Synthesis of Isoquinolines and Pyridines by the Palladium/Copper-Catalyzed Coupling and Cyclization of Terminal Acetylenes and Unsaturated Imines:  The Total Synthesis of Decumbenine B

Abstract

Monosubstituted isoquinolines and pyridines have been prepared in good to excellent yields via coupling of terminal acetylenes with the tert-butylimines of o-iodobenzaldehydes and 3-halo-2-alkenals in the presence of a palladium catalyst and subsequent copper-catalyzed cyclization of the intermediate iminoalkynes. In addition, isoquinoline heterocycles have been prepared in excellent yields via copper-catalyzed cyclization of iminoalkynes. The choice of cyclization conditions is dependent upon the nature of the terminal acetylene that is employed, as only aryl and alkenyl acetylenes cyclize under the palladium-catalyzed reaction conditions that have been developed. However, aryl-, vinylic-, and alkyl-substituted acetylenes undergo palladium-catalyzed coupling and subsequent copper-catalyzed cyclization in excellent yields. The total synthesis of the isoquinoline natural product decumbenine B has been accomplished in seven steps and 20% overall yield by employing this palladium-catalyzed coupling and cyclization methodology.

Tandem imination/annulation of γ- and δ-ketoalkynes in the presence of ammonia/amines

“…A more comprehensive study showed that microwaves heating gave comparable or better yields in reduced reaction times (Scheme 8) [17]. The product derived from a 5-exo-dig cyclization mode has never isolated or Isoquinoline heterocycles have been also prepared in excellent yields via copper-catalyzed cyclization of tert-butylimine derivatives of 2-alkynylbenzaldehydes [18]. Dirhodium acetate and silver triflates cooperatively catalyzed tandem cyclization/three-component reactions of 2-alkynylarylaldimines with diazo compounds and water or alcohols afforded 1,2-dihydroisoquinolines bearing a-hydroxyl-b-amino carboxylate skeleton in high yield [19].…”

A Two‐Step, Three‐Component Queuing Cascade Leading to Dihydrobenzoxepine and Dihydrobenzazepine Derivatives

“…Solvents for column chromotography, ethyl acetate and light petroleum were distilled in a rotary evaporator. The following compounds were prepared according to known literature methods: methylenespiropentane (11), [4] 2,3-dihydrobenzo [1,4]dioxine-6-carbaldehyde, [12] benzo [1,3]dioxole-4-carbaldehyde, [12] (3,4-dimethoxyphenyl)methanol, [13] piperonylic alcohol, [14] (2,3-dihydrobenzo [1,4]dioxin-6-yl)-methanol, [14] (benzo [1,3]dioxol-4-yl)methanol, [15] 2-iodo-4,5-dimethoxybenzyl alcohol (33c), [16] (6-iodobenzo [1,3]dioxol-5-yl)-methanol (33d), [17] (5-iodobenzo [1,3]dioxol-4-yl)methanol (33g), [15] 5-chloromethyl-6-iodobenzo [1,3]dioxole, [18] 2-iodobenzyl methanesulfonate, [19] (benzyl)(2-iodobenzyl)amine (33b), [20] 2-(2-iodophenyl)ethanol (40). [21] Heck Reaction of Methylenespiropentane (11) with Iodobenzene (12).…”

Recent Strategies for the Synthesis of Pyridine Derivatives

“…[28] Palladium-catalyzed coupling of vinylic imines with terminal alkynes followed by subsequent copper-catalyzed cyclization gave aryl-, vinyl-, and alkyl-substituted pyridines in moderate yields. Significantly, this method was extended to the synthesis of alkaloid decumbenine B and various other isoquinolines.…”

“…The [4 + 2] palladium-/copper-catalyzed route to pyridines. [28] Scheme 18. The [4 + 2] rhodium-/palladium-catalyzed route to pyridines.…”