Research

Development of New Catalytic Methods

Given our current knowledge, organic chemists have the ability - granted unlimited time and resources - to make almost any organic scaffold. Thus the fundamental motivations in modern chemistry have shifted to the development of efficient processes that accelerate synthesis and reduce associated waste. Research in the Hull group focuses on the development and mechanistic evaluation of transition metal-catalyzed methodologies with the direct goal of reducing the time and waste associated with synthetic organic chemistry. A common goal of all of our research is to strategically design new methodologies that either utilize or override the inherent reactivity of simple functionalities to generate desirable products. We aim to reduce multi-step sequences into a single transformation on easily accessible starting materials to form complex products.

I. Regioselective hydro- and oxidative olefin functionalization

Despite the prevalence of C–X (X = N, S, O) bonds in pharmaceuticals, their selective incorporation into organic compounds is often both time- and resource- consuming. The selective addition of X–H across a C=C multiple bond would allow for the single step installation of diverse functionalities from readily available starting materials. Given this potential versatility and utility, the development of intermolecular, regio-, chemo-, and stereoselective hydrofunctionalization reactions represents an unmet need in synthetic chemistry.

Our initial efforts towards developing a selective hydrofunctionalization reaction utilize olefinic substrates bearing Lewis basic groups (L~C=C). Incorporation of this coordinating group has several advantages. First, the Lewis basic site binds to the metal, prior to functionalization of the olefin, and increases its concentration relative to the catalyst, promoting its coordination. Additionally, the Lewis basic group should direct the nucleometallation to form the favored metallacycle. Therefore the tether length, Lewis basic group, and catalyst can influence selectivity for either the Markovnikov or anti-Markovnikov product. We have successfully demonstrated this strategy for the Markovnikov selective hydroamination of allyl imines and anti-Markovnikov selective hydroamination of homoallylic amines. Additionally, we have shown the regiodivergent hydrothiolation of allyl amines, where depending on the catalyst employed either the Markovnikov or anti-Markovnikov product is formed selectively.

Although directing groups are an excellent approach to promoting a regioselective hydrofunctionalization reaction, we are also interested in developing a catalyst controlled approach that does not rely on a prefunctionalized substrate. The oxidative amination of alkenes, also known as the aza-Wacker oxidation, is an excellent approach for the synthesis of a new C–N bond while simultaneously oxidizing the substrate and thus reestablishing an alkene for subsequent functionalization. Further, it couples two easily accessible starting materials and, when O₂ is used as the oxidant, an equivalent of H₂O is the only byproduct. While two different regioisomeric products are possible, unactivated alkenes undergo oxidative amination to afford the Markovnikov product – where the new C–N bond is formed at the more substituted carbon of the alkene. We hypothesized that in the presence of excess chloride a palladate complex may form and promote the aza-Wacker oxidation, which would occur through an anti-Markovnikov selective trans-aminopalladation with the relatively large phthalimide nucleophile attacking the coordinated alkene to form the less hindered C–N bond.

Key References:

Ho, A. T., Ensign, S. C., Vanable, E. P., Portillo, D., Humke, J. N., Kortman, G. D., & Hull, K. L. (2022). Rhodium-/Iridium-Catalyzed Hydroamination for the Synthesis of 1,2-, 1,3-, or 1,4-Diamines. ACS Catalysis, 12(14), 8331–8340.

Ickes, A. R.; Ensign, S. C.; Gupta, A. K.; Hull, K. L. "Regio- and Chemoselective Intermolecular Hydroamination of Allyl Imines for the Synthesis of 1,2-Diamines," J. Am. Chem. Soc. 2014, 136, 11256-11259.

Ensign, S. C.; Vanable, E. P.; Kortman, G. D.; Weir, L. J.; Hull, K. L. "Anti-Markovnikov Hydroamination of Homoallylic Amines," J. Am. Chem. Soc.2015, 137, 13748-13751.

Kennemur, J. L.; Kortman, G. D.; Hull, K. L. "Rhodium-Catalyzed Regiodivergent Hydrothiolation of Allyl Amines and Imines," J. Am. Chem. Soc.2016, 138, 11914-11919.

Kohler, D. G.; Gockel, S. N.; Kennemur, J. L.; Waller, P. L.; Hull, K. L. "Anti-Markovnikov Selective Pd-Catalyzed Oxidative Amination," Nat. Chem. 2018, 10, 333-340.

II. Oxidative Amidation of Allylic Alcohols and Amines

Amides are a common functionality found throughout biomolecules and biologically active small molecules. Widely employed approaches that allow for the direct coupling between an activated carboxylic acid derivative and an amine nucleophile have significant inherent drawbacks, i.e.: they generate super stoichiometric amounts of high molecular weight byproducts and often require extensive protecting group manipulations. The oxidative functionalization of aldehydes via transfer hydrogenation has become a promising alternative to traditional coupling methods. We have demonstrated that cationic rhodium catalysts promote the oxidative amidation of allyl alcohols, allyl amines, and stereically hindered alcohols and aldehydes.

Further, combining an asymmetric 1,3-hydride shift with an oxidative functionalization, we can generate amides while simultaneously establishing proximal stereocenters.

The enantioselectivity of our asymmetric oxidative amidation of allylic amines relies on the ability to generate diastereomerically pure trisubstituted olefins. As this remains a significant synthetic challenge, we sought to develop a copper-catalyzed hydroarylation reaction for the syn-addition of an aryl ring and a hydrogen across an alkyne.