Iodine-Mediated Cyclization of Enamines to Imidazole-4-Carboxylic Derivatives with Sequential Removal of Nitrogen Atoms from TMSN₃

Abstract

An iodine-mediated oxidative [4+1] cyclization of enamines with TMSN3 for the synthesis of 2,5-disubstituted imidazole-4-carboxylic derivatives has been developed. The mechanistic studies revealed that the reaction proceeds through a sequential removal of two nitrogen atoms from TMSN3. The synthetic utility was further demonstrated with a gram-scale reaction and various derivatization transformations of the products.

Multicomponent Cascade Reaction of 3-Cyanochromones: Highly Site-Selective Synthesis of 2-(1H-Imidazol-1-yl)-4H-chromen-4-one Derivatives

“…The classic methods for synthesizing imidazoles include the cyclization of 1,2-diketones and aldehydes in the presence of NH 4 OAc; metal-catalyzed cyclization of O -pentafluoro-benzoylamidoximes; [3 + 2] cyclization of 2-azidoacrylates and nitrones, amidines and alkynes, or enamines and TMSN 3 ; and the Van Leusen imidazole synthesis . Recently, novel strategies have been developed to synthesize imidazoles, including nitrile–alkyne domino-type cyclizations; [2 + 2 + 1] annulations of aryl methyl ketones, 2-aminobenzyl alcohols, and p -toluenesulfonylmethyl isocyanide (TosMIC); and others. , However, these reactions are limited in functional scope (i.e., only 2–3 bonds are typically formed in these reactions).…”

Pummerer-like Rearrangement Induced Cascade Reactions: Synthesis of Highly Functionalized Imidazoles

“…There are a number of synthetic methods developed for the synthesis of imidazole derivatives, and selected recent methods are indicated in Scheme , including palladium mediated decarboxylative couplings using amidonitriles with 2,6-dimethoxybenzoic acid, gold mediated cyclization using S , S -dimethylsulfilimine and N -allylynamides, base-promoted cyclization of nitriles and alkynes, acid-catalyzed three-component reactions of amidines with ynals and boronic acids, neighboring group assisted three-component cyclizations of aryl methyl ketones with 2-aminobenzyl alcohols and p -toluenesulfonylmethyl isocyanide, and iodine-mediated cyclization of β-enamino derivatives with TMSN 3 . The existing methods targeting the highly functional imidazoles still have some disadvantages, such as limited substitute patterns, requiring transition metal catalysts, high reaction temperature, toxic or expensive reagents, and/or commercially unavailable starting materials.…”

“…In comparison with the well-established [3 + 2] cyclization and multicomponent condensation approaches, few [4 + 1] cyclizations are documented, although they represent a straightforward strategy for imidazoles. ,, Given the importance of imidazole structure units in medicinal chemistry, it is highly desirable to provide more novel imidazoles from cheap and commercially available starting materials. Recently, we reported methods leading to the construction of highly functionalized pyridines and isothiazoles from N - tert -butanesulfinamide derivatives .…”