Palladium-catalyzed allylic alkylation via decarboxylative and retro-Claisen C-C cleavage methods

Presented herein is the development of new methods for Pd-catalyzed allylic alkylation with a central focus on reactions that generate molecular complexity rapidly with little waste byproduct. With this simply stated, yet challenging goal in mind, we present the decarboxylative allylation (DcA) of nitroalkanes and the conceptually novel deacylative allylation (DaA, or retro-Claisen) reaction. The main unifying themes of this research are (a) Pd-catalyzed allylation, (b) in-situ generation of nucleophilic and electrophilic coupling partners, and (c) "green" synthetic methods. Regarding the former topic, DcA of nitroalkanes, we have developed methods for the synthesis of both tertiary and secondary allylated nitroalkanes using decarboxylation as a strategy. Carbon dioxide is the only byproduct and the organic building blocks prepared by this method are easily converted into nitrogen-containing heterocycles by functional group pairing. The conceptually new deacylative allylation (DaA) reaction has been shown to be a useful method for allylation of various in situ generated nucleophiles. The reaction leads to similar products as can be accessed by the DcA method, but has many added benefits. For example, both nucleophilic and electrophilic coupling partners are prepared in situ by a single retro-Claisen event. Furthermore, DaA substrate synthesis begins from commercial/readily available active methylene nucleophiles (β-dicarbonyl compounds) and can utilize robust methods previously developed for these compounds (e.g. Cu/Pd-catalzyed arylation, Tsuji-Trost allylation, etc.). The DaA reaction itself directly couples allylic alcohols, which is desirable due to their availability and reduced toxicity compared to other allylating agents. In terms of utility, DaA can rapidly construct 1,6-heptadienes (cycloisomerization substrates) via 1-pot 3-component coupling. We have also utilized the reaction to construct an important intermediate ¬en route ¬to the drug verapamil as well an asymmetric DaA reaction that allows formal access to (+)-hamigeran and other enantioenriched tetralone derivatives

Deacylative allylation of nitroalkanes: unsymmetric bisallylation via 3-component coupling

Use it and lose it! Allylic alcohols were used directly for the synthesis of diallylated nitroalkanes in a three-component coupling based on the strategy of deacylative allylation for the in situ generation of a nucleophile and an allyl electrophile (see scheme)

Rapid decarboxylative allylation of nitroalkanes

Allyl nitroacetates undergo decarboxylative allylation to provide tertiary nitroalkanes in high yield. Moreover, the transformations are complete within several minutes under ambient conditions. High yields result because O-allylation of the intermediate nitronates, which is typically problematic, is reversible under conditions of the decarboxylative allylation process. Lastly, the preparation of substrate allyl nitroacetates by tandem Knoevenagel/Diels-Alder sequences allows the facile synthesis of relatively complex substrates that undergo diastereoselective decarboxylative allylation

Deacylative allylation: allylic alkylation via retro-Claisen activation

This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of the American Chemical Society, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/ja205717f.A new method for allylic alkylation of a variety of relatively non-stabilized carbon nucleophiles is described herein. In this process of “deacylative allylation” the coupling partners, an allylic alcohol and a ketone pronucleophile, undergo in situ retro-Claisen activation to generate an allylic acetate and a carbanion. In the presence of palladium, these reactive intermediates undergo catalytic coupling to form a new C–C bond. In comparision to unimolecular decarboxylative allylation, a commonly utilized method for allylation of carbon anions, deacylative allylation is an intermolecular process. Moreover, deacylative allylation allows the direct coupling of readily available allylic alcohols. Lastly, the full utility of deacylative allylation is demonstrated by the rapid construction of a variety 1,6-heptadienes via 3-component couplings

Transient [3,3] Cope rearrangement of 3,3-dicyano-1,5-dienes: computational analysis and 2-step synthesis of arylcycloheptanes.

A simple and modular route to arylcycloheptene scaffolds is reported. The two-step route from Knoevenagel adducts and allylic electrophiles is made possible through the design of a Cope rearrangement that utilizes a "traceless" activating group to promote an otherwise thermodynamically unfavorable transformation. Experimentally, the [3,3] rearrangement occurrs transiently at room temperature with a computed barrier of 19.5 kcal mol-1, which ultimately allows for three-component bis-allylation. Ring-closing metathesis delivers the arylcycloheptane and removes the activating group. This report describes the design and optimization of the methodology, scope and mechanistic studies, and computational analysis

Palladium-catalyzed substitution of (coumarinyl)methyl acetates with C-, N-, and S-nucleophiles

The palladium-catalyzed nucleophilic substitution of (coumarinyl)methyl acetates is described. The reaction proceeds though a palladium π-benzyl-like complex and allows for many different types of C-, N-, and S-nucleophiles to be regioselectively added to the biologically active coumarin motif. This new method was utilized to prepare a 128-membered library of aminated coumarins for biological screening.We thank the National Institutes of Health KU Chemical Methodologies and Library Development Center of Excellence (P50 GM069663) for funding. We are indebted to Dr. Conrad Santini and Ben Neuenswander for help in library production and purification

Transition Metal-Catalyzed Decarboxylative Allylation and Benzylation Reactions

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Chemical Reviews, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/cr1002744A review. Transition metal catalyzed decarboxylative allylations, benzylations, and interceptive allylations are reviewed

Development of Asymmetic Deacylative Allylation

Herein we present the development of asymmetric deacylative allylation of ketone enolates. The reaction directly couples readily available ketone pronucleophiles with allylic alcohols using facile retro-Claisen cleavage to form reactive intermediates in situ. The simplicity and robustness of the reaction conditions is demonstrated by the preparation of > 6 grams of an allylated tetralone from commercially available materials. Furthermore, use of non-racemic PHOX ligands allows intermolecular formation of quaternary stereocenters directly from allylic alcohols

Factors Governing and Application of the Cope Rearrangement of 3,3-Dicyano-1,5-dienes and Related Studies

Cope and co-workers reported the [3,3] rearrangement of 3,3-dicyano-1,5-dienes in the early 1940s (“The Cope rearrangement”). However, these original substrates have remained largely unstudied until recently. Herein we explore styrene-deconjugating Cope rearrangements, a diastereoselective Cope rearrangement/deconjugative α-allylation sequence, and factors governing α- vs γ-allylation regioselectivity of Knoevenagel adduct allyl anions. Ultimately, these studies result in the synthesis of diverse and functionally dense polycycloalkane frameworks from abundant reagents using simple chemistry

Sedimentazione geografica dei nonluoghi: transito/arrivo/ritorno

Lo studio si indirizza verso l’analisi sociologica e urbana delle eterotopie (Michel Foucault) e i non-luoghi (Marc Augé) come continuum eterogeneo in relazione al fenomeno della migrazione. In particolare esempi calzanti vengo forniti da donne migranti (Emine Sevgi Özdamar, Marisa Fenoglio and Terézia Mora) che hanno vissuto l’esperienza della sedimentazione geografica dei non-luoghi attraverso tre fasi ben distinte e conseguenti: il transito, l’arrivo e il ritornoThe aim of the present study is addressed to the urban and sociological analysis of the heterotopies (Michel Foucault) and nonplaces (Marc Augé) as heterogeneous continuum in relation to the phenomenon of migrations. In particular, examples are given of immigrant women (Emine Sevgi Özdamar, Marisa Fenoglio and Terézia Mora) who have experienced the geographical sedimentation of the non-places through three phases: transit/arrival/return