Direct Synthesis of Protoberberine Alkaloids by Rh‐Catalyzed C−H Bond Activation as the Key Step

Abstract

A one-pot reaction of substituted benzaldehydes with alkyne-amines by a Rh-catalyzed C-H activation and annulation to afford various natural and unnatural protoberberine alkaloids is reported. This reaction provides a convenient route for the generation of a compound library of protoberberine salts, which recently have attracted great attention because of their diverse biological activities. In addition, pyridinium salt derivatives can also be formed in good yields from α,β-unsaturated aldehydes and amino-alkynes. This reaction proceeds with excellent regioselectivity and good functional group compatibility under mild reaction conditions by using O2 as the oxidant.

A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry

“… 306 The second protocol was only a two component reaction, because the amine carried already an alkyne function for a subsequent intramolecular cyclisation. 307 Also for this much more complex ring systems, good to excellent yields were reported surpassing 80% in almost every example. Via this route, facilitated access to protoberine alkaloids was granted.…”

“…Both contributions in this field stem from the group of Cheng and run under Rh catalysis. 306 , 307 In the first report, a three component reaction was carried out between a ketone or an aldehyde, an amine, and an internal alkyne. Via the imine intermediate, the desired pyridinium salts were formed quite efficiently with typical yields of >80%.…”

Recent Advances in [Cp*MIII] (M = Co, Rh, Ir)‐Catalyzed Intramolecular Annulation Through C–H Activation

“…The pyridinium skeleton is another important feature found in numerous natural products such as protoberberine alkaloids that possess numerous biological activities such as antimalarial, antitumor, etc. To access this scaffold, Cheng and co‐workers developed a one procedure with in‐situ formation of an imine functionality from benzaldehydes 72 (or heteroaromatic aldehydes) and suitable amines 73 (Scheme ) . Thus, the in‐situ generated directing group allowed the C–H activation reaction in the presence of [Cp*RhCl 2 ] 2 or [Cp*Rh(MeCN) 3 ][SbF 6 ] 2 as catalyst, with Cu(BF 4 ) 2 · 6H 2 O (45 mol‐% or 60 mol‐%) and O 2 (1 atm) as oxidants, in MeOH (60 °C) or t BuOH (90 °C).…”

Cascade One‐Pot Synthesis of Orange‐Red‐Fluorescent Polycyclic Cinnolino[2,3‐f]phenanthridin‐9‐ium Salts by Palladium(II)‐Catalyzed C−H Bond Activation of 2‐Azobiaryl Compounds and Alkenes

“…The product 4 ab‐OH resulted from a reaction using pivalic acid as an additive, and this adduct was further converted into 1,2‐diazo ylide 5 ab by an addition reaction. To improve its stability, 4 ab‐Cu , in which the anion is likely to be CuCl 3 − , was further treated with AgBF 4 to give the stable BF 4 − salt product 4 ab , and AgCl and Cu were precipitated (see Figure S1).…”