Exploiting Phosphonate Chemistry in Metal-Mediated Dearomatization:  Stereoselective Construction of Functionalized Spirolactams from Arene Ruthenium Complexes

Abstract

Arene ruthenium complexes possessing beta-amido phosphonate side chains participate in intramolecular spirocyclization reactions to deliver stable cyclohexadienyl ruthenium adducts. Spirocyclization is accomplished via a tandem two-step sequence that involves stereoselective nucleophilic aromatic addition to the ipso position of the coordinated arene, followed by intermolecular Horner-Wadsworth-Emmons olefination. The resulting eta5-cyclohexadienyl complexes can then be diastereoselectively converted to metal-free azaspiro[4.5]decane derivatives upon oxidative demetalation in the presence of suitable nucleophiles. An asymmetric spirocyclization was demonstrated through application of this procedure to a beta-amido phosphonate prepared from (S)-(-)-alpha-methyl benzylamine. The expected spirolactam product was obtained as a single enantiomer.

Discovery of Stabilized Bisiodonium Salts as Intermediates in the Carbon–Carbon Bond Formation of Alkynes

“…[10] The introduction of nucleophiles in known spirocyclization procedures has rarely been reported. [11] Thus, the range of products 4 obtained by our method was quite different from that described by others, [12] and various spirocycles that are difficult to obtain, such as spiro products containing fluoro, oxygen, and nitrogen functionalities, could be prepared. This flexibility is the distinct advantage of the method with the stabilized salts 1.…”

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

“…[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.…”

“…and the resulting cyclohexadienyl complex was spectroscopically indistinguishable from material prepared previously by reaction of 2 and formaldehyde. [12] The choice of solvent proved to be critical for the success of this transformation. While reactions performed in CH 3 CN also provided 4 (albeit in diminished yield relative to that in dimethoxyethane (DME)), the use of CH 2 Cl 2 , THF, or dimethylformamide (DMF) resulted in no reaction.…”

“…[12,15] These procedures are applicable to the products of MBH-type spirocyclizations as well. For example, mild oxidation of 14 and 26 b cleanly delivered the demetalated dienones 27 and 28, respectively (Scheme 5).…”

“…A particularly salient example is illustrated in Equation (2), in which chiral nonracemic (S)-16 is converted to enantiomerically pure (À)-29 with recovery of the {CpRu} fragment. [12] Thus, this combination of metal-assisted cyclization followed by oxidative demetalation results in heterocycle construction by means of net Ru-mediated dearomatization. [16] The facility with which N-benzyl and N-phenethyl acrylamide complexes participate in the spirocyclizations described above is in stark contrast to the sluggish reactivity normally displayed in conventional MBH-type reactions.…”