One-Pot Preparation of 9,10-Dihydrophenanthrenes Initiated by Rhodium(III)-Catalyzed C–H Activation and Relay Diels–Alder Reaction

Abstract

An efficient one-pot synthesis of multisubstituted 9,10-dihydrophenanthrenes from easily available 2-arylazaarenes and cyclohexadienone-tethered terminal alkynes (1,6-enynes) has been successfully achieved. This domino reaction proceeded smoothly through Cp*Rh­(III)-catalyzed C–H activation, direct protonation of alkenyl-Rh intermediates, intramolecular Diels–Alder reaction, alkene isomerization, subsequent ring-opening aromatization, and acetylation. This strategy was pot-economical and tolerated a wide range of functional groups. Moreover, the potent anticancer activities against HepG2 cells were observed for these artificial 9,10-dihydro­phenanthrene derivatives.

Discovery of 9,10-dihydrophenanthrene derivatives as SARS-CoV-2 3CLpro inhibitors for treating COVID-19

“…Of them, some compounds showed good inhibitory activities and were selected for further IC 50 values investigation. It was worth noting that the functional groups of our screened compounds varied at the positions R 1 , R 2 , and R 3 , which was because of the limitations of our invented synthetic methodology [ 37 ]. As shown in Table 1 , we summarized the SARs of the tested 9,10-dihydrophenanthrene derivatives.…”

“…The designed compounds were prepared according to our previously reported synthetic method, which is shown in Scheme 1 [ 37 ]. First, the substrates cyclohexadienone-containing 1,6-enynes 16 and 17 were prepared from commercially available 4-bromo-4′-hydroxybiphenyl and 4-cyclohexylphenol, respectively, using propargyl alcohol and phenyliodine (III) diacetate (PIDA).…”

Propargylic Alcohols as Coupling Partners in Transition‐Metal‐Catalyzed Arene C−H Activation

“…This domino reaction proceeded through Micheal addition/protonation of alkenyl‐Rh intermediates, intramolecular Diels‐Alder reaction, alkene isomerization, successive ring‐opening aromatization, and acetylation by the aid of AcOH (Scheme 48). [50] Interestingly, a novel 9,10‐dihydrophenanthrene alcohol adduct ( A ) exhibited excellent anticancer activity against human hepatocellular carcinomas (HepG2) cells (IC50=0.20 μM). The utility of this method was showcased by applying this strategy to various other directing groups like quinoline, isoquinoline, pyrazole, pyrimidine and purine went successful with moderate yields.…”

Synthesis of Decahydrocyclobuta[cd]indene Skeletons: Rhodium(III)‐Catalyzed Hydroarylation and Relay Thiophene‐Promoted Intramolecular [2+2] Cycloaddition

“…Very recently, we reported a Rh(III)‐catalyzed one‐pot preparation of 9,10‐dihydrophenanthrenes . During the exploration of different substrates, it was serendipity that the expected intramolecular Diels‐Alder (IMDA) product 3aa’ was not observed when 1,6‐enyne 1 a was treated with 2‐(thiophen‐2‐yl)pyridine ( 2 a ) under standard conditions.…”

“…Very recently, we reported a Rh(III)-catalyzed onepot preparation of 9,10-dihydrophenanthrenes. [13,14] During the exploration of different substrates, it was serendipity that the expected intramolecular Diels-Alder (IMDA) product 3aa' was not observed when 1,6-enyne 1 a was treated with 2-(thiophen-2-yl) pyridine (2 a) under standard conditions. Instead, a thermally forbidden [2 + 2] cycloaddition product 3 aa was obtained in 48% yield and its structure was unambiguously confirmed by the X-ray crystallographic analysis (Scheme 2).…”