Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Palladium-Catalyzed Hydride Addition/C−H Bond Activation Cascade: Cycloisomerization of 1,6-Diynes Jose ́ F. Rodríguez, Katherine I. Burton, Ivan Franzoni,† David A. Petrone,‡ Ina Scheipers,§ and Mark Lautens* Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada
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ABSTRACT: The use of ammonium halide salts as metal hydride precursors in a new Pd-catalyzed cycloisomerization of 1,6-diynes, which affords unexplored silylated 2-azafluorenes, is reported. This cascade process includes the addition of a Pd−hydride species to a π-system, intramolecular carbopalladation, and C(sp2)−H bond activation. A variety of functional groups are tolerated, and the synthetic utility of the resulting products has been demonstrated by a series of derivatizations.
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Scheme 1. Ammonium Halides in Palladium-Catalyzed Domino Processes
he functionalization of C−H bonds has emerged as an effective tool in the construction of complex and valuable scaffolds due to its high step- and atom-economy.1,2 A typical drawback of these approaches is the requirement for a suitable preinstalled or transient directing group to place the metal center in close proximity to the desired C−H bond.3−6 In addition, strategies relying on cascade transformations initiated by oxidative addition to a carbon−halogen bond have been applied in the synthesis of complex poly(hetero)cyclic motifs.7−9 Despite the rapid progress in this field, the use of palladium−hydride (Pd−H) species in the functionalization of remote C−H bonds remains underexplored.10 Herein, we present the exploitation of these intermediates for the cycloisomerization of 1,6-diynes within a domino hydride insertion/C−H bond activation sequence. Pd−H species have been employed in various transformations including hydroxycarboxylation of alkynes, alkenes, and allenes,11 hydroaminocarbonylation of alkenes,12 isomerization of alkenes and alkynes,13a,14 hydroboration of alkenes, alkynes, and allenes,15 intermolecular coupling reactions,16 and in the cycloisomerization of 1,n-enynes, diynes, and dienes.13,17 The use of a Pd−H species in domino processes represents an attractive method for the synthesis of carbo- and heterocyclic compounds, as it circumvents the need for preinstalled carbon−(pseudo)halogen bonds.16,18 Recently, our group has reported a palladium-catalyzed hydrohalogenation of 1,6-enynes, which demonstrated the application of ammonium halide salts and alkyl halides as safe and practical HX (X = halogen) transfer reagents. The reaction between a suitable Pd0 source and Et3N·HX generates a H− PdII−X species that triggers a domino process that consists of hydride insertion, isomerization, intramolecular carbopalladation, and reductive elimination to afford halogenated heterocycles (Scheme 1a).19 We sought to explore the impact of replacing the tethered alkene with the corresponding silylated © XXXX American Chemical Society
alkyne in a related process, wherein insertion of an alkyne into a Pd−H bond would lead to an analogous vinyl−PdII−X intermediate.20 Following an E-to-Z isomerization, a 6-exo-dig carbopalladation would occur. The question that arose was whether the sequence would be terminated by reductive elimination to form a C−X bond or by C−H activation. We have found here that a previously remote C(sp2)−H bond contained in the arene moiety reacted, resulting in a sixmembered palladacycle that undergoes a carbon−carbon bond-forming event (Scheme 1b). The silylated 2-azafluorene products represent an unexplored class of heterocycles that contain several synthetically useful functional groups. In fact, azafluorene scaffolds are found in Onychine alkaloids and have spurred interest due to their antimicrobial, anticandidal, antimalarial, and other biological activities.21−23 Furthermore, fluorene cores exhibit broad applications in the fields of Received: September 24, 2018
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DOI: 10.1021/acs.orglett.8b03057 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 3. Substrate Scopeb
organic (opto)electronics24,25 and artificial molecular machines.26,27 At the outset of our investigation, we employed the reaction conditions used in the previously reported hydrohalogenation method: [Pd(PtBu3)2] (10 mol %) and Et3N·HI (1.2 equiv) in 1,4-dioxane (0.05 M) at 120 °C for 2 h.19 The use of substrate 1a, bearing a tosyl group on the nitrogen atom, led to 2a in 30% yield, with complete consumption of starting material. No other products were observed in appreciable amounts (
