59th Annual Report on Research 2014

Introduction. The discovery of new methods for efficient and flexible functionalization of alkenes is an important goal in synthetic organic chemistry. One strategy is to add vinyl anion equivalents, such as organolithiums or Grignard species, to an electrophile. However, there are several disadvantages inherent in this approach, including the need for a vinyl bromide precursor, the use of stoichiometric amounts of a strong base, limited functional group compatibility and limited electrophile scope. We are interested in developing alternative methods for the formal addition of alkene “nucleophiles” to a series of common electrophiles that address the major problems associated with conventional vinyl anions. Our initial strategy was to investigate transition metal-catalyzed dehydrogenative metallation of alkenes in situ to yield hydrometallated species with the potential to react with an added electrophile, thus achieving formal vinyl addition and valuable synthetic building blocks.

Divergent reactivity of nickel in styrene functionalization. Our first goal was to examine the possibility of using first-row transition metal catalysts to achieve dehydrogenative metallation to a vinyl metal species. Not only would this be advantageous from an economic point-of-view, but it would shed insight into the challenges associated with coaxing first-row metals to exhibit reactivity comparable to precious metal catalysts. Initial studies focused on promising preliminary results using nickel catalysts. Three different products (Scheme 1) could be selectively obtained from a styrene depending on the identity of the nickel catalyst and the ligand. For example, use of a Ni(0) catalyst with no ligand gave Markovnikov hydroboration with substrates bearing electron-withdrawing groups, while the electron-rich tricyclohexylphosphine ligand gave moderate yields when the styrene contained an electron-donating group. Interestingly, a coordinating acac ligand on Ni resulted in the anti-Markovnikov hydroboration product. This is the first example of a tunable regioselective hydroboration catalyzed by nickel. Finally, the desired dehydro-genative borylation was promoted using electron-neutral or electron-withdrawing phosphine ligands.

Scheme 1. Divergent reactivity of Ni via the ligand choice.

The proposed mechanistic pathways for all three products are illustrated in Scheme 2. Studies are ongoing to improve the scope, yields and tunability of Ni-catalyzed styrene functionalization. The information obtained from these investigations used as design principles for exploring similar reactivity with Cu and Fe catalysts in the context of dehydrogenative borylation.

Scheme 2. Mechanistic pathways for Ni-catalyzed transformations of styrenes.

Mechanistic of Cu-catalyzed styrene functionalization via 1,3-halogen migration. Despite significant initial efforts to promote dehydrogenation metallation using copper catalysts in combination with a variety of ligands, we have not yet been successful. We felt mechanistic insight into another type of new reactivity promoted by Cu(I) recently discovered in our lab might aid in designing new ligands to promote the desired dehydrogenative metallation. Scheme 3 illustrates the mechanistic pathway for an unusual Cu(I)-catalyzed 1,3-halogen migration reaction. All structures in Scheme 3 were optimized with Gaussian 09 using the B3LYP functional with a 6-311G* basis set for H, B, C, O, P, and Br and a LANL2TZ+ basis set designed for copper. A steering molecular dynamics solvent continuum model was used with THF. All minima were checked for absence of imaginary vibrational modes and all transition states were checked for one imaginary vibrational mode and confirmed with intrinsic reaction coordinate (IRC) calculations. These computations show that coordination of a copper hydride to the styrene is followed by regioselective hydrometallation to yield a benzyl copper species. An unexpected dearomatization/rearomatization sequence, followed by a 1,4-bromide shift, yields the key aryl Cu(I) intermediate. A final σ-bond metathesis with HBpin yields the observed product. While the proposed aryl(I) copper species is not the originally desired vinyl metal intermediate, it does provide access to a metallated sp² carbon nucleophile via a new reaction pathway. We are confident that the insight gained in these studies will help to extend this halogen migration chemistry to the generation of a reactive vinyl Cu species.

Scheme 3. Computational studies on the Cu-catalyzed 1,3-migration of 2-bromostyrenes.

Enantioselective Cu-catalyzed 1,3-halogen migration. The computational studies of the copper-catalyzed 1,3-halogen migration indicated that an asymmetric halogenation could likely be achieved using an enantioenriched ligand. Indeed, a ligand was identified (S,S-Ph-BPE, Scheme 4, left) that gave er of up to 99:1 for the formal enantioselective addition of HBr to a variety of substituted styrenes. The benzyl bromides could be displaced with a variety of nucleophiles, including sulfur, selenium, nitrogen and carbon (Scheme 4, right) to give benzyl- and aryl-functionalized products in high enantiomeric ratios.

Scheme 4. Asymmetric Cu-catalyzed 1,3-migration of 2-bromostyrenes.

Further functionalizations of metallated aryl copper(I) species with electrophiles. In lieu of continued investigations into generating vinyl copper species through dehydrogenative metallation, we decided to explore the reactivity of the aryl copper(I) intermediates produced as a result of 1,3-halogen migration reaction. The fact that little is known about the reactivity of such species presents us with the potential for further exciting applications of this new copper chemistry. Initial investigations have focused on the use of N-heterocyclic carbene ligands with copper (IPrCuCl) to would generate isolable amounts of the aryl Cu(I) intermediate from 2-bromostyrene (Scheme 5). Treatment of the aryl copper with a variety of coupling partners, including an electrophilic nitrogen source and benzyl bromide, results in the formation of new C-N and C-C bonds. Other electrophiles likely to be reactive with the aryl copper(I) include benzyl bromide, CO₂, isothiocyanates and acyl chlorides.

Scheme 5. Further functionalization of ArCu(I) species with electrophiles.

Impact of funding on students involved in this research. The students supported by this research grant have received an unusually broad training experience, gaining skills in a number of important areas, including organic synthesis, methodology development, catalyst design, the determination of reaction mechanisms, the development of predictive models for catalysis and computational chemistry. Graduate students have also assisted in manuscript preparation and wrote a perspective article describing the advances and impact of this chemistry. In addition, graduate students have presented their work at two national ACS meetings, as well as a departmental seminar, while an undergraduate involved in this work has presented a poster at a department-wide research symposium.