-ethylhexyl), LiNH2, LiNEt2(Et=ethyl), NaHMDS, KHMDS, sodium tri-sec-butylborohydride and potassium tri-sec-butylborohydride.

[0397] - the Lewis acid is used in an amount of 0.005 to 0.009 mol per mol of the compound (II) or (III) not used in excess, and

[0398] The alkali metal base is used in an amount of 0.01 to 0.04 mol per mol of the compound (II) or (III) which is not used in excess.

[0399] The reaction can be carried out in one or more solvents. Suitable solvents are all those which do not have a negative effect on the amidation reaction and which are suitable for dispersing or dissolving the reactants.

[0400] Suitable solvents are, for example, hydrocarbons, such as alkanes, for example pentane, hexane, heptane or octane, cycloalkanes, for example cyclopentene, cyclohexane, methylcyclohexane, cycloheptane or cyclooctane, or aromatic compounds, for example benzene, toluene, xylene, chlorobenzene, dichlorobenzene, trifluoromethylbenzene or anisole; open-chain ethers, for example diethyl ether, dipropyl ether, dibutyl ether or methyl tert-butyl ether, cyclic ethers, for example tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane, glycol ethers, for example diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, polyethylene glycol dimethyl ether or polypropylene glycol dimethyl ether, ketones, for example acetone or ethyl methyl ketone, nitriles, for example acetonitrile, sulfoxides, for example dimethyl sulfoxide, sulfones, for example sulfolane, alkanols, for example isopropanol or tert-butanol, or mixtures of two or more of the above-mentioned solvents.

[0401] Hydrocarbons, particularly cycloalkanes and aromatic solvents are preferred. Specifically, cyclohexane, methylcyclohexane or toluene is used.

[0402] Some of the Lewis acids and bases are commercially available in solvents, for example in alkanes, aromatic hydrocarbons and / or ethers. In this case, the solvent is typically a solvent mixture which, in addition to the intended solvent, comprises the solvent in which the Lewis acid and base are commercially available.

[0403] Alternatively, the reaction can be carried out neat, ie without any additional solvent, in particular if one of the starting materials (II) and / or (III) is liquid under the reaction conditions.

[0404] According to the present invention, the reaction is carried out under anhydrous conditions, i.e. the water content in the reaction mixture is at most 0.15% by weight relative to the total weight of the reaction mixture. Preferably, the water content in the reaction mixture is at most 0.1% by weight relative to the total weight of the reaction mixture, more preferably less than 0.1% by weight, and even more preferably less than 0.08% by weight.

[0405] The water content can be calculated from the water content of the starting materials (the reaction must be carried out without or substantially without additional water entering the system); or it can be determined analytically, for example by Karl-Fischer titration.

[0406] The given water content in the reaction mixture generally includes the water contained as water of crystallization. Therefore, the reaction carried out under anhydrous conditions means that the water content in the reaction mixture (including the water contained as water of crystallization) is at most 0.15% by weight, preferably at most 0.1% by weight, more preferably less than 0.1% by weight, and even more preferably less than 0.08% by weight relative to the gross weight of the reaction mixture. The reaction mixture is generally composed of starting materials (II) and (III), Lewis acid, base, and optionally solvent. Along with the reaction, the reaction mixture also contains the formed product and any intermediate or by-product (as the case may be).

[0407] Anhydrous conditions can be ensured by common means. For example, the reactants used (compounds (II) and (III), Lewis acid, base and optionally solvent) are provided in anhydrous form and reacted to avoid any moisture entry, for example by using a drying apparatus, by reacting under an inert atmosphere, for example under (dry) nitrogen or argon, and / or by reacting under the inherent pressure formed when using a closed reaction vessel and heating the reaction (see description below), to prevent air entry (which may bring moisture).

[0408] The reaction is carried out at a temperature of preferably 80 to 180°C, more preferably 90 to 160°C, for example 100 to 160°C or 120 to 160°C.

[0409] The reaction pressure is not critical in principle. However, since high temperatures are preferred and in the case of solvents used having a boiling point below the desired temperature, the reaction is usually carried out in a closed vessel or under reflux in this case. This leads to an inherent pressure which is usually in the range of 1.1 to 30 bar, in particular 1.5 to 5 bar, in particular 2 to 4 bar. In another embodiment, when the alcohol R formed is 4 When OH has a high boiling point and should be removed continuously (see below), the pressure can also be reduced to a range of 0.01 to 1 bar, in particular 0.1 to 1 bar. Thus, the reaction pressure can range from vacuum through atmospheric pressure to higher pressures, for example 0.01 to 30 bar or to 20 bar or to 5 bar or to 4 bar.

[0410] If the reaction is conducted under pressure, a closed apparatus (such as an autoclave or other reaction vessel suitable for pressurized reactions) is generally used, and the pressure is applied by an inert gas or by heating the reaction mixture (thus inherently generating pressure), or both.

[0411] Regardless of whether the reaction is carried out under pressure or not, the reaction is preferably carried out under an inert atmosphere, for example under (dry) nitrogen or argon.

[0412] The reaction is generally carried out by combining all reactants (starting compounds (II) and (III), Lewis acid, base) and optionally solvent in a suitable reaction vessel / reactor and bringing the reaction mixture to the desired temperature for the necessary reaction time, under an inert atmosphere (if desired) and under pressure (if desired) (e.g. by using a closed reaction vessel / reactor and optionally inserting a noble gas).

[0413] If necessary, the reactants and solvents are dried by conventional means before introduction into the reaction. In addition, the solvents may also be degassed.

[0414] The reaction can be carried out in the conventional device / reactor for the purpose of the present invention. In principle, any reactor suitable for liquid reaction under the desired reaction temperature and pressure can be used. Standard reactors suitable for gas-liquid and liquid-liquid reaction systems are known to those skilled in the art and are described in, for example, Ullmann's Encyclopedia of Industrial Chemistry, 2005, Wiley-VCH Verlag GmbH & Co.KGaA, Chapter 3.3, Reactor Types and Their Industrial Applications and Reactors for Gas-Liquid Reactions. Suitable examples include, for example, stirred tank reactors, tubular reactors or bubble column reactors. The reaction can be carried out discontinuously in batch mode, or continuously or semi-continuously in the case of recirculation or no longer circulation.

[0415] The average reaction time / residence time in the reaction space can vary within wide ranges, preferably in the range from 15 minutes to 100 hours, more preferably in the range from 1 to 50 hours, for example from 1 to 20 hours or from 10 to 20 hours.

[0416] If desired, the alcohol R formed during the amidation can be removed continuously or periodically. 4 -OH, in order to further carry out the amidation reaction and achieve a higher conversion. This can be achieved, for example, by continuously or periodically distilling off the alcohol R formed. 4 OH is achieved, especially if the reaction is carried out in pure form or if an alcohol R is used which has a boiling point higher than that formed 4 OH, or when using a solvent with a boiling point lower than R 4 OH solvent or with R 4 OH forms an azeotrope with the solvent (thus converting R 4OH is distilled off together with the organic solvent).

[0417] After the reaction is completed to the desired extent, the reaction mixture is worked up by conventional means, such as addition of water or aqueous solution to remove salts (Lewis acid, base) and phase separation, neutralization (if necessary / desirable), filtration, extraction, removal of solvent, etc. Suitable work-up depends on the starting materials, solvent used and product formed, and can be determined by one skilled in the art.

[0418] The product can be isolated and purified by known means (such as precipitation, filtration, crystallization, removal of solvent, etc.), the appropriate method depending on the starting material, solvent used and product formed, and can be determined by a person skilled in the art.

[0419] The process of the invention allows the direct amidation of esters and amines starting from a very wide substrate range for both esters and amines. In particular, (hetero)aromatic esters and amines, even weakly nucleophilic amines, such as those carrying electron-withdrawing groups on their (hetero)aromatic moieties, can be used. Lewis acids and bases can be used in substoichiometric catalytic amounts, thus reducing the amount of potentially hazardous or environmentally problematic and in any case uneconomical waste.

[0420] The present invention will now be illustrated by the following examples.

[0421] Examples

[0422] Analytical methods

[0423] In the pre-coated Macherey-Nagel Analytical thin layer chromatography (TLC) was performed on SIL G / UV254 aluminum sheets.

[0424] use column Silica D10, using cyclohexane and ethyl acetate (EtOAc) as eluents, on an automated Isolera equipped with a high performance rapid purification system TM Standard flash chromatography was performed on a Spektra system.

[0425] 1 H. 13 C and 19 F NMR spectra were recorded on a Bruker AVANCE III 300 spectrometer in CDCl3 or d6-DMSO. Chemical shifts are reported in parts per million (ppm) and referenced to the residual solvent resonance (CHCl3: for 1 HNMR δ = 7.26 ppm, and CDCl3: for 13C NMR δ = 77.16 ppm). Data are reported as follows: chemical shift, multiplicity (br s = broad singlet, s = singlet, d = doublet, dd = doublet of doublet, dt = doublet of triplet, t = triplet, m = multiplet), coupling constant (Hz), and integration.

[0426] Gas-liquid chromatography (GLC) was performed by CS-Chromatographie Service on an Agilent Technologies 6890N gas chromatograph equipped with a DB-5 capillary column (30 m×0.32 mm, 0.25 μm film thickness) using the following program: He carrier gas, injection temperature 250°C, detector temperature 300°C, flow rate: 3.42 mL / min; temperature program: start temperature 60°C for 1 min, heating rate 5°C / min, end temperature 120°C, then heating rate 15°C / min until 270°C, end temperature 270°C for 2 min. The retention time of mesitylene is 4.65 min. The retention time of p-toluidine (4-methylaniline) is 7.00 min. The retention time of methyl benzoate is 7.56 min. The retention time of N-(p-tolyl)benzamide is 21.75 min.

[0427] abbreviation

[0428] KOtBu Potassium tert-butoxide

[0429] EtOAc Ethyl acetate

[0430] DCM Dichloromethane

[0431] OAc Acetate

[0432] OiPr Isopropoxide (isopropyl alcohol)

[0433] AcAc Acetylacetonate

[0434] Me Methyl

[0435] Et Ethyl

[0436] Ph Phenyl

[0437] Examples 1 to 11: Preparation of N-(p-tolyl)benzamide - Lewis acid variant

[0438]

[0439] In a glove box, the Lewis acid indicated in Table 1 below (xx mg, see Table 1; in each case, 0.01 mmol, 0.84 mol%), followed by KOtBu (4.5 mg, 0.04 mmol, 3.4 mol%), 4-methylaniline (128.6 mg, 1.2 mmol, 1 eq; purity> 99.9%) and methyl benzoate (150 μL, 1.2 mmol, 1 eq; purity> 99.9%) were loaded into a 38 mL Ace-tube equipped with a magnetic stir bar. Dry and degassed methylcyclohexane (0.3 mL; 0.001% water content) was added. The water content in the reaction mixture (consisting of amine, ester, Lewis acid, base, solvent) was a maximum of 0.1% by weight relative to the total weight of the reaction mixture (calculated by the given maximum water content of the reagents and solvents used). The tube was sealed with a stopper, removed from the glove box and inserted into a metal block preheated at 140°C. The reaction was run at this temperature for 16 h while stirring at about 750 rpm. The reaction was cooled to room temperature, diluted with EtOAc or DCM, and mesitylene (138.1 μL, 1.0 mmol, 0.83 equivalent) was added as an internal standard. A small aliquot was filtered through a diatomaceous earth plug (eluent EtOAc) and analyzed by GC.

[0440] exist Comparative Example Comp-1 The reaction was carried out as described above, but without the addition of Lewis acid.

[0441] exist Comparative Examples Comp-2 and Comp-3 The reaction was carried out as described above, but without the addition of base.

[0442] The results are listed in Table 1.

[0443] Examples 12 and 13: Preparation of N-(p-tolyl)benzamide - Lewis acid variant

[0444]

[0445] The procedure of Examples 1 to 11 was repeated, but using twice the amount of reactants (2.4 mmol of 4-methylaniline and methyl benzoate, respectively, 0.02 mmol of Lewis acid, 0.08 mmol of KOtBu and 0.6 mL of methylcyclohexane).

[0446] exist Comparative Example Comp-4 The reaction was carried out as described above, but using a Lewis acid with crystal water. The water content of the reaction mixture was about 0.24% by weight relative to the total weight of the reaction mixture.

[0447] The results are listed in Table 1.

[0448] Table 1

[0449]

[0450] As shown in Comp-1, the presence of Lewis acid is necessary to obtain satisfactory yields.

[0451] As shown in Comp-2 and Comp-3, the presence of a base is essential to obtain satisfactory yields.

[0452] Comp-4 shows the importance of anhydrous conditions.

[0453] Examples 14 to 20: Preparation of N-(p-tolyl)benzamide - Base variations

[0454]

[0455] In a glove box, MnCl2 (2.5 mg, 0.02 mmol, 0.84 mol%), followed by the base indicated in Table 2 below (xx mg; see Table 2; 0.08 mmol, 3.4 mol%), 4-methylaniline (257.2 mg, 2.4 mmol, 1 eq.) and methyl benzoate (300 μL, 2.4 mmol, 1 eq.) were loaded into a 38 mL Ace-tube equipped with a magnetic stirring bar. Dry and degassed methylcyclohexane (0.6 mL; 0.001% water content) was added. The water content in the reaction mixture (consisting of amine, ester, Lewis acid, base, solvent) was a maximum of 0.15% by weight relative to the gross weight of the reaction mixture. The tube was sealed with a stopper, removed from the glove box and inserted into a metal block preheated at 140°C. The reaction was run at this temperature for 16 h while stirring at about 750 rpm. The reaction was cooled to room temperature, diluted with EtOAc or DCM, and mesitylene (276.2 μL, 2.0 mmol, 0.83 equiv) was added as an internal standard. A small aliquot was filtered through a plug of celite (eluent EtOAc) and analyzed by GC.

[0456] exist Comparative Example Comp-5 The reaction was carried out as described above, but without the addition of base.

[0457] The results are listed in Table 2.

[0458] Table 2

[0459]

[0460] As shown in Comp-5 as well as Comp-2 and Comp-3, the presence of a base is essential to obtain satisfactory yields.

[0461] Examples 21 and 22: Preparation of N-(p-tolyl)benzamide - Leaving Group OR in Ester 4 Variations

[0462]

[0463] In glove box, by MnCl2 (2.5mg, 0.02mmol, 0.84mol%), then KOtBu (8.9mg, 0.08mmol, 3.4mol%), 4-methylaniline (257.2mg, 2.4mmol, 1 equivalent) and the benzoate indicated in the following table 3 (2.4mmol, 1 equivalent) are loaded into a 38mL Ace-tube equipped with a magnetic stirring bar. Add dry and degassed methylcyclohexane (0.6mL). Pipe is sealed with a stopper, taken out from the glove box and inserted into a metal block preheated at 140 ℃. The reaction is run at this temperature for 16h, while stirring at about 750rpm. The reaction is cooled to room temperature, diluted with EtOAc or DCM, and mesitylene (276.2 μL, 2.0mmol, 0.83 equivalent) is added as an internal standard. A small aliquot was filtered through a plug of celite (eluent EtOAc) and analyzed by GC.

[0464] In the comparative example Comp-6 The reaction is carried out as described above, but using the corresponding carboxylic acid instead of the ester.

[0465] The results are listed in Table 3.

[0466] Table 3

[0467]

[0468]

[0469] Examples 23 to 47: Variations of substrates

[0470] General Procedure 1 (1.2 mmol scale, closed system)

[0471] In glove box, by MnCl (1.3mg, 0.01mmol, 0.84mol%), then KOtBu (4.5mg, 0.04mmol, 3.4mol%), corresponding aniline (1.2mmol, 1 equivalent) and corresponding ester (1.2mmol, 1 equivalent) are loaded in the 38mL Ace-tube equipped with magnetic stirring bar.Add dry and degassed methylcyclohexane (0.3mL).The pipe is sealed with stopper, taken out from glove box and inserted into the metal block preheated at 140 ℃.The reaction is operated at this temperature for 16h, stirring at about 750rpm simultaneously.The reaction is cooled to room temperature, 2 drops of H are added O, and the mixture is diluted with EtOAc or DCM, stirred for 5min and filtered through diatomite plug (eluent EtOAc or DCM). The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography on silica gel or by washing with cyclohexane and further drying under high vacuum (hv).

[0472] General Procedure 2 (2.4 mmol scale, closed system)

[0473] In glove box, by MnCl (2.5mg, 0.02mmol, 0.84mol%), followed by KOtBu (8.9mg, 0.08mmol, 3.4mol%), corresponding aniline (2.4mmol, 1 equivalent) and corresponding ester (2.4mmol, 1 equivalent) are loaded into 38mL Ace-tube equipped with magnetic stirring bar. Add dry and degassed methylcyclohexane (0.6mL). Pipe is sealed with stopper, taken out from glove box and inserted into the metal block preheated at 140 ℃. The reaction is run at this temperature for 16h, stirring at about 750rpm simultaneously. The reaction is cooled to room temperature, 2 drops of H are added O, and the mixture is diluted with EtOAc or DCM, stirred for 5min and filtered through diatomite plug (eluent EtOAc or DCM). The solvent is removed under reduced pressure, and the crude product is purified by silica gel flash column chromatography or by washing with cyclohexane and further drying under high vacuum.

[0474] General Procedure 3 (2.4 mmol scale, closed system)

[0475] In glove box, by MnCl (2.5mg, 0.02mmol, 0.84mol%), then KOtBu (8.9mg, 0.08mmol, 3.4mol%), corresponding aniline (2.4mmol, 1 equivalent) and corresponding ester (2.4mmol, 1 equivalent) are loaded in the 38mL Ace-tube equipped with magnetic stirring bar.Add dry and degassed methylcyclohexane (0.6mL).The pipe is sealed with stopper, taken out from glove box and inserted into the metal block preheated at 160 ℃.The reaction is moved at this temperature for 16h, stirring at about 750rpm simultaneously.The reaction is cooled to room temperature, 2 drops of H are added O, and the mixture is diluted with EtOAc or DCM, stirred for 5min and filtered through diatomite plug (eluent EtOAc or DCM). The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography on silica gel or by washing with cyclohexane and further drying under high vacuum (hv).

[0476] Amine variants

[0477] Example 23 - Preparation of N-(p-tolyl)benzamide

[0478]

[0479] Following general procedure 1, p-toluidine (128 mg, 1.2 mol, 1 eq) and methyl benzoate (150 ul, 1.2 mmol, 1 eq) were reacted to give the amide (215.5 g, 85%) as a colorless solid after washing the crude with cyclohexane.

[0480] 1 H NMR(301MHz, CDCl3)δ8.17(bs,1H),7.90-7.78(m,2H),7.58-7.50(m,2H),7.51 -7.46(m,1H),7.40(dd,J=8.3,6.8Hz,2H),7.13(d,J=8.1Hz,2H),2.33(s,3H).

[0481] 13 C NMR (76MHz, CDCl3) δ166.0,135.5,135.1,134.2,131.7,129.6,128.7,127.2,120.6,21.0.

[0482] Example 2 Preparation of 4-N-(4-methoxyphenyl)benzamide

[0483]

[0484] Following General Procedure 2, 4-methoxyaniline (295.6 mg, 2.4 mol, 1 eq.) and methyl benzoate (300 μl, 2.4 mmol, 1 eq.) were reacted to give the amide (468.8 mg, 86%) as a colorless solid after washing the crude with cyclohexane.

[0485] 1 H NMR (301MHz, DMSO) δ10.13 (s, 1H), 7.96 (dt, J = 6.6, 1.7Hz, 2H), 7.76-7.65 (m, 2H), 7.63-7.46 (m, 3H), 7.01-6.86 (m, 2H), 3.75 (s, 3H).

[0486] 13 C NMR (76MHz, DMSO) δ165.1,155.6,135.1,132.3,131.4,128.3,127.5,122.0,113.7,55.2.

[0487] Example 2 Preparation of 5-N-(4-nitrophenyl)benzamide

[0488]

[0489] Following General Procedure 2, 4-nitroaniline (331.5 mg, 2.4 mol, 1 eq.) and methyl benzoate (300 μl, 2.4 mmol, 1 eq.) were reacted to afford the amide (411.9 mg, 71%) as a beige solid after washing the crude with Et2O.

[0490] 1H NMR (301MHz, DMSO) δ10.80(bs,1H),8.30-8.21(m,2H),8.12-8.02(m,2H),8.02-7.92(m,2H),7.69-7.50(m,3H).

[0491] 13 C NMR (76MHz, DMSO) δ166.3,145.5,142.4,134.2,132.1,128.5,127.9,124.8,119.8.

[0492] Example 26 Preparation of N-(4-chlorophenyl)benzamide

[0493]

[0494] Following General Procedure 2, 4-chloroaniline (306.2 mg, 2.4 mol, 1 eq.) and methyl benzoate (300 μl, 2.4 mmol, 1 eq.) were reacted to give the amide (472.4 mg, 85%) as a colorless crystalline powder after washing the crude with cyclohexane.

[0495] 1 H NMR (301MHz, DMSO) δ10.38(bs,1H),8.02-7.91(m,2H),7.89-7.78(m,2H),7.65-7.47(m,3H),7.45-7.34(m,2H).

[0496] 13 C NMR (76MHz, DMSO) δ165.6,138.2,134.7,131.7,128.5,128.4,127.7,127.3,121.8.

[0497] Example 2 Preparation of 7-N-(4-fluorophenyl)benzamide

[0498]

[0499] Following General Procedure 2, 4-fluoroaniline (227.9 uL, 1.2 mol, 1 eq) and methyl benzoate (300 μ, 12.4 mmol, 1 eq) were reacted to give the amide as a grey solid (423.6 mg, 82%) after washing the crude with cyclohexane.

[0500] Example 28 - Preparation of N-(2-phenylphenyl)benzamide (N-(2-biphenylyl)benzamide)

[0501]

[0502] Ph = Phenyl

[0503] Following General Procedure 2, reaction of 2-aminobiphenyl (406.2 mg, 2.4 mol, 1 eq) and methyl benzoate (300 μl, 1.2 mmol, 1 eq) afforded the amide (460.1 mg, 70%) as a colorless solid after purification of the crude by flash column chromatography on silica (0%-8% EtOAc in cyclohexane).

[0504] 1 H NMR (301MHz, CDCl3) δ6.65 (dd, J=8.3, 1.2Hz, 1H), 6.14 (bs, 1H), 5.76-5.68 (m, 2H), 5.66- 5.52(m,7H),5.51-5.45(m,2H),5.42(dd,J=7.6,1.7Hz,1H),5.33(td,J=7.5,1.2Hz,1H).

[0505] 13 C NMR (76MHz, CDCl3) δ165.0,138.2,135.0,134.9,132.5,131.8,130.1,129.4,129.3,128.8,128.7,128.3,126.9,124.5,121.3.

[0506] Example 29 - Preparation of N-(2-fluorophenyl)benzamide

[0507]

[0508] Following General Procedure 2, reaction of 2-fluoroaniline (231.9 uL, 2.4 mol, 1 eq) and methyl benzoate (300 μl, 2.4 mmol, 1 eq) afforded the amide (411.6 mg, 80%) as a colorless solid after purification of the crude by flash column chromatography on silica (0%-10% EtOAc in cyclohexane).

[0509] 1 H NMR (301MHz, CDCl3) δ8.46 (td, J = 8.1, 1.8Hz, 1H), 8.11 (bs, 1H), 7.96-7.80 (m, 2H), 7.64-7.42 (m, 3H), 7.22-7.02 (m, 3H).

[0510] 19 F NMR (283MHz, CDCl3) δ-131.1.

[0511] Example 30 Preparation of indolin-1-yl (phenyl)methanone

[0512]

[0513] Following General Procedure 2, indoline (267.3 uL, 2.4 mol, 1 eq) and methyl benzoate (300 μl, 2.4 mmol, 1 eq) were reacted to give the amide (434.0 mg, 81%) as a colorless solid after washing the crude with cyclohexane.

[0514] Example 3 Preparation of 1-N-(2-pyridyl)benzamide

[0515]

[0516] Following General Procedure 2, reaction of 2-aminopyridine (201.9 mg, 2.4 mol, 1 eq) and methyl benzoate (300 μl, 1.2 mmol, 1 eq) afforded the amide (291.0 mg, 61%) as a colorless solid after purification of the crude by flash column chromatography (0%-40% EtOAc in cyclohexane).

[0517] 1 H NMR (301MHz, CDCl3) δ9.18 (bs, 1H), 8.46-8.34 (m, 1H), 8.12 (ddd, J = 4.9, 1.9, 0.9Hz, 1H), 7.96-7.87 (m, 2H) ,7.73(ddd,J=8.4,7.3,1.9Hz,1H),7.58-7.50(m,1H),7.50-7.42(m,2H),7.01(ddd,J=7.3,4.9,1.0Hz,1H).

[0518] 13 C NMR (76MHz, CDCl3) δ166.1,151.9,147.9,138.6,134.5,132.3,128.9,127.4,119.9,114.4.

[0519] Example 3 Preparation of 2-N-(8-quinolyl)benzamide

[0520]

[0521] Following General Procedure 2, reaction of 8-aminoquinoline (346.0 mg, 2.4 mol, 1 eq) and methyl benzoate (300 μl, 1.2 mmol, 1 eq) afforded the amide (359.7 mg, 60%) as a colorless solid after purification of the crude by flash column chromatography (0%-10% EtOAc in cyclohexane).

[0522] 1H NMR (301MHz, CDCl3) δ10.73(bs,1H),8.95(dd,J=7.5,1.6Hz,1H),8.82(dd,J=4.2,1.7Hz,1H),8.14(dd,J=8.3,1.7Hz,1H),8.12 -8.06(m,2H),7.62-7.49(m,5H),7.44(dd,J=8.3,4.3Hz,1H).

[0523] 13 C NMR (76MHz, CDCl3) δ165.5,148.3,138.8,136.4,135.2,134.7,131.9,128.9,128.1,127.5,127.4,121.8,121.8,116.6.

[0524] Example 33 Preparation of N-methyl-N-phenylbenzamide

[0525]

[0526] Following General Procedure 3, reaction of N-methylaniline (260.0 μL, 2.4 mol, 1 eq) and methyl benzoate (300 μL, 1.2 mmol, 1 eq) afforded the amide (408.5 mg, 80%) as a yellow oil after purification of the crude by flash column chromatography (0%-12% EtOAc in cyclohexane).

[0527] 1 H NMR (301MHz, CDCl3) δ7.35-7.12(m,8H),7.09-7.02(m,2H),3.52(s,3H).

[0528] Ester variants

[0529] Example 34 Preparation of 4-fluoro-N-(p-tolyl)benzamide

[0530]

[0531] Following General Procedure 2, p-toluidine (257.2 mg, 2.4 mol, 1 eq.) and methyl 4-fluorobenzoate (311 μl, 2.4 mmol, 1 eq.) were reacted to give the amide (445.5 mg, 81%) as a colorless powder after washing the crude with cyclohexane.

[0532] 1H NMR (301MHz, CDCl3) δ7.91-7.83(m,2H),7.82(d,J=7.4Hz,1H),7.53-7.45(m,2H),7.20-7.08(m,4H),2.34(s,3H).

[0533] 19 F NMR (283MHz, CDCl3) δ-107.68.

[0534] 13 C NMR (76MHz, CDCl3) δ 166.7, 164.1 (d, J = 112.1Hz), 135.2.134.4.129.6, 129.4 (d, J = 9.1Hz), 120.4, 115.8 (d, J = 22.0Hz), 20.9.

[0535] Example 35- Preparation of 4-methoxy-N-(p-tolyl)benzamide

[0536]

[0537] Following General Procedure 2, p-toluidine (257.2 mg, 2.4 mol, 1 eq.) and methyl 4-methoxybenzoate (398.3 mg, 2.4 mmol, 1 eq.) were reacted to give the amide (495.4 mg, 86%) as a colorless white powder after washing the crude with cyclohexane.

[0538] 1 H NMR (301MHz, CDCl3) δ7.89-7.79(m,3H),7.55-7.47(m,2H),7.18-7.11(m,2H),6.98-6.90(m,2H),3.85(s,3H),2.33(s,3H).

[0539] 13 C NMR (76MHz, CDCl3) δ165.4,162.5,135.7,134.1,129.6,129.0,127.4,120.5,114.20,55.6,21.0.

[0540] Example 36 Preparation of 3-methyl-N-(p-tolyl)benzamide

[0541]

[0542] Following General Procedure 2, p-toluidine (257.2 mg, 2.4 mol, 1 eq) and methyl m-toluate (344.2 μL, 2.4 mmol, 1 eq) were reacted to afford the amide (393.0 mg, 73%) as a colorless solid after purification of the crude by flash column chromatography (0%-15% EtOAc in cyclohexane).

[0543] 1 H NMR (301MHz, CDCl3) δ7.86 (bs, 1H), 7.67 (q, J=1.2Hz, 1H), 7.63 (ddd, J=5.3, 3.6, 2.0Hz, 1H),7.55–7.49(m,2H),7.36–7.30(m,2H),7.19–7.13(m,2H),2.41(s,3H),2.34(s,3H).

[0544] 13 C NMR (76MHz, CDCl3) δ166.0,138.7,135.6,135.2,134.2,132.6,129.7,128.7,127.9,124.1,120.4,21.5,21.0.

[0545] Example 37- Preparation of 3-fluoro-N-(p-tolyl)benzamide

[0546]

[0547] Following General Procedure 2, p-toluidine (257.2 mg, 2.4 mol, 1 eq) and methyl 3-fluorobenzoate (315.9 μL, 2.4 mmol, 1 eq) were reacted to afford the amide (339.9 mg, 62%) as a colorless solid after purification of the crude by flash column chromatography (0%-10% EtOAc in cyclohexane).

[0548] 1 H NMR (301MHz, CDCl3) δ7.97 (bs, 1H), 7.63-7.58 (m, 1H), 7.55 (ddd, J = 9.3, 2.6, 1.6Hz, 1H), 7.52-7.46 (m, 2H), 7.40 (td, J=8.0, 5.5Hz, 1H), 7.21 (tdd, J=8.3, 2.6, 1.0Hz, 1H), 7.14 (d, J=8.3Hz, 2H), 2.33 (s, 3H).

[0549] 19 F NMR (283MHz, CDCl3) δ-111.45.

[0550] Example 38 Preparation of N-(p-tolyl)pyridine-3-carboxamide

[0551]

[0552] Following General Procedure 2, p-toluidine (257.2 mg, 2.4 mol, 1 eq.) and methyl nicotinate (328.9 mg, 2.4 mmol, 1 eq.) were reacted to give the amide (402.5 mg, 79%) as a brown solid after washing the crude with cyclohexane.

[0553] 1 H NMR (301MHz, DMSO) δ10.38 (s, 1H), 9.11 (d, J = 2.5Hz, 1H), 8.75 (dd, J = 4.8, 1.7Hz, 1H), 8.29 (dt, J = 8. 0, 2.1Hz, 1H), 7.66 (d, J = 8.5Hz, 2H), 7.55 (dd, J = 8.0, 4.7Hz, 1H), 7.17 (d, J = 8.4Hz, 2H), 2.28 (s, 3H).

[0554] 13 C NMR (76MHz, DMSO) δ163.8,152.0,148.7,136.3,135.4,133.0,130.7,129.1,123.5,120.4,20.5.

[0555] Example 39-Preparation of N-(p-tolyl)pyridine-2-carboxamide

[0556]

[0557] Following General Procedure 2, p-toluidine (257.2 mg, 2.4 mol, 1 eq) and methyl picolinate (289.5 μL, 2.4 mmol, 1 eq) were reacted to give the amide (452.9 mg, 89%) as a light brown solid after washing the crude with cyclohexane.

[0558] 1 H NMR (301MHz, CDCl3) δ9.96 (bs, 1H), 8.58 (dd, J=4.9, 1.7Hz, 1H), 8.33-8.23 (m, 1H), 7.87 (td, J=7.7, 1.6Hz, 1H), 7.71-7.62 (m, 2H), 7.44 (ddd, J=7.7, 4.7, 1.2Hz, 1H), 7.18 (d, J=8.2Hz, 2H), 2.33 (s, 3H).

[0559] 13C NMR (76MHz, CDCl3) δ161.9,145.0,148.0,137.7,135.3,133.9,129.6,126.4,122.4,119.7,21.0.

[0560] Example 40 Preparation of 2-phenyl-N-(p-tolyl)acetamide

[0561]

[0562] Following General Procedure 2, p-toluidine (257.2 mg, 2.4 mol, 1 eq) and methyl phenylacetate (364.0 μL, 2.4 mmol, 1 eq) were reacted to give the amide (479.2 mg, 89%) as a colorless solid after washing the crude with cyclohexane.

[0563] 1 H NMR (301MHz, CDCl3) δ7.49 (bs, 1H), 7.41-7.27 (m, 7H), 7.07 (d, J = 8.2Hz, 2H), 3.69 (s, 2H), 2.30 (s, 3H).

[0564] 13 C NMR (76MHz, CDCl3) δ164.4,135.3,134.8,134.1,129.6,129.5,129.2,127.6,120.2,44.7,20.9.

[0565] Example 41 Preparation of 3-phenyl-N-(p-tolyl)propionamide

[0566]

[0567] Following General Procedure 2, p-toluidine (257.2 mg, 2.4 mol, 1 eq) and methyl 3-phenylpropanoate (378.9 μL, 2.4 mmol, 1 eq) were reacted to give the amide (464.1 mg, 81%) as a colorless powder after washing the crude with cyclohexane.

[0568] 1 H NMR (301MHz, CDCl3) δ7.37-7.24(m,5H),7.27-7.15(m,3H),7.08(d,J=8.2Hz,2H),3.03(t,J=7.6Hz,2H),2.67-2.59(m,2H),2.30(s,3H).

[0569] 13C NMR (76MHz, CDCl3) δ170.5,140.8,135.3,134.0,129.5,128.7,128.5,126.4,120.3,39.4,31.72 21.0.

[0570] Example 4 Preparation of 2-(E)-3-phenyl-N-(p-tolyl)prop-2-enamide

[0571]

[0572] Following General Procedure 2, p-toluidine (257.2 mg, 2.4 mol, 1 eq) and methyl cinnamate (389.3 mg, 2.4 mmol, 1 eq) were reacted to afford the amide (447.5 mg, 72%) as a colorless solid after purification of the crude by flash column chromatography (0%-100% EtOAc in cyclohexane).

[0573] 1 H NMR (301MHz, CDCl3) δ7.75 (d, J = 15.5Hz, 1H), 7.57-7.45 (m, 4H), 7.42-7.35 (m, 3H), 7.33 (bs, 1H), 7.15 (d, J = 8.3Hz, 2H), 6.54 (d, J = 15.5Hz, 1H), 2.33 (s, 3H).

[0574] 13 C NMR (76MHz, CDCl3) δ164.5,142.0,135.7,134.8,134.2,129.9,129.6,128.9,128.0,121.3,120.6,21.0.

[0575] Example 43 - Preparation of N-(p-tolyl)oleamide

[0576]

[0577] Following General Procedure 2, p-toluidine (257.2 mg, 2.4 mol, 1 eq) and methyl oleate (214.2 μL, 2.4 mmol, 1 eq) were reacted to afford the amide (755.6 mg, 85%) as a light yellow waxy solid after purification of the crude by flash column chromatography (0%-15% EtOAc in cyclohexane).

[0578] 1H NMR (301MHz, CDCl3) δ7.44 (bs, 1H), 7.44-7.35 (m, 2H), 7.09 (d, J = 8.2Hz, 2H), 5.42-5.27 (m, 2H), 2.37-2.24(m,5H),2.08-1.93(m,4H),1.78-1.61(m,2H),1.43-1.20(m,20H),0.94-0.83(m,3H).

[0579] 13 C NMR (76MHz, CDCl3) δ171.6,135.6,133.8,130.1,129.8,129.5,120.1,37.8, 32.0,29.9,29.8,29.6,29.4,29.4,29.3,27.3,27.3,25.8,22.8,20.9,14.2.

[0580] Example 44 Preparation of 3-(difluoromethyl)-1-methyl-N-(p-tolyl)pyrazole-4-carboxamide

[0581]

[0582] Following General Procedure 1, p-toluidine (128 mg, 1.2 mol, 1 eq) and methyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate (228.1 mg, 1.2 mmol, 1 eq) were reacted to afford the amide (220.5 mg, 69%) as a colorless solid after purification of the crude by flash column chromatography (0%-10% EtOAc in cyclohexane).

[0583] 1 H NMR (301MHz, CDCl3) δ8.53 (bs, 1H), 7.94-7.82 (m, 1H), 7.44-7.35 (m, 2H), 7.17 (t, J = 54.1Hz, 1H), 7.10-7.04 (m, 2H), 3.75 (s, 3H), 2.29 (s, 3H).

[0584] 19 F NMR (283MHz, CDCl3) δ-111.26.

[0585] 13 C NMR (76MHz, CDCl3) δ 160.0, 144.1 (t, J = 26.4Hz), 135.0, 134.4, 133.9, 129.4, 120.8, 116.7, 111.0 (t, J = 234.2Hz), 39.3, 20.8.

[0586] Ester and amine variants

[0587] Example 45 Preparation of 4-cyano-N-(2-fluorophenyl)benzamide

[0588]

[0589] Following General Procedure 2, 2-fluoroaniline (231.9 uL, 2.4 mol, 1 eq) and methyl 4-cyanobenzoate (327.5 μL, 2.4 mmol, 1 eq) were reacted for 24 h to give the amide (508.7 mg, 88%) as a colorless solid after purification of the crude by flash column chromatography (0%-20% EtOAc in cyclohexane).

[0590] 1 H NMR (301MHz, CDCl3) δ8.40 (ddd, J=8.2, 6.9, 1.3Hz, 1H), 8.06 (s, 1H), 8.02-7.95 (m, 2H), 7.84-7.76 (m, 2H), 7.24-7.09 (m, 3H).

[0591] 19 F NMR (283MHz, CDCl3) δ-130.75.

[0592] Example 4 Preparation of 6-indolin-1-yl-(3,4,5-trimethoxyphenyl)methanone

[0593]

[0594] Following General Procedure 2, indoline (267.3 μL, 2.4 mol, 1 eq.) and methyl 3,4,5-trimethoxybenzoate (542.9 mg, 2.4 mmol, 1 eq.) were reacted to afford the amide (691,8 mg, 92%) as a colorless solid after purification of the crude by flash column chromatography (0%-20% EtOAc in cyclohexane).

[0595] 1 H NMR(301MHz, CDCl3)δ7.20(d,J=7.3Hz,1H),7.11(bs,1H),7.00(t,J=7.4Hz,1H), 6.77(s,2H),4.19-4.03(m,2H),3.89(s,3H),3.85(s,6H),3.12(t,J=8.2Hz,2H).

[0596] Diamide

[0597] Example 47-Preparation of N,N'-bis(p-tolyl)malonamide

[0598]

[0599] In glove box, by MnCl (2.5mg, 0.02mmol, 0.84mol%), followed by KOtBu (8.9mg, 0.08mmol, 3.4mol%), p-toluidine (512.0mg, 4.8mmol, 2 equivalents) and methyl malonate (273.4 μ L, 2.4mmol, 1 equivalent) are loaded into a 38mL Ace-tube equipped with a magnetic stirring bar. Add dry and degassed methylcyclohexane (0.6mL). Pipe is sealed with a stopper, taken out from glove box and inserted into a metal block preheated at 140 ℃. The reaction is run at this temperature for 16h, while stirring at about 750rpm. The reaction is cooled to room temperature, 2 drops of H are added O, and the mixture is diluted with EtOAc or DCM, stirred for 5min and filtered through a diatomite plug. Most of the reaction mixture is insoluble in these solvents. After eluting the plug with EtOAc, the remaining material was dissolved in acetone and filtered through celite. The acetone fractions were collected and the solvent was removed under reduced pressure to give the bisamide (355.0 mg, 52%) as a white powder.

[0600] 1 H NMR (301MHz, DMSO) δ10.06(bs,2H),7.68-7.32(m,4H),7.30-6.92(m,4H),3.43(s,2H),2.25(s,6H).

[0601] 13 C NMR (76MHz, DMSO) δ165.2, 136.5, 132.3, 129.1, 119.1, 45.8, 20.4.

[0602] Example 48 - Preparation of N-(p-tolyl)benzamide - Open system

[0603]

[0604] In glove box, by MnCl2(5.2mg, 0.04mmol, 0.84mol%), followed by KOtBu(18.0mg, 0.16mmol, 3.4mol%), 4-methylaniline(514.4mg, 4.8mmol, 1 equivalent) and methyl benzoate(600uL, 4.8mmol, 1 equivalent) are loaded in a 25mL round-bottom flask equipped with a magnetic stirring bar.Dry and degassed toluene (6mL) is added.Flask is closed with rubber septum and taken out from glove box.Flask is connected to a dry reflux condenser under argon (note: there is no water in the cooling part).The top of condenser is closed with rubber septum, and a long needle (0.80x120mm) is used as Ar inlet.Shorter needle (0.9x 40mm) is inserted to produce Ar stream.Flask is inserted into preheated oil bath (oil temperature 140 ℃) and refluxed 17h under Ar stream. (Note: there is no water cooling during this time). The reaction is cooled to room temperature. Most of the solvent volume is evaporated during the reaction process. The reaction is diluted with EtOAc and filtered through a diatomaceous earth plug (eluent EtOAc). The solvent is removed under reduced pressure, and the crude product is diluted in a minimum amount of DCM. 10mL of cyclohexane is added, and DCM is evaporated under reduced pressure to precipitate the product as a colorless solid. About 50% of the cyclohexane is further removed under reduced pressure, and then the (Pasteur pipette) residue is taken out. The precipitate is washed with cyclohexane and further dried under reduced pressure to obtain the title compound (947.3mg, 93%) as a colorless solid.

[0605] 1 H NMR(301MHz, CDCl3)δ8.17(bs,1H),7.90-7.78(m,2H),7.58-7.50(m,2H),7.51 -7.46(m,1H),7.40(dd,J=8.3,6.8Hz,2H),7.13(d,J=8.1Hz,2H),2.33(s,3H).

[0606] 13 C NMR (76MHz, CDCl3) δ166.0,135.5,135.1,134.2,131.7,129.6,128.7,127.2,120.6,21.0.

Claims

1. A method for preparing an amide of formula (I-1) or a diamide of formula (I-2) in R 1 is selected from the group consisting of: hydrogen, unsubstituted or carrying m groups R a C1-C 30 -alkyl, unsubstituted or with m groups R a C1-C 30 -haloalkyl, unsubstituted or with m groups R a C2-C 30 -alkenyl, unsubstituted or with m groups R a C2-C 30 -haloalkenyl, unsubstituted or with m groups R a C2-C 30 -alkynyl, unsubstituted or with m groups R a C2-C 30 -haloalkynyl, unsubstituted or with m groups R b C3-C 30 - cycloalkyl, unsubstituted or with m groups R b C6-C 22 - aryl and unsubstituted or with m groups R b a 3- to 30-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from N, O, S, SO and SO2 as ring members; R 2 is unsubstituted or carries m groups R b C6-C 22 -aryl, or a 5- to 30-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members, wherein the heteroaromatic ring is unsubstituted or carries m radicals R b ; R 3 is selected from the group consisting of: hydrogen, unsubstituted or carrying m groups R a C1-C 30 -alkyl, unsubstituted or with m groups R a C1-C 30 -haloalkyl, unsubstituted or with m groups R a C2-C 30 -alkenyl, unsubstituted or with m groups R a C2-C 30 -haloalkenyl, unsubstituted or with m groups R a C2-C 30 -alkynyl, unsubstituted or with m groups R a C2-C 30 -haloalkynyl, unsubstituted or with m groups R b C3-C 30 - cycloalkyl, unsubstituted or with m groups R b C6-C 22 - aryl and unsubstituted or with m groups R b a 3- to 30-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from N, O, S, SO and SO2 as ring members; or R 3 Formed with the aromatic or heteroaromatic ring R 2 a saturated or unsaturated 2-, 3- or 4-membered linking group of a carbon or nitrogen ring atom of ; wherein the linking group may contain 1 or 2 heteroatoms or heteroatom groups selected from N, O, S, SO and SO2; wherein the linking group may carry 1, 2 or 3 groups selected from the group consisting of halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; A is a divalent aliphatic, alicyclic, aliphatic-alicyclic, aromatic, aromatic-aliphatic or heterocyclic moiety; Each R a independently selected from the group consisting of cyano, nitro, hydroxy, C1-C4-alkoxy, C1-C4-haloalkoxy, C(=O)R c , amino, C1-C4-alkylamino, di-(C1-C4-alkyl)-amino, C3-C 20 - cycloalkyl, unsubstituted or with m groups R d C6-C 22 - aryl and unsubstituted or with m groups R d a 3- to 20-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from N, O, S, SO and SO2 as ring members; Each R b independently selected from the group consisting of halogen, cyano, nitro, hydroxy, C1-C4-alkoxy, C1-C4-haloalkoxy, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)-amino, NR e R f 、C(=O)NR e R f 、C1-C 20 -alkyl, C1-C 20 -haloalkyl, C2-C 20 -alkenyl, C2-C 20 -haloalkenyl, C2-C 20 -alkynyl, C2-C 20 -haloalkynyl, C3-C 20 - cycloalkyl, unsubstituted or with m groups R d C6-C 22 - aryl and unsubstituted or with m groups R d a 3- to 20-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from N, O, S, SO and SO2 as ring members; Each R c are independently selected from the group consisting of: C1-C4-alkyl, C1-C4-haloalkyl, e R f C1-C4-alkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; Each R d independently selected from the group consisting of halogen, cyano, hydroxy, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; Each R e independently selected from the group consisting of: hydrogen and C1-C4-alkyl; Each R f independently selected from the group consisting of: -C(=O)-phenyl and phenyl which is unsubstituted or substituted by 1, 2 or 3 groups selected from the group consisting of halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; Each m is independently 1, 2, 3, 4 or 5; The method comprises making an ester compound (II) having formula (II-1) or (II-2) in R 1 and A are as defined above; and R 4 Selected from the group consisting of: C1-C 30 -alkyl, C6-C 14 -Aryl and C6-C 14 -Aryl-C1-C4-alkyl; With an amine having formula (III) Where R 2 and R 3 As defined above, reacting in the presence of an alkali metal base and a Lewis acid; wherein the reaction is carried out under anhydrous conditions, wherein the water content in the reaction mixture is at most 0.15% by weight relative to the total weight of the reaction mixture.

2. The method according to claim 1, wherein: 1, 2, 3 or 4 of the following conditions a), b), c) and / or e); or 1, 2, 3 or 4 of the following conditions a), b), d) and / or e) apply: a) R 1 Selected from the group consisting of: C1-C 20 -alkyl, with 1 or 2 groups R a C1-C4-alkyl, C2-C 20 -alkenyl, C2-C4-alkenyl with a phenyl ring, unsubstituted or with m groups R b C3-C6-cycloalkyl, unsubstituted or with m groups R b C6-C 10 - aryl and unsubstituted or with m groups R b a 5- to 10-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members; in Each R a are independently C1-C4-alkoxy, C1-C4-haloalkoxy, C(=O)R c or phenyl; and Each R b independently halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and unsubstituted or with m groups R d A 5-membered or 6-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members; wherein each R d independently selected from the group consisting of halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; b) R 2 Selected from the group consisting of: unsubstituted or with m groups R b C6-C 10 - aryl, and unsubstituted or carrying m groups R b A 5- to 10-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members; wherein Each R b independently selected from the group consisting of halogen, cyano, hydroxyl, nitro, C(=O)NR e R f , C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and unsubstituted or with m radicals R d Phenyl; Each R d independently selected from the group consisting of halogen, C1-C4-alkyl and C1-C4-haloalkyl; Each R e are independently selected from the group consisting of: hydrogen and C1-C4-alkyl; and Each R f independently selected from the group consisting of: -C(=O)-phenyl and phenyl which is unsubstituted or substituted by 1, 2 or 3 groups selected from the group consisting of halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; c) R 3 is hydrogen or C1-C4-alkyl, preferably hydrogen; d) R 3 Formed with the aromatic or heteroaromatic ring R 2 The connecting group of the carbon or nitrogen ring atom is -(CH2)2-, -(CH2)3- or -CH=CH-, preferably -(CH2)2-; wherein -NR 2 R 3 Preferably forming 2,3-dihydroindolin-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl or indol-1-yl and more preferably 2,3-dihydroindolin-1-yl; e) A is C1-C8-alkanediyl, C2-C 8- alkanediyl, C3-C6-cycloalkanediyl or phenylene; wherein A is preferably C1-C8-alkanediyl and more preferably -CH2-.

3. A method according to any one of the preceding claims, wherein: R 1 Selected from the group consisting of: C1-C 20 -alkyl, C1-C4-alkyl with a phenyl ring, C2-C 20 -alkenyl, C2-C4-alkenyl with a phenyl ring, unsubstituted or with m groups R b C6-C 10 - aryl and unsubstituted or with m groups R b a 5- to 10-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members; Each R b are independently halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy.

4. The method according to claim 3, wherein: R 1 Selected from the group consisting of: C1-C4-alkyl with a phenyl ring, C2-C 20 -alkenyl, C2-C4-alkenyl with a phenyl ring, unsubstituted or with m groups R b Phenyl and unsubstituted or with m groups R b a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N, O and S as ring members; Each R b are independently halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and m is 1, 2 or 3.

5. The method according to claim 4, wherein: R 1 Selected from the group consisting of: C1-C2-alkyl with a phenyl ring, C2-C 20 -alkenyl, C2-alkenyl with a phenyl ring, unsubstituted or with m groups R b Phenyl and unsubstituted or with m groups R b A 5-membered or 6-membered heteroaromatic ring containing 1 or 2 nitrogen atoms as ring members; Each R b are independently halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and m is 1, 2 or 3.

6. A method according to any one of the preceding claims, wherein: R 2 Selected from the group consisting of: unsubstituted or with m groups R b C6-C 10 - aryl, and unsubstituted or carrying m groups R b a 5- to 10-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members; Each R b independently selected from the group consisting of halogen, cyano, nitro, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and phenyl; and m is 1, 2 or 3.

7. The method according to claim 6, wherein: R 2 Selected from the group consisting of: unsubstituted or with m groups R b phenyl, and unsubstituted or with m groups R b A 6- to 10-membered heteroaromatic ring containing 1 or 2 nitrogen atoms as ring members; Each R b independently selected from the group consisting of halogen, nitro, C1-C4-alkyl, C1-C4-alkoxy and phenyl; and m is 1, 2 or 3.

8. A method according to any one of the preceding claims, wherein: R 4 is selected from the group consisting of: C1-C4-alkyl, phenyl and benzyl; wherein R 4 Preferred is C1-C4-alkyl or phenyl, and more preferably C1-C4-alkyl.

9. A method according to any one of the preceding claims, wherein: R 1 Selected from the group consisting of: C1-C2-alkyl with a phenyl ring, C2-C 20 -alkenyl, C2-alkenyl with a phenyl ring, unsubstituted or with m groups R b Phenyl and unsubstituted or with m groups R b A 5-membered or 6-membered heteroaromatic ring containing 1 or 2 nitrogen atoms as ring members; in Each R b are independently halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and m is 1, 2, or 3; R 2 Selected from the group consisting of: unsubstituted or with m groups R b phenyl, and unsubstituted or with m groups R b A 6- to 10-membered heteroaromatic ring containing 1 or 2 nitrogen atoms as ring members; in Each R b are independently selected from the group consisting of halogen, nitro, C1-C4-alkyl, C1-C4-alkoxy and phenyl; and m is 1, 2, or 3; R 3 is hydrogen or C1-C4-alkyl; or -NR 2 R 3 represents 2,3-dihydroindolin-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl or indol-1-yl; A is C1-C4-alkanediyl; and R 4 is C1-C4-alkyl or phenyl; Among them, preferably R 1 Selected from the group consisting of: C1-C2-alkyl with a phenyl ring, C2-C 20 -alkenyl, C2-alkenyl with a phenyl ring, unsubstituted or with m groups R b Phenyl and unsubstituted or with m groups R b A 5-membered or 6-membered heteroaromatic ring containing 1 or 2 nitrogen atoms as ring members; in Each R b are independently halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and m is 1, 2, or 3; R 2 Selected from the group consisting of: unsubstituted or with m groups R b phenyl, pyridyl and quinolyl; in Each R b are independently selected from the group consisting of halogen, nitro, C1-C4-alkyl, C1-C4-alkoxy and phenyl; and m is 1, 2, or 3; R 3 It is hydrogen; or -NR 2 R 3 represents 2,3-dihydroindole-1-yl; A is -CH2-; and R 4 It is C1-C4-alkyl.

10. A method according to any one of the preceding claims, wherein: The compound of formula (II-1) and the compound of formula (III) are used in a molar ratio of 5:1 to 1:5, preferably 2:1 to 1:2, more preferably 1.5:1 to 1:1.5 and in particular about 1:1; and the compound of formula (II-2) and the compound of formula (III) are used in a molar ratio of 2.5:1 to 1:10, preferably 1:1 to 1:4, more preferably 0.75:1 to 1:3 and in particular about 1:

2.

11. A method according to any one of the preceding claims, wherein: The Lewis acid is selected from the group consisting of: halides, nitrates of metals of Groups 4, 6 to 10, 12, 13 or 15 of the Periodic Table of the Elements, wherein the anion has the formula R-COO - Carboxylates - where R is C1-C 10 -alkyl, C3-C6-cycloalkyl or C3-C6-cycloalkyl-C1-C 10 - alkyl, acetylacetonate, C1-C4-alkoxide and carbonyl complexes; The Lewis acid is preferably selected from halides, nitrates of Ti, Zr, Hf, Cr, Mo, Mn, Fe, Co, Ni, Zn, Al, Sb or Bi, wherein the anion has the formula R-COO - Carboxylates - where R is C1-C 10 -alkyl, wherein the anion has the formula R-COO - Carboxylates wherein R is a C3-C6-cycloalkyl group and wherein the anion has the formula R-COO - Carboxylates - where R is C3-C6-cycloalkyl-C1-C 10 -alkyl, acetylacetonate, C1-C4-alkoxide and carbonyl complexes.

12. The method according to claim 11, wherein: The Lewis acid is selected from the group consisting of: halides of Mn, Co, Zn or Bi, wherein the anion has the formula R-COO - Carboxylates of - wherein R is C1-C4-alkyl and wherein the anion has the formula R-COO - Carboxylates - where R is C3-C6-cycloalkyl-C1-C 10 - alkyl, acetylacetonate, C1-C4-alkoxide and carbonyl complexes; The Lewis acid is preferably selected from the group consisting of: Mn, Co, Zn or Bi halides, Mn, Co, Zn or Bi carboxylates wherein the anion has the formula R-COO - , where R is C1-C4-alkyl, Mn, Co, Zn or Bi carboxylates - where the anion has the formula R-COO - , wherein R is C3-C6-cycloalkyl-C1-C 10 -alkyl, Mn, Co, Zn or Bi acetylacetonate, C1-C4-alkoxide of Mn, Co, Zn or Bi, and carbonyl complex of Mn.

13. The method according to claim 11, wherein: The Lewis acid is selected from the group consisting of: MnCl2, MoCl3, CrCl3, BiCl 3、 SbCl3, ZnCl2, FeCl3, FeCl2, CoCl2, NiCl2, TiCl4, ZrCl4, HfCl4, MnBr2, Mn(NO3)2, Co(NO3)2, Mn(OAc)2, Mn(4-cyclohexylbutyric acid)2, Fe (OAc)3, Bi(OAc)3, Mn(AcAc)2, Mn(AcAc)3, Fe(AcAc)2, Fe(AcAc)3, Ni(AcAc)2, Bi(OiPr)3, Ti(OiPr)4, Al(OiPr)3, Mn2(CO) 10 , Mn(CO)5Br, Cr(CO)6, Fe(CO)4 and Co2(CO)8; wherein OAc means acetate, AcAc means acetylacetonate and OiPr means isopropoxide; The Lewis acid is preferably selected from the group consisting of: MnCl2, MnBr2, BiCl3, CoCl2, ZnCl2, NiCl2, Mn(OAc)2, Mn(AcAc)2, Mn(AcAc)3, Mn(4-cyclohexylbutyric acid)2, Bi(OiPr)3, Mn(CO)5Br and Mn2(CO) 10 .

14. The method according to claim 13, wherein: The Lewis acid is selected from the group consisting of: MnCl2, MnBr2, BiCl3, CoCl2, ZnCl2, Mn(OAc)2, Mn(AcAc)2, Mn(AcAc)3, Mn(4-cyclohexylbutyric acid)2, Bi(OiPr)3, Mn(CO)5Br and Mn2(CO) 10 ; The Lewis acid is preferably selected from the group consisting of: MnCl2, MnBr2, BiCl3, CoCl2, ZnCl2, Mn(OAc)2, Mn(AcAc)2, Mn(AcAc)3, Bi(OiPr)3 and Mn2(CO) 10 ;and Wherein the Lewis acid is in particular selected from the group consisting of: MnCl2 and MnBr2.

15. A method according to any one of the preceding claims, wherein: The Lewis acid is used in an amount of 0.00001 to 0.2 mol, preferably 0.00001 to 0.1 mol, more preferably 0.0001 to 0.05 mol.

16. The method according to claim 15, wherein: The Lewis acid is used in an amount of 0.001 to 0.01, preferably 0.005 to 0.009 mol, per mol of the compound (I1) or (III) not used in excess.

17. A method according to any one of the preceding claims, wherein: the alkali metal-containing base is selected from the group consisting of alkali metal alkoxides, amides, hydrides, borohydrides, and aluminides; The alkali metal base is preferably selected from the group consisting of: alkali metal C1-C 10 -alkoxide, having the formula M + [N(R g )2] - Alkali metal amides, wherein M + is an alkali metal cation and R g is hydrogen, C1-C4-alkyl or Si(C1-C4-alkyl)2, and has the formula M + [BH(C1-C4-alkyl)3] - Alkali metal borohydride, where M + It is an alkali metal cation.

18. A method according to any one of the preceding claims, wherein: The alkali metal base is used in an amount of 0.00001 to 0.1 mol, preferably 0.0001 to 0.05 mol, more preferably 0.001 to 0.04 mol, even more preferably 0.01 to 0.04 mol, per mol of the compound (II) or (III) not used in excess.

19. A method according to any one of the preceding claims, wherein: The Lewis acid is selected from the group consisting of: halides of Mn, Co, Zn or Bi, wherein the anion has the formula R-COO - Carboxylates of - wherein R is C1-C4-alkyl and wherein the anion has the formula R-COO - Carboxylates - where R is C3-C6-cycloalkyl-C1-C 10 - alkyl, acetylacetonate, C1-C4-alkoxide and carbonyl complexes; and The alkali metal base is selected from the group consisting of: alkali metal C1-C 10 -alkoxide, having the formula M + [N(R g )2] - Alkali metal amides, wherein M + is an alkali metal cation and R g is hydrogen, C1-C4-alkyl or Si(C1-C4-alkyl)2, and has the formula M + [BH(C1-C4-alkyl)3] - Alkali metal borohydride, where M + It is an alkali metal cation.

20. A method according to any one of the preceding claims, wherein: The water content in the reaction mixture is less than 0.1% by weight, preferably less than 0.08% by weight, relative to the total weight of the reaction mixture.

Images