Rhodium(III)-Catalyzed Arene and Alkene C−H Bond Functionalization Leading to Indoles and Pyrroles

Abstract

Recently, the rhodium(III)-complex [Cp*RhCl(2)](2) 1 has provided exciting opportunities for the efficient synthesis of aromatic heterocycles based on a rhodium-catalyzed C-H bond functionalization event. In the present report, the use of complexes 1 and its dicationic analogue [Cp*Rh(MeCN)(3)][SbF(6)](2) 2 have been employed in the formation of indoles via the oxidative annulation of acetanilides with internal alkynes. The optimized reaction conditions allow for molecular oxygen to be used as the terminal oxidant in this process, and the reaction may be carried out under mild temperatures (60 °C). These conditions have resulted in an expanded compatibility of the reaction to include a range of new internal alkynes bearing synthetically useful functional groups in moderate to excellent yields. The applicability of the method is exemplified in an efficient synthesis of paullone 3, a tetracyclic indole derivative with established biological activity. A mechanistic investigation of the reaction, employing deuterium labeling experiments and kinetic analysis, has provided insight into issues of reactivity for both coupling partners as well as aided in the development of conditions for improved regioselectivity with respect to meta-substituted acetanilides. This reaction class has also been extended to include the synthesis of pyrroles. Catalyst 2 efficiently couples substituted enamides with internal alkynes at room temperature to form trisubstituted pyrroles in good to excellent yields. The high functional group compatibility of this reaction enables the elaboration of the pyrrole products into a variety of differentially substituted pyrroles.

Wenn C‐H‐Bindungen sprechen könnten – selektive Oxidationen von C‐H‐Bindungen

“…[79] Bei der oxidativen Anellierung des Acetanilids 63 mit 1-Phenyl-1-propin zu einem Indol wird bei der C-H-Aktivierung mit [Cp*Rh(MeCN) 3 ][SbF 6 ] 2 eine hervorragende Selektivität für die weniger gehinderte C-H-Bindung beobachtet. [80] Eine Differenzierung zwischen elektronisch ähnlichen Positionen mit nur geringen Unterschieden in ihrer sterischen Umgebung gelang durch palladiumkatalysierte C-H-Aktivierungen mit geschützten Aminosäureliganden (64). [81] In diesem Beispiel wurde ohne Liganden nahezu keine Selektivität beobachtet; eine erste mechanistische Untersuchung sowie eine Optimierung der ursprünglichen Bedingungen wurden kürzlich veröffentlicht.…”

An Atom-Economic Synthesis of Nitrogen Heterocycles from Alkynes

“…4 The addition of terminal alkyne 2 to suitably activated propargyl amine 1 under alkyne cross-coupling conditions 5 would result in ynenoate 3, whose isomerization via a 5-endo-dig cyclization and tautomerization would then provide pyrrole 5 (Scheme 1). 6 While this sequence represents an efficient, isohypsic 7 entry into 2,4-disubstituted pyrroles, 8 we anticipated that intermediates 3 and 4 could serve as strategic points of product diversification if suitable conditions could be found for their selective preparation. 9 In this regard, we viewed the design of a flexible route to topologically varied 5-membered nitrogen heterocycles as an intriguing challenge for atom-economic reaction design.…”

Synthesis of π-Conjugated Polymers Containing Benzodipyrrole Moieties in the Main Chain through Cleavage of C–H Bonds in 1,4-Bis(acetylamino)benzene

“…7 Fagnou and co-workers developed facile synthesis of indoles by rhodium-catalyzed C−H bond cleavage of acetanilide and alkyne insertion. 8 The reaction proceeded under mild condition and gave indoles in good yield and high regioselectivity. Herein, we applied the C−H functionalization leading to indoles to synthesis of π-conjugated polymers containing N-heteroarenes in the main chain.…”