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Abstract
A novel and safe reaction protocol for the enantioselective enamine-catalysed addition of acetaldehyde to nitroalkenes is presented; this protocol makes use of a safe acetaldehyde precursor to access important intermediates to Active Pharmaceutical Ingredients (APIs), and allows the use of fewer equivalents of acetaldehyde and lower catalyst loadings. The reaction developed proved to be suitable to be performed on gram-scale and to produce key intermediates for the synthesis of pharmacologically active compounds such as pregabalin.
Highlights
Nowadays, organocatalysis is a key technology platform and is routinely assessed in industry when taking a process to manufacture [1,2,3,4]
The enamine-catalysed [6,7,8,9] addition of acetaldehyde to a nitroalkene holds high potential for a cost-efficient process; the raw materials are widely available at low prices and the catalyst needed can be accessed at a reasonable cost
Whereas different types of ketones and aldehydes have been activated as nucleophiles, few attempts of using acetaldehyde as nucleophile have been reported with aminocatalysis [10,11]
Summary
Organocatalysis is a key technology platform and is routinely assessed in industry when taking a process to manufacture [1,2,3,4]. By using two supported catalysts, Pericàs ingeniously employed paraldehyde to enable the same reaction and avoid the use of acetaldehyde [15] (Scheme 1c). They used equivalents of masked acetaldehyde (i.e., 3.3 eq of paraldehyde) and a relatively high catalyst loading of supported organocatalysts that, despite the potential recyclability, bring a considerable cost contribution to the manufacture process. By employing a simple masked acetaldehyde, we could tackle the challenges that acetaldehyde brings to an industrial process, lower the catalyst loading, use fewer equivalents of acetaldehyde, and use affordable raw materials and catalyst. The desired γ-nitroaldehydes derivatives were obtained in high yields and enantioselectivities using a very simple, safe, and cost-efficient protocol
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