A Novel Approach towards 2,3,5‐Trisubstituted Thiophenes via tandem Michael addition/intramolecular Knoevenagel condensation

Starting from the easily available, highly functionalized acetylenic ketories 4a–i (Scheme 1), novel 2,3,5‐trisubstituted thiophenes 1a–i (Scheme 2) were synthesized in good yields using a tandem Michael‐addition/intramolecular Knoevenagel‐condensation strategy, featuring Cs2CO3/MgSO4 (1:2) as an efficient base to effect the cyclization. Subsequent simple one‐step transformations yielded 2,3‐disubstituted thiophene‐5‐carbaidehydes 7a–c, carboxylic‐acid derivatives 8, 9, and 11, and alcohol 10 (Scheme 3). These molecules constitute interesting novel thiophene‐containing building blocks, useful for the preparation of low‐molecular‐weight compound libraries by combinatorial and parallel‐chemistry techniques.