New Four-Component Ugi-Type Reaction. Synthesis of Heterocyclic Structures Containing a Pyrrolo[1,2-a][1,4]diazepine Fragment

Abstract

[reaction: see text] We present a convenient synthesis of novel heterocyclic structures containing pyrrolo[1,2-a][1,4]diazepine fragment using a novel modification of four-component Ugi condensation. We demonstrate the usefulness and versatility of the developed approach for the synthesis of variously substituted compounds and discuss the scope and limitations of the chemistry involved.

A General Way to Construct Arene‐Fused Seven‐Membered Nitrogen Heterocycles

“…When the resulting carboxylate solution was neutralized, the desired product precipitated from the solution (additional crystallization was required to obtain these compounds in analytically pure form). In a number of cases (Table 2, entries 13,15,[18][19][20][21][23][24][25][26], we managed to separate the cis and trans diastereomers of compounds 9, and these were characterized individually. As a result, the protocol involving basic extraction followed by neutralization produced impure product mixtures.…”

“…This observation is perhaps unsurprising, considering that the very concept of privileged structures was coined in a Merck publication devoted to benzodiazepines. That such an ambitious goal can, in principle, be realized has already been elegantly demonstrated by the "intramolecular" Ugi reaction of benzene-tethered oxocarboxylic acids; this delivered tetrahydro versions of benzo[c]azepines, [16] benzo[f ] [1,4]thiazepines, [17] benzo[f ] [1,4]oxazepines, [18] and benzo[e] [1,4]diazepines [19] (i.e., all four of the scaffolds shown in Figure 1). That such an ambitious goal can, in principle, be realized has already been elegantly demonstrated by the "intramolecular" Ugi reaction of benzene-tethered oxocarboxylic acids; this delivered tetrahydro versions of benzo[c]azepines, [16] benzo[f ] [1,4]thiazepines, [17] benzo[f ] [1,4]oxazepines, [18] and benzo[e] [1,4]diazepines [19] (i.e., all four of the scaffolds shown in Figure 1).…”

The Chemistry of Benzodiazepines

“…In particular, oxazolobenzodiazepines and oxazinobenzodiazepines have been studied extensively. Representative members of these families of heterocycles are oxazolam (40), cloxazolam (41), and mexazolam (42) for the oxazolobenzodiazepines, and ketazolam 43 for the oxazinobenzodiazepines. The latter is an analog of diazepam (11) that features good anxiolytic activity with low secondary effects.…”

“…Thus, employment of the bifunctional pyrrole 94, which features both the carboxylic acid and the aldehyde functionalities in the Ugi condensation, leads directly to the benzodiazepines with the pyrrole fused at the a side (Scheme 25.19) [40].…”

The Design and Synthesis of Novel 2,3-Dihydrobenzo[f]isoquinolin-4(1H)-ones via Sequential Ugi-Heck Reactions by Using an Efficient Heterogeneous Palladium Nanocatalyst

“…The ability of multi‐component reactions to design synthetic routes for making of desired heterocyclic compounds has been shown to be unique . In the present paper, we report on the design and synthesis of N ‐alkyl‐2‐(1,2 dihydro‐1‐methylene‐4‐oxo benzo[f] isoquinoline‐3(4H)‐yl)‐2‐phenyl acetamides by combination of Ugi and Heck reactions (Scheme ).…”