Organic Pedagogical Electronic Network An Introduction to Catalytic Nitrene C–H Oxidation Ashley M. Adams, Justin Su, And J. Du Bois

Nitrenes & Nitrenoids 1. Acc. Chem. Res. 1987, 20, For general reviews, see: a) Chem. Rev. 2008, 108, b) Catalyzed Carbon-Heteroatom Bond Formation; Weinheim, 2011; pp c) Chem. Commun. 2009, 5061–5074. d) Top. Curr. Chem., 2010, 292, e) Acc. Chem. Res. 2012, 45, Electron deficient with only six valence electrons (analogous to carbenes); hyper-reactive 1 Can be generated through thermal or photochemical extrusion of N 2 from organoazides Nitrene reactivity can be tempered through association with certain metal complexes The use of dirhodium complexes is particularly effective for nitrenoid formation Nitrenes NitreneCarbene Nitrenoids (aka a metal-bound nitrene) Examples include:

Rh-Catalyzed C–H Amination 1.Angew. Chem. Int. Ed. 2001, 40, ; J. Am. Chem. Soc. 2004, 126, 15378– J. Am. Chem. Soc. 2009, 131, Tetrahedron, 2009, 65, Reaction initiates with condensation of carbamate or sulfamate and PhI(OAc) 2 to generate an iodoimine  Modern methods for nitrenoid C–H amination can be used to generate heterocyclic products  Reactions rely on catalytic amounts of dirhodium complex and an iodine(III) oxidant Iodoimine coordination to dirhodium catalyst results in Rh-nitrene formation Step 1: Step 2: Step 3: Nitrenoid C–H insertion

Reaction Selectivity 1.Modern Rhodium-Catalyzed Organic Reactions, Ed.: P. A. Evans, Wiley-VCH Verlag, Weinheim, 2005, Org. Lett. 2003, 5, ; Angew. Chem. Int. Ed 2009, 48, ; Tetrahedron 2009, 65, , Choice of functional group alters selectivity between 5- and 6-membered ring formation Competition between different C–H bond types favors 3° and benzylic C–H bonds Tces = S(O) 2 OCH 2 CCl 3 Despite intrinsic reactivity differences, choice of metal catalyst can alter C–H bond selectivity

Suggested Problems 1.J. Am. Chem. Soc. 2003, 125, Angew. Chem. Int. Ed 2009, 48, Predict the product for the following reaction en route to the complex natural product (−)-tetrodotoxin, the poisonous constituent of the puffer fish. 2. Provide two stereochemical models to rationalize the following results: 3. Oxidative cyclization of substrate A gives a single, major product as shown. Conversely, reaction of a 1:1 mixture of substrates B and C give a 1:1 mixture of the corresponding heterocyclic products. Provide a mechanistic rationale for these disparate results.