Knoevenagel Adducts as Trimethylenemethane Dipole Surrogates

Abstract

Knoevenagel adducts derived from readily available acetoxyacetone and malonic acid derivatives served as trimethylenemethane surrogates for formal 1,3-difunctionalization through a sequence of selective γ-deprotonation/α-alkylation and palladium(0)-catalyzed allylic alkylation. Herein, we report the discovery and development of a three-component 1,3-difunctionalization of Knoevenagel adducts as well as a unique palladium(0)-catalyzed branch-selective allylic alkylation.

Transient [3,3] Cope rearrangement of 3,3-dicyano-1,5-dienes: computational analysis and 2-step synthesis of arylcycloheptanes

“…The regioselectivity was also unexpected as alkyl electrophiles ( e.g. alkyl halides and allyl acetates/carbonates) tend to yield deconjugative alkylation products 19,20. Thus, this result raises the question as to whether 3 is accessed by a [3,3] rearrangement21 as originally proposed or by a direct γ-allylation mechanism 20.…”

Assembly of Terpenoid Cores by a Simple, Tunable Strategy

“…Our goal is to devise an analog‐oriented 11 synthetic route to polycyclic terpenoid frameworks where sole carbon sources are abundantly available and the reactions utilized are operationally simple thus allowing for rapid structural tuning. We have envisaged a sequence utilizing ketone‐derived Knoevenagel adducts 1 and allylic electrophiles 2/2′ (Scheme ) . Specifically, deconjugative alkylation between Knoevenagel adduct 1 and allylic electrophile 2 yields 1,5‐dienes 3 , which can undergo a conjugation‐driven [3,3] Cope rearrangement to γ‐allyl Knoevenagel adduct 4 ,,,.…”

“…We have envisaged a sequence utilizing ketone‐derived Knoevenagel adducts 1 and allylic electrophiles 2/2′ (Scheme ) . Specifically, deconjugative alkylation between Knoevenagel adduct 1 and allylic electrophile 2 yields 1,5‐dienes 3 , which can undergo a conjugation‐driven [3,3] Cope rearrangement to γ‐allyl Knoevenagel adduct 4 ,,,. Repeating the deconjugative alkylation with allylic electrophile 2′ followed by ring‐closing metathesis (RCM) yields common terpenoid cores 6 where substitution patterns can be modified by choice of Knoevenagel adduct 1 and allylic electrophiles 2 and 2′ .…”

Function‐Oriented and Modular (+/−)‐cis‐Pseudoguaianolide Synthesis: Discovery of New Nrf2 Activators and NF‐κB Inhibitors

“…Specifically,w ee nvisaged formationo ft he quaternary center on 3 by an alkylation reaction betweenc yclopentane-1,3-dione 1 and ab utyne-1,4-diol derivative 2.F rom here, Knoevenagel condensation with am alonic acid derivative 4 would yield an alkylidenemalonic acid derivative 5 that in turn can undergo mild deconjugativea llylation (with 6)d ue to the increased acidity of the g-CÀHb ond. [56,57] Finally,r ing-closing enyne metathesis [58] would yield an advanced intermediate 8 (via 7) that bears the enone (albeit deconjugated) and an allyl alcohol, which can be converted into the targeted acrylate moiety by straightforward functional group interconversions (deprotection then oxidation). Recently,ring-closing enyne metathesis was used to synthesize the related guaianolide framework in % 12 steps.…”