Domino Conjugate Addition-1,4-Aryl Migration for the Synthesis of α,ß-Difunctionalized Amides.

A domino difunctionalization of sulfonyl(acryl)imides to form ß-substituted α-aryl amides is reported. This transformation involves a 1,4-addition followed by a polar Truce-Smiles rearrangement process, entropically driven by release of SO2. A wide range of carbon- and heteroatom-based nucleophiles and sulfonyl imides were employed, allowing rapid access to highly functionalized amides. In contrast to related reactions with a radical pathway, unbiased substrates could be employed. Despite the usual requirement of an electron-poor migrating moiety for the SNAr event, we herein report unique and unprecedented vinylogous migrations of electron-neutral arenes. Additionally, a one-pot process toward ß-amido amides starting from acrylic acids has been developed.

Methoxide-Enabled Zirconium-Catalyzed Migratory Alkene Hydrosilylation.

A zirconocene dichloride-catalyzed alkene hydrosilylation is reported that can be applied to non-activated and conjugated terminal and internal alkenes. It involves a catalytic Zr-walk process and leads to a selective conversion to the linear product. Lithium methoxide serves as mild catalyst activating agent, which significantly increases the applicability and operational simplicity in comparison to earlier zirconium(II)-based protocols. Supported by additional experiments and calculations, a mechanism via zirconium(IV) intermediates is proposed. Due to the benign nature and ready-availability of the zirconium catalyst, the reaction is an attractive alternative to established alkene hydrosilylation methods.

Lewis Base-assisted Arylation of Unsaturated Carbonyls.

The combination of Lewis bases with α,ß-unsaturated carbonyls allows the in-situ generation of enolates without the need for strong Brønsted bases. Recently developed synthetic methods employ this approach for arylation followed by elimination of the Lewis base, regenerating the alkene. This strategy has been deployed for formal α- or ß-C-H arylation in different contexts, namely (a) transition metal catalysis, (b) rearrangement reactions utilizing hypervalent main group elements and (c) organocatalysis. This concept article provides an overview of the developed strategies, highlighting and contextualizing their features.

Synthesis of α-Aryl Acrylamides via Lewis-Base-Mediated Aryl/Hydrogen Exchange.

Herein we report a method for the synthesis of α-aryl acrylamides leveraging polar S-to-C aryl migrations induced by a Lewis basic organocatalyst. In contrast to previously reported radical aryl migrations of sulfonyl acrylimides, this polar process enables subsequent elimination, ultimately leading to a formal aryl/hydrogen exchange including SO2 extrusion. This reaction is selective for electron-deficient aromatic groups, while tolerating a variety of substituents on nitrogen and in the ß-position, and it delivers useful building blocks for further transformations, including cycloaddition and cyclisation reactions. The mechanism was investigated in detail using quantum chemical calculations, which unexpectedly revealed the Lewis base to be involved in several decisive steps.

HFIP Mediates a Direct C-C Coupling between Michael Acceptors and Eschenmoser's salt.

A direct C-C coupling process that merges Michael acceptors and Eschenmoser's salt is presented. Although reminiscent of the Morita-Baylis-Hillman reaction, this process requires no Lewis base catalyst. The underlying mechanism was unveiled by a combination of kinetic, isotopic labelling experiments as well as computational investigations, which showcased the critical role of HFIP as a superior mediator for proton-transfer events as well as the decisive role of the halide counterion.

Chemoselective γ-Oxidation of ß,γ-Unsaturated Amides with TEMPO.

A chemoselective and robust protocol for the γ-oxidation of ß,γ-unsaturated amides is reported. In this method, electrophilic amide activation, in a rare application to unsaturated amides, enables a regioselective reaction with TEMPO resulting in the title products. Radical cyclisation reactions and oxidation of the synthesised products highlight the synthetic utility of the products obtained.

Unified Approach to the Chemoselective α-Functionalization of Amides with Heteroatom Nucleophiles.

Functionalization at the α-position of carbonyl compounds has classically relied on enolate chemistry. As a result, the generation of a new C-X bond, where X is more electronegative than carbon requires an oxidation event. Herein we show that, by rendering the α-position of amides electrophilic through a mild and chemoselective umpolung transformation, a broad range of widely available oxygen, nitrogen, sulfur, and halogen nucleophiles can be used to generate α-functionalized amides. More than 60 examples are presented to establish the generality of this process, and calculations of the mechanistic aspects underline a fragmentation pathway that accounts for the broadness of this methodology.

Synthesis, Structure, and Reactivity of Binaphthyl Supported Dihydro[1,6]diazecines.

A short approach to chiral diaza-olefines from protected 2,2'-diamino-1,1'-binaphthyl is presented. Cis- and trans-olefines can be selectively obtained by twofold N-allylation followed by RCM or by bridging a 2,2'-diamino-1,1'-binaphthyl precursor with trans-1,4-dibromo-2-butene. Deprotection afforded cis- and trans-dihydro[1,6]diazecines 1 in 58 and 64% overall yield. The reactivity of the but-2-ene-1,4-diyl fragment was investigated yielding corresponding epoxides, diols, and mono- and dibromo products. In several cases rearrangements and participation of the proximate N-Boc group was observed. In no case could allylic substitution be accomplished. From 13 compounds X-ray structure analyses could be obtained.

Amide activation: an emerging tool for chemoselective synthesis.

It is textbook knowledge that carboxamides benefit from increased stabilisation of the electrophilic carbonyl carbon when compared to other carbonyl and carboxyl derivatives. This results in a considerably reduced reactivity towards nucleophiles. Accordingly, a perception has been developed of amides as significantly less useful functional handles than their ester and acid chloride counterparts. However, a significant body of research on the selective activation of amides to achieve powerful transformations under mild conditions has emerged over the past decades. This review article aims at placing electrophilic amide activation in both a historical context and in that of natural product synthesis, highlighting the synthetic applications and the potential of this approach.

Regioselective synthesis of pyridines by redox alkylation of pyridine N-oxides with malonates.

ABSTRACT: A regioselective synthesis of pyridines by the addition of malonate anions to pyridine N-oxide derivatives, which have been activated by trifluoromethanesulfonic anhydride, is reported. The reaction selectively affords either 2- or 4-substituted pyridines in good yields.