Ruthenium-Coordinated Spirolactams via Intramolecular Nucleophilic Addition to η⁶-Arene Metal Complexes

Abstract

Cyclohexadienyl ruthenium(II) complexes incorporating an azaspirocyclic ring system have been prepared from (η6-N-benzyl acetoacetamide)CpRu(II) precursors via an intramolecular nucleophilic aromatic addition/enolate trapping reaction sequence. The spirocyclization process was found to be applicable to a variety of alkyl-, alkoxy-, and chloro-substituted N-benzyl acetoacetamide ligands, and isolated yields of the cyclohexadienyl products ranged from 44% to 86%. In contrast, related arene ruthenium complexes prepared from benzyl acetoacetate and phenethyl acetoacetamide failed to undergo spirocyclization, but were found to participate in intramolecular SNAr reactions (leading to formation of tetralone and benzazepinone ring systems, respectively). Thus, the conformational mobility of the side chain linking the nucleophilic center to the coordinated arene ring appears to be important in governing the regioselectivity of aromatic addition in these reactions. Several spirolactam complexes were reduced with LiAlH4 to the corresponding Ru-coordinated spirocyclic amines; however, attempts to remove the cyclohexadienyl moiety from the CpRu(II) center via ligand protonation were unsuccessful.

3 Transition metals in organic synthesis : Part (ii) Stoichiometric applications

“…Pigge and co-workers have addressed this, reporting that Ru-coordinated spirolactams may be been synthesised by an intramolecular nucleophilic aromatic addition-enolate trapping sequence with (η 6 -arene)Ru complexes. 91 It was originally envisaged that the stabilised anion generated from A would be capable of participating in a Ru-mediated intramolecular S N Ar reaction to deliver tetrahydroisoquinolinone B (Scheme 18). However the stereo-and regioselective aromatic addition leading to C is the favoured process.…”

Synthesis of Polycyclic Cyclohexadienyl Ruthenium(II) Complexes from η6-Arene Precursors via Phosphine-Promoted Intramolecular Nucleophilic Aromatic Addition

“…For the past several years we have been developing Ru-mediated dearomatization reaction sequences that lead to generation of 2-azaspiro[4.5]decanes starting from various (η 6 - N -benzylamide) complexes. , A particularly straightforward procedure utilizing simple benzyl acrylamides is illustrated in Scheme . Conversion of 1 to 2 is envisioned to proceed via Michael-type addition of a phosphine promoter to the acrylamide side chain.…”

Synthesis of 1-substituted 2-azaspiro[4.5]deca-6,9-dien-8-ones and 2-azaspiro[4.5]deca-1,6,9-trien-8-ones by condensation of 2,6-dimethylphenol with isobutyraldehyde and nitriles

“…2-Azaspiranes can also be obtained by oxidative radical ipsocyclization of N-[p-methoxy(hydroxy)benzyl]acetamides [18] and substituted N-benzyltrichloroacetamides [19]. Pigge et al [20][21][22][23][24] developed a procedure for the synthesis of 2-azaspiranes via aromatic nucleophilic substitution in the presence of (η 6 -arene)RuCp + complexes. Another possible way to 2-azaspiranes is based on the reaction of tricarbonyl (η 5 -1-alkyl-4-methoxycyclohexadienylium)iron with difunctional nucleophiles [25].…”