Practical Intermolecular Hydroarylation of Diverse Alkenes via Reductive Heck Coupling

Abstract

The hydroarylation of alkenes is an attractive approach to construct carbon–carbon (C–C) bonds from abundant and structurally diverse starting materials. Herein we report a palladiumcatalyzed reductive Heck hydroarylation of unactivated and heteroatom-substituted terminal alkenes with an array of (hetero)aryl iodides. The reaction is anti-Markovnikov selective and tolerates a wide variety of functional groups on both the alkene and (hetero)aryl coupling partners. Additionally, applications of this method to complex molecule diversifications were demonstrated. Deuteriumlabeling experiments are consistent with a mechanism in which the key alkylpalladium(II) intermediate is intercepted with formate and undergoes a decarboxylation/C–H reductive elimination cascade to afford the saturated product and turn over the cycle.

Alkyl halides as both hydride and alkyl sources in catalytic regioselective reductive olefin hydroalkylation

“…In contrast, reactions with unactivated aliphatic C=C bonds are typically plagued by lower substrate reactivity and/or poorer regiochemical differentiation leading to unsatisfactory levels of site selectivity. Notwithstanding these difficulties, remarkable advances for both anti-Markovnikov [18][19][20][21][22][23][24][25] (linear)-and Markovnikov [26][27][28][29][30] (branched)-selective hydroarylations of alkyl-substituted alkenes have been made. A single report on Pd-catalyzed olefin hydroalkynylation/hydroalkenylation to afford linear products was also recently disclosed 31 .…”

Palladium‐Catalyzed Asymmetric Intramolecular Reductive Heck Desymmetrization of Cyclopentenes: Access to Chiral Bicyclo[3.2.1]octanes

“…On the basis of the above mentioned results and previous literature, a proposed mechanism of this reaction is shown in Scheme . Firstly, 1 a undergoes oxidative addition of the active Pd catalyst to give the cationic Pd II intermediate A .…”

“…In these reactions, the rigidity of the carbocyclic frameworks prevented the alkylpalladium intermediates from undergoing rotation and β‐hydride elimination. Very recently, the racemic reductive Heck reactions of unactivated aliphatic alkenes possessing eliminable β‐hydrogen atoms have been realized by the groups of Loh and Engle . However, to the best of our knowledge, protocols that enable asymmetric reductive Heck reactions of unactivated aliphatic alkenes have not been described until now.…”

Synthesis of 3-Substituted Pyrrolidines via Palladium-Catalysed Hydroarylation

“…We recently reported 30 In theory, interception of 1 and 5 by a hydride source could lead to saturated products, rather than alkenes; in practice, such hydroarylation reactions 31,32 are narrowly confined to conjugate-like additions (Figure 3a), 33 constrained alkenes, 34,35 and intramolecular processes ( Figure 3b). 36,37,38,39 Though a rhodium-catalysed process has been reported ( Figure 3c), 40 to date, only one intermolecular palladium-catalysed hydroarylation reaction to give pyrrolidines has been described ( Figure 3d); 41 we report here the first broad-scope palladium-catalysed hydroarylation of pyrrolines ( Figure 3e), directly furnishing 3-substituted pyrrolidines efficiently. During the course of the optimisation of the route to preclamol shown in Figure 2c, it became clear that redox side-reactions were significant competitors to the desired arylation process; in addition to mono-arylated product, hydroarylated product 6 was also obtained (Figure 4a).…”