Iron-catalyzed Cross Coupling reactions: From Rust to a Rising Star Weijun Liu

Transition metal catalyzed cross couplings have seen incredible advances and applications, have wide scope and compatibility. But…..typically use palladium and nickel which are generally toxic and expensive. Expensive and/or sensitive ancillary ligands are required. Alkyl iodides, bromides and triflates are best. With special ligands alkyl chlorides may be used.

Iron: A More Practical Alternative Iron is one of the most abundant metals on earth. (5.6% of earth’s crust. 4th most abundant element after oxygen, silicon, and aluminum. Nickel is 0.0084%, palladium is 0.0000015%, gold is 0.0000004% of Earth’s continental crust.) 2. Cheap •PdCl2: $4005/150g $26.70/g •NiCl2: $98.40/250g $0.39/g •FeCl3: $30.40/1kg $0.03/g 3. nontoxic •Prevalent in biological systems

Content: Early Examples 2. Alkenyl Derivatives as Substrates 3. Aryl Derivatives as Substrates 4. Alkyl Derivatives as Substrates 5. O, N, S-Arylation 6. Oxidative Cross-coupling

Early Examples J. Kochi, J. Am. Chem. Soc. 1971, 93, 1487

Kochi, J. J. Org. Chem. 1976, 41, 502

2. Alkenyl Derivatives as Substrates NMP as cosolvent Cahiez, G. Synthesis 1998, 1199

Cahiez, G. Synthesis 1998, 1199

60% 60% Cahiez, G.; Knochel, P. Synlett 2001, 1901

3. Aryl Derivatives as Substrates Furster, A. Angew. Chem., Int. Ed. 2002, 41, 609

Proposed Formal Catalytic Cycle

4. Alkyl Derivatives as Substrates Furster, A. Angew. Chem., Int. Ed. 2004, 43, 3955

Furster, A. Angew. Chem., Int. Ed. 2004, 43, 3955

Furster, A. Angew. Chem., Int. Ed. 2004, 43, 3955

Only tertiary halides and alky chlorides were found be inert.

Nakamura, E. J. Am. Chem. Soc. 2004, 126, 3686

Hayashi, T. Org. Lett. 2004, 6, 1279

Cossy, J. Angew. Chem., Int. Ed. 2007, 46, 6521

51% Chai, C.L.L. Adv. Synth., Catal. 2007, 349, 1015

5. O, N, S-Arylation Bolm, C. Angew. Chem., Int. Ed. 2007, 46, 8862

Bolm, C. Angew. Chem., Int. Ed. 2007, 47, 586 Bolm, C. Angew. Chem., Int. Ed. 2008, 47, 2880

6. Oxidative Cross-coupling Iron-Catalyzed Homo-Coupling FeI/FeIII or Fe0/FeII Fe-II/Fe0 Cahiez, G. Org. Lett. 2005, 7, 1943

Cahiez, G. J. Am. Chem. Soc. 2007, 129, 13788

Oxidative Heterocoupling Cahiez, G. Angew. Chem., Int. Ed. 2009, 43, ASAP

Iron-Catalyzed Direct Arylation through Directed C-H Bond Activation

Nakamura, E. J. Am. Chem. Soc. 2008, 130, 5858

Iron-Catalyzed Chemoselective ortho Arylation of Aryl Imines by Directed C-H Bond Activation Nakamura, E. Angew. Chem., Int. Ed. 2009, 48, ASAP

Li, Z.-P.; Li, C.-J. Angew. Chem., Int. Ed. 2007, 46, 6505

X = N, O, S Li, Z.-P. Angew. Chem., Int. Ed. 2008, 47, 7497

Summary 1. Iron catalysts activate alkenyl, aryl, and alkyl derivatives. 2. Iron catalysts activate aryl chlorides, triflates and tosylates under ligand free conditions. 3. Iron-catalyzed cross-coupling shows excellent functional group tolerance. 4. Iron-catalyzed cross-coupling needs only short reaction (typically 5-30 min) time and are performed at low temperatures (typically -20 oC to 0 oC). 6. Iron salts has been successfully applied in the C-H bond activation and oxidative coupling reactions But the iron-catalyzed cross coupling is not nearly as mature as its palladium and nickel counterparts. And the reaction mechanisms are needed to be proved.