Partridge, Benjamin M. and Callingham, Michael and Lewis, William and Lam, Hon Wai (2017) Arylative intramolecular allylation of ketones with 1,3-enynes enabled by catalytic alkenyl-to-allyl 1,4-Rh(I) migration

Alkenyl-to-allyl 1,4-rhodium(I) migration enables the generation of nucleophilic allylrhodium(I) species by remote C@H activation. This new mode of reactivity was employed in the diastereoselective reaction of arylboron reagents with substrates containing a 1,3-enyne tethered to a ketone, to give products containing three contiguous stereocenters. The products can be obtained in high enantioselectivities using a chiral sulfur-alkene ligand. Catalytic C@H functionalizations have revolutionized chemical synthesis by providing powerful new tools for bond construction. However, a critical objective for the advancement of this field is its application to a more diverse range of transformations. Nucleophilic allylations are important reactions that could benefit from C@H functionalization principles. Most typically, these processes have employed allylmetal(loid) reagents such as allyltin, allylboron, or allylsilicon compounds. The generation of nucleophilic allylmetal species by the activation of allylic C@H bonds would bypass the need to prepare such reagents and potentially increase efficiency by streamlining synthetic sequences. This strategy would also be a valuable complement to nucleophilic allylations involving migratory insertions of allenes, 4] the use of simple p-unsaturated compounds in hydrogenative or redox-triggered additions, 6] hetero-ene reactions, and Prins reactions. Although generating electrophilic allylmetal species by allylic C@H activation is well-known, 10] there is, to our knowledge, limited precedent for corresponding processes that provide nucleophilic allylmetals. Very recently, the groups of Schneider, Kanai, and Mita and Sato described the formation and trapping of nucleophilic allylmetal species from simple hydrocarbons. In view of the nucleophilic character of allylrhodium(I) species, we envisaged that activation of a remote C@H bond by 1,4rhodium(I) migration could also achieve this goal. Specifically, rhodium(I)-catalyzed reaction of an arylboron reagent with the alkyne of a 1,3-enyne would provide the alkenylrhodium species A (Scheme 1). This intermediate could then undergo a 1,4-rhodium(I) shift to the cis-allylic substituent to give the allylrhodium(I) species B, which could be trapped by an electrophile. This approach was expected to be challenging, given that there is only very limited precedent for rhodium(I) to migrate to C(sp) centers. Nevertheless, the generation of electrophilic allylrhodium(III) species by a similar strategy in our rhodium(III)-catalyzed oxidative annulations of 1,3-enynes provided some encouragement. Herein, we describe the implementation of this strategy in arylative intramolecular allylations of ketones to give stereochemically complex fused bicycles with high diastereoselectivities. Preliminary results of enantioselective reactions are also provided. This study began with the reaction of the enynone 1a with 3,5-dimethylphenyl pinacol boronate (1.3 equiv), [{Rh(cod)Cl}2] (1.5 mol%), and K3PO4 (0.3 equiv) at 65 8C for 16 hours in various solvents (Table 1). A 3,5-disubstituted arylboron reagent was used to minimize 1,4-rhodium(I) migration onto the aryl group as described previously, as it is well-known that migration onto an aryl ring ortho to a substituent is unfavorable. 15a] Pinacol boronates were used because 3,5-disubstituted variants are easily accessed through iridium-catalyzed C@H borylation. The reaction conducted in THF/MeOH (10:1) gave diastereomeric bicycles 2aa and 2ab in a 13:87 ratio (entry 1). After purification, 2aa and 2ab were isolated in 11 and 46% yield, respectively. Traces of the diketone 3awere also formed, and resulted from arylrhodation of the alkyne of 1a with the regioselectivity opposite to that seen in the formation of 2aa/2ab, followed by a cyclization-fragmentation pathway. 19] Notably, switching Scheme 1. Proposed alkenyl-to-allyl 1,4-rhodium(I) migration. [*] Dr. B. M. Partridge, M. Callingham, Dr. W. Lewis, Prof. H. W. Lam School of Chemistry, University of Nottingham University Park, Nottingham, NG7 2RD (UK) E-mail: [email protected] Homepage: http://www.nottingham.ac.uk/~pczhl/ M. Callingham, Prof. H. W. Lam The GSK Carbon Neutral Laboratories for Sustainable Chemistry, University of Nottingham Jubilee Campus, Triumph Road, NG7 2TU (UK)