Electrochemical process for coupling of phenol to aniline
View Patent ↗An electrochemical method for C—C 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 ΔE 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.
1. Electrochemical process for C—C cross-coupling a phenol to an anilide, wherein selectivity of producing a C—C cross-coupled compound selected from the group consisting of formulae (I) to (V) to C—C 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 Ox 1 to the reaction vessel, and
c′) adding an anilide having an oxidation potential E Ox 2 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 Ox 2> E Ox 1 and E Ox 2− E Ox 1=Δ E,
the anilide being added in excess relative to the phenol,
and the solvent or solvent mixture being selected such that ΔE 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):
where the substituents R 1 to R 50 are each independently selected 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, (C 4 -C 14 )-aryl-O—(C 1 -C 12 )-alkyl, (C 3 -C 14 )-heteroaryl, (C 3 -C 14 )-heteroaryl-(C 1 -C 12 )-alkyl, (C 3 -C 12 )-cycloalkyl, (C 3 -C 12 )-cycloalkyl-(C 1 -C 12 )-alkyl, (C 3 -C 12 )-heterocycloalkyl, (C 3 -C 12 )-heterocycloalkyl-(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 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, halogens, S—(C 1 -C 12 )-alkyl, S—(C 1 -C 12 )-heteroalkyl, S—(C 4 -C 14 )-aryl, S—(C 4 -C 14 )-aryl-(C 1 -C 14 )-alkyl, S—(C 3 -C 14 )-heteroaryl, S—(C 3 -C 14 )-heteroaryl-(C 1 -C 14 )-alkyl, S—(C 3 -C 12 )-cycloalkyl, S—(C 3 -C 12 )-cycloalkyl-(C 1 -C 12 )-alkyl, S—(C 3 -C 12 )-heterocycloalkyl, (C 1 -C 12 )-acyl, (C 4 -C 14 )-aroyl, (C 4 -C 14 )-aroyl-(C 1 -C 14 )-alkyl, (C 3 -C 14 )-heteroaroyl, (C 1 -C 14 )-dialkylphosphoryl, (C 4 -C 14 )-diarylphosphoryl, (C 3 -C 12 )-alkylsulphonyl, (C 3 -C 12 )-cycloalkylsulphonyl, (C 4 -C 12 )-arylsulphonyl, (C 1 -C 12 )-alkyl-(C 4 -C 12 )-arylsulphonyl, (C 3 -C 12 )-heteroarylsulphonyl, (C═O)O—(C 1 -C 12 )-alkyl, (C═O)O—(C 1 -C 12 )-heteroalkyl, or (C═O)O—(C 4 -C 14 )-aryl,
where the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups mentioned are optionally mono- or polysubstituted; and
where R 1 or R 2 in formula (I), R 11 or R 12 in formula (II), R 21 or R 22 in formula (III), R 32 or R 33 in formula (IV); and R 43 or R 44 in formula (V) are selected from the group consisting of (C 1 -C 12 )-acyl, (C 4 -C 14 )-aroyl, (C 4 -C 14 )-aroyl-(C 1 -C 14 )-alkyl, (C 3 -C 14 )-heteroaroyl, (C═O)O—(C 1 -C 12 )-alkyl, (C═O)O—(C 1 -C 12 )-heteroalkyl, and (C═O)O—(C 4 -C 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 ΔE 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:
where the substituents R 1 to R 50 are each independently selected from the group consisting 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, (C 4 -C 14 )-aryl-O—(C 1 -C 12 )-alkyl, (C 3 -C 14 )-heteroaryl, (C 3 -C 14 )-heteroaryl-(C 1 -C 12 )-alkyl, (C 3 -C 12 )-cycloalkyl, (C 3 -C 12 )-cycloalkyl-(C 1 -C 12 )-alkyl, (C 3 -C 12 )-heterocycloalkyl, (C 3 -C 12 )-heterocycloalkyl-(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 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, halogens, S—(C 1 -C 12 )-alkyl, S—(C 1 -C 12 )-heteroalkyl, S—(C 4 -C 14 )-aryl, S—(C 4 -C 14 )-aryl-(C 1- C 14 )-alkyl, S—(C 3 -C 14 )-heteroaryl, S—(C 3 -C 14 )-heteroaryl-(C 1 -C 14 )-alkyl, S—(C 3 -C 12 )-cycloalkyl, S—(C 3 -C 12 )-cycloalkyl-(C 1 -C 12 )-alkyl, S—(C 3 -C 12 )-heterocycloalkyl, (C 1 -C 12 )-acyl, (C 4 -C 14 )-aroyl, (C 4 -C 14 )-aroyl-(C 1 -C 14 )-alkyl, (C 3 -C 14 )-heteroaroyl, (C 1 -C 14 )-dialkylphosphoryl, (C 4 -C 14 )-diarylphosphoryl, (C 3 -C 12 )-alkylsulphonyl, (C 3 -C 12 )-cycloalkylsulphonyl, (C 4 -C 12 )-arylsulphonyl, (C 1 -C 12 )-alkyl-(C 4 -C 12 )-arylsulphonyl, (C 3 -C 12 )-heteroarylsulphonyl, (C═O)O—(C 1 -C 12 )-alkyl, (C═O)O—(C 1 -C 12 )-heteroalkyl, and (C═O)O—(C 4 -C 14 )-aryl,
where the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups mentioned are optionally mono- or polysubstituted; and
where R 1 or R 2 in formula (I), R 11 or R 12 in formula (II), R 21 or R 22 in formula (III), R 32 or R 33 in formula (IV); and R 43 or R 44 in formula (V) are selected from the group consisting of (C 1 -C 12 )-acyl, (C 4 -C 14 )-aroyl, (C 4 -C 14 )-aroyl-(C 1 -C 14 )-alkyl, (C 3 -C 14 )-heteroaroyl, (C═O)O—(C 1 -C 12 )-alkyl, (C═O)O—(C 1 -C 12 )-heteroalkyl, and (C═O)O—(C 4 -C 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 C—C cross-coupling the phenol to the anilide according to claim 1 , wherein the anilide is an acetanilide and the selectivity of producing the C—C cross-coupled compound selected from the group consisting of formulae (I) to (V) to C—C homo-coupled product is greater than 100:1.
13. An electrochemical process for C—C cross-coupling phenol or C-substituted phenol to an anilide, wherein selectivity of producing a C—C cross-coupled biaryl compound having both hydroxyl and amino functions to C—C 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 Ox 1 to the reaction vessel,
c′) adding the anilide having an oxidation potential E Ox 2 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 Ox 2> E Ox 1 and E Ox 2− E Ox 1=Δ 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 ΔE 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 C—C cross-coupling the phenol to the anilide according to claim 1 , wherein the selectivity of producing the C—C cross-coupled compound selected from the group consisting of formulae (I) to (V) to C—C homo-coupled product is greater than 100:1.
15. The electrochemical process for C—C cross-coupling the phenol or C-substituted phenol to the anilide according to claim 13 , wherein the selectivity of producing the C—C cross-coupled biaryl compound having both hydroxyl and amino functions to C—C homo-coupled product is greater than 100:1.
16. The electrochemical process for C—C 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 C—C cross-coupled biaryl compound having both hydroxyl and amino functions to C—C homo-coupled product is greater than 100:1.