Morita–Baylis–Hillman Cyclizations of Arene–Ruthenium‐Functionalized Acrylamides

Abstract

The conventional Morita-Baylis-Hillman (MBH) reaction entails condensation of an a,b-unsaturated carbonyl compound with an aldehyde to afford an a-hydroxyalkyl enone. [1] The reaction proceeds by initial conjugate addition between an enone and a nucleophilic promoter (usually a tertiary amine or trialkyl phosphine) to generate a zwitterionic enolate. Addition to an aldehyde electrophile and elimination of the nucleophilic promoter completes the reaction (Scheme 1). The products of MBH reactions are useful synthetic intermediates and building blocks; hence, considerable effort has been directed toward determining the mechanistic details of this transformation.[2] Variations of MBH reactions have been reported in which reactive enolates are prepared from enones in the presence of transition-metal or Lewis acid reagents.[1a] The range of electrophilic reaction partners also has been expanded to include activated ketones, other enones, [3] allylic electrophiles (including p-allyl-palladium complexes), [4,5] alkyl halides, [6] epoxides, [7] and aryl bismuth reagents. [8] Despite these noteworthy advances, the MBH reaction remains limited in scope owing to the reluctant participation of nonactivated and/or substituted a,b-unsaturated carbonyl compounds. Acrylamides especially have proven to be particularly difficult substrates, and only a few examples of MBH reactions between simple acrylamides and activated aldehydes have been reported. [9] In contrast to this generally observed reactivity profile, we have found that N-benzyl acrylamides metalated with a {CpRu II } fragment (Cp = cyclopentadienyl) readily undergo intramolecular MBH cyclizations in the presence of added nucleophile and base (Scheme 2). The ruthenium-arene fragment serves as the electrophilic reaction partner in these transformations, resulting in formation of ruthenium-cyclohexadienyl complexes as the initial products. Subsequent demetalation then delivers highly functionalized spirolactams. These transformations represent the first examples of direct metal-arene participation in MBH-type reactions. [10] We first became interested in exploring the feasibility of the reaction sequence shown in Scheme 2 after discovering that both N-benzyl acetoacetamides (1) and N-benzyl-bamidophosphonates (2) can be converted to 2-azaspirocyclic cyclohexadienyl complexes by an initial nucleophilic aromatic addition followed by enolate trapping and olefination, respectively. [11,12] Generation of a reactive enolate by means of an MBH-type reaction of a coordinated acrylamide, however, offers a more direct and potentially more versatile entry into the azaspiro[4.5]decane framework. Initial attempts to effect the conversion of the simple (N-benzyl acrylamide)-ruthenium complex 3 to the corresponding spirocyclic derivative under MBH conditions seemingly confirmed the sluggish reactivity of unsaturated amide substrates. After considerable experimentation, however, we were pleased to find that the reaction conditions shown in Equation (1) delivered the desired produc...

Organische Chemie 2007

“…Auch bei Übergangsmetall‐Aren‐Komplexen wurde 2007 eine neue Reaktivität entdeckt: Pigge beschrieb eine Morita‐Baylis‐Hillman‐Cyclisierung an einem Ruthenium‐Aren‐Komplex (80), die zum entsprechenden Spiro‐Komplex (81) führt. Abschließende oxidative Dekomplexierung liefert Dienon (82) 75…”

Ruthenium(VIII)-Catalyzed ipso-Dearomative Spiro-Etherification and Spiro-Amidation of Phenols

“…Among the various spirocycles, spiro-oxacyclohexadienones and spiro-azacyclohexadienones are the primary targets . Extensive efforts were focused on the development of efficient methods based on hypervalent iodine reagents, ipso -halocyclization, radical cyclization, arene–Ru complex-mediated dearomatization, and Cu-catalyzed oxygenation of R- azido - N -arylamides …”

Asymmetric Construction of Quaternary Stereocenters: Synthesis of Enantiopure Amino Acid‐Based Tricyclic α,β‐Enones through an ipso‐Friedel–Crafts/Michael Addition Cascade

“…Similar structures have found applications such as novel alkaloid natural products [2] and were also evaluated for their anti-HBV (hepatitis B virus) activity. [3] Several methodologies have been previously described for the synthesis of some related structures: (i) radical cyclizations; [4] (ii) arene-Ru complex-mediated dearomatization; [5] (iii) Cu-catalyzed oxygenation of a-azido-N-arylamides; [6] (iv) hypervalent iodine reagents; [7] (v) ipso-halocyclizations [8] and (vi) Pd-catalyzed intramolecular ipso-Friedel-Crafts allylic alkylations of phenols. [9] It is noteworthy that all these reported methodologies are very limited in terms of enantioselectivity since no asymmetric versions have been developed.…”