Toward the Scale-Up of a Bicyclic Homopiperazine via Schmidt Rearrangement and Photochemical Oxaziridine Rearrangement in Continuous-Flow

Abstract

The scale-up of a chiral bicyclic homopiperazine of pharmaceutical interest was investigated. The outcome and safety profile of a key batch ring-expansion step via Schmidt rearrangement was improved using continuous-flow chemistry. The selectivity of nitrogen insertion for the ring expansion was improved via an alternative photochemical oxaziridine rearrangement under mild conditions, which when converted to continuous-flow in a simple and efficient flow reactor allowed the first photochemical scale-up of a homopiperazine.

Technological Innovations in Photochemistry for Organic Synthesis: Flow Chemistry, High-Throughput Experimentation, Scale-up, and Photoelectrochemistry

“…The oxaziridine rearrangement to chiral lactams was later also used to generate chiral bicyclic homopiperazines (Scheme 42B). 407 In a first attempt, a nonphotochemical method involving a Schmidt rearrangement to the chiral lactams was employed, but productivity and enantioselectivity to the desired lactam were limited. Instead, more successful was the photochemical Lattes−Aubéreaction in a parallel tube reactor.…”

Copper‐Nitrene‐Catalyzed Desymmetric Oxaziridination/1,2‐Alkyl Rearrangement of 1,3‐Diketones toward Bicyclic Lactams

“…Based on the above results and previous literature, [2,7,8] a possible reaction mechanism was proposed, as shown in Table 3: Scope of 1,3-cyclopentanedione substrate. [a] [a] Unless otherwise specified, reactions were conducted at room temperature with 1 a (0.2 mmol, 1 equiv), CuCl (0.02 mmol, 0.1 equiv), AgSbF 6 (0.024 mmol, 0.12 equiv), L1 (0.024 mmol, 0.12 equiv), NaBArF (0.5 equiv) in 4 mL DCM.…”

“…However, the development of chemical transformations based on chiral copper-nitrene has mainly focused on the aziridination of C=C bonds to generate synthetically important aziridines [7] (Scheme 1 a). To further explore other novel transformations involving chiral copper-nitrene species, we speculated that a polarized C = O bond could react with in situ generated copper-nitrene and the resulting highly active intermediate oxaziridine [8] could subsequently rearrange to produce a synthetically challenging chiral lactam [4,9] (Scheme 1 b). Such an asymmetric transformation could efficiently address the intrinsic challenges of the classic intramolecular Schmidt reaction, [10] including the use of azides with low nucleophilicity as a substrate, the general requirement for stoichiometric amounts of a strong Lewis or Brønsted acid to activate the carbonyl group of the other reactant, the relatively strong Lewis basic nature of the resulting lactam, and the lack of the corresponding catalytic asymmetric fashion.…”

Continuous-Flow Technology for Chemical Rearrangements: A Powerful Tool to Generate Pharmaceutically Relevant Compounds

“…In 2021, Brown et al reported a flow-based scale-up of chiral bicyclic homopiperazines through the SR . Batch issues related to a long reaction time and acid neutralization prompted the authors to explore continuous flow, exploiting the previous work by Jia and co-workers on the generation of the homopiperazine moiety.…”

“…In 2021, Brown et al reported a flow-based scale-up of chiral bicyclic homopiperazines through the SR. 34 Batch issues related to a long reaction time and acid neutralization prompted the authors to explore continuous flow, exploiting the previous work by Jia and co-workers on the generation of the homopiperazine moiety. A solution of sulfuric acid in 1,2-dimethoxyethane (DME) was mixed with (1R,4S)-2-(4-ethoxyphenyl)-7,7dimethyl-2-azabicyclo[2.2.2]octan-5-one 35 and tetrabutylammonium azide in DME.…”