Synlett 2010(5): 749-752  
DOI: 10.1055/s-0029-1219344
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of 3-Nitropyrrolidines via Dipolar Cycloaddition Reactions Using a Modular Flow Reactor

Marcus 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:;
Further Information

Publication History

Received 20 November 2009
Publication Date:
25 January 2010 (online)


The generation and subsequent use of unstabilised azomethine ylides in dipolar cycloaddition reactions within a flow microreactor is demonstrated. The 3-nitropyrrolidines produced were furthermore subjected to chemoselective hydrogenation reactions using the H-Cube® system. To ensure product purities in excess of 90-95%, immobilised scavengers were successfully employed.

    References and Notes

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Vapourtec R2+/R4 units are available from Vapourtec Ltd, Place Farm, Ingham, Suffolk, IP31 1NQ, UK. Website:


Commercially available Omnifit® glass chromatography columns with adjustable height-end pieces(plunger). Typically, the polymer-supported reagent is placed in an appropriately sized Omnifit column®, usually 10 mm bore by 150 mm length, or shorter and the plungers are adjusted to relevant bed heights and the polymer swelled/washed with solvent. Website:


QuadraPure benzylamine (QP-BZA) is a high-loading scavenger commercially available from Reaxa. Website:


The H-Cube® flow hydrogenator is commercially available from ThalesNano Nanotechnology Inc., Graphisoft Park,
H-1031 Budapest, Záhony u. 7, Hungary; Website:


MP-carbonate is a basic anion-exchange resin (3.2 mmol/g) commercially available from Biotage. Website:


In a typical flow experiment stock solutions of the alkene component (1.5 equiv, containing 1.0 equiv TFA in MeCN) and N-(methoxymethyl)-N-(trimethylsilyl)benzylamine (1.0 equiv in MeCN) were prepared and injected into the two individual sample loops of the R2+ unit of the Vapourtec system. The resulting streams were mixed in a static mixing tee and then directed into a flow coil (10 mL volume, 1.0 mm i.d., temperature 60-120 ˚C) mounted on the R4 unit to give residence times between 30-90 min depending on the reactivity of the substrate used. After leaving this coil the reaction mixture was directed into a glass column (typically 10 cm length, 10 mm bore) containing the scavenging resin (QP-BZA, 2.5 equiv and a 1 cm plug of silica). The purified product was then collected and isolated after solvent removal.
For Experiments Involving the Use of the Fluoride Monolith
The two starting materials were dissolved at the same concentrations in MeCN and injected into the two corresponding sample loops of the R2+ [alkene 1.5 mmol in MeCN and N-(methoxymethyl)-N-(trimethylsilyl)benzyl-amine 1.0 mmol in MeCN]. After mixing both streams in a T-piece the resulting mixture was directed into the fluoride monolith (in a column; 10 cm length, 15 mm bore, ca. 12 mmol fluoride) heated between 50-80 ˚C with a combined flow rate of 200 µL/min. The exiting stream was then passed through a glass column (10 cm length, 10 mm bore) containing the scavenging resin (QP-BZA, 2.5 equiv) for final in-line purification.
For the chemoselective reduction of 3-nitropyrrolidines using the H-Cube® system in full hydrogen mode the starting material was dissolved in a EtOH-EtOAc (1:1) solvent system (0.2-0.5 M; containing catalytic amounts of AcOH) and passed through the appropriate catalyst cartridge heated to 60 ˚C with a flow rate of 1.0 mL/min. In order to remove the acetate counterion the out flow stream is subsequently directed through a glass column containing 1 equiv polymer-supported carbonate.¹9