Synthesis of Azides in Flow
The generation and handling of organic azides using traditional batch methods brings with it a number of safety concerns, particularly on scale, which can limit the use of these important compounds. We have therefore developed several flow procedures to provide flexible working methods for the safe generation of a range of aryl and alkyl azides. These compounds can either be isolated as final products or more often progressed for further transformations without isolation within the contained flow system.
Generation and purification of aryl azides
We have developed a protocol that enables facile generation and purification of aryl azides in flow, providing safe and efficient access to clean aryl azides as intermediates or final products .
Monolithic reactor for azide generation
We have developed the use of a monolithic azide reagent for flow chemistry applications . While the reagent is more generally applicable, it was originally developed to conduct Staudinger aza-Wittig reactions in flow to afford imines. But more recently it has been useful in the conversion of alkyl bromides to amines.
We have also used these monolithic reactor devices as immobilised azide sources for the conversion of acid chlorides under Curtius rearrangements (below) .
However, the first time we used azides in a flow synthesis was during our synthesis of the natural product, oxomaritidine in 2006 . In the first step of the synthesis 4-(2-bromoethyl)phenol was quantitatively was converted to its corresponding azide. We accomplished by packing a glass column with an azide exchange resin (azide on Amberlite¬Æ IRA-400) and flowing a solution of the bromide through the supported reagent using a Syrris AFRICA¬Æ flow reactor system (below).
1. Fully automated, multistep flow synthesis of 5-Amino-4-cyano-1,2,3-triazoles
C.J. Smith, I.R. Baxendale, H. Lange, S.V. Ley
Org. Biomol. Chem. 2011, 9, 1938-1947
2. Flow synthesis of organic azides and the multistep synthesis of imines and amines using a new monolithic triphenylphosphine reagent
C.J. Smith, C.D. Smith, N. Nikbin, S.V. Ley, I.R. Baxendale
Org. Biomol. Chem. 2011, 9, 1927-1937
3. Azide monoliths as convenient flow reactors for efficient Curtius rearrangement reactions
M. Baumann, I.R. Baxendale, S.V. Ley, N. Nikbin, C.D. Smith
Org. Biomol. Chem. 2008, 6, 1587-1593
4. A flow process for the multi-step synthesis of the alkaloid natural product oxomaritidine: a new paradigm for molecular assembly
I.R. Baxendale, J. Deeley, C.M. Griffiths-Jones, S.V. Ley, S. Saaby, G. Tranmer
Chem. Commun. 2006, 2566-2568