C-H Functionalization

C-H bond functionalization has become one of the most important new methods in synthesis (Figure 1). With an appropriate catalyst, C-H bond functionalization can be performed without a strong acid or base and is highly functional group tolerant thus enabling the efficient synthesis and/or elaboration of drugs and natural products, which typically are rich in functionality. In addition, because virtually every organic compound has C-H bonds, in terms of starting material availability, C-H functionalization approaches theoretically cannot be surpassed.

Figure 1. Elemental reaction between a C-H bond substrate and a coupling partner

The Bergman and Ellman labs collaborated on the discovery and investigation of new methods centered on catalytic C-H functionalization early in the field’s development, with their first series of publications appearing in 2001. This highly enjoyable collaboration, which continued for more than a decade, also included detailed mechanistic studies of C-H functionalization methods as well as their application to the synthesis of drugs and natural products.

Over the past few years the Ellman lab has explored a new approach for C-H functionalization based upon the three-component sequential coupling of a C-H bond substrate and two different types of coupling partners (Figure 2). This approach provides access to complex structures from simple precursors with the formation of two new bonds. Vast structural diversity is theoretically possible given the enormous number of potential combinations of coupling partners that might be considered

Figure 2. Basic connection for three-component sequential addition of a C-H bond substrate to two different types of coupling partners

As one example of this type of sequential three-component C-H functionalization reaction, the lab has recently reported on the synthesis of α-branched amines from readily available C-H bond substrates, alkenes, and electrophilic aminating agents (Figure 3). This transformation is highly functional group compatible, can be performed at low catalyst loading, and using chiral catalysts, can be performed in asymmetric fashion.

Figure 3. Synthesis of pharmaceutically relevant α-branched amines by Rh(III)-catalyzed three-component coupling of C-H bond substrates, terminal alkenes, and electrophilic aminating reagents

The Ellman lab continues to be highly motivated to develop efficient methods to prepare nitrogen heterocycles, which are present in ~60% of drugs. Annulations proceeding through imidoyl C-H activation is an active area of investigation (Figure 4). Imines, which are easily prepared by condensing large numbers of readily available aldehydes and primary amines, have served as versatile and extremely useful intermediates, though predominantly for nucleophilic additions as exemplified by the well-known Strecker, Mannich, Ugi and Petasis reactions. We believe that imidoyl C-H functionalization for nitrogen heterocycle synthesis opens up a new reaction manifold with the potential to be similarly impactful. Figure 4 depicts select examples of drug relevant heterocycles that we have prepared by catalytic imidoyl C-H activation and annulation using different coupling partners. For some of these transformations, the imines can be prepared in situ enabling straightforward heterocycle synthesis in a single step.

Figure 4. Heterocycle synthesis from readily available precursors by catalytic C-H imidoyl activation and annulation

We have also focused on the use of simple and readily available inputs for the convergent assembly of the piperidine framework, the most prevalent nitrogen heterocycle in drugs. Rh(I)-catalyzed C-H alkenylation followed by electrocyclization provides 1,2-dihydropyridines, which in the same pot or after simple filtration, can then be transformed into highly functionalized piperidine derivatives (Figure 5). Heterocycles from low to high levels of substitution as well as polycyclic derivatives can readily be accessed using this approach.

Figure 5. 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 6 depicts representative structures of metal complexes that have been characterized in the context of mechanistic inquiry.

Figure 6. Examples of x-ray structures of transition metal complexes from mechanistic studies

As we develop new C-H bond functionalization methods, we also apply them to the synthesis of relevant natural products and drugs (Figure 7). This includes the first total synthesis of (+)-lithospermic acid and the first total synthesis of the semi-synthetic opioid antidote (-)-naltrexone.

Figure 7. Representative natural products and drugs synthesized using C-H bond functionalization

Relevant Publications

Vargas-Rivera, M. A.; Liu, A. S.; Ellman, J. A.
Visible-Light-Mediated, Diastereoselective Epimerization of Exocyclic Amines
Org. Lett.  202325, 9197–9201.  
Chu, D.; Ellman, J. A.
Stereospecific Synthesis of Unprotected, α,β-Disubstituted Tryptamines and Phenethylamines from 1,2-Disubstituted Alkenes via a One-Pot Reaction Sequence
Org. Lett.  202325, 3654–3658.  
Zoll, A. J.; Molas, J. C.; Mercado, B. Q.; Ellman, J. A.
Imine Directed Cp*Rh(III)-Catalyzed N–H Functionalization and Annulation with Amino Amides, Aldehydes, and Diazo Compounds
Angew. Chem. Int. Ed.  202362, e202210822.  
Tassone, J. P.; Yeo, J. Ellman, J. A.
Three-component carboformylation: α-quaternary aldehyde synthesis via Co(III)-catalysed sequential C–H bond addition to dienes and acetic formic anhydride
Chem. Sci.  202213, 14320–14326.  
Shen, Z.; Vargas-Rivera, M.; Rigby, E. L.; Chen, S.; Ellman, J. A.
Visible Light-Mediated, Highly Stereoselective Epimerization of Morpholines and Piperazines to the More Stable Isomers
ACS Catal.  202212, 12860–12868.  
Brandes, D. S.; Ellman, J. A.
C–H bond activation and sequential addition to two different coupling partners: a versatile approach to molecular complexity
Chem. Soc. Rev.  202251, 6738 - 6756.  
Kazerouni, A. M.; Brandes, D. S.; Davies, C. C.; Cotter, L. F.; Mayer, J. M.; Chen, S.; Ellman, J. A.
Visible Light-Mediated, Highly Diastereoselective Epimerization of Lactams from the Most Accessible to the More Stable Stereoisomer
ACS Catal.  202212, 7798–7803.  
Xu, C.; Tassone, J. P.; Mercado, B. Q.; Ellman, J. A.
Stereoselective Synthesis of Allenyl Alcohols by Cobalt(III)-Catalyzed Sequential C−H Bond Addition to 1,3-Enynes and Aldehydes
Angew. Chem. Int. Ed.  202261, e202202364 [Hot Paper].  
Chu, D.; Ellman, J. A.
Three-Component Friedel–Crafts Transformations: Synthesis of Alkyl and Alkenyl Trifluoromethyl Sulfides and Alkenyl Iodides
Org. Lett.  202224, 2921–2925.  
Brandes, D. S.; Muma, A. D.; Ellman, J. A.
Synthesis of α-Branched Amines by Three- and Four-Component C–H Functionalization Employing a Readily Diversifiable Hydrazone Directing Group
Org. Lett.  202123, 9597–9601.  
Brandes, D. S.; Sirvent, A.; Mercado, B. Q.; Ellman, J. A.
Three-Component 1,2-Carboamidation of Bridged Bicyclic Alkenes via RhIII-Catalyzed Addition of C–H Bonds and Amidating Reagents
Org. Lett.  202123, 2836–2840.  
Dongbang, S.; Confair, D. N.; Ellman, J. A.
Rhodium-Catalyzed C–H Alkenylation/Electrocyclization Cascade Provides Dihydropyridines That Serve as Versatile Intermediates to Diverse Nitrogen Heterocycles
Acc. Chem. Res.  202154, 1766-1778.  
Shen, Z.; Walker, M. M.; Chen, S.; Parada, G. A.; Chu, D. M.; Dongbang, S.; Mayer, J. M.; Houk, K. N.; Ellman, J. A.
General Light-Mediated, Highly Diastereoselective Piperidine Epimerization: From Most Accessible to Most Stable Stereoisomer
J. Am. Chem. Soc.  2021143, 126–131.  
Dongbang, S.; Ellman, Jonathan A.
Synthesis of Nitrile Bearing Acyclic Quaternary Centers via Co(III)‐Catalyzed Sequential C–H Bond Addition to Dienes and N‐Cyanosuccinimide
Angew. Chem. Int. Ed.  202160, 2135-2139.  
Confair, D. N.; Greenwood, N. S.; Mercado, B. Q.; Ellman, J. A.
Rh(III)-Catalyzed Imidoyl C–H Carbamylation and Cyclization to Bicyclic [1,3,5]Triazinones
Org. Lett.   202022, 8993–8997.  
Walker, M. M.; Koronkiewicz, B.; Chen, S.; Houk, K. N.; Mayer, J. M.; Ellman, J. A.
Highly Diastereoselective Functionalization of Piperidines by Photoredox Catalyzed α-Amino C–H Arylation and Epimerization
J. Am. Chem. Soc.  2020142, 8194-8202 [ChemRxiv, 2019: doi.org/10.26434/chemrxiv.11336642.v1].  
Streit, A. D.; Zoll, A. J.; Hoang, G. L.; Ellman, J. A.
Annulation of Hydrazones and Alkynes via Rhodium(III)-Catalyzed Dual C–H Activation: Synthesis of Pyrrolopyridazines and Azolopyridazines
Org. Lett.  202022, 1217-1221.  
Shen, Z.; Li, C.; Mercado, B. Q.; Ellman, J. A.
Cobalt(III)-Catalyzed Diastereoselective Three-Component C–H Bond Addition to Butadiene and Activated Ketones
Synthesis  202052, 1239-1246 [Domino C–H functionalization reaction/cascade catalysis in honor of Prof. Mark Lautens].  
Scamp, R. J.; deRamon, E.; Paulson, E. K.; Miller, S. J.; Ellman, J. A.
Co(III)-Catalyzed C-H Amidation of Dehydroalanine for the Site-Selective Structural Diversification of Thiostrepton
Angew. Chem. Int. Ed.  202059, 890-895.  
Maity, S.; Potter, T. J.; Ellman, J. A.
α-Branched Amines by Catalytic 1,1-Addition of C–H Bonds and Aminating Agents to Terminal Alkenes
Nat. Catal.  20192, 756–762.  
Dongbang, S.; Shen, Z.; Ellman, J. A.
Synthesis of Homoallylic Alcohols with Acyclic Quaternary Centers via CoIII‐Catalyzed Three‐Component C–H Bond Addition to Internally Substituted Dienes and Carbonyls
Angew. Chem. Int. Ed.  201958, 12590–12594 [Hot Paper].  
Hoang, G. L.; Zoll, A. J.; Ellman, J. A.
Three-Component Coupling of Aldehydes, 2-Aminopyridines, and Diazo Esters via Rhodium(III)-Catalyzed Imidoyl C–H Activation: Synthesis of Pyrido[1,2-a]pyrimidin-4-ones
Org. Lett.  201921, 3886-3890 [cover picture for issue 11, June 7].  
Dongbang, S.; Pedersen, B.; Ellman, J. A.
Asymmetric Synthesis of (−)-Naltrexone
Chem. Sci.  201910, 535–541 [Editor's Choice].  
Hoang, G. L.; Streit, A. D.; Ellman, J. A.
Three-Component Coupling of Aldehydes, Aminopyrazoles, and Sulfoxonium Ylides via Rhodium(III)-Catalyzed Imidoyl C–H Activation: Synthesis of Pyrazolo[1,5-a]pyrimidines
J. Org. Chem.  201883, 15347-15360.  
Boerth, J. A.; Maity, S.; Williams, S. K.; Mercado, B. Q.; Ellman, J. A.
Selective and Synergistic Cobalt(III)-Catalysed Three-Component C–H Bond Addition to Dienes and Aldehydes
Nat. Catal.  20181, 673–679.  
Hoang, G. L.; Li, Y.; Halskov, K. S.; Ellman, J. A
Synthesis of Azolo[1,3,5]triazines via Rhodium(III)-Catalyzed Annulation of N-Azolo Imines and Dioxazolones
J. Org. Chem.  201883, 9522–9529.  
Potter, T.J.; Li, Y.; Ward, M. D.; Ellman, J. A.
Rh(III)-Catalyzed Synthesis of Isoquinolones and 2-Pyridones via Annulation of N-Methoxyamides and Nitroalkenes
Eur. J. Org. Chem.  20182018, 4381–4388 [International Adivsory Board 20th Anniversary Issue].  
Walker, M. M.; Chen, S.; Houk, K.; Ellman, J. A.
Formation of Aminocyclopentadienes from Silyldihydropyridines: Ring Contractions Driven by Anion Stabilization
Angew. Chem. Int. Ed.  201857, 6605–6609.  
Hoang, G. L.; Ellman, J. A.
Rhodium(III)-Catalyzed C–H Functionalization of C-Alkenyl Azoles with Sulfoxonium Ylides for the Synthesis of Bridgehead N-Fused [5,6]-bicyclic Heterocycles
Tetrahedron  201874, 3318–3324 [Herzon Tetrahedron Young Investigator Award Issue].  
Halskov, K. M.; Witten, M. R.; Hoang, G. L.; Mercado, B. Q.; Ellman, J. A.
Rhodium(III)-Catalyzed Imidoyl C−H Activation for Annulations to Azolopyrimidines
Org. Lett.  201820, 2464–2467.