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

Abstract

Monocyclic azetidin‐2,3‐diones provide easy extensions to spiro‐fused azetidin‐2‐ones upon p‐toluenesulfonic acid (p‐TSA) catalyzed cyclocondensation reaction with difunctionalized substrates [mercaptoacids (mercaptoacetic acid, 2‐mercaptopropionic acid, 3‐mercaptopropionic acid), ethan‐1,2‐dithiol, ortho‐difunctionalized benzenes (ortho‐phenylenediamine, ortho‐aminothiophenol)]. 1,3‐Oxathiolan‐5‐one/6‐one, 1,3‐dithiolane, 2,3‐dihydrobenzo[d]imidazole and 2,3‐dihydrobenzo[d]thiazole tethered spirocyclic azetidin‐2‐ones were obtained in good overall isolated yields (69–89 %) in a very short‐time duration (max 1 min) using toluene Dean‐Stark reflux/dichloromethane rt stirring conditions. The stereochemical and spectral studies, stabilities and diastereoisomeric ratio for trans and cis spiro‐fused products are reported. The trans and cis configuration has been assigned to spiro‐β‐lactams wrt the stereochemical relationship between sulfur atom (at spiro centre) and the vicinal methine hydrogen atom at C3/C2. The absolute configuration of one trans 1,3‐oxathiolan‐5‐one fused spirocyclic azetidin‐2‐one was clearly identified by X‐ray single crystal structure analysis.

p-Toluenesulfonic acid-promoted organic transformations for the generation of molecular complexity

“…Recently, Bhalla et al constructed synthetically important spirocyclic azetidin-2-ones where easily accessible monocyclic azetidin-2,3-diones and difunctionalized substrates were used as starting precursors (Scheme 77). 124 The stabilities, diastereoisomeric ratios, as well as stereochemical and spectral analyses for the trans and cis spiro-fused products have also been well established. The reaction is catalysed by p -TSA, and cyclocondensation occurs efficiently with a short reaction time.…”

Synthesis and Biological Activities of Some Metal Complexes of 2-Thiouracil and Its Derivatives: A Review

“…It is important that complexes of 2-thiouracil with Cu(II), Ni(II), Co(II) and Fe(III) have been synthesized [30]. The compounds have been characterized via IR, UV-Vis spectroscopic methods, as well as magnetochemical measurements and DTA (Differential thermal analysis).…”

C7‐Halomethylene/methyl‐C3‐thiophenyl‐spirocyclic‐β‐lactams: Synthesis, X‐ray Analysis, Antimicrobial Evaluation, Cytotoxicity Profile and Molecular Docking Interactions

“…[33][34][35] Our previous studies have been dedicated towards the synthesis of aryl/pyrazolyl substituted spirocyclic and pyrazolo[5,1b]thiazole-3-carboxylate/(4-thiophenyl)pyrazolyl/benzimidazolyloxyphenyl conjugated heterocyclic β-lactams. [36][37][38][39] Moreover, the advancement in spirocyclic systems and charismatic contour of thiophene analogs in discovering new pharmaceutically active compounds, encouraged us to design spiro-hybrid heterocyclic building blocks with improved pharmacokinetics and safety profile. By blending various aliphatic and heterocyclic elements, we crafted a focused collection of pioneering spirocyclic-β-lactams poised as potential antimicrobial candidates.…”

“…Unsubstituted or multi‐substituted thiophene ring behaves as structural stone in diverse drug derivatives which might be assigned to its consequential pharmacokinetic significance [33–35] . Our previous studies have been dedicated towards the synthesis of aryl/pyrazolyl substituted spirocyclic and pyrazolo[5,1‐ b ]thiazole‐3‐carboxylate/(4‐thiophenyl)pyrazolyl/benzimidazolyloxyphenyl conjugated heterocyclic β‐lactams [36–39] . Moreover, the advancement in spirocyclic systems and charismatic contour of thiophene analogs in discovering new pharmaceutically active compounds, encouraged us to design spiro‐hybrid heterocyclic building blocks with improved pharmacokinetics and safety profile.…”