Literature Meeting March 25, 2008 Buchwald-Hartwig Coupling : Discovery, Optimization, and Applications David Marcoux Charette’s Laboratories

2 Importance (Natural Products)

3 Importance (Drugs)

4

5 Importance (Materials)

6 Common C(aryl)-N Bond Formation (Reductive Amination and Alkylation)

7 Common C(aryl)-N Bond Formation (S N Ar)

8 Common C(aryl)-N Bond Formation (Nitration)

9 Common C(aryl)-N Bond Formation (Ullman Reaction)

10 Common C(aryl)-N Bond Formation(Larock Indole Synthesis)

11 Common C(aryl)-N Bond Formation (Aryne Chemistry)

12 Common C(aryl)-N Bond Formation (Pd-Mediated)

13 Hartwig-Buchwald Pd-Catalyzed C(Aryl)-X Coupling

14 Pd-Catalyzed C-C Coupling

15 Catalytic Cycle

16 Generation of the Active Catalyst

17 Oxidative Addition

18 Transmetallation

19 Isomerisation

20 Reductive Elimination

21  -H Elimination

22 Migita First Results in Pd-Catalyzed C(Aryl)-N Bond Formation

23 Prof. John F. Hartwig

24 Hartwig First Look

25 Hartwig First Look

26 Catalytic Cycle with Tin Amide

27 Prof. Stephen L. Buchwald

28 Buchwald First Look

29 First Coupling Using Free Amine

30 First Coupling Using Free Amine

31 Intramolecular Version

32 Side Product

33 Real Problem

34 2 Weeks Later

35 Hartwig’s Conditions

36 Unsolved Problems

37 BINAP Scope

38 Back-to-Back

39 Mechanism

40 Why ArI are Less Reactive

41 Etheral Solvents

42 Lower Temperature

43 Why 18-C-6 ?

44 Pyridine Containing Substrates

45 Chiral Amine

46 Bidentate Ligand

47 Mechanism

48 Scope

49 Limitation

50 Ligand Screening

51 Scope

52 Why?

53 From ArylOTf

54 Functionnal Groups Tolerance

55 Lower Temperature

56 Lower Temperature and ArCl

57 Lower Temperature and ArCl

58 Chloropyridines

59 Functionalized Arylclorides

60 Enlarging the Scope

61 C-H Functionalization

62 But Why NH 3 Can’t Be Used ?

63 Specific Case: Ammonia

64 Specific Case: Ammonia

65 Specific Case: Ammonia

66 Specific Case: Ammonia

67 Specific Case: Ammonia

68 Specific Case: Ammonia

69 First Coupling with NH 3(g)

70 More Convenient NH 3 Source

71 Reductive Elimination

72 With Ammonia

73 Triarylamine

74 Sequential Addition

75 Total Synthesis

76 Total Synthesis

77 Total Synthesis

78 Synthesis of Analogs

79 Aryl Piperazine (large scale)

80 Merck

81 Wyeth

82 Conclusion