EP2964811B1 - Electrochemical coupling of anilines - Google Patents

Description

The following invention relates to an electrochemical process for coupling anilines to biaryldiamines.

The term aniline is used in this application as a generic term and thus also includes substituted anilines. Two different anilines can be coupled with each other.

Previously used methods for the preparation of biaryldiamines use the detour of a sigmatropic rearrangement of diarylhydrazines (see: S.-E. Suh, I.-K. Park, B.-Y. Lim, C.-G. Cho, Eur. J. Org. Chem. 2011, 3, 455 . H.-Y. Kim, W.-J. Lee, H.-M. Kang, C.-G. Cho, Org. Lett. 2007, 16, 3185 . HM. Kang, Y.-K. Lim, I.-J. Shin, H.-Y. Kim, C.-G. Cho, Org. Lett. 2006, 10, 2047 . Y.-K. Lim, J.-W. Jung, H. Lee, C.-G. Cho, J. Org. Chem. 2004, 17, 5778 ) to generate biaryl systems, since a direct oxidative cross-coupling of aniline derivatives with inorganic oxidants such as Cu (II) gives poor yields and has been described only for naphthylamines (see: M. Smrcina, S. Vyskocil, B. Maca, M. Polasek, TA Claxton, AP Abbott, P. Kocovsky, J. Org. Chem. 1994, 59, 2156 )
Benzidine / semidine rearrangements are usually less selective and yield many carcinogenic by-products. The synthesis of the hydrazines is often carried out with the help of transition metal catalysts, which represents an additional cost factor.

In BACON J ET AL, "ANODIC OXIDATIONS OF AROMATIC AMINES III SUBSTITUTED ANILINES IN AQUEOUS MEDIA", Journal of The American Chemical Chemical, ACS Publications, (19681120), Vol , ISSN 0002-7863, pages 6596-6599 , the "head-to-tail" coupling of para-substituted aniline is described.

In DOMAGALA S ET AL, "Cross-coupling processes in chemical and electrochemical oxidation of the aniline derivatives and 4-aminophenol mixtures", THE 4TH INTERNATIONAL SYMPOSIUM ELECTROCHEMISTRY IN PRACTICE AND THEORY: LODZ, SEPTEMBER 11-13, 1996, (19970101), ISBN 83-7171-011-9, pages 177-187 , the cyclic voltammograms of single- and double-linked aniline derivatives are studied.

In AXEL KIRSTE ET AL, "Efficient Anodic and Direct Phenol-Arene C, C Cross-Coupling: The Benign Role of Water or Methanol", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, (20120222), Vol. 7, doi: 10.1021 / ja211005g, ISSN 0002-7863, pages 3571-3576 , the influence of water and methanol on the phenol-arene coupling is investigated.

In the US 2012/0080320 A1 a method for the production of biaryls is described. Here, a phenol derivative are electrochemically coupled with an arene.

Rodney L. Hand ET AL .: "Anodic Oxidation Pathways of N-alkylanilines", Journal of the American Chemical Society, Vol. 96, No. 3, 1 February 1974 (1974-02-01), pages 850-860, ISSN: 0002-7863 discloses the anodic self-coupling of anilines to biaryldiamines.

A major disadvantage of the above-mentioned methods for aniline-aniline cross-coupling is the frequent need for dry solvents and air exclusion. Furthermore, sometimes large amounts of partially toxic oxidizing agents are used. During the reaction often occur toxic by-products, which must be separated from the desired product consuming and expensive to dispose of. Due to scarcer raw materials and the increasing relevance of environmental protection, the price of such transformations is increasing. Especially when using multi-level sequences, a change of different solvents is necessary. Here also very toxic intermediates occur.

By electrochemical treatment Biaryldiamine be prepared without the organic oxidizing agent must be added, worked under exclusion of moisture or anaerobic reaction guides must be complied with. This direct method of C, C coupling opens up a cost-effective and environmentally friendly alternative to previously existing multistage, classically organic synthetic routes.

The object of the following invention was to provide an electrochemical process in which anilines can be coupled together, and can be dispensed with multi-stage syntheses using metallic reagents. Furthermore, it should enable access to new products in this way.

The object is achieved by a method according to claim 1. Compounds according to one of the general formulas (I) to (IV) can be prepared by the process described:

Wherein the substituents R ¹ to R ⁴⁸ are defined in the claims.

Alkyl is a non-branched or branched aliphatic radical.

Aryl for aromatic (hydrocarbon) radicals, preferably having up to 14 carbon atoms, for. As phenyl (C ₆ H ₅ -), naphthyl (C ₁₀ H ₇ -), anthryl (C ₁₄ H ₉ -), preferably phenyl.

Cycloalkyl for saturated cyclic hydrocarbons containing exclusively carbon atoms in the ring.

Heteroalkyl for a non-branched or branched aliphatic radical which may contain one to four, preferably one or two, heteroatoms selected from the group consisting of N, O, S and substituted N.

Heteroaryl is an aryl radical in which one to four, preferably one or two, carbon atoms may be replaced by heteroatoms selected from the group consisting of N, O, S and substituted N, wherein the heteroaryl radical may also be part of a larger condensed ring structure.

Heterocycloalkyl for saturated cyclic hydrocarbons, which may contain one to four, preferably one or two, heteroatoms selected from the group consisting of N, O, S and substituted N.

Heteroaryl radical, which may be part of a fused ring structure, is preferably understood to mean systems in which fused five- or six-membered rings are formed, for example Benzofuran, isobenzofuran, indole, isoindole, benzothiophene, benzo (c) thiophene, benzimidazole, purine, indazole, benzoxazole, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, acridine.

The abovementioned substituted N can be monosubstituted; the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups can be monosubstituted or polysubstituted, particularly preferably monosubstituted, disubstituted or trisubstituted by radicals selected from the group consisting of selected from among hydrogen, (C ₁ -C ₁₄ ) -alkyl, (C ₁ -C ₁₄ ) -heteroalkyl, (C ₄ -C ₁₄ ) -aryl, (C ₄ -C ₁₄ ) -aryl (C ₁ -C ₁₄ ) Alkyl, (C ₃ -C ₁₄ ) -heteroaryl, (C ₃ -C ₁₄ ) -heteroaryl (C ₁ -C ₁₄ ) -alkyl, (C ₃ -C ₁₂ ) -cycloalkyl, (C ₃ -C ₁₂ ) -Cycloalkyl- (C ₁ -C ₁₄ ) -alkyl, (C ₃ -C ₁₂ ) -heterocycloalkyl, (C ₃ -C ₁₂ ) -heterocycloalkyl- (C ₁ -C ₁₄ ) -alkyl, CF ₃ , halogen (fluoro, Chlorine, bromine, iodine), (C ₁ -C ₁₀ ) -haloalkyl, hydroxy, (C ₁ -C ₁₄ ) -alkoxy, (C ₄ -C ₁₄ ) -acyloxy, O- (C ₁ -C ₁₄ ) -alkyl - (C ₄ -C ₁₄ ) -aryl, (C ₃ -C ₁₄ ) -heteroaryloxy, N ((C ₁ -C ₁₄ ) -alkyl) ₂ , N ((C ₄ -C ₁₄ ) -aryl) ₂ , N ((C ₁ -C ₁₄ ) alkyl) ((C ₄ -C ₁₄ ) -aryl), wherein alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl are the above meanings.

In one embodiment, R ¹ , R ² , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ²² , R ²³ , R ²⁵ , R ²⁶ , R ³³ , R ³⁴ , R ³⁸ , R ³⁹ , R ⁴⁶ , R ⁴⁷ selected from: -H, and / or one in " Greene's Protective Groups in Organic Synthesis "by PGM Wuts and TW Greene, 4th edition, Wiley Interscience, 2007, pp. 696-926 protecting groups described for amino functions.

In one embodiment, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²⁴ , R ²⁷ , R ²⁸ , R ²⁹ R ³⁰ R ³¹ R ³² R ³⁵ R ³⁶ R ³⁷ R ⁴⁰ R ⁴¹ R ⁴² R ⁴³ R ⁴⁴ R ⁴⁵ , R ⁴⁸ selected from the group of hydrogen, hydroxyl, (C C ₁ -C ₁₂ ) -alkyl, (C ₁ -C ₁₂ ) -heteroalkyl, (C ₄ -C ₁₄ ) -aryl, (C ₄ -C ₁₄ ) -aryl (C ₁ -C ₁₂ ) -alkyl, (C ₁ -C ₁₂ ) -alkyl, O- (C ₁ -C ₁₂ ) -heteroalkyl, O- (C ₄ -C ₁₄ ) -aryl, O- (C ₄ -C ₁₄ ) -aryl (C ₁ -) C ₁₄ ) alkyl, O- (C ₃ -C ₁₄ ) heteroaryl, O- (C ₃ -C ₁₄ ) heteroaryl (C ₁ -C ₁₄ ) alkyl, O- (C ₃ -C ₁₂ ) - Cycloalkyl, O- (C ₃ -C ₁₂ ) -cycloalkyl- (C ₁ -C ₁₂ ) -alkyl, O- (C ₃ -C ₁₂ ) -heterocycloalkyl, O- (C ₃ -C ₁₂ ) -heterocycloalkyl- (C ₁ -C ₁₂ ) -alkyl, S- (C ₁ -C ₁₂ ) -alkyl, S- (C ₄ -C ₁₄ ) -aryl, halogens "
wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted one or more times.

In one embodiment, R ¹ , R ² , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ²² , R ²³ , R ²⁵ , R ²⁶ , R ³³ , R ³⁴ , R ³⁸ , R ³⁹ , R ⁴⁶ , R ⁴⁷ selected from: -H, (C ₁ -C ₁₂ ) acyl.

In one embodiment, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²⁴ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³⁵ , R ³⁶ , R ³⁷ , R ⁴⁰ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁸ out: Hydrogen, hydroxyl, (C ₁ -C ₁₂ ) alkyl, (C ₄ -C ₁₄ ) aryl, O- (C ₁ -C ₁₂ ) alkyl, O- (C ₁ -C ₁₂ ) heteroalkyl, O (C ₄ -C ₁₄ ) -aryl, O- (C ₃ -C ₁₂ ) -cycloalkyl, S- (C ₁ -C ₁₂ ) -alkyl, S- (C ₄ -C ₁₄ ) -aryl, halogens,
wherein said alkyl, heteroalkyl, cycloalkyl, aryl groups are optionally substituted one or more times.

Claimed is a method for the electrochemical coupling of anilines.

The process can be performed on different carbon (glassy carbon, boron-doped diamond, graphites, carbon fibers, nanotubes, etc.), metal oxide and metal electrodes. Current densities in the range of 1-50 mA / cm ^{2 are} applied.

The workup and recovery of the biaryldiamines is very simple and takes place after completion of the reaction according to generally accepted separation methods. First, the electrolyte solution is first distilled and recovered the individual compounds in the form of different fractions separately. Further purification can be carried out, for example, by crystallization, distillation, sublimation or chromatographic.

The electrolysis is carried out in the usual, known in the art electrolysis cells. Suitable electrolysis cells are known to the person skilled in the art.

With the method according to the invention, the problem mentioned at the beginning is solved.

In this way, biaryldiamines can be prepared by the electrochemical coupling of two different anilines.

Here, anilines are coupled with different oxidation potential.

• a') Einfüllen eines Lösungsmittels oder Lösungsmittelgemisches sowie eines Leitsalzes, in ein Reaktionsgefäß,
• b') Zugabe eines ersten Anilins mit einem Oxidationspotential |E_Ox1| in das Reaktionsgefäß,
• c') Zugabe eines zweiten Anilins mit einem Oxidationspotential |E_Ox 2| in das Reaktionsgefäß, wobei gilt: |E_Ox2| > |E_Ox1| und |E_Ox2| - |E_Ox1| = |ΔE |, wobei das zweite Anilin gegenüber dem ersten Anilin im Überschuss zugesetzt wird,
  und das Lösungsmittel oder Lösungsmittelgemisch so gewählt ist, dass |ΔE| im Bereich von 10 mV bis 450 mV liegt,
• d') Einbringen zweier Elektroden in die Reaktionslösung,
• e') Anlegen einer Spannung an die Elektroden,
• f') Kupplung des ersten Anilin mit dem zweiten Anilin zu einem Biaryldiaminen.

Electrochemical process for the preparation of biaryldiamines comprising the process steps:

• a ') filling a solvent or solvent mixture and a conductive salt, in a reaction vessel,
• b ') Addition of a first aniline with an oxidation potential | E _Ox 1 | into the reaction vessel,
• c ') addition of a second aniline with an oxidation potential | E _Ox 2 | into the reaction vessel, where: | E _Ox 2 | > | E _Ox 1 | and | E _Ox 2 | - | E _Ox 1 | = | ΔE | in which the second aniline is added in excess to the first aniline,
  and the solvent or solvent mixture is selected such that | ΔE | in the range of 10 mV to 450 mV,
• d ') introducing two electrodes into the reaction solution,
• e ') applying a voltage to the electrodes,
• f ') Coupling of the first aniline with the second aniline to a Biaryldiaminen.

• E_Ox : Elektrodenpotential für die Oxidationsreaktion (= Oxidationspotential)
• E°: Standardelektrodenpotential
• n: Anzahl der übertragenen Elektronen
• [Ox]: Konzentration der oxidierten Form
• [Red]: Konzentration der reduzierten Form

A problem that arises in the electrochemical coupling of different molecules is that the reactants usually have different oxidation potentials E _Ox . As a result, the molecule with the lower oxidation potential has a higher tendency to donate an electron (e ^- ) to the anode and an H ⁺ ion to, for example, the solvent than the molecule with the lower oxidation potential. The oxidation potential E _Ox can be calculated using the Nernst equation: $$e_{\mathit{Ox}}=\mathit{e\; °}+\left(0.059/n\right)*\lg \left(\left[\mathrm{Ox}\right]/\left[\mathrm{Red}\right]\right)$$

• E _Ox : electrode potential for the oxidation reaction (= oxidation potential)
• E °: standard electrode potential
• n : number of transferred electrons
• [Ox]: concentration of the oxidized form
• [Red]: Concentration of the reduced form

Applying the methods mentioned above in the literature to two different anilines would result in predominantly radical formation of the molecule, which has a lower oxidation potential, and would then react with itself. As a clearly predominant main product would therefore receive a Biaryldiamin, which has arisen from two identical anilines.
This problem does not occur in the coupling of identical molecules.

If the first condition is not met, the main product is the biaryldiamine, which is formed by coupling two molecules of aniline.

• das Anilin mit dem höheren Oxidationspotential muss im Überschuss zugegeben werden, und
• die Differenz der beiden Oxidationspotentiale (ΔE), muss in einem bestimmten Bereich liegen.

For efficient reaction in the coupling of two different anilines, two reaction conditions are necessary:

• the aniline with the higher oxidation potential must be added in excess, and
• the difference between the two oxidation potentials ( ΔE ) must be in a certain range.

Knowledge of the absolute oxidation potentials of the two anilines is not absolutely necessary for the process according to the invention. It is sufficient if the difference between the two oxidation potentials is known to one another.

Another partial aspect of the invention is that the difference between the two oxidation potentials (| ΔE |) can be influenced by the solvents or solvent mixtures used.

Thus, the difference between the two oxidation potentials (| ΔE |) can be shifted into the desired range by suitable choice of the solvent / solvent mixture.

Assuming 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as the base solvent, it can be too small | ΔE | increase for example by adding alcohol. Too big | ΔE | however, can be lowered by adding water.

Biaryldiamines could be prepared electrochemically for the first time with the aid of the process according to the invention and multi-step syntheses using metallic reagents could be dispensed with.

In a variant of the method, the second aniline is used at least twice the amount of the first aniline.

In a variant of the method, the ratio of first aniline to second aniline is in the range of 1: 2 to 1: 4.

In a variant of the process, the conductive salt is selected from the group of alkali metal, alkaline earth metal, tetra (C ₁ -C ₆ alkyl) ammonium, 1,3-di (C ₁ -C ₆ alkyl) imidazolium or tetra (C ₁ -C ₆ alkyl) phosphonium salts.

In a variant of the process, the counterions of the conducting salts are selected from the group consisting of sulfate, hydrogensulfate, alkylsulfates, arylsulfates, alkylsulfonates, arylsulfonates, halides, phosphates, carbonates, alkylphosphates, alkylcarbonates, nitrate, tetrafluoroborate, hexafluorophosphate, hexafluorosilicate, fluoride and perchlorate.

In a variant of the process, the conductive salt is selected from tetra (C ₁ -C ₆ -alkly) ammonium salts and the counter ion selected from sulfate, alkyl sulfate, aryl sulfate.

In a variant of the method, the reaction solution is free of fluorinated compounds.

In a variant of the method, the reaction solution is free of transition metals.

In a variant of the method, the reaction solution is free of organic oxidizing agents.

In a variant of the method, the reaction solution is free of substrates having leaving functionalities other than hydrogen atoms.
In the claimed process can be dispensed leaving groups at the coupling sites except hydrogen atoms.

wobei die Substituenten R¹ bis R⁴⁸ in den Ansprüchen definiert sind.In a variant of the method, the first aniline and the second aniline are selected from: Ia , Ib, IIa, IIb, IIIa, IIIb, IVa, IVb:

wherein the substituents R ¹ to R ⁴⁸ are defined in the claims.

Aryl for aromatic (hydrocarbon) radicals, preferably having up to 14 carbon atoms, for. As phenyl (C ₆ H ₅ -), naphthyl (C ₁₀ H ₇ -), anthryl (C ₁₄ H ₉ -), preferably phenyl.

Cycloalkyl for saturated cyclic hydrocarbons containing exclusively carbon atoms in the ring.

Heteroalkyl for a non-branched or branched aliphatic radical which may contain one to four, preferably one or two, heteroatoms selected from the group consisting of N, O, S and substituted N.

Heteroaryl is an aryl radical in which one to four, preferably one or two, carbon atoms may be replaced by heteroatoms selected from the group consisting of N, O, S and substituted N, wherein the heteroaryl radical may also be part of a larger condensed ring structure.

Heterocycloalkyl for saturated cyclic hydrocarbons, which may contain one to four, preferably one or two, heteroatoms selected from the group consisting of N, O, S and substituted N.

By heteroaryl radical which may be part of a fused ring structure is preferably understood systems in which fused five- or six-membered rings are formed, e.g. Benzofuran, isobenzofuran, indole, isoindole, benzothiophene, benzo (c) thiophene, benzimidazole, purine, indazole, benzoxazole, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, acridine.

The abovementioned substituted N can be monosubstituted; the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups can be monosubstituted or polysubstituted, particularly preferably monosubstituted, disubstituted or trisubstituted by radicals selected from the group consisting of selected from among hydrogen, (C ₁ -C ₁₄ ) -alkyl, (C ₁ -C ₁₄ ) -heteroalkyl, (C ₄ -C ₁₄ ) -aryl, (C ₄ -C ₁₄ ) -aryl (C ₁ -C ₁₄ ) Alkyl, (C ₃ -C ₁₄ ) -heteroaryl, (C ₃ -C ₁₄ ) -heteroaryl (C ₁ -C ₁₄ ) -alkyl, (C ₃ -C ₁₂ ) -cycloalkyl, (C ₃ -C ₁₂ ) -Cycloalkyl- (C ₁ -C ₁₄ ) -alkyl, (C ₃ -C ₁₂ ) -heterocycloalkyl, (C ₃ -C ₁₂ ) -heterocycloalkyl- (C ₁ -C ₁₄ ) -alkyl, CF ₃ , halogen (fluoro, Chlorine, bromine, iodine), (C ₁ -C ₁₀ ) -haloalkyl, hydroxy, (C ₁ -C ₁₄ ) -alkoxy, (C ₄ -C ₁₄ ) -acyloxy, O- (C ₁ -C ₁₄ ) -alkyl - (C ₄ -C ₁₄ ) -aryl, (C ₃ -C ₁₄ ) -heteroaryloxy, N ((C ₁ -C ₁₄ ) -alkyl) ₂ , N ((C ₄ -C ₁₄ ) -aryl) ₂ , N ((C ₁ -C ₁₄ ) alkyl) ((C ₄ -C ₁₄ ) -aryl), wherein alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl are the above meanings.

In one embodiment, R ¹ , R ² , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ²² , R ²³ , R ²⁵ , R ²⁶ , R ³³ , R ³⁴ , R ³⁸ , R ³⁹ , R ⁴⁶ , R ⁴⁷ selected from: -H, and / or one in " Greene's Protective Groups in Organic Synthesis "by PGM Wuts and TW Greene, 4th edition, Wiley Interscience, 2007, pp. 696-926 protecting groups described for amino functions.

In one embodiment, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²⁴ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³⁵ , R ³⁶ , R ³⁷ , R ⁴⁰ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁸ from the group of hydrogen, hydroxyl, (C ₁ -C ₁₂ ) -alkyl, (C ₁ -C ₁₂ ) -heteroalkyl, (C ₄ -C ₁₄ ) -aryl, (C ₄ -C ₁₄ ) -aryl (C ₁ -C ₁₂ ) alkyl, O- (C ₁ -C ₁₂ ) alkyl, O- (C ₁ -C ₁₂ ) heteroalkyl, O- (C ₄ -C ₁₄ ) aryl, O- (C ₄ -C ₁₄₎ -aryl- (C ₁ -C ₁ 4) alkyl, O- (C ₃ -C ₁₄₎ -heteroaryl, O- (C ₃ -C ₁₄₎ -heteroaryl- (C ₁ -C ₁₄₎ -Alkyl, O- (C ₃ -C ₁₂ ) -cycloalkyl, O- (C ₃ -C ₁₂ ) -cycloalkyl- (C ₁ -C ₁₂ ) -alkyl, O- (C ₃ -C ₁₂ ) -heterocycloalkyl, O - (C ₃ -C ₁₂ ) -heterocycloalkyl- (C ₁ -C ₁₂ ) -alkyl, S- (C ₁ -C ₁₂ ) -alkyl, S- (C ₄ -C ₁₄ ) -aryl, halogens.

In one embodiment, R ¹ , R ² , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ²² , R ²³ , R ²⁵ , R ²⁶ , R ³³ , R ³⁴ , R ³⁸ , R ³⁹ , R ⁴⁶ , R ⁴⁷ selected from: -H and / or (C ₁ -C ₁₂ ) acyl

In one embodiment, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²⁴ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³⁵ , R ³⁶ , R ³⁷ , R ⁴⁰ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁸ from: the group of hydrogen, hydroxyl, (C ₁ -C ₁₂ ) -alkyl, (C ₄ -C ₁₄ ) -aryl, O- (C ₁ -C ₁₂ ) -alkyl, O- (C ₁ -C ₁₂ ) Heteroalkyl, O- (C ₄ -C ₁₄ ) -aryl, O- (C ₃ -C ₁₂ ) -cycloalkyl, S- (C ₁ -C ₁₂ ) -alkyl, S- (C ₄ -C ₁₄ ) - Aryl, halogens.

The following combinations are possible: first aniline Ia IIb second aniline Ia IIb first aniline Ia ib IIa IIb IIIa IIIb IVa IVb second aniline ib Ia IIb IIa IIIb IIIa IVb IVa

In the following, the invention is based on the FIGS. 1 and 2 explained in more detail.

The FIG. 1 shows a reaction apparatus in which the coupling reaction described above can be carried out. The apparatus comprises a nickel cathode (1) and an anode of boron-doped diamond (BDD) on silicon or another carrier material or another electrode material (5) known to the person skilled in the art. The apparatus can be cooled by means of the cooling jacket (3). The arrows indicate the flow direction of the cooling water. The reaction space is closed with a Teflon stopper (2). The reaction mixture is mixed through a magnetic stir bar (7). On the anodic side, the apparatus is closed by screw clamps (4) and seals (6).

The FIG. 2 shows a reaction apparatus in which the coupling reaction described above can be carried out on a larger scale. The apparatus comprises two glass flanges (5 '), on which are pressed by screw clamps (2') and seals electrodes (3 ') of boron-doped diamond (BDD) coated carrier materials or other, known in the art, electrode materials. The reaction space can be provided with a reflux condenser via a glass sleeve (1 '). The reaction mixture is mixed with the aid of a magnetic stirring bar (4 ').

Examples: General working instructions Cyclic voltammetry (CV)

A VA stand Metrohm 663 VA equipped with a μAutolab type III potentiostat was used (Metrohm AG, Herisau, Switzerland). WE : glassy carbon electrode, 2 mm in diameter; AE : glass wool rod; RE : Ag / AgCl in saturated LiCl / EtOH. Solvent: HFIP + 0-25% v / v MeOH. Oxidation criterion: j = 0.1 mA / cm ² , v = 50 mV / s, T = 20 ° C. Mixing during the measurement. c (aniline derivative) = 151 mM, conductive salt: Et ₃ NMe O ₃ SOMe (MTES), c (MTES) = 0.09M.

chromatography

The preparative liquid chromatographic separations via "flash chromatography" were carried out with a maximum pressure of 1.6 bar on silica gel 60 M (0.040-0.063 mm) from Macherey-Nagel GmbH & Co, Düren. The separations without pressurization were carried out on silica gel Geduran Si 60 (0.063-0.200 mm) from Merck KGaA, Darmstadt. The solvents used as eluents (ethyl acetate (technical), cyclohexane (technical)) were previously purified by distillation on a rotary evaporator.
For thin-layer chromatography (TLC), PSC precast plates Kieselgel 60 F254 from Merck KGaA, Darmstadt were used. The Rf values are given as a function of the solvent mixture used. For staining the TLC plates, a cerium-molybdophosphoric acid solution was used as the dipping reagent. Cerium molybdophosphoric acid reagent: 5.6 g molybdophosphoric acid, 2.2 g cerium (IV) sulfate tetrahydrate and 13.3 g concentrated sulfuric acid to 200 mL water.

Gas chromatography (GC / GCMS)

The gas chromatographic investigations (GC) of product mixtures and pure substances was carried out with the aid of the gas chromatograph GC-2010 from Shimadzu, Japan. It is on a fused silica capillary column HP-5 Agilent Technologies, USA (length: 30 m; inner diameter: 0.25 mm; film thickness of the covalently bound stationary phase: 0.25 microns; carrier gas: hydrogen; injector temperature: 250 ° C; detector temperature: 310 ° C Program: method "hard": 50 ° C start temperature for 1 min, heating rate: 15 ° C / min, 290 ° C final temperature for 8 min) measured. Gas chromatographic mass spectra (GCMS) of product mixtures and pure substances were recorded using the gas chromatograph GC-2010 combined with the mass detector GCMS-QP2010 from Shimadzu, Japan. It is attached to a quartz capillary column HP-1 from Agilent Technologies, USA (length: 30 m, internal diameter: 0.25 mm, film thickness of the covalently bonded stationary phase: 0.25 μm, carrier gas: hydrogen, injector temperature: 250 ° C, detector temperature: 310 ° C Program: Method "hard": 50 ° C starting temperature for 1 min, heating rate: 15 ° C / min, 290 ° C final temperature for 8 min, GCMS: temperature of ion source: 200 ° C).

melting points

Melting points were measured using the melting point determination device SG 2000 from HW5, Mainz and are uncorrected.

Elemental analysis

The elemental analyzes were prepared in the analytical department of the Institute of Organic Chemistry of Johannes Gutenberg University Mainz on a Vario EL Cube of the company Foss- Heraeus, Haunau.

Mass spectrometry

All electrospray ionization (ESI +) measurements were carried out on a QTof Ultima 3 from Waters Micromasses, Milford, Massachusetts. EI mass spectra and the high-resolution EI spectra were measured on a MAT 95 XL sector field device from Thermo Finnigan, Bremen.

NMR spectroscopy

The NMR spectroscopic investigations were carried out on multicore resonance spectrometers of the type AC 300 or AV II 400 from Bruker, Analytical Messtechnik, Karlsruhe. The solvent used was CDCl3. The ¹ H and ¹³ C spectra were calibrated according to the residual content of non-deuterated solvent according to the NMR Solvent Data Chart from Cambridge Isotopes Laboratories, USA. The assignment of the ¹ H and ¹³ C signals was carried out in part by means of H, H-COZY, H, H-NOESY, H, C-HSQC and H, C-HMBC spectra. The chemical shifts are given as δ values in ppm. The following abbreviations were used for the multiplicities of the NMR signals: s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublet), dt (doublet of triplet), tq (triplet of quartet). All coupling constants J were given in terms of the number of bound bonds in hertz (Hz). The numbering specified in the signal assignment corresponds to the numbering specified in the formula diagrams, which does not have to match the IUPAC nomenclature.

AAV1: Instructions for electrochemical cross-coupling

2-4 mmol of the respective sub-component are dissolved with 6-12 mmol of each to be coupled second component in the specified amounts of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) and MeOH and reacted in an undivided beaker cell with glassy carbon electrodes , The electrolysis takes place galvanostatically. The reaction is stirred and heated to 50 ° C by means of a water bath. After the end of the electrolysis, the cell contents are transferred with HFIP into a 50 ml round-bottomed flask and the solvent is removed under reduced pressure on a rotary evaporator at 50 ° C., 200-70 mbar. Unreacted educt is recovered by short path distillation or Kugelrohr distillation (100 ° C, 10 ^-3 mbar).

electrode material

Anode: Glaskohlensoff Cathode: Glaskohlensoff

Electrolysis conditions:

Temperature [T]: 50 ° C Current [I]: 25mA Current density [j]: 2.8 mA / cm ² Charge amount [Q]: 2 F (per deficit component) Clamping voltage [U _max ]: 3-5 v

N - (6- (2-acetamido-4-methoxy-5-methylphenyl) 3,4-methylenedioxyphenyl) acetamide

• Ausbeute: 718 mg (55%, 2.1 mmol)
• Selektivität: 15 :1 (Kreuzkupplung : Homokupplung)
• GC (Methode hart, HP-5): t_R= 17.37 min
• R_f (CH:EE= 1:3)= 0.21
  ¹H-NMR (300 MHz, CDCl3) δ= 1.94 (s, 3H), 1.98 (s, 3H), 2.18 (s, 3H), 3.86 (s, 3H), 5.95-6.07 (m, 2H), 6.62 (s, 1 H), 6.89 (bs, 1 H), 7.02 (bs, 1 H), 7.48 (m, 2H), 7.70 (s, 1 H);
  ¹³C-NMR (75 MHz, CCl3) δ= 15.79, 23.84, 24.19, 55.50, 101.67, 104.89, 105.42, 110.01, 119.90, 122.70, 123.59, 129.47, 132.04, 134.26, 145.22, 147.76, 157.88, 169.36, 169.44.
• HRMS für C₁₉H₂₀N₂O₅ (ESI+) [M+Na⁺]: ber: 379.1270, gef.: 379.1265
• MS (EI, GCMS): m/z(%): 356 (80) [M]⁺˙, 297 (80) [M-CH₃CONH₂˙]⁺.

The electrolysis is carried out in accordance with AAV1 in an undivided glass beaker cell with glassy carbon electrodes. For this purpose, 0.68 g N (3.8 mmol, 1.0 equiv.) - (3,4-methylenedioxyphenyl) acetamide and 2.04g (11.4 mmol, 3.0 equiv.) Of N - (3,4-dimethoxyphenyl) acetamide in 25 mL HFIP solved, 0.77 g MTBS added and the electrolyte transferred to the electrolysis cell. The solvent and unreacted Eduktmengen be removed after the electrolysis under reduced pressure, the crude product was purified on silica gel 60 as a "flash chromatography" in the eluent 1: 3 (CH: EE) + 1% acetic acid and the product obtained as ocher-brown solid.

• Yield: 718 mg (55%, 2.1 mmol)
• Selectivity: 15: 1 (cross-coupling: homocoupling)
• GC ( hard method , HP-5): t _R = 17.37 min
• R _f (CH: EE = 1: 3) = 0.21
  ¹ H-NMR (300 MHz, CD Cl3) δ = 1.94 (s, 3H), 1.98 (s, 3H), 2.18 (s, 3H), 3.86 (s, 3H), 5.95-6.07 (m, 2H), 6.62 (s, 1H), 6.89 (bs, 1H), 7.02 (bs, 1H), 7.48 (m, 2H), 7.70 (s, 1H);
  ¹³ C-NMR (75 MHz, CCl3) δ = 15.79, 23.84, 24.19, 55.50, 101.67, 104.89, 105.42, 110.01, 119.90, 122.70, 123.59, 129.47, 132.04, 134.26, 145.22, 147.76, 157.88, 169.36, 169.44.
• HRMS for C ₁₉ H ₂₀ N ₂ O ₅ (ESI +) [M + Na ^+]: calc: 379.1270, obs .: 379.1265
• MS (EI, GCMS): m / z (%): 356 (80) [M] ⁺ ˙, 297 (80) [M-CH ₃ CONH ₂ ˙] ^+.

Claims (6)

1. Electrochemical process for preparing biaryldiamines, comprising the process steps of:

   a') introducing a solvent or solvent mixture and a conductive salt into a reaction vessel,

   b') adding a first aniline having an oxidation potential IE_Ox1I to the reaction vessel,

   c') adding a second aniline having an oxidation potential IE_Ox2I to the reaction vessel, where: IE_Ox2I > IE_Ox1I and IE_Ox2I - IE_Ox1I = IΔEI,
   the second aniline being added in excess relative to the first aniline,
   and the solvent or solvent mixture being selected such that IΔEI is in the range from 10 mV to 450 mV,

   d') introducing two electrodes into the reaction solution,

   e') applying a voltage to the electrodes,

   f') coupling the first aniline to the second aniline to give a biaryldiamine.
2. Process according to Claim 1,
   wherein the second aniline is used in at least twice the amount relative to the first aniline.
3. Process according to either of Claims 1 and 2,
   wherein the ratio of first aniline to second aniline is in the range from 1:2 to 1:4.
4. Process according to any of Claims 1 to 2,
   wherein the solvent or solvent mixture is selected such that |ΔE| is in the range from 20 mV to 400 mV.
5. Process according to any of Claims 1 to 4,
   wherein the reaction solution is free of organic oxidizing agents.
6. Process according to any of Claims 1 to 5,
   wherein the first aniline and the second aniline are selected from: Ia, Ib, IIa, IIb, IIIa, IIIb, IVa, IVb:

   

   

   

   

   where the substituents R¹ to R⁴⁸ are each independently selected from the group of hydrogen, hydroxyl, (C₁-C₁₂)-alkyl, (C₁-C₁₂) -heteroalkyl, (C₄-C₁₄) -aryl, (C₄-C₁₄) -aryl-(C₁-C₁₂) -alkyl, (C₄-C₁₄) -aryl-O- (C₁-C₁₂) -alkyl, (C₃-C₁₄)-heteroaryl, (C₃-C₁₄) -heteroaryl- (C₁-C₁₂)-alkyl, (C₃-C₁₂)-cycloalkyl, (C₃-C₁₂) -cycloalkyl- (C₁-C₁₂) -alkyl, (C₃-C₁₂)-heterocycloalkyl, (C₃-C₁₂) -heterocycloalkyl- (C₁-C₁₂)-alkyl, O- (C₁-C₁₂)-alkyl, 0- (C₁-C₁₂) -heteroalkyl, O-(C₄-C₁₄) -aryl, O-(C₄-C₁₄)-aryl-(C₁-C₁₄)-alkyl, O-(C₃-C₁₄)-heteroaryl, O-(C₃-C₁₄)-heteroaryl- (C₁-C₁₄)-alkyl, O-(C₃-C₁₂)-cycloalkyl, O-(C₃-C₁₂) -cycloalkyl- (C₁-C₁₂)-alkyl, O-(C₃-C₁₂) -heterocycloalkyl, O-(C₃-C₁₂)-heterocycloalkyl-(C₁-C₁₂) -alkyl, halogens, S-(C₁-C₁₂)-alkyl, S-(C₁-C₁₂)-heteroalkyl, S-(C₄-C₁₄)-aryl, S-(C₄-C₁₄)-aryl-(C₁-C₁₄)-alkyl, S-(C₃-C₁₄)-heteroaryl, S-(C₃-C₁₄) -heteroaryl-(C₁-C₁₄) -alkyl, S-(C₃-C₁₂)-cycloalkyl, S-(C₃-C₁₂) -cycloalkyl-(C₁-C₁₂) -alkyl, S-(C₃-C₁₂)-heterocycloalkyl, (C₁-C₁₂)-acyl, (C₄-C₁₄)-aroyl, (C₄-C₁₄) -aroyl-(C₁-C₁₄) -alkyl, (C₃-C₁₄)-heteroaroyl, (C₁-C₁₄)-dialkylphosphoryl, (C₄-C₁₄)-diarylphosphoryl, (C₃-C₁₂)-alkylsulphonyl, (C₃-C₁₂)-cycloalkylsulphonyl, (C₄-C₁₂) -arylsulphonyl, (C₁-C₁₂)-alkyl- (C₄-C₁₂) -arylsulphonyl, (C₃-C₁₂)-heteroarylsulphonyl, (C=O) O-(C₁-C₁₂)-alkyl, (C=O) O-(C₁-C₁₂)-heteroalkyl, (C=O) 0- (C₄-C₁₄) -aryl,
   where
   heteroalkyl is an unbranched or branched aliphatic radical which may contain one to four heteroatom(s) selected from the group consisting of N, 0, S and substituted N;
   heteroaryl is an aryl radical in which one to four carbon atom(s) are replaced by heteroatoms selected from the group consisting of N, 0, S and substituted N, where the heteroaryl radical may also be part of a larger fused ring structure;
   heterocycloalkyl is saturated cyclic hydrocarbons containing one to four heteroatom(s) selected from the group consisting of N, 0, S and substituted N;
   the substituted N mentioned may be monosubstituted, and the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups may be mono- or polysubstituted, by radicals selected from the group consisting of hydrogen, (C₁-C₁₄) -alkyl, (C₁-C₁₄)-heteroalkyl, (C₄-C₁₄)-aryl, (C₄-C₁₄) -aryl-(C₁-C₁₄)-alkyl, (C₃-C₁₄) -heteroaryl, (C₃-C₁₄) -heteroaryl- (C₁-C₁₄) -alkyl, (C₃-C₁₂) -cycloalkyl, (C₃-C₁₂) -cycloalkyl- (C₁-C₁₄) -alkyl, (C₃-C₁₂)-heterocycloalkyl, (C₃-C₁₂)-heterocycloalkyl- (C₁-C₁₄)-alkyl, CF₃, halogen (fluorine, chlorine, bromine, iodine), (C₁-C₁₀)-haloalkyl, hydroxyl, (C₁-C₁₄)-alkoxy, (C₄-C₁₄) -aryloxy, O-(C₁-C₁₄)-alkyl- (C₄-C₁₄)-aryl, (C₃-C₁₄)-heteroaryloxy, N ((C₁-C₁₄) -alkyl) ₂, N ((C₄-C₁₄) -aryl) ₂, N ((C₁-C₁₄) -alkyl) ((C₄-C₁₄) -aryl),
   where the following combinations are possible here: first aniline Ia Ib IIa IIb IIIa IIIb IVa IVb second aniline Ib Ia IIb IIa IIIb IIIa IVb IVa

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