CaltechAUTHORS
  A Caltech Library Service

Direct Functionalization of Nitrogen Heterocycles via Rh-Catalyzed C−H Bond Activation

Lewis, Jared C. and Bergman, Robert G. and Ellman, Jonathan A. (2008) Direct Functionalization of Nitrogen Heterocycles via Rh-Catalyzed C−H Bond Activation. Accounts of Chemical Research, 41 (8). pp. 1013-1025. ISSN 0001-4842. PMCID PMC2610463. https://resolver.caltech.edu/CaltechAUTHORS:20170125-103406029

[img] PDF - Accepted Version
See Usage Policy.

5Mb

Use this Persistent URL to link to this item: https://resolver.caltech.edu/CaltechAUTHORS:20170125-103406029

Abstract

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(PCy3)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(PCy3)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 PCy3 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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/ar800042pDOIArticle
http://pubs.acs.org/doi/abs/10.1021/ar800042pPublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2610463/PubMed CentralArticle
ORCID:
AuthorORCID
Bergman, Robert G.0000-0002-3105-8366
Additional Information:© 2008 American Chemical Society. Received 4 February 2008. Published online 11 July 2008. Published in print 1 August 2008. This work was supported by the NIH, Grant GM069559 to J.A.E., and by the Director and Office of Energy Research, Office of Basic Energy Sciences, Chemical Sciences Division, U.S. Department of Energy, under Contract DE-AC03-76SF00098 to R.G.B.
Funders:
Funding AgencyGrant Number
NIHGM069559
Department of Energy (DOE)DE-AC03-76SF00098
Issue or Number:8
PubMed Central ID:PMC2610463
Record Number:CaltechAUTHORS:20170125-103406029
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170125-103406029
Official Citation:Direct Functionalization of Nitrogen Heterocycles via Rh-Catalyzed C−H Bond Activation Jared C. Lewis, Robert G. Bergman, and Jonathan A. Ellman Accounts of Chemical Research 2008 41 (8), 1013-1025 DOI: 10.1021/ar800042p
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:73714
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:25 Jan 2017 20:39
Last Modified:09 Mar 2020 13:18

Repository Staff Only: item control page