Exploiting the Acylating Nature of the Imide-Ugi Intermediate: A Straightforward Synthesis of Tetrahydro-1,4-benzodiazepin-2-ones

Abstract

We describe a simple and novel protocol for the synthesis of tetrahydro-1,4-benzodiazepin-2-ones with three points of diversity, exploiting the acylating properties of the recently rediscovered Ugi-imide. The final compounds can be easily prepared in three synthetic steps using a multicomponent reaction, a Staudinger reduction, and an acylative protocol, with good to excellent yields for each synthetic step.

Off the Beaten Track: The Use of Secondary Amines in the Ugi Reaction

“…Tetrahydro-1,4-benzodiazepinones of type 128 [35] (Scheme 22, Figure 7), for example, have been prepared in only three simple synthetic steps, a considerable simplification of the long routes previously used for their synthesis. [36] The key step is an intramolecular acylation between the aniline nitrogen and the Ugi imide, with extrusion of the amide deriving from the acid and the isocyanide.…”

Benzodiazepines: Their Use either as Essential Medicines or as Toxics Substances

“…The synthesis of 1,4-benzodiazepin-2-ones includes the previous synthesis of the intermediate amino-ketone [18]. Moreover, cyclization processes involving an Ugi reaction as a first step [19,20]. Finally, other methods include the cascade coupling/ condensation process of 2-bromobenzylamines with amino acids [21] and Buchwald reaction [22] (Figure 3).…”

Convenient two-step synthesis of highly functionalized benzo-fused 1,4-diazepin-3-ones and 1,5-diazocin-4-ones by sequential Ugi and intramolecular S N Ar reactions

“…45-48 49-66 Among them, the Ugi-deprotection-cyclization (UDC) strategy is the most commonly used and was shown to be very powerful to prepare benzodiazepinone derivatives. 35-38, 41-44, 49-66 To perform the cyclization step, several strategies including ester or amide aminolysis, 9,10,[49][50][51][52][53][54][55][56][57][58] imine formation, 55,59 aromatic nucleophilic substitution (S N Ar), 60,61 Staudinger/aza-Wittig [62][63][64][65] aza-Michael, 33 and Mitsunobu 66 reactions have been used. However, because they often involve modified or hardly accessible building blocks and/or Boc protecting group removal prior to cyclization, most reported UDC methodologies generate limited functional diversity on benzodiazepinone scaffolds.…”