Aza-Povarov Reaction. A Method for the Synthesis of Fused Tetracyclic Chromeno[4,3-<i>d</i>]pyrido[1,2-<i>a</i>]pyrimidines

Martín-Encinas, Endika; Lopez-Aguileta, Leyre; Palacios, Francisco; Alonso, Concepción

doi:10.1021/acs.joc.3c02220

Palladium-catalyzed cascade of aza-Wacker and Povarov reactions of aryl amines and 1,6-dienes for hexahydro-cyclopenta[b]quinoline framework

Wu,

Tan,

Wu

et al. 2024

Nat Commun

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Palladium catalyzed tandem reaction represents a one-pot synthetic approach to efficiently synthesize complex functionalized molecules while reducing synthetic steps, aligning with the principles of green chemistry. However, achieving a direct cascade of the aza-Wacker and Povarov reactions in one-pot synthesis presents a challenge due to substrate compatibility issues between the two reactions. In this work, we describe an aza-Wacker/Povarov reaction employing a highly electrophilic palladium catalyst, which effectively converts anilines and 1,6-dienes into hexahydro-cyclopenta[b]quinolines. The optimized conditions yield up to 79%, with a diastereoselectivity > 20:1. Substrate range testing reveals compatibility with various sensitive functional groups, and successful late-stage modifications are performed on several natural products and drug molecules, demonstrating the versatility and practicality of the method. Additionally, a preliminary investigation into the reaction mechanism suggests an aza-Wacker process followed by a Povarov process.Transition metal catalysis represents a well-established and continually advancing field of research, providing a robust platform for the incorporation of oxygen-or nitrogen-containing functional groups onto readily available substrates such as alkynes and alkenes 1-5 . This methodology enables the efficient synthesis of valuable, complex, functionalized molecules in a cost-effective and expeditious manner. There is a challenge to balance the requirement for atom utilization, step economy, the demand for lengthy synthetic routes, reaction selectivity, and yield in the synthesis of complex molecules. Arranging and combining existing elementary ingeniously reactions in one-pot synthesis presents an effective strategy that concurrently addresses the need for rapid synthesis of complex molecular skeletons with high yields by decreasing the number of synthesis steps 6-10 .As a classic example of transition metal catalyzed reactions, the aza-Wacker reaction exhibits superior utility and versatility, particularly in the synthesis of natural products and bioactive compounds, with the Heck-type process typically serving as the primary subsequent transformation method (Fig. 1a) [11][12][13][14][15][16][17] . While the cascade cyclization reaction of dienes via an aminopalladation/Heck process has been reported [18][19][20][21][22][23][24][25][26] , further exploration is warranted to uncover more diverse subsequent reactions in series with the aza-Wacker process.To expand upon our previous investigations involving anilines and alkenes [27][28][29][30][31] , we aimed to diversify the range of reaction modes following the aza-Wacker process in a one-pot synthesis. Povarov reaction, characterized by mild conditions, excellent diastereoselectivity, and robust reaction compatibility, utilizing anilines, aldehydes, and alkenes as starting materials that overlap with the substrates or products of the aza-Wacker reaction, emerged as a promising candidate for the subsequent step following th...

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Brønsted Acid-Mediated Intramolecular Cyclization of 1,3-Azadienes Derived from Imines

2024

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Palladium Catalyzed Aza-Wakcer/Povarov Reaction of Aryl Amines and 1,6-Dienes: Synthesis of Hexahydro-Cyclopenta[b]quinoline Framework

Jiang,

Wu,

Tan

et al. 2024

Preprint

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Palladium catalyzed tandem reaction represents a one-pot synthetic approach to efficiently synthesize complex functionalized molecules while reducing synthetic steps, aligning with the principles of green chemistry. However, achieving a direct cascade of the aza-Wacker and Povarov reactions in one-pot synthesis presents a challenge due to substrate compatibility issues between the two reactions. In this work, we describe an aza-Wacker/Povarov reaction employing a highly electrophilic palladium catalyst, which effectively converts anilines and 1,6-dienes into hexahydro-cyclopenta[b]quinolines. The optimized conditions yield up to 79%, with a diastereoselectivity > 20:1. Substrate range testing revealed compatibility with various sensitive functional groups, and successful late-stage modifications were performed on several natural products and drug molecules, demonstrating the versatility and practicality of the method. Additionally, a preliminary investigation into the reaction mechanism suggests an aza-Wacker process followed by a Povarov process.

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Aza-Povarov Reaction. A Method for the Synthesis of Fused Tetracyclic Chromeno[4,3-d]pyrido[1,2-a]pyrimidines

Cited by 3 publications

References 37 publications

Palladium-catalyzed cascade of aza-Wacker and Povarov reactions of aryl amines and 1,6-dienes for hexahydro-cyclopenta[b]quinoline framework

Palladium-catalyzed cascade of aza-Wacker and Povarov reactions of aryl amines and 1,6-dienes for hexahydro-cyclopenta[b]quinoline framework

Brønsted Acid-Mediated Intramolecular Cyclization of 1,3-Azadienes Derived from Imines

Palladium Catalyzed Aza-Wakcer/Povarov Reaction of Aryl Amines and 1,6-Dienes: Synthesis of Hexahydro-Cyclopenta[b]quinoline Framework

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