One-Step Continuous Flow Synthesis of Highly Substituted Pyrrole-3-carboxylic Acid Derivatives via in Situ Hydrolysis of tert-Butyl Esters

• Published in: Organic letters Vol. 12; no. 22; pp. 5182 - 5185
• Main Authors: Herath, Ananda, Cosford, Nicholas D. P
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 19.11.2010; Amer Chemical Soc
• Subjects: Amides - chemical synthesis; Amides - chemistry; Carboxylic Acids - chemical synthesis; Carboxylic Acids - chemistry; Chemistry; Chemistry, Organic; Combinatorial Chemistry Techniques; Esters; Hydrolysis; Molecular Structure; Physical Sciences; Pyrroles - chemical synthesis; Pyrroles - chemistry; Science & Technology; Stereoisomerism; ORGANIC-SYNTHESIS; ATOM ECONOMY; N-BOC-AMINES; 1,3-DIPOLAR CYCLOADDITION; REGIOSELECTIVE SYNTHESIS; CYCLOISOMERIZATION; MICROREACTOR; HANTZSCH PYRROLE SYNTHESIS; DEPROTECTION; MULTISTEP SYNTHESIS
• ISSN: 1523-7060; 1523-7052
• DOI: 10.1021/ol102216x

The first one-step, continuous flow synthesis of pyrrole-3-carboxylic acids directly from tert-butyl acetoacetates, amines, and 2-bromoketones is reported. The HBr generated as a byproduct in the Hantzsch reaction was utilized in the flow method to hydrolyze the t-butyl esters in situ to provide the corresponding acids in a single microreactor. The protocol was used in the multistep synthesis of pyrrole-3-carboxamides, including two CB1 inverse agonists, directly from commercially available starting materials in a single continuous process.