Lewis Acid‐Mediated [3+3] Annulation for the Construction of Substituted Pyrimidine and Pyridine Derivatives

Abstract

A direct and single‐step procedure towards substituted pyrimidine and pyridine derivatives via Lewis acid‐promoted [3+3] annulation between 3‐ethoxycyclobutanones and enamines or amidines is presented. Diverse substituted pyrimidine and pyridine derivatives were obtained in good to high yields with a wide substrate scope.magnified image

Lewis‐acid Promoted Chemoselective Condensation of 2‐Aminobenzimidazoles or 3‐Aminoindazoles with 3‐Ethoxycyclobutanones to Construct Fused Nitrogen heterocycles

“…To understand the reaction mechanism, we cultivated several crystals and the X‐ ray crystallographic analysis of 3 a , 3 g and 3 o confirmed the accurate position of the isopropyl, which was in sharp contrast to previous documents. Based on the reaction mechanism of previous reports,, when anilines, hydrazines, enamine and amidines reacted with 3‐ethoxycyclobutanones, the free primary NH 2 group condensed of the carbonyl group preferentially and then other intramolecular annulation reactions occurred. If so, the product in this transformation should be 3 aa in which the isopropyl was adjacent to nitrogen‐atom of the free primary NH 2 group (path b in Scheme ).…”

“…For example, Matsuo's group developed the [4+2] cycloaddition reactions and Rao's group discovered the [3+3] annulation reactions by employing 3‐ethoxycyclobutanones as annulation partners. Very recently, our group also demonstrated a [3+3] annulation reaction between 3‐ethoxycyclobutanones and enamines or amidines towards substituted pyrimidine and pyridine derivatives . Although 3‐ethoxycyclobutanones have been used for preparation of various nitrogen heterocycles, the 3‐ethoxycyclobutanones have never been employed to construct the important benzo[4,5]‐imidazo[1,2‐a]pyrimidine and pyrimido[1,2‐ b ]‐indazole derivatives.…”

“…However, the product we acquired was 3 a , which implied the presence of unique reaction mechanism of this transformations and it might undergo the path a in Scheme to give the product 3 a . Firstly, BF 3 ⋅Et 2 O activates cyclobutanone 2 a via cleaving the more substituted C2−C3 bond to form the zwitterionic intermediate A ,, which further was attacked by 3‐aminoindazole 1 a to generate the intermediate B . Elimination of Lewis‐acids and one molecule of EtOH from intermediate B provides intermediate C .…”

“…Although 3‐ethoxycyclobutanones have been used for preparation of various nitrogen heterocycles, the 3‐ethoxycyclobutanones have never been employed to construct the important benzo[4,5]‐imidazo[1,2‐a]pyrimidine and pyrimido[1,2‐ b ]‐indazole derivatives. As part of our ongoing interest in activation of cyclobutanones,, we herein report transition‐metal free synthesis of benzo[4,5]‐imidazo[1,2‐ a ]pyrimidine and pyrimido[1,2‐ b ]‐indazole derivatives via chemoselective condensation of 2‐aminobenzimidazoles and 3‐aminoindazoles with 3‐ethoxycyclobutanones, in which the heteroatomic nitrogen rather than the free primary NH 2 of 2‐aminobenzimidazoles or 3‐aminoindazoles condensed 3‐ethoxycyclobutanones preferentially (Scheme b).…”

Acid-controlled multicomponent selective synthesis of 2,4,6-triaryl pyridines and pyrimidines by using hexamethyldisilazane as a nitrogen source under microwave irradiation

“…Among them, substituted amidines are frequently applied as versatile nitrogen-containing blocks to react with various cyclization partners to form a pyrimidine ring to utilize the inherent nitrogen on the substrate. 21 The MCRs for the preparation of pyrimidines from amidines have also been recognized as an efficient strategy. 22 Some other synthetic routes utilized the extrinsic nitrogen-containing reagents, including ammonium acetate, 23 ammonium iodide, 24 hydroxylamine, 25 and urea 26 to generate in situ ammonia surrogate and condensed with carbonyl synthons to construct pyrimidine structures.…”