Raising the pK_a Limit of “Soft” Nucleophiles in Palladium-Catalyzed Allylic Substitutions: Application of Diarylmethane Pronucleophiles

Abstract

The Tsuji-Trost allylic substitution reaction provides a useful and efficient approach to construct C-C bonds between sp3-hybridized carbons. The widely accepted paradigm for classifying the mode of attack of nucleophiles on palladium π-allyl intermediates in the Tsuji-Trost reaction is based on the pKa of the pronucleophile: (1) stabilized or “soft” carbon nucleophiles and heteroatom nucleophiles (e.g., pronucleophiles with pKa’s < 25), and (2) unstabilized or “hard” nucleophiles (those from pronucleophiles with pKa’s > 25). One of the keys to the continuing development of allylic substitution processes remains broadening the scope of “soft” nucleophiles. Herein we report a general method for the room temperature Pd-catalyzed allylic substitution with diarylmethane derivatives (pKa’s up to 32). The synthetic significance of the method is that it provides a rapid access to products containing allylated diarylmethyl motifs. The method is general for a wide range of nucleophiles derived from diarylmethanes and heterocyclic derivatives. A procedure for the Pd-catalyzed allylic substitutions to afford diallylation products with quaternary centers is also described. With triarylmethanes and, alkylated diarylmethanes the corresponding allylated products are isolated. We anticipate that the described method will be a valuable complement to the existing arsenal of nucleophiles in Pd-catalyzed allylic substitutions. Mechanistic studies show that the nucleophile derived from diphenylmethane undergoes external attack on π-allyl palladium species under our reaction conditions. This unexpected observation indicates that diarylmethane derivatives behave as “soft” or stabilized nucleophiles. The results of this study indicate that the cutoff between “soft” and “hard” nucleophiles should be raised from a pronucleophile pKa of 25 to at least 32.

Palladium‐Catalyzed Asymmetric Allylic Alkylations with Toluene Derivatives as Pronucleophiles

“…Comparison of the 1 HNMR coupling constants with those of related compounds led to the conclusion that this reaction proceeded by the soft-nucleophile pathway. [20] To demonstrate the utility of our protocol, anonsteroidal anti-inflammatory drug analogue (NSAID) [28] was prepared in two steps (Scheme 6). Beginning with the pyridyl-contain-…”

“…[19] Using these pronucleophiles,wealso explored palladium-catalyzed allylic substitution of diverse cyclic and acyclic electrophiles to give racemic products. [20] Despite significant progress in palladium-catalyzed Tsuji-Trost reactions,highly enantioselective processes with benzylic nucleophiles (toluene derivatives) remain alimitation of this method. Our prior demonstration of ad ouble-inversion reaction pathway with Cr(CO) 3 -activated benzylic nucleophiles to afford racemic products inspired us to pursue palladium-catalyzed AAA reactions.…”

“…Our prior demonstration of ad ouble-inversion reaction pathway with Cr(CO) 3 -activated benzylic nucleophiles to afford racemic products inspired us to pursue palladium-catalyzed AAA reactions. [20] Given the known difficulty of identifying chiral ligands which can moderate all of the steps of ac omplex catalytic cycle and provide useful enantioselectivity,w ei nitially examined over 140 diverse enantioenriched mono-and bidentate phosphine ligands (see the Supporting Information for full ligand structures and results). We employed 1equivalent of (h 6 -C 6 H 5 CH 3 )Cr(CO) 3 (1a)a st he pronucleophile, 2equivalents of tert-butyl cyclohex-2-enyl carbonate (2a), 3equivalents of LiN(SiMe 3 ) 2 ,1equivalent of PMDTA( pentamethyldiethylenetriamine) as an additive, [21] 10 mol %P d-(COD)Cl 2 ,and either 10 mol %ofachiral bidentate ligand or 20 mol %o fam onodentate phosphine in THF at room temperature for 12 hours (Table 1).…”

Photoredox/Nickel‐Catalyzed Single‐Electron Tsuji–Trost Reaction: Development and Mechanistic Insights

“…[4] Recent reports by Walsh and co-workers have reported the utility of diarylmethane nucleophiles (pK a up to 32) in palladium-catalyzed allylic substitution reactions,broadening the nucleophile window of Tsuji-Trost reactions. [5] Alternatively,Z n-, [6] Sn-, [7] B-, [8] Mg-, [9] Si-, [10] and Li-based [11] enolates have been used successfully as nucleophilic partners in related transformations. [2b, 12] However,amajor limitation of enolate-based methods is the prerequisite for highly basic conditions.T o overcome these limitations,pioneering work by the group of Tu nge shifted efforts toward radical-based intramolecular allylations by ap alladium/photoredox cross-coupling,f acilitating the decarboxylative allylation of a-amino carboxylic acids.U nfortunately,w hen Tunge and co-workers moved to intermolecular allylation chemistry,o nly unsubstituted allyl groups were successfully coupled with alkyl carboxylic acid partners.…”

Allyl Alkyl Carbonates

“…In general, C-H acidic compounds are used, but nucleophiles like diphenylmethane are also suitable. 8 …”