Complex N-Heterocycle Synthesis via Iron-Catalyzed, Direct C-H Bond Amination Elisabeth T. Hennessy & Theodore A. Betley* Science 2013, 340, 591 Also featured in Driver, T. Nat. Chem. 2013, 5, 736 Literature Meeting 11/13/2013 Daniela Sustac

Hoffmann-Löffler-Freytag Reaction a. Hoffmann, A.W. Berichte 1885, 18, 109. b. Wolff, M.W. Chem. Rev. 1963, 63, 55.

Intramolecular C(sp 3 )-H Amination Strategies Perspective: Leffrey, J.L.; Sarpong, R. Chem. Sci. 2013, 4, 4092.

Nitrene Examples: Aliphatic C-H Amination White: Iron porphyrin –based catalyst, allylic position favoured White: Iron porphyrin –based catalyst, allylic position favoured Zhang: Cobalt porphyrin catalyst Zhang: Cobalt porphyrin catalyst Lebel: avoids the use of an oxidant Lebel: avoids the use of an oxidant (TPA = triphenylacetate)

Nitrenes from Azides Bach: Aminochlorination Bach: Aminochlorination Driver: Rhodium catalysis, azides Driver: Rhodium catalysis, azides Cundari&Warren: copper nitrene complex Cundari&Warren: copper nitrene complex Review of N-atom transfer from azides: Driver, T. Org. Biomol. Chem. 2010, 8, 3809

Aliphatic C-H Amination Chen: Picolinamide directing group, Pd (II)-Pd(IV) cat. cycle, oxidant Chen: Picolinamide directing group, Pd (II)-Pd(IV) cat. cycle, oxidant Li&Zhang: via dianion formation Li&Zhang: via dianion formation

“How To” Design Your Own Amination Reaction C-H Amination as an Inverse Correlation of C-H bond strength C-H Amination as an Inverse Correlation of C-H bond strength N-Atom source N-Atom source Catalyst: Rh, Fe, Co etc. (nitrene formation), Pd (directing group) Catalyst: Rh, Fe, Co etc. (nitrene formation), Pd (directing group) Other requirements: ligand (porphyrin type), oxidant (hypervalent iodine) Other requirements: ligand (porphyrin type), oxidant (hypervalent iodine)

Ted Betley 1999 – B.S.E. Chemical Engineering at University of Michigan 1999 – B.S.E. Chemical Engineering at University of Michigan – PhD at Caltech (Prof. Jonas Peters) – PhD at Caltech (Prof. Jonas Peters) - Coordination chemistry at trigonally coordinated iron platforms: chemistry related to dinitrogen reduction - Coordination chemistry at trigonally coordinated iron platforms: chemistry related to dinitrogen reduction – NIH Postdoctoral fellow at MIT (Prof. Daniel Nocera) – NIH Postdoctoral fellow at MIT (Prof. Daniel Nocera) – Harvard, Assistant Professor – Harvard, Assistant Professor 2011-now – Harvard, Associate Professor 2011-now – Harvard, Associate Professor Research interests: Research interests: - Polynuclear complexes for cooperative redox chemistry - Polynuclear complexes for cooperative redox chemistry - Iron-mediated, catalytic C-H bond functionalization - Iron-mediated, catalytic C-H bond functionalization

Inspiration: Cytochrome P450 Synthesis of Fe imido complexes as surrogates of Fe oxo complexes to achieve effective nitrene transfer Synthesis of Fe imido complexes as surrogates of Fe oxo complexes to achieve effective nitrene transfer Heme Iron IV -oxo Proposed Catalytic Cycle of Cytochrome P450 Oxidation mechanism of cytochrome P450: Chem. Rev. 2004, 104, 3947.

Initial communication & article (Inorg. Chem. 2009, 48, 2361; JACS 2011, 133, 4917) Iron dipyrromethene complexes as heme surrogates Iron dipyrromethene complexes as heme surrogates Application: intermolecular aziridination and amination Application: intermolecular aziridination and amination High-spin Fe III antiferromagnetically coupled to an imido radical High-spin Fe III antiferromagnetically coupled to an imido radical

Proposed Mechanism Key features: high spin Fe(III) (S = 2) featuring an imido radical putative group transfer reagent Key features: high spin Fe(III) (S = 2) featuring an imido radical putative group transfer reagent KIE studies: C-H bond-breaking rate-limiting (12 for pre-catalyst) KIE studies: C-H bond-breaking rate-limiting (12 for pre-catalyst) Betley JACS 2011, 133, 4917

Challenges Saturated hydrocarbons chemically inert due to large C-H bond dissociation energies (93 to 105 kcal/mol), C-H bond non polarized Saturated hydrocarbons chemically inert due to large C-H bond dissociation energies (93 to 105 kcal/mol), C-H bond non polarized Aliphatic C-H bond harder to preferentially react in presence of other functionalities Aliphatic C-H bond harder to preferentially react in presence of other functionalities Avoid the synthetic requirement for an EWG on N or an oxidant Avoid the synthetic requirement for an EWG on N or an oxidant Solution Non-heme iron complex, sterically hindered, high spin ground state, akin to iron-oxo Non-heme iron complex, sterically hindered, high spin ground state, akin to iron-oxo Extension of their previous Fe complex to linear, aliphatic azides to synthesize complex N-heterocycles in one step Extension of their previous Fe complex to linear, aliphatic azides to synthesize complex N-heterocycles in one step

Synthesis of Iron Complexes

Proof of Concept: Stoichiometric Reaction

Towards a Catalytic Version No catalyst turnover due to product inhibition: formation of a tight Lewis acid/base pair No catalyst turnover due to product inhibition: formation of a tight Lewis acid/base pair Solution: perform cyclization in presence of a Nitrogen protecting group Solution: perform cyclization in presence of a Nitrogen protecting group

Catalytic Scope

Catalytic Scope - Continued

Varying Ring Size

Proposed Mechanisms

Mechanistic Studies Retention of stereochemical information: spatial constraints imposed by bulky adamantyl ligand to inhibit racemization of intermediate carboradical Retention of stereochemical information: spatial constraints imposed by bulky adamantyl ligand to inhibit racemization of intermediate carboradical Intramolecular KIE Study Intramolecular KIE Study Radical Clock Experiment Radical Clock Experiment

Mechanism? Stepwise mechanism for benzylic substrates; Stepwise mechanism for benzylic substrates; If a stepwise mechanism is operative, then the radical intermediate following H-abstraction must be short-lived; If a stepwise mechanism is operative, then the radical intermediate following H-abstraction must be short-lived; Direct C-H insertion when stronger C-H bonds are functionalized Direct C-H insertion when stronger C-H bonds are functionalized

Conclusion Have demonstrated the utility of Fe imido high-spin radical for the intramolecular functionalization of activated and unactivated aliphatic C-H bonds; Nitrene formation from azide (N 2 only by-product); Synthesis of complex N-heterocycles from readily available starting materials; These products cannot be easily obtained by HLF or photolysis (usually require EWG, oxidant);