FeCl₃-Mediated Synthesis of β-Alkynyl Ketones via Domino Nucleophilic-Substitution/Intramolecular-Cyclization/Reverse Claisen Condensation of N-Cyclohexyl Propargylamines and 1,3-Diketones

Abstract

The synthesis of β-alkynyl ketones was achieved in good to excellent yields by an iron-catalyzed domino reaction of N-cyclohexyl propargylamines and 1,3-diketones. A plausible mechanism involving nucleophilic substitution, intramolecular cyclization, and reverse Claisen condensation for this process is proposed.

Scope and advances in the catalytic propargylic substitution reaction

“…70 Shang and co-workers in 2015 described a FeCl 3 -catalyzed domino reaction of N-cyclohexyl propargylamines 95 with 1,3diketones 96 towards the synthesis of b-alkynyl ketones 97 in good to excellent yields, Scheme 40. 71 Several Lewis acid catalysts like CuBr 2 , CuI, Sc(OTf) 3 and Brønsted acid like H 2 SO 4 were tested but the highest yield was achieved using FeCl 3 . Even altering the catalyst loading did not have any positive impact on the reaction yield.…”

Selective synthesis of 2‐(5‐oxo‐1‐arylhex‐1‐yn‐3‐yl)phenyl benzoates via FeCl3‐mediated cascade reactions of propargylamines with β‐enamino ketones

“…Combining the experimental results and the literature precedents, [ 12,20 ] a plausible mechanism of compounds 1a and 2a as model substrates was proposed, as shown in Scheme 4. Initially, alkynyl o ‐quinone methide ( o ‐AQM) intermediate could be formed in the presence of FeCl 3 as a Lewis acid.…”

“…Furthermore, screening of the solvents showed that the reaction using acetonitrile as solvent gave the product 3a in the highest yield (Table 1, entry 17). Variation of the reaction temperature confirmed that 80 C was the optimal condition for this protocol, with lower and higher temperatures affording decreased yields ( Table 1, entries [18][19][20]. Additionally, the yield could not be improved by increasing or decreasing the reaction time (Table 1, entries 21 and 22).…”

“…[ 19 ] Recently, we found that 1,3‐diketones can play a key role as new carbonyl sources in the acylation reaction of ortho ‐hydroxyl propargylamines or 2‐(aryl (piperidin‐1‐yl)methyl)phenols to form phenyl acetates (Scheme 1a). [ 20 ] We herein disclose the FeCl 3 ‐mediated cascade reactions of ortho ‐hydroxyl propargylamines or 2‐(aryl (piperidin‐1‐yl)methyl)phenols with β‐enamino ketones in the selective synthesis of benzoates in good to excellent yields under mild conditions (Scheme 1b).…”

Piperazine as Leaving Group in A3 Adducts: Fast Access to Alkynyl Indoles

“…Beside two references of sulfonamide substitution, 6 the use of an A3 adduct as an electrophilic propargylation reagent may only be found in a recent study on FeCl 3 -triggered alkylation of dicarbonyl derivatives. 7 In the latter case, a relatively large amount of 50% FeCl 3 was required and the reaction was only reported with salicilaldehyde as the starting A3 aldehyde component. Thus, our new conditions offer an interesting metal-free alternative to this previous system.…”