Transition-metal-catalyzed carbon-nitrogen and carbon-carbon bond-forming reactions
One aspect of the present invention relates to ligands for transition metals. A second aspect of the present invention relates to the use of catalysts comprising these ligands in various transition-metal-catalyzed carbon-heteroatom and carbon-carbon bond-forming reactions. The subject methods provide improvements in many features of the transition-metal-catalyzed reactions, including the range of suitable substrates, number of catalyst turnovers, reaction conditions, and efficiency. For example, improvements have been realized in transition metal-catalyzed: aryl amination reactions; aryl amidation reactions; Suzuki couplings; and Sonogashira couplings. In certain embodiments, the invention relates to catalysts and methods of using them that operate in aqueous solvent systems.
1. A method represented by Scheme 1:
wherein
Z is selected from the group consisting of optionally substituted aryl, heteroaryl and alkenyl;
X is selected from the group consisting of Cl, Br, I, —OS(O) 2 alkyl, and —OS(O) 2 aryl;
R′ and R″ are selected, independently for each occurrence, from the group consisting of H, alkyl, heteroalkyl, aryl, formyl, acyl, alkoxycarbonyl, alkylaminocarbonyl, heteroaryl, aralkyl, alkoxyl, amino, trialkylsilyl, and triarylsilyl;
R′ and R″, taken together, may form an optionally substituted ring consisting of 3-10 backbone atoms inclusive; said ring optionally comprising one or more heteroatoms beyond the nitrogen to which R′ and R″ are bonded;
R′ and/or R″ may be covalently linked to Z;
the transition metal is selected from the Group 10 metals;
the base is selected from the group consisting of fluorides, hydrides, hydroxides, carbonates, phosphates, alkoxides, metal amides, and carbanions; and
the ligand is selected from the group consisting of compounds represented by L:
wherein
R is selected independently for each occurrence from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and —(CH 2 ) m —R 80 ;
R 1 is selected independently for each occurrence from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, —OR 8 , —N(R 8 ) 2 , —Si(R 8 ) 3 , and —(CH 2 ) m —R 80 ;
R 2 is selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, —OR 8 , —N(R 8 ) 2 , —Si(R 8 ) 3 , and —(CH 2 ) m —R 80 ;
R 3 is selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, —OR 8 , —N(R 8 ) 2 , —Si(R 8 ) 3 , —R 7 , and —(CH 2 ) m —R 80 ;
R 4 is selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, —OR 8 , —N(R 8 ) 2 , —Si(R 8 ) 3 , —R 7 , and —(CH 2 ) m —R 80 ;
R 5 is selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, —OR 8 , —N(R 8 ) 2 , —Si(R 8 ) 3 , —R 7 , and —(CH 2 ) m —R 80 ;
R 6 is selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, —OR 8 , —N(R 8 ) 2 , —Si(R 8 ) 3 , and —(CH 2 ) m —R 80 ;
R 7 is selected independently for each occurrence from the group consisting of —C(O)OM, —C(O)SM, —C(S)SM, —C(NR 8 )OM, —C(NR 8 )SM, —S(O)OM, —S(O)SM, —S(O) 2 OM, —S(O) 2 SM, —P(O)(OM) 2 , —P(O)(OR 8 )OM, —P(O)(OR 8 )NR 8 M, —P(O)(OR 8 )SM, —N(R 8 ) 3 M, —P(R 8 ) 3 M, —P(OR 8 ) 3 M and —N(R 8 )C(NR 8 R 8 )NR 8 R 8 M;
R 8 is selected independently for each occurrence from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;
M is an alkali metal or an alkali earth metal;
R 80 represents an unsubstituted or substituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle;
m is independently for each occurrence an integer in the range 0 to 8 inclusive;
provided that at least one of R 3 , R 4 or R 5 is R 7 ; and
the ligand is achiral, or when chiral, is a single stereoisomer or a mixture of stereoisomers.
2. A method represented by Scheme 2:
wherein
Z and Ar′ are independently selected from the group consisting of optionally substituted aryl, heteroaryl and alkenyl;
X is selected from the group consisting of Cl, Br, I, —OS(O) 2 alkyl, and —OS(O) 2 aryl;
Z and Ar′ may be covalently linked;
the transition metal is selected from the Group 10 metals;
the base is selected from the group consisting of fluorides, hydrides, hydroxides, carbonates, phosphates, alkoxides, metal amides, and carbanions; and
the ligand is selected from the group consisting of compounds represented by L:
wherein
R is selected independently for each occurrence from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and —(CH 2 ) m —R 80 ;
R 1 is selected independently for each occurrence from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, —OR 8 , —N(R 8 ) 2 , —Si(R 8 ) 3 , and —(CH 2 ) m —R 80 ;
R 2 is selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, —OR 8 , —N(R 8 ) 2 , —Si(R 8 ) 3 , and —(CH 2 ) m —R 80 ;
R 3 is selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, —OR 8 , —N(R 8 ) 2 , —Si(R 8 ) 3 , —R 7 , and —(CH 2 ) m —R 80 ;
R 4 is selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, —OR 8 , —N(R 8 ) 2 , —Si(R 8 ) 3 , —R 7 , and —(CH 2 ) m —R 80 ;
R 5 is selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, —OR 8 , —N(R 8 ) 2 , —Si(R 8 ) 3 , —R 7 , and —(CH 2 ) m —R 80 ;
R 6 is selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, —OR 8 , —N(R 8 ) 2 , —Si(R 8 ) 3 , and —(CH 2 ) m —R 80 ;
R 7 is selected independently for each occurrence from the group consisting of —C(O)OM, —C(O)SM, —C(S)SM, —C(NR 8 )OM, —C(NR 8 )SM, —S(O)OM, —S(O)SM, —S(O) 2 OM, —S(O) 2 SM, —P(O)(OM) 2 , —P(O)(OR 8 )OM, —P(O)(OR 8 )NR 8 M, —P(O)(OR 8 )SM, —N(R 8 ) 3 M, —P(R 8 ) 3 M, —P(OR 8 ) 3 M and —N(R 8 )C(NR 8 R 8 )NR 8 R 8 M;
R 8 is selected independently for each occurrence from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;
M is an alkali metal or an alkali earth metal;
R 80 represents an unsubstituted or substituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle;
m is independently for each occurrence an integer in the range 0 to 8 inclusive;
provided that at least one of R 3 , R 4 or R 5 is R 7 ; and
the ligand is achiral, or when chiral, is a single stereoisomer or a mixture of stereoisomers.
3. The method of claim 1 , wherein the transition metal is palladium.
4. The method of claim 3 , further comprising irradiating with microwave radiation.
5. The method of claim 3 , wherein R is cyclohexyl; R 1 is hydrogen; R 2 and R 6 are selected independently from the group consisting of hydrogen, alkyl and alkoxy; R 3 is R 7 ; and R 4 and R 5 are hydrogen.
6. The method of claim 3 , wherein R is cyclohexyl; R 1 is hydrogen; R 2 and R 6 are selected independently from the group consisting of hydrogen, alkyl and alkoxy; R 4 is R 7 ; and R 3 and R 5 are hydrogen.
7. The method of claim 3 , wherein R is cyclohexyl; R 1 is hydrogen; R 2 and R 6 are methoxy; R 3 is —S(O) 2 ONa; and R 4 and R 5 are hydrogen.
8. The method of claim 3 , wherein R is cyclohexyl; R 1 is hydrogen; R 2 and R 6 are isopropyl; R 4 is —S(O) 2 ONa; and R 3 and R 5 are hydrogen.
9. The method of claim 3 , wherein R is cyclohexyl; R 1 is hydrogen; and R 2 is alkyl or alkoxy.
10. The method of claim 3 , wherein R is cyclohexyl; R 1 is hydrogen; R 3 is R 7 ; and R 4 and R 5 are hydrogen.
11. The method of claim 3 , wherein R is cyclohexyl; R 1 is hydrogen; R 4 is R 7 ; and R 3 and R 5 are hydrogen.
12. The method of claim 3 , wherein R is cyclohexyl; R 1 is hydrogen; R 2 and R 6 are selected independently from the group consisting of hydrogen, alkyl and alkoxy; R 3 is R 7 ; and R 4 and R 5 are selected independently from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, —OR 8 , —N(R 8 ) 2 , —Si(R 8 ) 3 , and —(CH 2 ) m —R 80 .
13. The method of claim 3 , wherein R is cyclohexyl; R 1 is hydrogen; R 2 and R 6 are selected independently from the group consisting of hydrogen, alkyl and alkoxy; R 4 is R 7 ; and R 3 and R 5 are selected independently from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, —OR 8 , —N(R 8 ) 2 , —Si(R 8 ) 3 , and —(CH 2 ) m —R 80 .
14. The method of claim 2 , wherein the transition metal is palladium.
15. The method of claim 14 , further comprising irradiating with microwave radiation.
16. The method of claim 14 , wherein R is cyclohexyl; R 1 is hydrogen; R 2 and R 6 are selected independently from the group consisting of hydrogen, alkyl and alkoxy; R 3 is R 7 ; and R 4 and R 5 are hydrogen.
17. The method of claim 14 , wherein R is cyclohexyl; R 1 is hydrogen; R 2 and R 6 are selected independently from the group consisting of hydrogen, alkyl and alkoxy; R 4 is R 7 ; and R 3 and R 5 are hydrogen.
18. The method of claim 14 , wherein R is cyclohexyl; R 1 is hydrogen; R 2 and R 6 are methoxy; R 3 is —S(O) 2 ONa; and R 4 and R 5 are hydrogen.
19. The method of claim 14 , wherein R is cyclohexyl; R 1 is hydrogen; R 2 and R 6 are isopropyl; R 4 is —S(O) 2 ONa; and R 3 and R 5 are hydrogen.
20. The method of claim 14 , wherein R is cyclohexyl; R 1 is hydrogen; and R 2 is alkyl or alkoxy.
21. The method of claim 14 , wherein R is cyclohexyl; R 1 is hydrogen; R 3 is R 7 ; and R 4 and R 5 are hydrogen.
22. The method of claim 14 , wherein R is cyclohexyl; R 1 is hydrogen; R 4 is R 7 ; and R 3 and R 5 are hydrogen.
23. The method of claim 14 , wherein R is cyclohexyl; R 1 is hydrogen; R 2 and R 6 are selected independently from the group consisting of hydrogen, alkyl and alkoxy; R 3 is R 7 ; and R 4 and R 5 are selected independently from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, —OR 8 , —N(R 8 ) 2 , —Si(R 8 ) 3 , and —(CH 2 ) m —R 80 .
24. The method of claim 14 , wherein R is cyclohexyl; R 1 is hydrogen; R 2 and R 6 are selected independently from the group consisting of hydrogen, alkyl and alkoxy; R 4 is R 7 ; and R 3 and R 5 are selected independently from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, —OR 8 , —N(R 8 ) 2 , —Si(R 8 ) 3 , and —(CH 2 ) m —R 80 .