Transition-metal-catalyzed carbon-nitrogen bond-forming methods using carbene ligands
The present invention relates to a process for the preparation of N-aryl amine and N-aryl amide compounds. Generally, the process of the present invention involves reacting a compound having a primary or secondary amino or amido group with an arylating compound, in the presence of a weak base and a transition metal catalyst, under reaction conditions effective to form an N-aryl amine or N-aryl amide compound, the transition metal catalyst comprising a Group 8 metal, e.g., Ni, Pd, or Pt, and at least one carbene-containing ligand. Typically, the transition metal catalyst is formed in a preceding step from the conjugate acid form of the carbene ligand, a stoichiometric amount of a strong base, and a Group 8 metal atom or ion.
1. A method represented by Scheme 1:
wherein
X represents I, Br, Cl, alkylsulfonate, or arylsulfonate;
Ar represents optionally substituted aryl or heteroaryl;
catalyst consists essentially of a Group 8 atom or ion; and at least one carbene-containing ligand;
base represents a phosphate, carbonate, bicarbonate, fluoride, tertiary amine, or hydride;
R represents alkyl, alkenyl, cycloalkyl, aralkyl, aryl, heteroaryl, formyl, acyl, —CO 2 alkyl, —CO 2 aryl, —CO 2 aralkyl, —N(R′)acyl, —N(R′)C(O)Oalkyl, —N(R′)C(O)Oaryl, —N(R′)C(O)Oaralkyl, —N═C(alkyl) 2 , or —N═C(aryl) 2 ;
R′ represents H, alkyl, cycloalkyl, aralkyl, aryl, heteroaryl, formyl, acyl, or amino;
R and R′ taken together may represent C(alkyl) 2 , or =C(aryl) 2 ; and
R and R′ are optionally connected by a covalent bond to form a cyclic structure which incorporates the amine nitrogen.
2. The method of claim 1 , wherein X is Br or Cl.
3. The method of claim 1 , wherein Ar represents optionally substituted phenyl.
4. The method of claim 1 , wherein R′ represents H, alkyl, cycloalkyl, aralkyl, aryl, or heteroaryl.
5. The method of claim 1 , wherein the catalyst consists essentially of a palladium atom or ion and at least one carbene-containing ligand.
6. The method of claim 1 , wherein X is Br or Cl; and Ar represents optionally substituted phenyl.
7. The method of claim 1 , wherein X is Br or Cl; Ar represents optionally substituted phenyl; and R′ represents H, alkyl, cycloalkyl, aralkyl, aryl, or heteroaryl.
8. The method of claim 1 , wherein X is Br or Cl; Ar represents optionally substituted phenyl; R′ represents H, alkyl, cycloalkyl, aralkyl, aryl, or heteroaryl; and the catalyst consists essentially of a palladium atom or ion and at least one carbene-containing ligand.
9. The method of claim 1 , 2 , 3 , 4 , 5 , 6 , 7 , or 8 , wherein the at least one carbene-containing ligand is represented by the following formula:
wherein R 1 and R 2 are independently selected from the group consisting of optionally substituted aryl; and R 3 and R 4 are independently selected from the group consisting of H and alkyl.
10. The method of claim 1 , 2 , 3 , 4 , 5 , 6 , 7 , or 8 , wherein the at least one carbene-containing ligand is represented by the following formula:
wherein R 1 and R 2 are independently selected from the group consisting of optionally substituted phenyl; and R 3 and R 4 are H.
11. The method of claim 1 , 2 , 3 , 4 , 5 , 6 , 7 , or 8 , wherein the at least one carbene-containing ligand is represented by the following formula:
wherein R 1 and R 2 are independently selected from the group consisting of optionally substituted aryl; and R 3 and R 4 are independently selected from the group consisting of H and alkyl.
12. The method of claim 1 , 2 , 3 , 4 , 5 , 6 , 7 , or 8 , wherein the at least one carbene-containing ligand is represented by the following formula:
wherein R 1 and R 2 are independently selected from the group consisting of optionally substituted phenyl; and R 3 and R 4 are H.
13. The method of claim 1 , 2 , 3 , 4 , 5 , 6 , 7 , or 8 , wherein base represents a phosphate.
14. The method of claim 1 , 2 , 3 , 4 , 5 , 6 , 7 , or 8 , wherein base represents potassium phosphate.
15. The method of claim 1 , 2 , 3 , 4 , 5 , 6 , 7 , or 8 , wherein R represents aryl or heteroaryl.
16. The method of claim 1 , 2 , 3 , 4 , 5 , 6 , 7 , or 8 , wherein R′ represents H.
17. The method of claim 1 , 2 , 3 , 4 , 5 , 6 , 7 , or 8 , wherein R represents aryl or heteroaryl; and R′ represents H.
18. The method of claim 1 , 2 , 3 , 4 , 5 , 6 , 7 , or 8 , wherein the method is practiced at a temperature less than about 150 C.
19. The method of claim 1 , 2 , 3 , 4 , 5 , 6 , 7 , or 8 , wherein the method is practiced at a temperature in the range from about 90 C to about 110 C.
20. The method of claim 1 , 2 , 3 , 4 , 5 , 6 , 7 , or 8 , wherein the method is practiced at about 100 C.