Benzodiazepines four-component reaction

An elegant two-step solution-phase methodology was developed for the synthesis of the benzodiazepine-2,5-diones (93 e.g. R1 = PhCH R2 = Me, R3 = Me, R4 = H, R5 = Me, 32%). The first step was a Ugi four-component reaction followed in the second step by a palladium-mediated intramolecular IV-arylation reaction. This methodology has considerable scope for further application in heterocyclic synthesis <06TL3423>. 

The famous Ugi reaction, the one-pot condensation of a carboxylic acid, an amine, an aldehyde or ketone and an isocyanide to yield an a-acylaminoamide, have recently been used as an efficient method for the synthesis of diverse libraries of small organic molecules such as benzodiazepines, pyrroles, lactams and diketopiperazines2. Even though some solution-phase Ugi reactions proceed rapidly, such reactions on solid phase have been found to take between one and several days. In 1999, Hoel and Nielsen17 performed the first microwave assisted, solid phase Ugi four-component condensation (see Scheme 5.5). 

Chucholowski A, Heinrich D, Mathys B, Muller C, Generation of benzodiazepine and benzodiazocine libraries through resin capture of Ugi-four component condensation reaction products, Book of Abstracts, 214th ACS National Meeting, Las Vegas, September 7-11, American Chemical Society, Washington, 1997. 

Stoichiometric amounts (1.75 mL) of 0.1 M solutions of the four Ugi components were combined in order of their participation in the Ugi reaction and stirred at room temperature for 20 h. The solvent was evaporated in vacuo at 40° and dried under high vacuum. A 10% solution of AcCl in MeOH (7 mL) was added to the crude material and stirred at room temperature for 15 h. The solvent was then evaporated in vacuo at 40°. The crude material was preabsorbed onto flash silica and purified by flash column chromatography (EtOAc hexane) to yield the desired product. The following benzodiazepines were prepared via this procedure. 

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