Cu-Catalyzed Pyridine Synthesis via Oxidative Annulation of Cyclic Ketones with Propargylamine

Abstract

A Cu-catalyzed, easily scalable one-pot synthesis of fused pyridines by the reaction of cyclic ketones with propargylamine is described. The protocol was optimized based on the results of more than 30 experiments. The highest product yields were achieved in i-PrOH as a solvent in the presence of 5.0 mol % CuCl 2 in air. In contrast to the wellknown Au-catalyzed protocol, our procedure is "laboratory friendly", costeffective, and suitable for preparing dozens of grams of fused pyridine-based building blocks and does not require a high-pressure autoclave technique. Decreasing the catalyst amount in the reaction to 1.25 mol % CuCl 2 provided a yield comparable to that achieved with 5 mol % catalyst, though a longer reaction time was required. A plausible reaction mechanism was proposed. The scope and limitation of the reaction were studied using 24 different cyclic ketones as starting materials. The fused pyridine yield decreased among cyclic ketones in the following order: six-membered ≫ eight-membered > five-membered ∼ seven-membered. The elaborated reaction conditions demonstrated tolerance to a number of protective functional groups in ketone such as ester, tertbutoxycarbonyl (Boc)-protected amine, and acetal moieties.

Facile One‐Pot Synthesis of Polysubstituted Pyridinium Salts by Annulation of Enamines with Alkynes

“…Alternatively, intermediate V undergoes a Grob‐type fragmentation to produce allenic imine VII (Scheme 3, path b). This imine may also be formed directly from N ‐propargylenamine I via a metal‐catalyzed propargyl aza‐Claisen rearrangement according to a previous proposal [19b] . However, this rearrangement pathway is unlikely because only unreacted starting material was obtained in our control experiments conducted in the presence of only Ag 2 CO 3 (Table 1, entries 4 and 5).…”

Expanding the Diversity of Pyridines Through Annulation of Keto and Diketo Compounds

“…in the presence of NaAuCl 4 .2H 2 O catalyst in a sealed tube to produce pyridine annulated products (Table 1). [21] A plausible mechanism for the pyridine annulation has been given in Scheme 5 from the previous studies. [21] SM cross-coupling reaction is regarded as one of the most versatile methods of CÀ C bond formation.…”

“…[21] A plausible mechanism for the pyridine annulation has been given in Scheme 5 from the previous studies. [21] SM cross-coupling reaction is regarded as one of the most versatile methods of CÀ C bond formation. [14] thousands of boronic acids are available commercially.…”

Scalable Synthesis of Silacyclohexanones and Ready Access to Silicon Building Blocks

“…Toward this goal, sila fused pyridines 17a−17c were obtained in 46−59% yields by the reaction of silacyclohexanones 5 with propargylamine in the presence of CuCl 2 catalyst (application VI). 19 Diels−Alder reaction of enamine derived from Silacyclohexanones 5 with 1,3,5-Triazines 18 gave 4,5-disubstituted sila-pyrimidines 19a−19c in moderate to good yields (application VII). 20 Silacyclohexanone derivatives 5a−5c underwent Schmidt reaction with NaN 3 in the presence of methanesulfonic acid to deliver sila-caprolactams 20a− 20c (52−73% yields, application VIII).…”

“…Next, we turned our attention to the synthesis of nitrogen-containing 6-membered heterocycles. Toward this goal, sila fused pyridines 17a – 17c were obtained in 46–59% yields by the reaction of silacyclohexanones 5 with propargylamine in the presence of CuCl 2 catalyst (application VI) . Diels–Alder reaction of enamine derived from Silacyclohexanones 5 with 1,3,5-Triazines 18 gave 4,5-disubstituted sila-pyrimidines 19a – 19c in moderate to good yields (application VII) …”