Copper-catalyzed formation of carbon-heteroatom and carbon—carbon bonds
The present invention relates to copper-catalyzed carbon-heteroatom and carbon-carbon bond-forming methods, such as the reaction of Z-X with C(L)(R)(R′) 2 in the present of a catalyst and a base, thereby forming C(Z)(R)(R′) 2 ; wherein X represents I, Cl, alkylsulfonate, or arylsulfonate; Z represents optionally substituted aryl, heteroaryl or alkenyl; L represents H or a negative charge; catalyst comprises a copper atom or ion, and a ligand, wherein the ligand is an optionally substituted aryl alcohol, alkyl amine, 1,2-diamine, 1,2-aminoalcohol, 1,2-diol, imidazolium carbene, pyridine, or 1,10-phenanthroline; the ligand is a chelating ligand; and the base represents a Bronsted base; R represents H, optionally substituted alkyl, cycloalkyl, aralkyl, aryl, or heteroaryl; R′ represents independently for each occurrence H, alkyl, cycloalkyl, aralkyl, aryl, or heteroaryl, formyl, acyl, —CO 2 R″, —C(O)N(R) 2 , sulfonyl, —P(O)(OR″) 2 , —CN, or —NO 2 ; R″ represents independently for each occurrence optionally substituted alkyl, cycloalkyl, aralkyl, aryl, or heteroaryl; and C(R′) 2 (R) taken together may represent nitrile.
1. A method comprising the step of reacting Z-X with
in the presence of a catalyst, a base, and a solvent, thereby forming
wherein
X represents I, Cl, alkylsulfonate, or arylsulfonate;
Z represents optionally substituted aryl, heteroaryl or alkenyl;
L represents H or a negative charge;
catalyst comprises a copper atom or ion, and a chelating ligand, wherein the chelating ligand is an optionally substituted aryl alcohol, alkyl amine, 1,2-diamine, 1,2-aminoalcohol, or 1,10-phenanthroline; and the chelating ligand is not the solvent;
base is a carbonate, phosphate, oxide, hydroxide, alkoxide, aryloxide, amine, metal amide, fluoride, or guanidine;
R represents H, optionally substituted alkyl, cycloalkyl, aralkyl, aryl, or heteroaryl;
R′ represents independently for each occurrence H, alkyl, cycloalkyl, aralkyl, aryl, or heteroaryl, formyl, acyl, —CO 2 R″, —C(O)N(R) 2 , sulfonyl, —P(O)(OR″) 2 , —CN, or —NO 2 , provided that at least one occurrence of R′ represents formyl, acyl, —CO 2 R″, —C(O)N(R) 2 , sulfonyl, —P(O)(OR″) 2 , —CN, or —NO 2 ;
R″ represents independently for each occurrence optionally substituted alkyl, cycloalkyl, aralkyl, aryl, or heteroaryl; and
C(R′) 2 (R) taken together may represent nitrile.
2. The method of claim 1 , wherein X represents I.
3. The method of claim 1 , wherein the chelating ligand is selected from the group consisting of 8-hydroxyquinoline, 2-(dimethylamino)ethanol, N,N-diethylsalicylamide, 2-(dimethylamino)glycine, N,N,N′,N′-tetramethyl-1,2-diaminoethane, 1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 5-methyl-1,10-phenanthroline, 5-chloro-1,10-phenanthroline, 5-nitro-1,10-phenanthroline, (methylimino)diacetic acid, and trans-1,2-cyclohexanediamine.
4. The method of claim 1 , wherein the chelating ligand is an optionally substituted 1,2-diaminocyclohexane, 1,10-phenanthroline, 2-hydroxyethyl amine, or 1,2-diaminoethane.
5. The method of claim 1 , wherein the base is potassium phosphate, potassium carbonate, cesium carbonate, sodium tert-butoxide, or sodium hydroxide.
6. The method of claim 1 , wherein the catalyst is present in less than or equal to about 5 mol % relative to Z-X.
7. The method of claim 1 , wherein the method is conducted at a temperature less than about 150 C.
8. The method of claim 1 , wherein the method is conducted at a temperature less than about 140 C.
9. The method of claim 1 , wherein the method is conducted at a temperature less than about 110 C.
10. The method of claim 1 , wherein Z represents optionally substituted aryl.
11. The method of claim 1 , wherein Z represents optionally substituted phenyl.
12. The method of claim 1 , wherein R represents H.
13. The method of claim 1 , wherein R′ represents independently for each occurrence acyl, or —CO 2 R″.
14. The method of claim 1 , wherein R″ represents independently for each occurrence alkyl, cycloalkyl, or aralkyl.
15. The method of claim 1 , wherein X represents I; and the chelating ligand is selected from the group consisting of 8-hydroxyquinoline, 2-(dimethylamino)ethanol, N,N-diethylsalicylamide, 2-(dimethylamino)glycine, N,N,N′,N′-tetramethyl-1,2-diaminoethane, 1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 5-methyl-1,10-phenanthroline, 5-chloro-1,10-phenanthroline, 5-nitro-1,10-phenanthroline, (methylimino)diacetic acid, and trans-1,2-cyclohexanediamine.
16. The method of claim 1 , wherein X represents I; and the chelating ligand is an optionally substituted 1,2-diaminocyclohexane, 1,10-phenanthroline, 2-hydroxyethyl amine, or 1,2-diaminoethane.
17. The method of claim 1 , wherein X represents I.
18. The method of claim 1 , wherein X represents I; and the chelating ligand is selected from the group consisting of 8-hydroxyquinoline, 2-(dimethylamino)ethanol, N,N-diethylsalicylamide, 2-(dimethylamino)glycine, N,N,N′,N′-tetramethyl-1,2-diaminoethane, 1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 5-methyl-1,10-phenanthroline, 5-chloro-1,10-phenanthroline, 5-nitro-1,10-phenanthroline, (methylimino)diacetic acid, and trans-1,2-cyclohexanediamine.
19. The method of claim 1 , wherein X represents I; and the chelating ligand is an optionally substituted 1,2-diaminocyclohexane, 1,10-phenanthroline, 2-hydroxyethyl amine, or 1,2-diaminoethane.
20. The method of claim 1 , wherein X represents I; and the base is potassium phosphate, potassium carbonate, cesium carbonate, sodium tert-butoxide, or sodium hydroxide.
21. The method of claim 1 , wherein X represents I; the chelating ligand is selected from the group consisting of 8-hydroxyquinoline, 2-(dimethylamino)ethanol, N,N-diethylsalicylamide, 2-(dimethylamino)glycine, N,N,N′,N′-tetramethyl-1,2-diaminoethane, 1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 5-methyl-1,10-phenanthroline, 5-chloro-1,10-phenanthroline, 5-nitro-1,10-phenanthroline, (methylimino)diacetic acid, and trans-1,2-cyclohexanediamine; and the base is potassium phosphate, potassium carbonate, cesium carbonate, sodium tert-butoxide, or sodium hydroxide.