Facile and rapid route for the synthesis of novel norstatine analogs via PADAM-cyclization methodology

Abstract

The following report describes novel methodology for the rapid synthesis of unique conformationally constrained norstatine analogs of potential biological relevance. A PADAM (Passerini reaction – Amine Deprotection – Acyl Migration reaction) sequence is followed by a TFA-mediated microwave-assisted cyclization to generate the final benzimidazole isostere of the norstatine scaffold in moderate to good yields. The applicability of this solution phase methodology to the preparation of a small collection of compounds is discussed.

Six‐Component Reactions and Beyond: The Nuts and Bolts

“…[20] This organic reaction is popular nowadays as the Passerini three-component reaction (P-3CR) and has found significant utility in the design of protease inhibitors. [21] About thirteen years later in 1934, we witnessed the report from Bucherer and Bergs who were the first to devise a fourcomponent reaction. The BuchererÀ Bergs reaction is the reaction of cyanohydrins or carbonyl compounds (ketones or aldehydes) with potassium cyanide and ammonium carbonate to render hydantoin derivatives.…”

“…The year 1921 was a pivotal tipping point with the report of the first isocyanide‐based multicomponent reaction (IMCR) by another Italian chemist Mario Passerini, who serendipitously discovered that isocyanides react with carbonyl compounds and carboxylic acids in one‐step to generate α‐acyloxycarboxamides [20] . This organic reaction is popular nowadays as the Passerini three‐component reaction (P‐3CR) and has found significant utility in the design of protease inhibitors [21] . About thirteen years later in 1934, we witnessed the report from Bucherer and Bergs who were the first to devise a four‐component reaction.…”

The 100 facets of the Passerini reaction

“…Using the special isocyanide 60, he obtained a series of benzimidazoles 63, isosteres of norstatines ( Scheme 14 ). 40 After the Passerini reaction, the depsipeptide 61 was converted as usual to 62. Further treatment under acidic conditions at higher temperatures brought about condensation to give the imidazole ring.…”

Unexpected Formation of 5‐Nitro‐1H‐benzimidazoles by Nucleophilic Recyclization of 1‐Methyl‐5‐nitropyridinium Salts

“…Modern methods of synthesis of benzimidazoles are presented by Pd‐catalyzed carbonylation of aryl halides with o ‐phenylenediamines and intramolecular Pd‐catalyzed N ‐arylation of o ‐bromophenylamidines . Also, the synthesis of benzimidazoles by cyclization of Passerini reaction products in the presence of trifluoroacetic anhydride is known . Recently, a new method for the synthesis of 2‐hetaryl benzimidazoles by acid‐catalyzed quinoxaline–benzimidazole rearrangement was proposed .…”