Synthesis of New Bis(spiro-β-lactams) via Interaction of Methyl 1-Bromocycloalcanecarboxylates with Zinc and N,N′-Bis(arylmethylidene)benzidines

Abstract

Interaction of the Reformatsky reagents, prepared from methyl 1-bromocyclopentane-1-carboxylate or methyl 1-bromocyclohexane-1-carboxylate, with N,N′-bis(arylmethylidene)benzidines has given rise to a set of intermediates as a result of nucleophilic addition to the C=N group of a substrate. Further intramolecular attack of the amide nitrogen atom onto the ester carbonyl group is responsible for the ring closure, which affords two series of spirocompounds: 2,2′-([1,1′-biphenyl]-4,4′-diyl)bis(3-aryl-2-azaspiro[3.4]octan-1-one) or 2,2′-([1,1′-biphenyl]-4,4′-diyl)bis(3-aryl-2-azaspiro[3.5]nonan-1-ones).

Recent Advances in the Synthesis of Spiro‐β‐Lactams and Spiro‐δ‐Lactams

“…Kirillov et al synthesized a library of eleven bis(spiro-β-lactams) containing a spiro cyclohexane ring 72, by exploring the Reformatsky reaction between methyl 1-bromocyclohexanecarboxylate 71 and N,N-bis(arylmethylidene)benzidines 70 as the first step (Scheme 19). [36] In the presence of Zn, methyl 1-bromocyclohexanecarboxylate forms Reformatsky reagent 73 which reacts with the bis-imine to form the corresponding adduct 74. The adduct spontaneously cyclizes and forms the lactam ring, affording the bis-spiro-cyclohexane-β-lactam 72 with elimination of bromozinc methoxide.…”

Recent synthetic strategies of spiro-azetidin-2-one, -pyrrolidine, -indol(one) and -pyran derivatives-a review

“…Kirillov et al synthesized a library of eleven bis(spiro- β -lactams) 24, using the Reformatsky reaction between methyl-1-bromo-cyclohexanecarboxylate (23) and N , N -bis-(arylmethylidene)benzidines 22 as the first step ( Scheme 6 ). 52 …”

“…51 Concerning the proposed reaction mechanism, 51 the rst step of the reaction involves a reaction between the aryl acetic acid Kirillov et al synthesized a library of eleven bis(spiro-b-lactams) 24, using the Reformatsky reaction between methyl-1-bromo-cyclohexanecarboxylate (23) and N,N-bis-(arylmethylidene)benzidines 22 as the rst step (Scheme 6). 52 Zinc metal would presumably react with methyl 1-bromocyclohexanecarboxylate to form Reformatsky reagent 25, which would react with the bis-imine to form the corresponding adduct 26 (Scheme 7). The adduct spontaneously cyclizes and forms the lactam ring, affording the bis-spiro-cyclohexane-b-lactam 24 52 with elimination of bromo-zinc methoxide.…”

“…52 Zinc metal would presumably react with methyl 1-bromocyclohexanecarboxylate to form Reformatsky reagent 25, which would react with the bis-imine to form the corresponding adduct 26 (Scheme 7). The adduct spontaneously cyclizes and forms the lactam ring, affording the bis-spiro-cyclohexane-b-lactam 24 52 with elimination of bromo-zinc methoxide. Bis(spiro-b-lactams) 24 were isolated in good yields (69-84%) (Scheme 7).…”

Synthesis of α‐Heterocycle Anchored Spirocyclic Azetidin‐2‐ones in a Minute by p‐TSA Catalyzed Cyclocondensation of Azetidin‐2,3‐diones with Difunctionalized Substrates

“…Effective cholesterol absorption inhibiting, anti‐MRSA active, antifungal and antibacterial properties have been disclosed for spirocyclic β‐lactams ( I – IV ) (Figure 1). [21] In addition, their efficacy as antiviral, [22] antimalarial, [23] antinociceptive, [24] anticancer, antitumor, antiproliferative [16b,25] and antibacterial agents [20b,26] is well documented in the literature. Further, these spiranic azetidin‐2‐ones have also been recognized as β‐lactamase inhibitors, [19,27] 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) inhibitors, [28] acyl‐CoA: cholesterol acyltransferase inhibitors, [18b] β‐turn nucleators and β‐turn mimetics [29a,b] as well as modulator of synaptic plasticity processes [29c]…”