Ir-Catalyzed Cascade C–H Fusion of Aldoxime Ethers and Heteroarenes: Scope and Mechanisms

Abstract

A concise synthesis of phenanthridine derivatives is achieved by an iridium-catalyzed direct fusion of oxime ethers and heteroarenes, which is a successful example of a cascade C–H/C–H cross-coupling/cyclization strategy for polycyclic heteroaromatic synthesis. By subtle tuning of the reaction conditions, both benzo- and simple five-membered heteroarenes are suitable substrates under similar but different conditions. The key is the right choice of a silver salt. The detailed mechanistic study discloses that the first C–H/C–H cross-coupling step involves an [IrII]–[IrIV] catalytic cycle, which needs Ag2O as the oxidant. For the second cyclization step, a radical process takes control in the reactions of benzoheteroarenes and Ag2O is required; however, a C–H cyclization functions in the reactions of simple five-membered heteroarenes involving an [IrI]–[IrIII] catalytic cycle, and AgTFA is necessary.

HFIP in Organic Synthesis

“…An iridium-catalyzed cascade C–H/C–H cross-coupling/cyclization of oxime ethers and heteroarenes provides phenthanthridine derivatives (Scheme ). HFIP provided significantly higher yields than TFE and DCE, and only trace amounts of product were observed in i -PrOH. Select substrates underwent competing diheteroarylation/cyclization, reducing scope; this could be ameliorated by switching the ratio of the oxime ether/heteroarene from 1:2 to 2:1.…”

Recent Advances in Heterocyclic Nanographenes and Other Polycyclic Heteroaromatic Compounds

“…Synthesis of heterofused pyrene derivative 145.3 was achieved by an iridium-catalyzed direct fusion of pyrene-1-oxime methyl ether 145.1 and benzothiophene 145.2 , which is a successful example of a cascade C–H/C–H cross-coupling/cyclization strategy ( Scheme 145 ). 282 The reaction was proposed to begin with an oxime-directed C–H activation of 145.1 followed by C–H arylation of benzothiophene in an [Ir II ]–[Ir IV ] catalytic cycle with Ag 2 O as the terminal oxidant. The resulting cross-coupled intermediate underwent cyclization via two consecutive one-electron oxidations by Ag 2 O.…”

“… a Reagents and conditions: (a) [Cp*IrCl 2 ] 2 , AgSbF 6 , Ag 2 O, Zn­(OTf) 2 , hexafluoroisopropanol, 140 °C, 24 h. …”

Ligand-promoted palladium-catalyzed β-methylene C–H arylation of primary aldehydes

“… 7 Although the masking of the aldehyde moiety into an oxime, for example, enabled the formation of stable 5-membered palladacycles, affording β-functionalized products, this system requires the installation of the directing group prior to the functionalization, as well as the subsequent unmasking upon the reaction completion, compromising the step economy and atom efficiency of the overall process. 8 Besides, some masking and unmasking protocols might not be compatible with select substrates, especially ones rich in functional groups. As a result, the development of a one-step direct approach to the β-C–H functionalization of free aliphatic aldehydes was a demanding target for synthetic chemists.…”