Merging Rh-catalyzed C-H Functionalization and Cascade Cyclization to Enable Propargylic Alcohols as Three-Carbon Synthons: Experimental and Computational Investigations

Abstract

Reported herein is an unprecedented reactivity of propargyl alcohols as “Three-Carbon Synthons” in a Rh(III)-catalyzed C-H functionalization of acetanilides, leading to the synthesis of core structures of isocryptolepine, gamma-carbolines, dihydrochromeno[2,3-b]indoles, and diindolylmethanes derivatives. The transformation involves a Rh(III)-catalyzed C-H functionalization and heteroannulation to yield indoles followed by a cascade cyclization with both external and internal nucleophiles to afford diverse products. The role of the hydroxy group, the key function of the silver additive, the origin of the unique reverse regioselectivity and the rate-determining step, are rationalized in conformity with the combination of experimental, noncovalent interaction analysis and DFT studies. This protocol is endowed with several salient features, including one-pot multistep cascade approach, exclusive regioselectivity, high bond-forming efficiency, and synthesis of a variety of molecular frameworks.

Silver‐Free C−H Activation: Strategic Approaches towards Realizing the Full Potential of C−H Activation in Sustainable Organic Synthesis

“… A) Rh‐catalyzed formation of indoles from aniline derivatives with alkynes [37] . B) Rh‐catalyzed synthesis of N ‐alkyl indoles via redox neutral C−H activation [86] .…”

“…A) Rh-catalyzed synthesis of indoles with alkynes. [37] B) Stoiichiometric Ag-free synthesis of indoles. [38] acetic acid at a gold disk electrode, it was deduced that quinones were reduced before the protons of the medium, whose reduction started at ca.…”

“…[36] Based on this approach, Cavallo, Tantillo, Kapur, and co-workers reported a Rh-catalyzed ortho-CÀ H activation of acetanilides specifically tuned to propargyl alcohols as alkyne reaction partners (Scheme 22A). [37] The authors coupled the resulting organometallic intermediate with an alkyne to form indole derivatives. Two equivalents of silver acetate were employed to regenerate the active species after product release.…”

Silberfreie C−H‐Aktivierung: Strategische Ansätze zur Erschließung des vollen Potenzials von C−H‐Aktivierungen in der nachhaltigen organischen Synthese

“…Wie bereits erwähnt, ist die Rh‐katalysierte oxidative Kupplung von Acetaniliden und internen Alkinen zu Indolen mit stöchiometrischen Cu‐Salzen als Oxidationsmittel gut etabliert und auf Alkine mit unterschiedlichen Substitutionsmustern anwendbar [36] . Basierend auf diesem Ansatz berichteten Cavallo, Tantillo, Kapur und Mitarbeiter über eine Rh‐katalysierte ortho ‐C−H‐Aktivierung von Acetaniliden, die speziell auf Propargylalkohole als Alkin‐Reaktionspartner abgestimmt ist (Schema 22A) [37] . Die Autoren kuppelten das entstehende metallorganische Intermediat mit einem Alkin, um Indolderivate zu bilden.…”

“… A) Rh‐katalysierte Synthese von Indolen aus Anilinderivaten mit Alkinen [37] . B) Rh‐katalysierte Synthese von N ‐Alkylindolen über redoxneutrale C−H‐Aktivierung [86] .…”