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Direct functionalization of nitrogen heterocycles via Rh-catalyzed C-H bond activation.
Acc Chem Res. 2008 Aug; 41(8):1013-25.AC

Abstract

[Reaction: see text]. Nitrogen heterocycles are present in many compounds of enormous practical importance, ranging from pharmaceutical agents and biological probes to electroactive materials. Direct functionalization of nitrogen heterocycles through C-H bond activation constitutes a powerful means of regioselectively introducing a variety of substituents with diverse functional groups onto the heterocycle scaffold. Working together, our two groups have developed a family of Rh-catalyzed heterocycle alkylation and arylation reactions that are notable for their high level of functional-group compatibility. This Account describes our work in this area, emphasizing the relevant mechanistic insights that enabled synthetic advances and distinguished the resulting transformations from other methods. We initially discovered an intramolecular Rh-catalyzed C-2 alkylation of azoles by alkenyl groups. That reaction provided access to a number of di-, tri-, and tetracyclic azole derivatives. We then developed conditions that exploited microwave heating to expedite these reactions. While investigating the mechanism of this transformation, we discovered that a novel substrate-derived Rh- N-heterocyclic carbene (NHC) complex was involved as an intermediate. We then synthesized analogous Rh-NHC complexes directly by treating precursors to the intermediate [RhCl(PCy 3)2] with N-methylbenzimidazole, 3-methyl-3,4-dihydroquinazoline, and 1-methyl-1,4-benzodiazepine-2-one. Extensive kinetic analysis and DFT calculations supported a mechanism for carbene formation in which the catalytically active RhCl(PCy 3) 2 fragment coordinates to the heterocycle before intramolecular activation of the C-H bond occurs. The resulting Rh-H intermediate ultimately tautomerizes to the observed carbene complex. With this mechanistic information and the discovery that acid cocatalysts accelerate the alkylation, we developed conditions that efficiently and intermolecularly alkylate a variety of heterocycles, including azoles, azolines, dihydroquinazolines, pyridines, and quinolines, with a wide range of functionalized olefins. We demonstrated the utility of this methodology in the synthesis of natural products, drug candidates, and other biologically active molecules. In addition, we developed conditions to directly arylate these heterocycles with aryl halides. Our initial conditions that used PCy 3 as a ligand were successful only for aryl iodides. However, efforts designed to avoid catalyst decomposition led to the development of ligands based on 9-phosphabicyclo[4.2.1]nonane (phoban) that also facilitated the coupling of aryl bromides. We then replicated the unique coordination environment, stability, and catalytic activity of this complex using the much simpler tetrahydrophosphepine ligands and developed conditions that coupled aryl bromides bearing diverse functional groups without the use of a glovebox or purified reagents. With further mechanistic inquiry, we anticipate that researchers will better understand the details of the aforementioned Rh-catalyzed C-H bond functionalization reactions, resulting in the design of more efficient and robust catalysts, expanded substrate scope, and new transformations.

Authors+Show Affiliations

Department of Chemistry and Chemical Engineering, California Insitute of Technology, 1200 East California Boulevard, MC 210-41, Pasadena, California 91125, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Review

Language

eng

PubMed ID

18616300

Citation

Lewis, Jared C., et al. "Direct Functionalization of Nitrogen Heterocycles Via Rh-catalyzed C-H Bond Activation." Accounts of Chemical Research, vol. 41, no. 8, 2008, pp. 1013-25.
Lewis JC, Bergman RG, Ellman JA. Direct functionalization of nitrogen heterocycles via Rh-catalyzed C-H bond activation. Acc Chem Res. 2008;41(8):1013-25.
Lewis, J. C., Bergman, R. G., & Ellman, J. A. (2008). Direct functionalization of nitrogen heterocycles via Rh-catalyzed C-H bond activation. Accounts of Chemical Research, 41(8), 1013-25. https://doi.org/10.1021/ar800042p
Lewis JC, Bergman RG, Ellman JA. Direct Functionalization of Nitrogen Heterocycles Via Rh-catalyzed C-H Bond Activation. Acc Chem Res. 2008;41(8):1013-25. PubMed PMID: 18616300.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Direct functionalization of nitrogen heterocycles via Rh-catalyzed C-H bond activation. AU - Lewis,Jared C, AU - Bergman,Robert G, AU - Ellman,Jonathan A, Y1 - 2008/07/11/ PY - 2008/7/12/pubmed PY - 2008/10/14/medline PY - 2008/7/12/entrez SP - 1013 EP - 25 JF - Accounts of chemical research JO - Acc Chem Res VL - 41 IS - 8 N2 - [Reaction: see text]. Nitrogen heterocycles are present in many compounds of enormous practical importance, ranging from pharmaceutical agents and biological probes to electroactive materials. Direct functionalization of nitrogen heterocycles through C-H bond activation constitutes a powerful means of regioselectively introducing a variety of substituents with diverse functional groups onto the heterocycle scaffold. Working together, our two groups have developed a family of Rh-catalyzed heterocycle alkylation and arylation reactions that are notable for their high level of functional-group compatibility. This Account describes our work in this area, emphasizing the relevant mechanistic insights that enabled synthetic advances and distinguished the resulting transformations from other methods. We initially discovered an intramolecular Rh-catalyzed C-2 alkylation of azoles by alkenyl groups. That reaction provided access to a number of di-, tri-, and tetracyclic azole derivatives. We then developed conditions that exploited microwave heating to expedite these reactions. While investigating the mechanism of this transformation, we discovered that a novel substrate-derived Rh- N-heterocyclic carbene (NHC) complex was involved as an intermediate. We then synthesized analogous Rh-NHC complexes directly by treating precursors to the intermediate [RhCl(PCy 3)2] with N-methylbenzimidazole, 3-methyl-3,4-dihydroquinazoline, and 1-methyl-1,4-benzodiazepine-2-one. Extensive kinetic analysis and DFT calculations supported a mechanism for carbene formation in which the catalytically active RhCl(PCy 3) 2 fragment coordinates to the heterocycle before intramolecular activation of the C-H bond occurs. The resulting Rh-H intermediate ultimately tautomerizes to the observed carbene complex. With this mechanistic information and the discovery that acid cocatalysts accelerate the alkylation, we developed conditions that efficiently and intermolecularly alkylate a variety of heterocycles, including azoles, azolines, dihydroquinazolines, pyridines, and quinolines, with a wide range of functionalized olefins. We demonstrated the utility of this methodology in the synthesis of natural products, drug candidates, and other biologically active molecules. In addition, we developed conditions to directly arylate these heterocycles with aryl halides. Our initial conditions that used PCy 3 as a ligand were successful only for aryl iodides. However, efforts designed to avoid catalyst decomposition led to the development of ligands based on 9-phosphabicyclo[4.2.1]nonane (phoban) that also facilitated the coupling of aryl bromides. We then replicated the unique coordination environment, stability, and catalytic activity of this complex using the much simpler tetrahydrophosphepine ligands and developed conditions that coupled aryl bromides bearing diverse functional groups without the use of a glovebox or purified reagents. With further mechanistic inquiry, we anticipate that researchers will better understand the details of the aforementioned Rh-catalyzed C-H bond functionalization reactions, resulting in the design of more efficient and robust catalysts, expanded substrate scope, and new transformations. SN - 1520-4898 UR - https://www.unboundmedicine.com/medline/citation/18616300/Direct_functionalization_of_nitrogen_heterocycles_via_Rh_catalyzed_C_H_bond_activation_ L2 - https://doi.org/10.1021/ar800042p DB - PRIME DP - Unbound Medicine ER -
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