Synthesis of Dihydroquinolinone Derivatives via the Cascade Reaction of o-Silylaryl Triflates with Pyrazolidinones

Abstract

Presented herein is a novel synthesis of dihydroquinolinone derivatives through an unprecedented cascade reaction of o-silylaryl triflates with pyrazolidinones. Mechanistically, the formation of the title products is believed to involve a cascade procedure including in situ formation of aryne and its addition with pyrazolidinone followed by N−N bond cleavage and intramolecular C−C bond formation/annulation. Compared with literature methods for the synthesis of dihydroquinolinones, this protocol has advantages such as multistep transformations accomplished in one pot, broad substrate scope, mild reaction conditions, and good tolerance of diverse functional groups. In addition, the products thus obtained demonstrated significant in vitro antiproliferative activity in selected human cancer cell lines.

Copper-catalyzed dehydrogenative cyclization/alkenylation towards dihydroquinolinones

“…Encouraged by this reaction outcome, we further optimized the reaction by adding TBAB : oxalic acid (1 : 1 (100 : 100 mg)) DES to step 2, leading to an increased product yield of 52% (Table 1, entry 12). Based on this result, the reactions were further explored using TBAB-based DESs such as TBAB : tartaric acid (1 : 1), TBAB : citric acid (1 : 1), TBAB : ethylene glycol (1 : 1), TBAB : succinic acid (1 : 1), TBAB : sucrose (1 : 1), TBAB : glycerol (1 : 1) and TBAB : PTSA (1 : 1) (Table 1, entries [13][14][15][16][17][18][19]. From these trials, we have observed that a 58% yield of product 4A was achieved using the TBAB : PTSA (1 : 1) DES ( 1, entries 23-27).…”

“…Meanwhile, here Cu( ii ) and TEMPO facilitate the dehydrogenation of alcohol 3 , to form aldehyde 3′ . 18 Then, aldehyde 3′ undergoes a nucleophilic addition to the enamine intermediate C′ , followed by condensation, leading to the formation of intermediate 4 . Furthermore, intermediate 4 undergoes a Knoevenagel condensation 43 with another mole of aldehyde ( 3′ ) to form the final product 5 .…”

“…15 Additionally, α-alkenylation of ketones and C(sp 3 )-H functionalization of 2-methyl azaarenes was achieved using a series of transition-metal catalysts, listed in Scheme 1b. [16][17][18][19][20] Although these methods described in the literature are broadly effective and successful, some of them still face challenges, in terms of lengthy multi-step protocols, environmentally harmful reaction conditions, limited diversity of the starting materials, costly metal catalysts and the utilization of volatile organic solvents. Hence, the development of easier, more straightforward, broadly applicable and versatile approaches for the synthesis of functionalized quinolinyl quinolinones remains in high demand.…”

“…Subsequently, intermediate B undergoes an O 2induced aromatization, leading to the formation of intermediate C. 13In addition, the DES induces imine-enamine tautomerism in intermediate C through H-bonding interactions with the nitrogen atom, which leads to the formation of intermediate C′. Meanwhile, here Cu(II) and TEMPO facilitate the dehydrogenation of alcohol 3, to form aldehyde 3′ 18. Then, aldehyde 3′ undergoes a nucleophilic addition to the enamine intermedi-ate C′, followed by condensation, leading to the formation of intermediate 4.…”

Recent Advances for the Synthesis of Dihydroquinolin-2(1H)-ones via Catalytic Annulation of α,β-Unsaturated N-Arylamides

“…The importance of this skeleton compound has stimulated activities of the synthesis community to develop new transformation strategies that can obtain DHQO compounds. In the past decades, some new synthetic methods have been continuously developed, such as the Pd-catalyzed Heck reduction-cyclization reaction [7], Pd-catalyzed cyclopropane ring expansion [8], Mn-mediated intramolecular cyclization [9], Rh-mediated Michaeladdition (1,4-additions) of the boronic acid to enone [10], Ru catalyzed cyclization of 1,4,2-dioxazol-5-ones [11], photoredox strategy from anilines, oxalyl chloride and electrondeficient alkenes [12], and so on [13][14][15][16][17][18][19]. Among these, using α,β-unsaturated N-arylamides as the key substrates via different cyclization reactions has been shown as a fast, simple, and atom-economic strategy.…”