Synthesis of nitrogen heterocycles via palladium-catalyzed annulation of acetylenes

Roesch, Kevin
Major Professor
Richard C. Larock
Committee Member
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A wide variety of substituted isoquinoline, tetrahydroisoquinoline, 5,6-dihydrobenz[ f]isoquinoline, pyrindine, and pyridine heterocycles have been prepared via annulation of internal acetylenes with the tert-butylimines of o-iodobenzaldehydes and 3-halo-2-alkenals in the presence of a palladium catalyst. The best results are obtained by employing 5 mol % Pd(OAc)2, an excess of the alkyne, one equivalent of sodium carbonate as a base, and 10 mol % PPh3 in DMF as the solvent. This annulation methodology is particularly effective for aryl- or alkenyl-substituted alkynes. Trimethyl silyl-substituted alkynes also undergo this annulation process to afford mono-substituted heterocyclic products. Other acetylenes, however, fail to undergo this annulation process;Mono-substituted isoquinolines and pyridines have been prepared 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, isoquinolines 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. Finally, the total synthesis of the isoquinoline natural product decumbenine B has been accomplished in 7 steps and 20% overall yield by employing this palladium-catalyzed coupling and cyclization methodology;A wide variety of substituted isoindolo[2,1-a]indoles have been prepared via annulation of internal alkynes by imines derived from o-iodoanilines in the presence of a palladium catalyst. This methodology provides an extremely efficient route for the synthesis of these tetracyclic heterocycles from readily available starting materials. The mechanism of this interesting annulation process appears to involve either electrophilic palladation of a sigma-palladium intermediate onto the adjacent aromatic ring of the internal alkyne, or oxidative addition of the neighboring aryl carbon-hydrogen bond. A variety of internal acetylenes have been employed in this annulation process in which the aromatic ring of the alkyne contains either a phenyl or a heterocyclic ring.