C-H Functionalization

C-H Bond Functionalization

C-H bond activation followed by carbon-carbon bond formation has become one of the most important new methods in synthesis. In contrast to many carbon-carbon bond-forming methods, C-H activation can be highly functional group tolerant and therefore should be directly applicable to the efficient synthesis of an enormous number of drugs and natural products that incorporate a variety of functionality. In addition, because almost every compound has a carbon-hydrogen bond, in terms of starting material availability C-H functionalization approaches cannot be surpassed.

One area of current focus of the Ellman Lab is the Rh(III)- and Co(III)-catalyzed addition of C-H bonds to polarized π-bonds (Figure 1). For example, the addition of C-H bonds to imines provides for the rapid synthesis of branched amines 1 (X = NP) without the production of any waste.  The directing group (DG) for C-H bond activation can also be designed to undergo cyclative capture of the functionality that is introduced to provide valuable heterocyclic products 2 that are prevalent in natural products and drugs. The exceptionally high functional group compatibility of these Rh(III)-catalyzed transformations adds to their utility.

Figure 1. Rh(III)- and Co(III)-catalyzed addition of C-H bonds to polarized π-bonds with representative structures that have been synthesized

In a second major area of current research we employ C-H bond functionalization approaches for the convergent assembly of simple and readily available inputs to give the piperidine framework, which is immensely important to drug discovery and is also present in many biologically active natural products (Figure 2). Rh(I)-catalyzed alkenylation followed by electrocylization provides 1,2-dihydropyridines 3, which in the same pot or after simple filtration through alumina, are then transformed into highly functionalized piperidine derivatives 4. Piperidines with unprecedented levels of substitution as well as multicyclic derivatives can readily be accessed using this approach.

Figure 2. Convergent synthesis of piperidines by C-H bond functionalization cascade processes

When new reactions are developed we investigate their mechanisms through the use of isotope labeling, kinetic analysis and x-ray structural characterization of catalyst resting states and intermediates. Figure 3 depicts representative structures of Rh-complexes that have been characterized in the context of mechanistic study.

Figure 3. Examples of x-ray structures of Rh-complexes from mechanistic studies

As we develop new C-H bond functionalization methods, we also apply them to the synthesis of relevant natural products, drugs and drug candidates (Figure 4). This includes the first total synthesis of lithospermic acid and a completely new strategy for the rapid asymmetric synthesis of the drug ketorphanol.

Figure 4. Representative natural products, drugs and drug candidates synthesized using C-H bond functionalization

Relevant Publications

Boerth, J. A.; Ellman, J. A.
A Convergent Synthesis of Functionalized Alkenyl Halides via Co(III)-Catalyzed Three-Component C-H Bond Addition
Angew. Chem. Int. Ed.  201756, 9976–9980.  
Potter, T. J.; Ellman, J. A.
Total Synthesis of (+)-Pancratistatin by the Rh(III)-Catalyzed Addition of a Densely Functionalized Benzamide to a Sugar-Derived Nitroalkene
Org. Lett.  201719, 2985–2988.  
Tran, G.; Hesp, K. D.; Mascitti, V.; Ellman, J. A.
Base-Controlled Completely Selective Linear or Branched Rhodium(I)-Catalyzed C−H ortho-Alkylation of Azines without Preactivation
Angew. Chem. Int. Ed.  201756, 5899–5903.  
Hummel, J. R.; Boerth, J. A.; Ellman, J. A.
Transition-Metal-Catalyzed C–H Bond Addition to Carbonyls, Imines, and Related Polarized π Bonds
Chem. Rev.  2017117, 9163–9227.  
Potter, T. J.; Kamber, D. N.; Mercado, B. Q.; Ellman, J. A.
Rh(III)-Catalyzed Aryl and Alkenyl C–H Bond Addition to Diverse Nitroalkenes
ACS Catal.  20177, 150–153.  
Chen, S.; Bacauanu, V.; Knecht, T.; Mercado, B. Q.; Bergman, R. G.; Ellman, J. A.
New Regio- and Stereoselective Cascades via Unstabilized Azomethine Ylide Cycloadditions for the Synthesis of Highly Substituted Tropane and Indolizidine Frameworks
J. Am. Chem. Soc.  2016138, 12664–12670.  
Potter, T. J.; Ellman, J. A.
Rh(III)-Catalyzed C–H Bond Addition/Amine-Mediated Cyclization of Bis-Michael Acceptors
Org. Lett.  201618, 3838–3841.  
Weinstein, A. B.; Ellman, J. A.
Convergent Synthesis of Diverse Nitrogen Heterocycles via Rh(III)-Catalyzed C–H Conjugate Addition/Cyclization Reactions
Org. Lett.  201618, 3294-3297.  
Boerth, J. A.; Hummel, J. R.; Ellman, J. A.
Highly Stereoselective Cobalt(III)-Catalyzed Three-Component C−H Bond Addition Cascade
Angew. Chem. Int. Ed.  201655, 12650-12654.  
Boerth, J. A.; Ellman, J. A.
Rh(III)-Catalyzed Diastereoselective C–H Bond Addition/Cyclization Cascade of Enone Tethered Aldehydes
Chem. Sci.  20167, 1474-1479.  
Phillips, E. M.; Mesganaw, T.; Patel, A. Duttwyler, S.; Mercado, B. Q.; Houk, K. N.; Ellman, J. A.
Synthesis of ent-Ketorfanol via a C–H Alkenylation/ Torquoselective 6π-Electrocyclization Cascade
Angew. Chem. Int. Ed.  201554, 12044–12048.  
Chen, S.; Bergman, R. G.; Ellman, J. A.
Facile Rh(III)-Catalyzed Synthesis of Fluorinated Pyridines
Org. Lett.  201517, 2567–2569.  
Hummel, J. R.; Ellman, J. A.
Cobalt(III)-Catalyzed C–H Bond Amidation with Isocyanates
Org. Lett.  201517, 2400–2403.  
Otley, K. D.; Ellman, J. A.
An Efficient Method for the Preparation of Styrene Derivatives via Rh(III)-Catalyzed Direct C–H Vinylation
Org. Lett.  201517, 1332–1335.  
Hummel, J. R.; Ellman, J. A.
Cobalt(III)-Catalyzed Synthesis of Indazoles and Furans by C–H Bond Functionalization/Addition/Cyclization Cascades
J. Am. Chem. Soc.  2015137, 490–498.  
Mesganaw, T.; Ellman, J. A.
Convergent Synthesis of Diverse Tetrahydropyridines via Rh(I)-Catalyzed C–H Functionalization Sequences
Org. Process Res. Dev.  201418, 1097–1104.  
Duttwyler, S.; Chen, S.; Lu, C.; Mercado, B. Q.; Bergman, R. G.; Ellman, J. A.
Regio- and Stereoselective 1,2-Dihydropyridine Alkylation/Addition Sequence for the Synthesis of Piperidines with Quaternary Centers
Angew. Chem. Int. Ed.  201453, 3877–3880.  
Lian, Y.; Hummel, J. R.; Bergman, R. G.; Ellman, J. A.
Facile Synthesis of Unsymmetrical Acridines and Phenazines by a Rhodium(III)-Catalyzed Amination, Cyclization and Aromatization Cascade
J. Am. Chem. Soc.  2013135, 12548-12551.  
Lian, Y.; Bergman, R. G.; Lavis, L. D.; Ellman, J. A.
Rhodium(III)-Catalyzed Indazole Synthesis by C-H Bond Functionalization and Cyclative Capture
J. Am. Chem. Soc.  2013135, 7122-7125.  
Ischay, M. A.; Takase, M. K.; Bergman, R. G.; Ellman, J. A.
Unstabilized Azomethine Ylides for the Stereoselective synthesis of Substituted Piperidines, Tropanes and Azabicyclo[3.1.0] systems
J. Am. Chem. Soc.  2013135, 2478-2481.  
Duttwyler, S.; Chen, S.; Takase, M. K.; Wiberg, K. B.; Bergman, R. G.; Ellman, J. A.
Proton Donor Acidity Controls Selectivity in Nonaromatic Nitrogen Heterocycle Synthesis
Science  2013339, 678-682.