title: Breaking Conjugation: Unusual Regioselectivity with 2-Substituted Allylic Substrates in the Tsuji-Trost Reaction.
abstract: η3-Allyl palladium complexes are key intermediates in Tsuji-Trost allylic substitution reactions. It is well known that (η3-1-aryl-3-alkyl substituted allyl)Pd intermediates result in nucleophilic attack at the alkyl substituted terminus. In contrast, the chemistry of (η3-1,2,3-trisubstituted allyl)Pd intermediates is relatively unexplored. Herein we probe the regioselectivity with 1,2,3-trisubstituted allylic substrates in Tsuji-Trost allylic substitution reactions. DFT investigation of cationic (η3-1-Ph-2-B(pin)-3-alkyl-allyl)Pd(PPh3)2intermediates predict that nucleophilic attack should occur preferentially onanti-allyls rather than thesyn-isomers to generate benzylic substitution products under Curtin-Hammett conditions. Experimentally, systematic studies with 1,2,3-trisubstituted allylic substrates revealed that a Linear Free Energy Relationship (LFER) is observed when Charton steric parameters of the C-2 substituents are plotted against the log of the ratio of regioisomers. Bulkier C-2 substituents in 1,2,3-trisubstituted η3-allyl palladium intermediates provide stronger preference for nucleophilic attack atanti-oriented benzylic termini. Additionally, the geometry of 1,4-elimination products supports the presence ofanti-allyl palladium intermediates.
authors.affiliation: P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 S. 34 Street, Philadelphia, PA 19104-6323, USA; pwalsh@sas.upenn.edu ; ; Tel: +1-2155732875.
authors.forename: Byeong-Seon
authors.initials: BS
authors.lastname: Kim
authors.affiliation: P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 S. 34 Street, Philadelphia, PA 19104-6323, USA; pwalsh@sas.upenn.edu ; ; Tel: +1-2155732875.
authors.forename: Mahmud M
authors.initials: MM
authors.lastname: Hussain
authors.affiliation: University of Gothenburg, Department of Chemistry and Molecular Biology, Kemigården 4, #8076, SE-412 96 Göteborg, Sweden; pon@chem.gu.se ; Pharmaceutical Development, Global Medicines Development, AstraZeneca, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Per-Ola
authors.initials: PO
authors.lastname: Norrby
authors.affiliation: P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 S. 34 Street, Philadelphia, PA 19104-6323, USA; pwalsh@sas.upenn.edu ; ; Tel: +1-2155732875.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Walsh