Pyrrolo[3,2-e][1,4]diazepin-2-one Synthesis: A Head-to-Head Comparison of Soluble versus Insoluble Supports

Abstract

Aryldiazepin-2-ones are known as "privileged structures", because they bind to multiple receptor types with high affinity. Toward the development of a novel class of aryldiazepin-2-one scaffolds, the synthesis of pyrrolo[3,2-e][1,4]diazepin-2-ones on a support was explored starting from N-(PhF)-4-hydroxyproline and featuring an acid-catalyzed Pictet-Spengler reaction to form the diazepine ring. Three supports [Wang resin, tetraarylphosphonium (TAP) soluble support, and Merrifield resin] were examined in the synthesis of the heterocycle and exhibited different advantages and disadvantages. Wang resin proved effective for exploratory optimization of the synthesis by identification of intermediates after resin cleavage under mild conditions; however, the acidic conditions of the Pictet-Spengler reaction caused premature loss of resin-bound material. Direct monitoring of reactions by TLC, RP-HPLC-MS, and in certain cases NMR spectroscopy was possible with the TAP support, which facilitated purification of intermediates by precipitation; however, incomplete precipitation of material led to overall yields lower than those from solid-phase approaches on resin. Merrifield resin proved stable to the conditions for the synthesis of the pyrrolo[3,2-e][1,4]diazepin-2-one targets and would be amenable to "split-and-mix" chemistry; however, relatively harsh conditions were necessary for final product cleavage. Perspective for the application of different solid-phase approaches in heterocycle library synthesis was thus obtained by demonstration of the respective utility of the three supports for preparation of pyrrolo[3,2-e][1,4]diazepin-2-one.

Synthesis of Thieno[3,2‐e][1,4]diazepin‐2‐ones: Application of an Uncatalysed Pictet–Spengler Reaction

“…[15,16] In the case of thiophene, degradation was observed with a Brønsted acid, such as TFA (Table 1, Entry 12), or with a Lewis acid, such as TiCl 4 ( Table 1, Entry 13). Indeed, Lubell et al reported that TFA was able to catalyse the Pictet-Spengler cyclization reaction on the pyrrole.…”

“…Indeed, Lubell et al reported that TFA was able to catalyse the Pictet-Spengler cyclization reaction on the pyrrole. [15,16] In the case of thiophene, degradation was observed with a Brønsted acid, such as TFA ( Table 1, Entry 12), or with a Lewis acid, such as TiCl 4 ( Table 1, Entry 13). Therefore, uncatalysed conditions in anhydrous toluene at 110°C were selected to perform all the Pictet-Spengler reactions described in this report.…”

“…[2] Aryldiazepine ring systems achieved popularity first in the 1960s with diazepam as the first orally active anxiolytic by interaction with GABA receptors. Much attention has been paid to the replacement of the fused benzene ring by a heterocyclic structure such as pyrazole, [11,12] imidazole, [13] pyrrole, [14][15][16] and indole. [3][4][5][6] Since the discovery of benzodiazepines as central nervous system depressants, many synthetic derivatives that display a wide range of therapeutic applications in antithrombotic, [7] antibiotic, [8] and antitumor [9,10] areas, have been extensively developed.…”

“…[3][4][5][6] Since the discovery of benzodiazepines as central nervous system depressants, many synthetic derivatives that display a wide range of therapeutic applications in antithrombotic, [7] antibiotic, [8] and antitumor [9,10] areas, have been extensively developed. Much attention has been paid to the replacement of the fused benzene ring by a heterocyclic structure such as pyrazole, [11,12] imidazole, [13] pyrrole, [14][15][16] and indole. [17,18] Recently, we focused our efforts on the development of a new azaheterocycle-fused [1,3]diazepine scaffold and successfully reported on the synthesis of the first series of imidazopyridine-fused [1,3]diazepinones.…”

Solid-Phase Synthesis of Seven-Membered Heterocycles with Two Nitrogen Atoms

“…In the field of research concerning dihydrobenzo[e] [1,4]diazepin-2-one heterocyclic analogues, an interesting strategy for the preparation of compounds with a differential modulation of urotensin II receptor-mediated vasoconstriction was recently introduced by Lubell [32,33]. As the key intermediate, resin-bound 65 was synthesized from immobilized 4-hydroxyproline.…”