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. 2012 Jun 19;45(6):814-25.
doi: 10.1021/ar200190g. Epub 2011 Dec 8.

Rhodium catalyzed chelation-assisted C-H bond functionalization reactions

Denise A Colby  1 , Andy S Tsai, Robert G Bergman, Jonathan A Ellman
Affiliations

Rhodium catalyzed chelation-assisted C-H bond functionalization reactions

Denise A Colby et al. Acc Chem Res. .

Abstract

Over the last several decades, researchers have achieved remarkable progress in the field of organometallic chemistry. The development of metal-catalyzed cross-coupling reactions represents a paradigm shift in chemical synthesis, and today synthetic chemists can readily access carbon-carbon and carbon-heteroatom bonds from a vast array of starting compounds. Although we cannot understate the importance of these methods, the required prefunctionalization to carry out these reactions adds cost and reduces the availability of the starting reagents. The use of C-H bond activation in lieu of prefunctionalization has presented a tantalizing alternative to classical cross-coupling reactions. Researchers have met the challenges of selectivity and reactivity associated with the development of C-H bond functionalization reactions with an explosion of creative advances in substrate and catalyst design. Literature reports on selectivity based on steric effects, acidity, and electronic and directing group effects are now numerous. Our group has developed an array of C-H bond functionalization reactions that take advantage of a chelating directing group, and this Account surveys our progress in this area. The use of chelation control in C-H bond functionalization offers several advantages with respect to substrate scope and application to total synthesis. The predictability and decreased dependence on the inherent stereoelectronics of the substrate generally result in selective and high yielding transformations with broad applicability. The nature of the chelating moiety can be chosen to serve as a functional handle in subsequent elaborations. Our work began with the use of Rh(I) catalysts in intramolecular aromatic C-H annulations, which we further developed to include enantioselective transformations. The application of this chemistry to the simple olefinic C-H bonds found in α,β-unsaturated imines allowed access to highly substituted olefins, pyridines, and piperidines. We observed complementary reactivity with Rh(III) catalysts and developed an oxidative coupling with unactivated alkenes. Further studies on the Rh(III) catalysts led us to develop methods for the coupling of C-H bonds to polarized π bonds such as those in imines and isocyanates. In several cases the methods that we have developed for chelation-controlled C-H bond functionalization have been applied to the total synthesis of complex molecules such as natural products, highlighting the utility of these methods in organic synthesis.

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Figures

Figure 1
Figure 1
Chelation-assisted C-H bond activation
Figure 2
Figure 2
Phosphoramidite ligands for enantioselective olefin hydroarylation
Figure 3
Figure 3
X-ray crystal structure (ORTEP diagram) of 37 with thermal ellipsoids drawn at the 50% probability level. Hydrogen atoms distant from the metal center have been omitted for clarity.
Figure 4
Figure 4
Methylation of 41. ORTEP diagram of 42 with thermal ellipsoids drawn at the 50% probability level.
Scheme 1
Scheme 1
Mechanism of chelation-assisted C-H alkylation
Scheme 2
Scheme 2
Synthesis of mescaline analogue 20
Scheme 3
Scheme 3
Cyclization of 25 in the first synthesis of (+)-lithospermic acid
Scheme 4
Scheme 4
Enantioselective cyclization and synthesis of 27
Scheme 5
Scheme 5
Diastereoselective synthesis of (−)-incarvillateine
Scheme 6
Scheme 6
Possible reaction pathways for 39
Scheme 7
Scheme 7
Proposed mechanism for the Rh(III) catalyzed oxidative coupling of alkenes.
Scheme 8
Scheme 8
Regioselectivity of insertion of imines into a rhodium-hydride intermediate
Scheme 9
Scheme 9
Rh(III) catalyzed arylation of imines
Chart 1
Chart 1
Intramolecular alkylation of aryl imines
Chart 2
Chart 2
Dihydropyridine synthesis from imines and alkynesa a Yields determined by NMR integration relative to 2,6-dimethoxytoluene as an internal standard.
Chart 3
Chart 3
One-pot synthesis of pyridines from imines and alkynes a a Yields given are isolated yields based on starting imine.
Chart 4
Chart 4
Substrate scope for oxidative coupling of alkenes
Chart 5
Chart 5
Scope of 2-aryl pyridine alkylation with imines
Chart 6
Chart 6
Substrate scope of N-acyl directed additions of C-H bonds to isocyanates
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References

    1. We recently published an Accounts review on the separate topic of direct functionalization of nitrogen heterocycles by Rh-catalyzed C-H bond functionalization: Lewis JC, Bergman RG, Ellman JA. Direct Functionalization of Nitrogen Heterocycles via Rh-Catalyzed C-H Bond Activation. Acc Chem Res. 2008;41:1013–1025.

    1. For reviews on C-H bond functionalization, see the following and leading references therein: Crabtree RH. Introduction to Selective Functionalization of C-H Bonds. Chem Rev. 2010;110:575.Colby DA, Bergman RG, Ellman JA. Rhodium-Catalyzed C-C Bond Formation via Heteroatom-Directed C-H Bond Activation. Chem Rev. 2010;110:624–655.Bellina F, Rossi R. Transition Metal-Catalyzed Direct Arylation of Substrates with Activated sp3-Hybridized C-H Bonds and Some of Their Synthetic Equivalents with Aryl Halides and Pseudohalides. Chem Rev. 2010;110:1082–1146.Lyons TW, Sanford MS. Palladium-Catalyzed Ligand-Directed C-H Functionalization Reactions. Chem Rev. 2010;110:1147–1169.Davies HML, Du Bois J, Yu JQ. C-H Functionalization in Organic Synthesis. Chem Soc Rev. 2011;40:1855–1856.

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