Oxalic amide ligands, and uses thereof in copper-catalyzed coupling reaction of aryl halides

A catalyst system for an aryl coupling reaction, which comprises:

• a copper catalyst, a ligand, a base, and an organic solvent;
• wherein the copper catalyst is selected from the group consisting of CuI, CuBr, CuCl, CuTc, Cu(OAc)2, CuSO4, Cu2O, CuBr2, CuCl2, CuO, CuSCN, CuCN, Cu(acac)2, and the combinations thereof;
• and preferably is CuI, Cu2O, or Cu(acac)2;
• the base is selected from the group consisting of potassium carbonate, cesium carbonate, potassium phosphate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, lithium hydroxide, sodium hydroxide, tetrabutyl ammonium hydroxide, and/or a hydrate of the base, and the combinations thereof;
• and preferably is potassium phosphate, cesium carbonate, orlithium hydroxide;
• the solvent is selected from the group consisting of DMSO, DMF, DMA, NMP, acetonitrile, isopropanol, 1,4-dioxane, tetrahydrofuran, toluene, tert-butanol, and the combinations thereof;
• and preferably is DMSO and/or DMF and/or DMSO/H2O;
• the ligand is of formula (I):
• wherein R is selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3- to 20-membered heteroaryl, substituted or unsubstituted C7-C25 alkyl-aryl, substituted or unsubstituted C1-C5 alkyl-3- to 20-membered heteroaryl, substituted or unsubstituted C3-C20 cycloalkyl, and substituted or unsubstituted 3- to 20-membered heterocyclic group;
• wherein the heteroaryl or heterocyclic group has 1 to 5 heteroatoms selected from the group consisting of N, O and S;
• the cycloalkyl or heterocyclic group may be a monocyclic, polycyclic, spiro or bridged ring structure;
• Ra is selected from (a) or (b):
• (a) OR′;
• wherein R′ is selected from the group consisting of substituted or unsubstituted C1-C6 alkyl;
• or
• (b) N(R″)2;
• wherein each R″ is independently selected from the group consisting of H, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3- to 20-membered heteroaryl, substituted or unsubstituted C7-C25 alkyl-aryl, substituted or unsubstituted C1-C5 alkyl-3- to 20-membered heteroaryl, substituted or unsubstituted C3-C20 cycloalkyl, and substituted or unsubstituted 3- to 20-membered heterocyclic group;
• wherein the heteroaryl or heterocyclic group has 1 to 5 heteroatoms selected from the group consisting of N, O and S;
• the cycloalkyl or heterocyclic group may be a monocyclic, polycyclic, spiro or bridged ring structure (preferably, N(R″)2 is NHR″);
• Rb is selected from the group consisting of H, and C1-C6 alkyl;
• or Rb and R, together with adjacent nitrogen atom, form a substituted or unsubstituted 3- to 20-membered heteroaryl, or substituted or unsubstituted 3- to 20-membered heterocyclic group;
• the term substituted means that one or more hydrogen atoms on the group is substituted by a substituent selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 aryl-oxy, C2-C10 ester group (alkyl-COO—), C2-C10 acyl-alkoxy (alkyl-OOC—), C2-C10 acyl (alkyl-CO—), C2-C10 acyl amino (alkyl/aryl-NHC(O)—), —COOH, nitro, hydroxy, amino, and amino substituted by one or two C1-C6 alkyl.

A process for preparation of a compound of formula (I):

• wherein R is selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3- to 20-membered heteroaryl, substituted or unsubstituted C7-C25 alkyl-aryl, substituted or unsubstituted C1-C5 alkyl-3- to 20-membered heteroaryl, substituted or unsubstituted C3-C20 cycloalkyl, and substituted or unsubstituted 3- to 20-membered heterocyclic group;
• wherein the heteroaryl or heterocyclic group has 1 to 5 heteroatoms selected from the group consisting of N, O and S:
• the cycloalkyl or heterocyclic group may be is a monocyclic, polycyclic, spiro or bridged ring structure;
• Ra is
• (a) OR′;
• wherein R′ is selected from the group consisting of Me and Et;
• or
• (b) N(R″)2;
• wherein each R″ is independently selected from the group consisting of H, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3- to 20-membered heteroaryl, substituted or unsubstituted C7-C25 alkyl-aryl, substituted or unsubstituted C1-C5 alkyl-3- to 20-membered heteroaryl, substituted or unsubstituted C3-C20 cycloalkyl, and substituted or unsubstituted 3- to 20-membered heterocyclic group;
• wherein the heteroaryl or heterocyclic group has 1 to 5 heteroatoms selected from the group consisting of N, O and S:
• the cycloalkyl or heterocyclic group is a monocyclic, polycyclic, spiro or bridged ring structure;
• Rb is selected from the group consisting of H, and C1-C6 alkyl;
• or Rb and R, together with adjacent nitrogen atom, form a substituted or unsubstituted 3- to 20-membered heteroaryl, or substituted or unsubstituted 3- to 20-membered heterocyclic group;
• and when Ra is selected from (a) and R′ is H, R is naphthyl substituted by methyl;
• the term substituted means that one or more hydrogen atoms on the group is substituted by a substituent selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 aryl-oxy, C2-C10 ester group (alkyl-COO—), C2-C10 acyl-alkoxy (alkyl-OOC—), C2-C10 acyl (alkyl-CO—), C2-C10 acyl amino (alkyl/aryl-NHC(O)—), —COOH, nitro, cyano, hydroxy, amino, and amino substituted by one or two C1-C6 alkvl;
• wherein the process is carried out by a method selected from the group consisting of process (i), process (ii) and process (II);
• wherein:
• process (i) comprises a step of:
• in which
• R—NH—Rb is reacted with
• in an inert solvent to produce the compound of formula (I);
• process (ii) comprises a step of:
• in which
• R″—NH2 is reacted with
• in an inert solvent to produce the compound of formula (I);
• and
• process (II) comprises a step of:
• in which
• R—NH2 is reacted with oxalyl chloride in an inert solvent to produce the compound of formula (I).