7‐Oxa‐4‐thia‐1‐aza‐bicyclo[3.2.1]octane 4,4‐Dioxides: Mechanochemical Synthesis by Tandem Michael Addition–1,3‐Dipolar Cycloaddition of Aldoximes and Evaluation of Antibacterial Activities

Abstract

A solvent‐free, green, and efficient mechanochemical method for the synthesis of a series of bridged bicyclo aza‐sulfone derivatives, namely 7‐oxa‐4‐thia‐1‐aza‐bicyclo[3.2.1]octane 4,4‐dioxides through tandem Michael addition–1,3‐dipolar cycloaddition of aldoximes was developed. Mechanochemical grinding/milling facilitates quick formation of aldoximes from corresponding aldehydes and hydroxylamine, which upon reaction with divinyl sulfone in a mixer mill affords 7‐oxa‐4‐thia‐1‐aza‐bicyclo[3.2.1]octane 4,4‐dioxide derivatives in good overall yields. The newly synthesized bicyclo aza‐sulfone derivatives 4 were screened for antibacterial activities. Mostly bicyclo aza‐sulfones derived from electron‐rich aromatic aldehydes inhibit the growth of Mycobacterium smegmatis (mc2155) and those from aliphatic aldehydes the growth of Escherichia coli (DH5α) in moderate to good effect. However, butyraldehyde‐derived compound 4r was very effective against both M. smegmatis and E. coli. The key advantages of this mechanochemical method are catalyst‐ and solvent‐free conditions, shorter reaction time, and formation of a new series of 7‐oxa‐4‐thia‐1‐aza‐bicyclo[3.2.1]octane 4,4‐dioxide derivatives, which are good antibacterial agents against M. smegmatis and E. coli.

A simple and efficient route to 2‐arylimidazo[1,2‐a]pyridines and zolimidine using automated grindstone chemistry

“…The reaction possibly proceeds via a dehydrogenative cyclocondensation 19 step instead of Ortoleva−King reaction 21 (Scheme 2). It is presumed because the reaction can be efficiently performed only by the catalytic and not stoichiometric amount of I 2 .…”

“…Next, the pyridyl nitrogen attacks the enamine to form the cyclic zwitterionic intermediate, which undergoes 1,2‐H shift to form 2,3‐dihydro‐imidazo[1,2‐a]pyridine ( B ). In the final step oxidative aromatization takes place by the areal oxygen 19 to afford the product.…”

“…In this direction, “mechanochemistry,” carried out by grinding or milling, has garnered a lot of attention over the last decade, owing to its green attributes such as solvent‐free (or solvent‐less), clean, safe, atom economic and time‐efficient method 16 . Although “ball‐milling” is an efficient and versatile technique for organic transformations, 16 simple manual grinding in a mortar‐pestle, introduced by Toda et al, 17 is gradually becoming an effective tool for a variety of organic reactions 18,19 including Micheal addition, 18 Claisen‐Schmidt condensation, 18 Wittig reaction, 18 Horner‐Wadsworth‐Emmons reaction 18 organocatalysis, 18 peptide synthesis, 18 heterocycle construction, 18,19 multicomponent reactions 18 and even the synthesis of APIs 18 . Operational and instrumentation simplicity makes it a very useful method at laboratory scale and scope for adequate experimental set‐up at large scale adds value from the industrial perspective as well.…”

“…However, the labor‐intensive hand‐grinding, carried out by a person, raises some concerns like does the reaction kinetics depend on the physical power, how long the grinding can be continued, or what about scalability. These can be largely addressed by automation in the grinding process 19 . We envisaged, electrical grinding with known parameters and uninterrupted grinding may provide better reproducibility and offers scope for scalability yet avoids intricate milling equipment.…”

“…We envisaged, electrical grinding with known parameters and uninterrupted grinding may provide better reproducibility and offers scope for scalability yet avoids intricate milling equipment. As a part of our ongoing interest in mechanochemical organosynthesis, 19,20 we report herein, the use of automated grindstone chemistry for efficient synthesis of a series of 2‐arylimidazo[1,2‐a]pyridines including the marketed drug zolimidine. The syntheses of 2‐arylimidazo[1,2‐a]pyridines were achieved by grinding a mixture of acetophenones with 2‐aminopyridines in the presence of I 2 as catalyst in an Agate mortar‐pestle (Scheme 1).…”