Synthesis of Medium-Ring-Sized Benzolactams by Using Strong Electrophiles and Quantitative Evaluation of Ring-Size Dependency of the Cyclization Reaction Rate

Abstract

Benzolactams with medium-sized rings were synthesized via the electrophilic aromatic substitution reaction of carbamoyl cations (R1R2N+CO) in good to high yields without dilution. These reactions were utilized to quantitatively examine the extent of retardation of medium-sized ring formation, compared to five- or six-membered ring formation. The order of reaction rates of formation of cyclic benzolactams is six- > five- > seven- > eight- > nine-membered ring at 25 °C. The present reaction provides a route to eight- and nine-membered benzolactams.

A Lewis Acid-Promoted Michael Addition and Ring-Expansion Cascade for the Construction of Nitrogen-Containing Medium-Sized Rings

“…In contrast, their analogs such as pyrrolidine, piperidine and nitrogen-containing macrocycles are commonly found in marketed drugs [ 13 ]. Although various factors contribute to the progression of leads that ultimately become clinically approved for use as prescription drugs [ 14 , 15 , 16 , 17 ], the lack of synthetic approaches may limit the drug development process based on privileged structures involving nitrogen-containing medium-sized rings [ 12 , 18 , 19 , 20 ]. Consequently, there is an urgent demand to develop efficient protocols to access libraries of nitrogen-containing medium-sized rings as candidates for drug discovery.…”

Convenient Approach to 10‐ and 11‐Membered Azalactams

“…[5] Therefore, relatively fewer methods based on conventional general cyclization or cycloaddition reactions are available to obtain medium ring heterocycles from acyclic precursors. [6,7] Nevertheless, some elegant cycloaddition and annulation approaches have also proved useful for the synthesis of such structures, in particular there are intramolecular metalmediated [8][9][10] (especially Pd) [11,12] cyclization, diene and enyne metathesis, [13] click-chemistry. [6,14] However, ring-expansion reactions turned out to be a by far prospective strategy, which allows avoiding difficult medium-ring cyclization.…”

Synthesis of medium-ring lactams and macrocyclic peptide mimetics via conjugate addition/ring expansion cascade reactions

“…3 Ring expansion reactions are also important in synthetic chemistry, 4,5 especially for the synthesis of biologically relevant medium-sized rings and macrocycles, 6 compounds that can be difficult to make using classical end-to-end cyclisation methods. 7 This manuscript is focused on combining these two individually powerful approaches for the synthesis of macrocyclic peptide mimetics, using a novel Conjugate Addition/Ring Expansion (CARE) cascade reaction sequence.…”