60th Annual Report on Research 2015

In the first year of funding from the ACS Petroleum Research Fund, we aimed to develop a new dehydrogenative biaryl coupling strategy for the synthesis of strained cyclophanes. Our strategy is inspired by nature’s ability to catalyze oxidative cross-coupling reactions using iron-containing P450 enzymes. Previous work reported by L. Que on dioxygen activation is consistent with our hypothesis. Based on this literature precedent and recent results from M. Kozlowski,i we hypothesize that a non-heme Fe(II) complex can be reoxidized to the corresponding active Fe(IV)-oxo complex upon conversion with biaryls such as 1 to close the catalytic cycle. In preliminary investigations, we were able to show that NaIO4 was able to successfully promote the catalytic dehydrogenative coupling reaction of phenol 1 to biaryl 2 with iron-salan catalyst 3 or vanadium-salen catalyst 4. Importantly, no product formation was observed in the absence of either catalyst or oxidant. In a proposed catalytic cycle, the phenol starting material 5 is oxidized to resonance-stabilized phenoxy radical 6. Intermediate 7, the keto form of the radical 6, can then undergo radical C-C bond formation at the ortho-position of the pendant phenol to form product radical 8. Oxidation of 8 and tautomerization leads to carbocation 9, which will undergo rearomatization via deprotonation to provide the desired dehydrogenative coupling product 10 and the reduced Fe(II)-complex. The stoichiometric oxidants described above will regenerate the active Fe(IV) species to close the catalytic cycle (Fig. 2). Based on our preliminary results described above, we are planning on extending the iron-source used in these reactions to additional non-heme and heme-iron catalysts, which are either commercially available or readily accessible based on literature precedence (see Fig. 2 for selected examples).ii,iii These catalysts contain modular tetradentate nitrogen-based ligands, which are readily accessible. Que and coworkers reported that activities of mononuclear non-heme Fe(IV)-oxo complexes such as 11 were significantly affected by their corresponding axial ligands (e.g. MeCN, O2CCF3, N3, SR),75,76 and a direct correlation between the reactivities of Fe(IV)-oxo species in H atom abstraction reactions and their reduction potential was observed. These data indicate that the reactivity of Fe(IV)-oxo complexes increases with the electron-donating ability of the axial ligand. After initial evaluation of additional iron catalysts 11-14 in the oxidative coupling reaction, we will focus our attention on tuning the reactivity of the corresponding iron-complexes, by replacing their respective axial ligands. Additionally, many more ligands for iron-metal complexes have been reported in the literature which are easily accessible and amenable to modifications. Subsequently, we plan on exploring other transition metal heme and non-heme complexes (e.g. ruthenium, manganese, vanadium) in the desired oxidative biaryl coupling reaction.iv All of these metals have been previously reported to be successful in either stoichiometric dehydrogenative coupling reactions or in a catalytic setting with napthols as the respective substrates.v After establishing a robust reaction protocol, we will focus on the evaluation of the substrate scope of this transformation. Initially, we will target intramolecular oxidative coupling reactions of unactivated phenols to form the corresponding small cyclophanes. Additionally, we will investigate the potential for selective formation of homodimeric vs. heterodimeric products. Finally, we plan on further refining our reaction concept by turning our attention to the optimization of intermolecular reaction conditions as well as chiral variants of this transformation.

In addition to our research program focused on the development of dehydrogenative biaryl coupling reactions, we endeavor to develop environmentally benign chemical methods which facilitate the activation of chemical bonds under mild reaction conditions. In this regard, we are focusing our efforts in the area of carbocyclization methods, in particular carbonyl-olefin metathesis reactions, based on iron as an earth abundant and environmentally benign transition metal and applications of these methods to complex alkaloid syntheses. The metathesis reaction between two alkenes is among the most powerful and general carbon-carbon bond forming reactions known. The corresponding carbonyl-olefin metathesis reaction similarly enables the direct construction of carbon-carbon bonds and has the potential to have an analogous impact on synthetic strategy. However, no general, catalytic protocol for the carbonyl-olefin metathesis exists without relying upon harsh reaction conditions or stoichiometric metal alkylidene reagents. Based on iron(III)-chloride as an environmentally benign catalyst, we have developed the first general, catalytic procedure for carbonyl-olefin ring-closing metathesis as a new tool for direct carbon-carbon bond construction, proceeding under mild reaction conditions with high functional group tolerance (A and F, Figure 3). On the basis of our mechanistic investigations into this reaction, we were able to establish complementary substrate reactivity modes by modulating the iron catalyst, providing access to new, carbocyclizations (interrupted carbonyl-olefin metathesis (B) and 1,2-hydride shift reactions to access cyclopentadienes (C) and indenes and azulenes (E)). These novel transfor-mations enable synthetic access to highly functionalized carbocyclic systems which represent ubiquitous synthons in a wide variety of biologically active target structures.

i Lee, Y.E.; Cao, T.; Torruellas, C.; Kozlowski, M.C. Selective Oxidative Homo- and Cross-Coupling of Phenols with Aerobic Catalysts. J. Am. Chem. Soc. 2014, 136, 6782.

ii Wu, M.; Miao, C.-X.; Wang, S.; Hu, X.; Xia, C.; Kuehn, F.E.; Sun, W. Chiral Bioinspired Non-Heme Iron Complexes for Enantioselective Epoxidation of ?,?-Unsaturated Ketones. Adv. Synth. Catal. 2011, 353, 3014.

iii Fillol, J.L., Codola, Z., Garcia-Bosch, I., Gomez, L., Pla, J.J., Costas, M. Efficient water oxidation catalysts based on readily available iron coordination complexes. Nature Chem. 2011, 3, 807.

iv A Manganese-porphyrin complex was reported to react with phenolic substrates to yield dimeric coupling products stoichiometrically: Lansky, D.E., Goldberg, D.P. An Isolable, Nonreducible High-Valent Manganese (V) Imido Corrolazine Complex. Inorg. Chem. 2006, 45, 5119.

v Matsushita, M., Kamata, K., Yamaguchi, K., Mizuno, N., Heterogeneously Catalyzed Aerobic Oxidative Biaryl Coupling of 2-Naphthols and Substituted Phenols in Water. J. Am. Chem. Soc. 2005, 127, 6632.