LETTER 749 Synthesis of 3-Nitropyrrolidines via Dipolar Cycloaddition Reactions Using a Modular Flow Reactor SynthesisMarcus of 3-Nitropyrrolidines Baumann, Ian R. Baxendale, Steven V. Ley* Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK Fax +44(1223)767798; E-mail:
[email protected] Received 20 November 2009 This modular platform consists of a dual pumping unit Abstract: The generation and subsequent use of unstabilised azomethine ylides in dipolar cycloaddition reactions within a flow which delivers the dissolved starting materials into a mix- microreactor is demonstrated. The 3-nitropyrrolidines produced ing device and directs the combined reaction stream were furthermore subjected to chemoselective hydrogenation reac- through a selection of convection flow coils (CFC) and/or tions using the H-Cube® system. To ensure product purities in ex- glass tubes13 filled with solid-supported reagents and cess of 90–95%, immobilised scavengers were successfully scavengers that can be maintained at a desired tempera- employed. ture and pressure. Furthermore, this system can be run Key words: microreactor, flow chemistry, pyrrolidine, dipolar cy- with the Flow Commander software also available from cloaddition, solid-supported reagents Vapourtec12 allowing for the use of a front-end liquid han- dler and a UV-directed fraction collector. The synthesis of highly functionalised heterocyclic com- H O pounds is of central importance to most modern medicinal N N chemistry programmes1 since these building blocks are N N N OH N N H N H readily manipulated to compounds with favourable phar- H -proline -prolinyl tetrazole nicotine L macophoric properties. Accordingly, the synthetic chem- L ist is expected to deliver these entities in a flexible, high- O yielding fashion yet avoiding time-consuming purifica- H O NH Ar tion procedures as well as hazardous or obnoxious chem- HO OTMS NH O 2 3 2 N ical inputs wherever possible.