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Title: Rh(I)-Catalyzed Alkylation of Quinolines and Pyridines via C-HBond Activation


No abstract prepared.

; ;
Publication Date:
Research Org.:
Ernest Orlando Lawrence Berkeley NationalLaboratory, Berkeley, CA (US)
Sponsoring Org.:
USDOE Director. Office of Science. Basic EnergySciences
OSTI Identifier:
Report Number(s):
Journal ID: ISSN 0002-7863; JACSAT; R&D Project: 402101; BnR: KC0302010; TRN: US200814%%199
DOE Contract Number:
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of the American Chemical Society; Journal Volume: 129; Related Information: Journal Publication Date: 2007
Country of Publication:
United States

Citation Formats

Lewis, Jared C., Bergman, Robert G., and Ellman, Jonathan A.. Rh(I)-Catalyzed Alkylation of Quinolines and Pyridines via C-HBond Activation. United States: N. p., 2007. Web. doi:10.1021/ja070388z.
Lewis, Jared C., Bergman, Robert G., & Ellman, Jonathan A.. Rh(I)-Catalyzed Alkylation of Quinolines and Pyridines via C-HBond Activation. United States. doi:10.1021/ja070388z.
Lewis, Jared C., Bergman, Robert G., and Ellman, Jonathan A.. Fri . "Rh(I)-Catalyzed Alkylation of Quinolines and Pyridines via C-HBond Activation". United States. doi:10.1021/ja070388z.
title = {Rh(I)-Catalyzed Alkylation of Quinolines and Pyridines via C-HBond Activation},
author = {Lewis, Jared C. and Bergman, Robert G. and Ellman, Jonathan A.},
abstractNote = {No abstract prepared.},
doi = {10.1021/ja070388z},
journal = {Journal of the American Chemical Society},
number = ,
volume = 129,
place = {United States},
year = {Fri Apr 06 00:00:00 EDT 2007},
month = {Fri Apr 06 00:00:00 EDT 2007}
  • The pyridine and quinoline nuclei are privileged scaffolds that occupy a central role in many medicinally relevant compounds. Consequently, methods for their expeditious functionalization are of immediate interest. However, despite the immense importance of transition-metal catalyzed cross-coupling for the functionalization of aromatic scaffolds, general solutions for coupling 2-pyridyl organometallics with aryl halides have only recently been presented. Direct arylation at the ortho position of pyridine would constitute an even more efficient approach because it eliminates the need for the stoichiometric preparation and isolation of 2-pyridyl organometallics. Progress towards this goal has been achieved by activation of the pyridine nucleus formore » arylation via conversion to the corresponding pyridine N-oxide or N-iminopyridinium ylide. However, this approach necessitates two additional steps: activation of the pyridine or quinoline starting material, and then unmasking the arylated product. The use of pyridines directly would clearly represent the ideal situation both in terms of cost and simplicity. We now wish to document our efforts in this vein, culminating in an operationally simple Rh(I)-catalyzed direct arylation of pyridines and quinolines. We recently developed an electron-rich Rh(I) system for catalytic alkylation at the ortho position of pyridines and quinolines with alkenes. Therefore, we initially focused our attention on the use of similarly electron-rich Rh(I) catalysts for the proposed direct arylation. After screening an array of electron-rich phosphine ligands and Rh(I) salts, only marginal yields (<20%) of the desired product were obtained. Much more efficient was an electron-poor Rh(I) system with [RhCl(CO){sub 2}]{sub 2} as precatalyst (Table 1). For the direct arylation of picoline with 3,5-dimethyl-bromobenzene, addition of P(OiPr){sub 3} afforded a promising 40% yield of the cross coupled product 1a (entry 1). The exclusion of phosphite additive proved even more effective, with the yield of 1a improving to 61% (entry 2). Further enhancement in yield was not observed upon the inclusion of other additives such as MgO (entry 3), various organic bases (entries 4, 5), or a protic acid source (entry 6). Absolute concentration proved very important, with the best results being obtained at relatively high concentrations of the aryl bromide (compare entries 7 and 8). A marginal improvement was observed upon running the reaction with 6 equivalents of 2-methyl pyridine (entry 9). The reaction temperature could also be increased to 175 or 190 C while maintaining reaction yield, to enable the reaction time to be reduced to 24 h (entries 10 and 11). In summary, we have developed a Rh(I)-catalyzed strategy for the direct arylation of pyridines and quinolines. The heterocycle is used without the need for prefunctionalization, and all reaction components are inexpensive and readily available. The strategy represents an expeditious route to an important class of bis(hetero)aryls and should be of broad utility.« less
  • An asymmetric total synthesis of (-)-incarvillateine, a natural product having potent analgesic properties, has been achieved in 11 steps and 15.4% overall yield. The key step is a rhodium-catalyzed intramolecular alkylation of an olefinic C-H bond to set two stereocenters. Additionally, this transformation produces an exocyclic, tetrasubstituted alkene through which the bicyclic piperidine moiety can readily be accessed.
  • A practical, functional group tolerant method for the Rh-catalyzed direct arylation of a variety of pharmaceutically important azoles with aryl bromides is described. Many of the successful azole and aryl bromide coupling partners are not compatible with methods for the direct arylation of heterocycles using Pd(0) or Cu(I) catalysts. The readily prepared, low molecular weight ligand, Z-1-tert-butyl-2,3,6,7-tetrahydrophosphepine, which coordinates to Rh in a bidentate P-olefin fashion to provide a highly active yet thermally stable arylation catalyst, is essential to the success of this method. By using the tetrafluoroborate salt of the corresponding phosphonium, the reactions can be assembled outside ofmore » a glove box without purification of reagents or solvent. The reactions are also conducted in THF or dioxane, which greatly simplifies product isolation relative to most other methods for direct arylation of azoles employing high-boiling amide solvents. The reactions are performed with heating in a microwave reactor to obtain excellent product yields in two hours.« less
  • The reaction of (C{sub 5}Me{sub 5}RhMe{sub 2}(Me{sub 2}SO)) with 2-, 3-, and 4-pyridinecarboxyaldehyde gave the appropriately substituted (C{sub 5}Me{sub 5}Rh(Me)(CO)(x-C{sub 5}H{sub 4}N)) (2, x = 2-4) in 80-90% yields; (C{sub 5}Me{sub 5}Ir(Me)(CO)(4-C{sub 5}H{sub 4}N)) was prepared analogously. The 2- and 3-pyridyl complexes were readily quaternized by reaction with MeI to give (C{sub 5}Me{sub 5}Rh(Me)(CO)(x-C{sub 5}H{sub 4}NMe))I, (x = 2, 3), but the (4-pyridyl)rhodium complex underwent coupling to give 1,4-dimethylpyridinium iodide and (C{sub 5}Me{sub 5}Rh(CO)Me(I)). The products from the last reaction with CD{sub 3}I were (C{sub 5}Me{sub 5}Rh(CO)Cd{sub 3}(I)) and (4-CH{sub 3}C{sub 5}H{sub 4}NCD{sub 3}{sup +}){sup {minus}}. On reaction of (C{submore » 5}Me{sub 5}Rh(Me)(CO)(4-C{sub 5}H{sub 4}N)) with other electrophiles (H{sup +}BF{sub 4}{sup {minus}}, Et{sub 3}O{sup +}BF{sub 4}{sup {minus}}), evidence for the formation of unstable salts, (C{sub 5}Me{sub 5}Rh(Me)(CO)(4-C{sub 5}H{sub 4}NH)){sup +} and (C{sub 5}Me{sub 5}Rh(Me)(CO)(4-C{sub 5}H{sub 4}NEt)){sup +}, was obtained. In contrast, the complex (C{sub 5}Me{sub 5}Rh(Me)(CO)(4-C{sub 5}H{sub 4}N)) reacted with methyl iodide to give the stable (C{sub 5}Me{sub 5}Ir(Me)(CO)(4-C{sub 5}H{sub 4}NMe)){sup +}I{sup {minus}}. (C{sub 5}Me{sub 5}Rh(Me)(CO)(x-C{sub 5}H{sub 4}N)) (x = 3, 4) reacted with (Rh{sub 2}(CO){sub 4}Cl{sub 2}) to give the novel dinuclear adducts (C{sub 5}Me{sub 5}Rh(Me)(CO){l brace}x-C{sub 5}H{sub 4}NRh(CO){sub 2}Cl{r brace}), in which a 3- or a 4-pyridyl bridges Rh(III) and Rh(I). An X-ray determination of (C{sub 5}Me{sub 5}Rh(Me)(CO){l brace}3-C{sub 5}H{sub 4}NRh(CO){sub 2}Cl{r brace}) confirmed the structure.« less
  • Nitrogen heterocycles are present in many compounds of enormous practical importance, ranging from pharmaceutical agents and biological probes to electroactive materials. Direct funtionalization 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 their work in this area, emphasizing the relevant mechanistic insights that enabled synthetic advances and distinguished the resulting transformations from other methods.more » They 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. They then developed conditions that exploited microwave heating to expedite these reactions. While investigating the mechanism of this transformation, they discovered that a novel substrate-derived Rh-N-heterocyclic carbene (NHC) complex was involved as an intermediate. They then synthesized analogous Rh-NHC complexes directly by treating precursors to the intermediate [RhCl(PCy{sub 3}){sub 2}] with N-methylbenzimidazole, 3-methyl-3,4-dihydroquinazolein, 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{sub 3}){sub 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 co-catalysts accelerate the alkylation, they 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. They demonstrated the utility of this methodology in the synthesis of natural products, drug candidates, and other biologically active molecules. In addition, they developed conditions to directly arylate these heterocycles with aryl halides. The initial conditions that used PCy{sub 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. They 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, they 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.« less