Electrochemical process for coupling of phenol to aniline

Abstract

An electrochemical method for CC coupling a phenol and an aniline in a reaction vessel containing a suitable solvent or solvent mixture and a conductive salt to produce biaryls having both hydroxyl and amino functions, wherein the difference in the oxidation potentials E of the substrates ranges from 10 mV to 450 mV and the substrate with the highest oxidation potential is in excess, which method dispenses with multi-step syntheses using metallic reagents.

Claims

1. Electrochemical process for CC cross-coupling a phenol to an anilide, wherein selectivity of producing a CC cross-coupled compound selected from the group consisting of formulae (I) to (V) to CC homo-coupled product is at least 3:1, comprising: a) introducing a solvent or solvent mixture and a conductive salt into a reaction vessel, b) adding a phenol having an oxidation potential E.sub.Ox1 to the reaction vessel, and c) adding an anilide having an oxidation potential E.sub.Ox2 to the reaction vessel, to form a reaction solution comprising the solvent or solvent mixture, the conductive salt, the phenol, and the anilide in the reaction vessel,
where: E.sub.Ox2>E.sub.Ox1 and E.sub.Ox2E.sub.Ox1=E, the anilide being added in excess relative to the phenol, and the solvent or solvent mixture being selected such that E is within the range from 10 mV to 450 mV, d) introducing two electrodes into the reaction solution, e) applying a voltage to the electrodes, and f) coupling the phenol and the anilide to produce the compound selected from the group consisting of formulae (I) to (V): ##STR00025## where the substituents R.sup.1 to R.sup.50 are each independently selected from the group of hydrogen, hydroxyl, (C.sub.1-C.sub.12)-alkyl, (C.sub.1-C.sub.12)-heteroalkyl, (C.sub.4-C.sub.14)-aryl, (C.sub.4-C.sub.14)-aryl-(C.sub.1-C.sub.12)-alkyl, (C.sub.4-C.sub.14)-aryl-O(C.sub.1-C.sub.12)-alkyl, (C.sub.3-C.sub.14)-heteroaryl, (C.sub.3-C.sub.14)-heteroaryl-(C.sub.1-C.sub.12)-alkyl, (C.sub.3-C.sub.12)-cycloalkyl, (C.sub.3-C.sub.12)-cycloalkyl-(C.sub.1-C.sub.12)-alkyl, (C.sub.3-C.sub.12)-heterocycloalkyl, (C.sub.3-C.sub.12)-heterocycloalkyl-(C.sub.1-C.sub.12)-alkyl, O(C.sub.1-C.sub.12)-alkyl, O(C.sub.1-C.sub.12)-heteroalkyl, O(C.sub.4-C.sub.14)-aryl, O(C.sub.4-C.sub.14)-aryl-(C.sub.1-C.sub.14)-alkyl, O(C.sub.3-C.sub.14)-heteroaryl, O(C.sub.3-C.sub.14)-heteroaryl-(C.sub.1-C.sub.14)-alkyl, O(C.sub.3-C.sub.12)-cycloalkyl, O(C.sub.3-C.sub.12)-cycloalkyl-(C.sub.1-C.sub.12)-alkyl, O(C.sub.3-C.sub.12)-heterocycloalkyl, O(C.sub.3-C.sub.12)-heterocycloalkyl-(C.sub.1-C.sub.12)-alkyl, halogens, S(C.sub.1-C.sub.12)-alkyl, S(C.sub.1-C.sub.12)-heteroalkyl, S(C.sub.4-C.sub.14)-aryl, S(C.sub.4-C.sub.14)-aryl-(C.sub.1-C.sub.14)-alkyl, S(C.sub.3-C.sub.14)-heteroaryl, S(C.sub.3-C.sub.14)-heteroaryl-(C.sub.1-C.sub.14)-alkyl, S(C.sub.3-C.sub.12)-cycloalkyl, S(C.sub.3-C.sub.12)-cycloalkyl-(C.sub.1-C.sub.12)-alkyl, S(C.sub.3-C.sub.12)-heterocycloalkyl, (C.sub.1-C.sub.12)-acyl, (C.sub.4-C.sub.14)-aroyl, (C.sub.4-C.sub.14)-aroyl-(C.sub.1-C.sub.14)-alkyl, (C.sub.3-C.sub.14)-heteroaroyl, (C.sub.1-C.sub.14)-dialkylphosphoryl, (C.sub.4-C.sub.14)-diarylphosphoryl, (C.sub.3-C.sub.12)-alkylsulphonyl, (C.sub.3-C.sub.12)-cycloalkylsulphonyl, (C.sub.4-C.sub.12)-arylsulphonyl, (C.sub.1-C.sub.12)-alkyl-(C.sub.4-C.sub.12)-arylsulphonyl, (C.sub.3-C.sub.12)-heteroarylsulphonyl, (CO)O(C.sub.1-C.sub.12)-alkyl, (CO)O(C.sub.1-C.sub.12)-heteroalkyl, or (CO)O(C.sub.4-C.sub.14)-aryl, where the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups mentioned are optionally mono- or polysubstituted; and where R.sup.1 or R.sup.2 in formula (I), R.sup.11 or R.sup.12 in formula (II), R.sup.21 or R.sup.22 in formula (III), R.sup.32 or R.sup.33 in formula (IV); and R.sup.43 or R.sup.44 in formula (V) are selected from the group consisting of (C.sub.1-C.sub.12)-acyl, (C.sub.4-C.sub.14)-aroyl, (C.sub.4-C.sub.14)-aroyl-(C.sub.1-C.sub.14)-alkyl, (C.sub.3-C.sub.14)-heteroaroyl, (CO)O(C.sub.1-C.sub.12)-alkyl, (CO)O(C.sub.1-C.sub.12)-heteroalkyl, and (CO)O(C.sub.4-C.sub.14)-aryl.

2. The process according to claim 1, wherein the anilide is added in at least twice the amount relative to the phenol.

3. The process according to claim 1, wherein the ratio of phenol to anilide is in the range from 1:2 to 1:4.

4. The process according to claim 1, wherein the solvent or solvent mixture is selected such that E is in the range from 20 mV to 400 mV.

5. The process according to claim 1, wherein the reaction solution is free of organic oxidizing agents.

6. The process according to claim 1, wherein the phenol is Ib when the anilide is Ia, the phenol is IIb when the anilide is IIa, the phenol is IIIb when the anilide is IIIa, the phenol is IVb when the anilide is IVa, and the phenol is Vb when the anilide is Va: ##STR00026## ##STR00027## where the substituents R.sup.1 to R.sup.50 are each independently selected from the group consisting of hydrogen, hydroxyl, (C.sub.1-C.sub.12)-alkyl, (C.sub.1-C.sub.12)-heteroalkyl, (C.sub.4-C.sub.14)-aryl, (C.sub.4-C.sub.14)-aryl-(C.sub.1-C.sub.12)-alkyl, (C.sub.4-C.sub.14)-aryl-O(C.sub.1-C.sub.12)-alkyl, (C.sub.3-C.sub.14)-heteroaryl, (C.sub.3-C.sub.14)-heteroaryl-(C.sub.1-C.sub.12)-alkyl, (C.sub.3-C.sub.12)-cycloalkyl, (C.sub.3-C.sub.12)-cycloalkyl-(C.sub.1-C.sub.12)-alkyl, (C.sub.3-C.sub.12)-heterocycloalkyl, (C.sub.3-C.sub.12)-heterocycloalkyl-(C.sub.1-C.sub.12)-alkyl, O(C.sub.1-C.sub.12)-alkyl, O(C.sub.1-C.sub.12)-heteroalkyl, O(C.sub.4-C.sub.14)-aryl, O(C.sub.4-C.sub.14)-aryl-(C.sub.1-C.sub.14)-alkyl, O(C.sub.3-C.sub.14)-heteroaryl, O(C.sub.3-C.sub.14)-heteroaryl-(C.sub.1-C.sub.14)-alkyl, O(C.sub.3-C.sub.12)-cycloalkyl, O(C.sub.3-C.sub.12)-cycloalkyl-(C.sub.1-C.sub.12)-alkyl, O(C.sub.3-C.sub.12)-heterocycloalkyl, O(C.sub.3-C.sub.12)-heterocycloalkyl-(C.sub.1-C.sub.12)-alkyl, halogens, S(C.sub.1-C.sub.12)-alkyl, S(C.sub.1-C.sub.12)-heteroalkyl, S(C.sub.4-C.sub.14)-aryl, S(C.sub.4-C.sub.14)-aryl-(C.sub.1-C.sub.14)-alkyl, S(C.sub.3-C.sub.14)-heteroaryl, S(C.sub.3-C.sub.14)-heteroaryl-(C.sub.1-C.sub.14)-alkyl, S(C.sub.3-C.sub.12)-cycloalkyl, S(C.sub.3-C.sub.12)-cycloalkyl-(C.sub.1-C.sub.12)-alkyl, S(C.sub.3-C.sub.12)-heterocycloalkyl, (C.sub.1-C.sub.12)-acyl, (C.sub.4-C.sub.14)-aroyl, (C.sub.4-C.sub.14)-aroyl-(C.sub.1-C.sub.14)-alkyl, (C.sub.3-C.sub.14)-heteroaroyl, (C.sub.1-C.sub.14)-dialkylphosphoryl, (C.sub.4-C.sub.14)-diarylphosphoryl, (C.sub.3-C.sub.12)-alkylsulphonyl, (C.sub.3-C.sub.12)-cycloalkylsulphonyl, (C.sub.4-C.sub.12)-arylsulphonyl, (C.sub.1-C.sub.12)-alkyl-(C.sub.4-C.sub.12)-arylsulphonyl, (C.sub.3-C.sub.12)-heteroarylsulphonyl, (CO)O(C.sub.1-C.sub.12)-alkyl, (CO)O(C.sub.1-C.sub.12)-heteroalkyl, and (CO)O(C.sub.4-C.sub.14)-aryl, where the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups mentioned are optionally mono- or polysubstituted; and where R.sup.1 or R.sup.2 in formula (I), R.sup.11 or R.sup.12 in formula (II), R.sup.21 or R.sup.22 in formula (III), R.sup.32 or R.sup.33 in formula (IV); and R.sup.43 or R.sup.44 in formula (V) are selected from the group consisting of (C.sub.1-C.sub.12)-acyl, (C.sub.4-C.sub.14)-aroyl, (C.sub.4-C.sub.14)-aroyl-(C.sub.1-C.sub.14)-alkyl, (C.sub.3-C.sub.14)-heteroaroyl, (CO)O(C.sub.1-C.sub.12)-alkyl, (CO)O(C.sub.1-C.sub.12)-heteroalkyl, and (CO)O(C.sub.4-C.sub.14)-aryl.

7. The process according to claim 6, wherein the phenol is Ib and the anilide is Ia.

8. The process according to claim 6, wherein the phenol is IIb and the anilide is IIa.

9. The process according to claim 6, wherein the phenol is IIIb and the anilide is IIIa.

10. The process according to claim 6, wherein the phenol is IVb and the anilide is IVa.

11. The process according to claim 6, wherein the phenol is Vb and the anilide is Va.

12. The electrochemical process for CC cross-coupling the phenol to the anilide according to claim 1, wherein the anilide is an acetanilide and the selectivity of producing the CC cross-coupled compound selected from the group consisting of formulae (I) to (V) to CC homo-coupled product is greater than 100:1.

13. An electrochemical process for CC cross-coupling phenol or C-substituted phenol to an anilide, wherein selectivity of producing a CC cross-coupled biaryl compound having both hydroxyl and amino functions to CC homo-coupled product is at least 3:1, comprising: a) introducing a solvent or solvent mixture and a conductive salt into a reaction vessel, b) adding the phenol or C-substituted phenol having an oxidation potential E.sub.Ox1 to the reaction vessel, c) adding the anilide having an oxidation potential E.sub.Ox2 to the reaction vessel, to form a reaction solution comprising the solvent or solvent mixture, the conductive salt, the phenol or C-substituted phenol, and the anilide in the reaction vessel, where:
E.sub.Ox2>E.sub.Ox1 and E.sub.Ox2E.sub.Ox1=E, the anilide being added in excess relative to the phenol or C-substituted phenol, and the solvent or solvent mixture being selected such that E is within the range from 10 mV to 450 mV, d) introducing two electrodes into the reaction solution, e) applying a voltage to the electrodes, and f) coupling the phenol or C-substituted phenol and the anilide to produce the biaryl compound having both hydroxyl and amino functions.

14. The electrochemical process for CC cross-coupling the phenol to the anilide according to claim 1, wherein the selectivity of producing the CC cross-coupled compound selected from the group consisting of formulae (I) to (V) to CC homo-coupled product is greater than 100:1.

15. The electrochemical process for CC cross-coupling the phenol or C-substituted phenol to the anilide according to claim 13, wherein the selectivity of producing the CC cross-coupled biaryl compound having both hydroxyl and amino functions to CC homo-coupled product is greater than 100:1.

16. The electrochemical process for CC cross-coupling the phenol or C-substituted phenol to the anilide according to claim 13, wherein the anilide is an acetanilide and the selectivity of producing the CC cross-coupled biaryl compound having both hydroxyl and amino functions to CC homo-coupled product is greater than 100:1.

Description

GENERAL PROCEDURES

(1) Cyclic Voltammetry (CV)

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

(3) Chromatography

(4) The preparative liquid chromatography separations via flash chromatography were conducted with a maximum pressure of 1.6 bar on 60 M silica gel (0.040-0.063 mm) from Macherey-Nagel GmbH & Co, Dren. The unpressurized separations were conducted on Geduran Si 60 silica gel (0.063-0.200 mm) from Merck KGaA, Darmstadt. The solvents used as eluents (ethyl acetate (technical grade), cyclohexane (technical grade)) had been purified beforehand by distillation on a rotary evaporator.

(5) For thin-layer chromatography (TLC), ready-made PSC silica gel 60 F254 plates from Merck KGaA, Darmstadt were used. The Rf values are reported as a function of the eluent mixture used. Staining of the TLC plates was effected using a cerium-molybdatophosphoric acid solution as a dipping reagent. Cerium-molybdatophosphoric acid reagent: 5.6 g of molybdatophosphoric acid, 2.2 g of cerium(IV) sulphate tetrahydrate and 13.3 g of concentrated sulphuric acid to 200 milliliters of water.

(6) Gas Chromatography (GC/GCMS)

(7) The gas chromatography analyses (GC) of product mixtures and pure substances were effected with the aid of the GC-2010 gas chromatograph from Shimadzu, Japan. Measurement is effected on an HP-5 quartz capillary column from Agilent Technologies, USA (length: 30 m; internal diameter: 0.25 mm; film thickness of the covalently bound stationary phase: 0.25 m; carrier gas: hydrogen; injector temperature: 250 C.; detector temperature: 310 C.; programme: hard method: start temperature 50 C. for 1 min, heating rate: 15 C./min, final temperature 290 C. for 8 min). Gas chromatography mass spectra (GCMS) of product mixtures and pure substances were recorded with the aid of the GC-2010 gas chromatograph combined with the GCMS-QP2010 mass detector from Shimadzu, Japan. Measurement is effected on an HP-1 quartz capillary column from Agilent Technologies, USA (length: 30 m; internal diameter: 0.25 mm; film thickness of the covalently bound stationary phase: 0.25 m; carrier gas: hydrogen; injector temperature: 250 C.; detector temperature: 310 C.; programme: hard method: start temperature 50 C. for 1 min, heating rate: 15 C./min, final temperature 290 C. for 8 min; GCMS: ion source temperature: 200 C.).

(8) Melting Points

(9) Melting points were measured with the aid of the SG 2000 melting point measuring instrument from HW5, Mainz and are uncorrected.

(10) Elemental Analysis

(11) The elemental analyses were conducted in the Analytical Division of the Department of Organic Chemistry at the Johannes Gutenberg University of Mainz on a Vario EL Cube from Foss-Heraeus, Hanau.

(12) Mass Spectrometry

(13) All electrospray ionization analyses (ESI+) were conducted on a QT of Ultima 3 from Waters Micromasses, Milford, Mass. EI mass spectra and the high-resolution EI spectra were measured on an instrument of the MAT 95 XL sector-field instrument type from Thermo Finnigan, Bremen.

(14) NMR Spectroscopy

(15) The NMR spectroscopy studies were conducted on multi-nuclear resonance spectrometers of the AC 300 or AV II 400 type from Bruker, Analytische Messtechnik, Karlsruhe. The solvent used was CDCl.sub.3. The .sup.1H and .sup.13C spectra were calibrated according to the residual content of undeuterated solvent according to the NMR Solvent Data Chart from Cambridge Isotopes Laboratories, USA. Some of the .sup.1H and .sup.13C signals were assigned with the aid of H,H COSY, H,H NOESY, H,C HSQC and H,C HMBC spectra. The chemical shifts are reported as values in ppm. For the multiplicities of the NMR signals, the following abbreviations were used: s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), dt (doublet of triplets), tq (triplet of quartets). All coupling constants J were reported with the number of bonds covered in Hertz (Hz). The numbers reported in the signal assignment correspond to the numbering given in the formula schemes, which need not correspond to IUPAC nomenclature.

(16) GM1: General Method for Electrochemical Cross-Coupling

(17) 2-4 mmol of the respective deficiency component are dissolved together with 6-12 mmol of the respective second component to be coupled in the amounts of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) and MeOH specified and converted in an undivided beaker cell with glassy carbon electrodes. The electrolysis is effected under galvanostatic conditions.

(18) The reaction is stirred and heated to 50 C. with the aid of a water bath. After the end of the electrolysis, the cell contents are transferred together with HFIP into a 50 ml round-bottom flask and the solvent is removed under reduced pressure on a rotary evaporator at 50 C., 200-70 mbar. Unconverted reactant is retained by means of short-path distillation or Kugelrohr distillation (100 C., 10.sup.3 mbar).

(19) Electrode Material

(20) Anode: glassy carbon

(21) Cathode: glassy carbon

(22) Electrolysis Conditions:

(23) Temperature [T]: 50 C.

(24) Current [I]: 25 mA

(25) Current density [j]: 2.8 mA/cm.sup.2

(26) Quantity of charge [Q]: 2 F (per deficiency component)

(27) Terminal voltage [U.sub.max]: 3-5 V

(28) Schematic Cell Structure

(29) FIG. 3 shows the structure of the cell in schematic form. This cell has the following components:

(30) 1: stainless steel holders for electrodes

(31) 2: Teflon stopper

(32) 3: beaker cell with attached outlet for reflux condenser connection

(33) 4: stainless steel clamp

(34) 5: glassy carbon electrodes

(35) 6: magnetic stirrer bar

N-Acetyl-2-amino-2-hydroxy-4,5-dimethoxy-3-(dimethylethyl)-5-methylbiphenyl

(36) ##STR00020##

(37) The electrolysis is conducted according to GM1 in an undivided beaker cell with glassy carbon electrodes. To this end, 0.62 g (3.79 mmol, 1.0 equiv.) of 2-(dimethylethyl)-4-methylphenol and 2.22 g (11.36 mmol, 3.0 equiv.) of N-(3,4-dimethoxyphenyl)acetamide are dissolved in 25 ml of HFIP, 0.77 g of MTBS is added and the electrolyte is transferred to the electrolysis cell. After the electrolysis, the solvent and unconverted amounts of reactant are removed under reduced pressure, the crude product is purified by flash chromatography on silica gel 60 in a 4:1 eluent (CH:EA) and the product is obtained as a colourless solid.

(38) Yield: 447 mg (33%, 1.3 mmol)

(39) GC (hard method, HP-5): t.sub.R=16.14 min

(40) R.sub.f(CH:EA=4:1)=0.17

(41) m.sub.p=182 C. (recrystallized from DCM)

(42) .sup.1H NMR (400 MHz, CDCl.sub.3) =1.43 (s, 9H), 1.99 (s, 3H), 2.31 (s, 3H), 3.86 (s, 3H), 3.94 (s, 3H), 6.76 (s, 1H), 6.83 (d, J=1.9 Hz, 1H), 6.94 (s, 1H), 7.14 (d, J=1.9 Hz, 1H), 7.85 (s, 1H);

(43) .sup.13C NMR (101 MHz, CDCl.sub.3) =20.95, 24.49, 29.68, 35.01, 56.22, 56.28, 77.16, 106.54, 113.45, 118.74, 124.10, 128.32, 128.97, 129.48, 129.66, 136.89, 146.42, 149.37, 149.40, 168.91.

(44) HRMS for C.sub.21H.sub.27NO.sub.4 (ESI+) [M+H.sup.+]: calc.: 358.2018. found: 358.2017.

(45) MS (EI, GCMS): m/z (%): 357 (100) [M].sup.+, 242 (100) [MCH.sub.3].sup.+, 315 (50) [MC.sub.2H.sub.2O].sup.+.

2-Amino-4-bromo-2-hydroxy-3,5-dimethoxy-5-methylbiphenyl

(46) ##STR00021##

(47) The electrolysis is conducted according to GM1 in an undivided beaker cell with glassy carbon electrodes. To this end, 0.43 g (2.15 mmol, 1.0 equiv.) of 4-bromo-3-methoxyaniline and 0.89 g (6.45 mmol, 3.0 equiv.) of 4-methylguaiacol are dissolved in 25 ml of HFIP, 0.77 g of MTBS is added and the electrolyte is transferred to the electrolysis cell. After the electrolysis, the solvent and unconverted amounts of reactant are removed under reduced pressure, the crude product is purified by flash chromatography on silica gel 60 in a 9:1 eluent (CH:EA) and the product is obtained as a brown oil.

(48) Yield: 70 mg (10%, 0.2 mmol)

(49) GC (hard method, HP-5): t.sub.R=16.82 min

(50) R.sub.f (CH:EA=4:1)=0.26

(51) .sup.1H NMR (400 MHz, DMSO-d6) =2.20 (s, 3H), 3.34 (bs, 3H), 3.75 (s, 3H), 3.77 (s, 3H), 6.48 (d, J=1.9 Hz, 1H), 6.59 (s, 1H), 6.75 (d, J=1.9 Hz, 1H), 7.06 (s, 1H);

(52) .sup.13C NMR (101 MHz, DMSO-d6) =20.68, 39.52, 55.81, 55.92, 98.31, 100.90, 111.86, 119.58, 120.97, 123.05, 124.50, 128.16, 134.14, 140.98, 143.99, 147.73, 154.88.

(53) HRMS for C.sub.15H.sub.16BrNO.sub.3 (ESI+) [M+Na.sup.+]: calc.: 339.0392. found: 339.0390.

(54) MS (EI, GCMS): m/z (%): 339 (100) [.sup.81M].sup.+, 337 (100) [.sup.79M].sup.+, 320 (12) [.sup.81MCH.sub.3].sup.+, 318 (12) [.sup.79MCH.sub.3].sup.+.

N-Acetyl-2-amino-2-hydroxy-5-methyl-2,4,5-trimethoxybiphenyl

(55) ##STR00022##

(56) The electrolysis is conducted according to GM1 in an undivided beaker cell with glassy carbon electrodes. To this end, 0.52 g (3.79 mmol, 1.0 equiv.) of 4-methylguaiacol and 2.22 g (11.37 mmol, 3.0 equiv.) of N-(3,4-dimethoxyphenyl)acetamide are dissolved in 25 ml of HFIP, 0.77 g of MTBS is added and the electrolyte is transferred to the electrolysis cell. After the electrolysis, the solvent and unconverted amounts of reactant are removed under reduced pressure, the crude product is purified by flash chromatography on silica gel 60 in a 2:3 eluent (CH:EA)+1% AcOH and the product is obtained as a viscous, pale yellow oil.

(57) Yield: 173 mg (14%, 0.52 mmol)

(58) GC (hard method, HP-5): t.sub.R=16.11 min

(59) R.sub.f(CH:EA=4:1)=0.26

(60) .sup.1H NMR (400 MHz, CDCl.sub.3) =2.13 (s, 3H), 2.33 (s, 3H), 3.71 (s, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 6.46 (s, 1H), 6.64-6.70 (m, 1H), 6.76 (d, J=8.1 Hz, 1H), 6.79 (d, J=1.9 Hz, 1H), 7.83 (bs, 1H), 8.07 (s, 1H);

(61) .sup.13C NMR (101 MHz, CDCl.sub.3) =21.35, 24.80, 56.01, 56.35, 77.16, 103.27, 105.06, 113.51, 119.03, 121.55, 123.10, 134.57, 139.32, 143.77, 145.07, 145.14, 150.05, 168.34.

(62) HRMS for C.sub.18H.sub.21NO.sub.5 (ESI+) [M+Na.sup.+]: calc.: 332.1498. found: 332.1499.

(63) MS (EI, GCMS): m/z (%): 331 (100) [M].sup.+, 289 (20) [MC.sub.2H.sub.2O].sup.+, 318 (12) [MC.sub.2H.sub.5NO].sup.+.

N-Acetyl-2-amino-3-methyl-4-(methylethyl)-4,5-dimethoxydiphenyl ether

(64) ##STR00023##

(65) The electrolysis is conducted according to GM1 in an undivided beaker cell with glassy carbon electrodes. To this end, 0.75 g (5.00 mmol, 1.0 equiv.) of 3-methyl-4-(methylethyl)phenol and 2.93 g (15.00 mmol, 3.0 equiv.) of N-(3,4-dimethoxyphenyl)acetamide are dissolved in 33 ml of HFIP, 1.02 g of MTBS are added and the electrolyte is transferred to the electrolysis cell. After the electrolysis, the solvent and unconverted amounts of reactant are removed under reduced pressure, the crude product is purified by flash chromatography on silica gel 60 in a 3:2 eluent (CH:EA) and the product is obtained as a colourless solid.

(66) Yield: 313 mg (18%, 0.91 mmol)

(67) GC (hard method, HP-5): t.sub.R=16.38 min

(68) R.sub.f (CH:EA=3:2)=0.26

(69) m.sub.p=112 C. (recrystallized from CH)

(70) .sup.1H NMR (400 MHz, CDCl.sub.3) =1.20 (s, 3H), 1.22 (s, 3H), 2.10 (s, 3H), 2.29 (s, 3H), 3.09 (hept, J=6.9, 6.9, 6.8, 6.8, 6.8, 6.8 Hz, 1H), 3.74 (s, 3H), 3.90 (s, 3H), 6.52 (s, 1H), 6.65-6.79 (m, 2H), 7.16 (d, J=8.4 Hz, 1H), 7.53 (s, 1H), 8.10 (s, 1H);

(71) .sup.13C NMR (101 MHz, CDCl.sub.3) =19.52, 23.43, 24.85, 28.84, 56.32, 56.35, 77.16, 104.23, 104.98, 114.49, 118.50, 123.77, 126.13, 137.07, 137.81, 141.81, 145.33, 145.44, 155.17, 168.31.

(72) HRMS for C.sub.20H.sub.23NO.sub.4 (ESI+) [M+Na.sup.+]: calc.: 366.1681. found: 366.1676.

(73) MS (EI, GCMS): m/z (%): 343 (100) [M].sup.+, 301 (20) [MC.sub.2H.sub.2O].sup.+, 286 (80) [MC.sub.2H.sub.5NO].sup.+.

2-Amino-3-chloro-2,4-dihydroxy-5,5-dimethyl-3-methoxybiphenyl

(74) ##STR00024##

(75) The electrolysis is conducted according to GM1 in an undivided beaker cell with glassy carbon electrodes. To this end, 0.60 g (3.79 mmol, 1.0 equiv.) of 2-chloro-3-hydroxy-4-methylaniline and 1.57 g (11.36 mmol, 3.0 equiv.) of 4-methylguaiacol are dissolved in 25 ml of HFIP, 0.77 g of MTBS is added and the electrolyte is transferred to the electrolysis cell. After the electrolysis, the solvent and unconverted amounts of reactant are removed under reduced pressure, the crude product is purified by flash chromatography on silica gel 60 in a 4:1 eluent (CH:EA) and the product is obtained as a dark brown solid.

(76) Yield: 221 mg (20%, 0.76 mmol)

(77) GC (hard method, HP-5): t.sub.R=15.64 min

(78) R.sub.f(CH:EA=4:1)=0.23

(79) .sup.1H NMR (400 MHz, DMSO-d6) =2.11 (s, 3H), 2.24 (s, 3H), 3.81 (s, 3H), 6.49 (s, 1H), 6.68 (s, 1H), 6.77 (s, 1H), 8.45 (bs, 1H), 8.77 (bs, 1H);

(80) .sup.13C NMR (101 MHz, DMSO-d6) =16.12, 20.74, 55.83, 107.30, 111.57, 113.52, 116.93, 123.46, 126.07, 128.05, 130.42, 140.28, 141.07, 147.65, 150.18.

(81) HRMS for C.sub.15H.sub.16ClNO.sub.3 (ESI+) [M+H.sup.+]: calc.: 294.0897. found: 294.0901.

(82) MS (EI, GCMS): m/z (%): 293 (100) [M].sup.+, 276 (100) [MOH].sup.+.

BRIEF DESCRIPTION OF THE DRAWINGS

(83) FIG. 1 shows a reaction apparatus for electrochemical CC coupling phenol to aniline;

(84) FIG. 2 shows a reaction apparatus for large scale electrochemical CC coupling phenol to aniline;

(85) FIG. 3 shows the schematic structure of an electrochemical cell;

(86) FIG. 4 shows E.sub.Ox as a function of various para substituents on aniline;

(87) FIG. 5 shows E.sub.Ox as a function of various 2,4-disubstituents on aniline;

(88) FIG. 6 shows E.sub.Ox as a function of various 3,4-disubstituents on aniline;

(89) FIG. 7 shows E.sub.Ox as a function of various other substituents on aniline;

(90) FIG. 8 shows E.sub.Ox as a function of various 4-substituents on N-acetylaniline;

(91) FIG. 9 shows E.sub.Ox as a function of various 2,4-disubstituents on N-acetylaniline;

(92) FIG. 10 shows E.sub.Ox as a function of various 3,4-disubstituents on N-acetylaniline.

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

(94) FIG. 2 shows a reaction apparatus in which the above-described coupling reaction can be conducted on a larger scale. The apparatus comprises two glass flanges (5), through which, by means of screw clamps (2) and seals, electrodes (3) of boron-doped diamond (BDD)-coated support materials or other electrode materials known to those skilled in the art are pressed on. The reaction chamber can be provided with a reflux condenser via a glass sleeve (1). The reaction mixture is mixed with the aid of a magnetic stirrer bar (4).

(95) FIGS. 4 to 10 each show the change in the oxidation potential (V) as a function of the proportion of methanol (MeOH) to which the solvent 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) has been added. The numbers in the legends indicate the position of the substituent on the benzene ring in relation to the NH.sub.2 or the NHCOCH.sub.3 group: 2=ortho, 3=meta, 4=para. It is clearly apparent from the figures that the oxidation potential can be altered by the addition of methanol.