Difluoroenoxysilane: Expanding Allenamide Hydrodifluoroalkylation for Diverse Carbon Frameworks.

This study presents an effective route to access functionalizable fluorinated enamides characterized by their high regiospecificity around the allenamide. Synthetic applications of the resulting difluorocarbonyl-bearing enamide products were pursued through straightforward synthetic transformations to prepare unknown functionalized valuable halogenated O-heterocycles and C5 skeletons. Experimental mechanistic studies showed that hydrodifluoroalkylation occurs via a hidden Brønsted acid activation, thereby establishing a new electrophilic activation mode for allenamide through a conjugated iminium intermediate.

Acetate Assistance in Regioselective Hydroamination of Allenamides: A Combined Experimental and Density Functional Theory Study.

A key factor in the development of selective nucleophilic addition to allenamides is controlling the reactivity of electrophilic intermediates, which is generally achieved using an electrophilic activator via conjugated iminium intermediates. In this combined experimental and computational study, we show that a general and highly chemoselective hydroamination of allenamides can be accomplished using a combination of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) and NaOAc. Experimental mechanistic studies revealed that HFIP mediates proton transfer to activate the allenamide, while the acetate additive significantly contributes to N-selective interception. This strategy enables a general hydroamination of allenamides without the use of metals. We demonstrated that various functionalized 1,3-diamines could be readily synthesized and diversified into value-added structural motifs. Detailed mechanistic investigations using the density functional theory revealed the role of NaOAc in the formation of reactive electrophilic intermediates, which ultimately governed the selective formation of 1,3-diamine products. Critically, calculations of the potential energy surface around the proton-transfer transition state revealed that two different reactive electrophilic intermediates were formed when NaOAc was added.

General Hydroamination of Allenamides: Mechanistic Insights with an Acetate Adduct and 1,1,1,3,3,3-Hexafluoro-2-propanol.

The 1,1,1,3,3,3-hexafluoro-2-propanol-assisted allenamide activation enables metal-free regioselective intermolecular interception of amines, constituting a general C-N bond formation process for accessing value-added 1,3-diamines. Exclusive N-chemoselectivity (vs C for anilines) and regioselectivity were achieved for a broad range of substrates. Late-stage modification and further transformations of the 1,3-diamine products showcased the practicability and benefits of this strategy. Experimental mechanistic studies revealed that 1,1,1,3,3,3-hexafluoro-2-propanol mediates the proton transfer for activation of the allenamide. Density functional theory computations revealed the role of NaOAc in the formation of the reactive electrophilic intermediate, which ultimately governs the selective formation of the 1,3-diamine product.

Chemoselective Coupling of π-Systems to Access Metallated 1,4- or 1,5-Skipped Dienes in Multicomponent Reactions.

Integrating distinct unsaturated C-C systems while simultaneously installing metallic groups has been significantly challenging to execute in a multicomponent reaction. Therefore, designing a suitable mechanistic pathway that provides the required reactivity and selectivity for target C-C bonds with metallic reagents to ensure successful coupling is the key to success. Copper-catalyzed borylallylation and silylallylation have emerged as the most efficient strategies for assembling borylated/silylated skipped (1,4 or 1,5) dienes by catalytically combining an organocopper intermediate with allyl electrophiles. However, reactions involving interelemental reagents (e. g., [Si]-[B]) to accomplish intermolecular atom-economic couplings have not been studied thoroughly. Therefore, to aid the development of new transformations in this research area, this article attempts to include all precedents, including recent studies by the authors. The present Concept article may be helpful for researchers working in this area as it provides a basic conceptual framework.

Silaborative Assembly of Allenamides and Alkynes: Highly Regio- and Stereocontrolled Access to Bi- or Trimetallic Skipped Dienes.

A highly stereo- and regiocontrolled multicomponent approach to skipped 1,4-dienes decorated with one boryl and two silyl functionalities is described. This Pd-catalyzed atom-economical union of allenamides, alkynes, and Me2 PhSiBpin (or Et3 SiBpin) proceeds without the use of phosphine ligands, instead relying on chelation through the internal amide group of the allenamide sulfonyl. A variety of alkynes, including those derived from complex bioactive molecules, can be efficiently coupled with allenamides and Me2 PhSiBpin in good yields and with excellent selectivity. The synthetic potential was demonstrated through multiple valuable chemoselective transformations, establishing new disconnections for functionalized dienes. Density functional theory calculations revealed that the reaction first proceeded through borylation of the allenamide, followed by silylation of the alkyne and then reductive elimination, which convergently assemble the skipped 1,4-diene.

Characterization and Utilization of the Elusive α,ß-Unsaturated N-Tosyliminium: the Synthesis of Highly Functionalizable Skipped Halo Enynes.

A formal haloalkynylation of allenamides has been described for the synthesis of highly stereo- and regioselective skipped halo enynes. Exclusive γ-regioselectivity is achieved through the intermediacy of a conjugated N-tosyliminium intermediate-direct evidence for the formation of which was validated by NMR and HRMS. Quantum mechanical computations reveal that the reactive intermediate geometry is key to controlling the 1,2- or 1,4-regioselectivity of alkyne interception. Divergent access to elusive unsaturated systems has also been reported.

Highly Chemoselective Esterification from O-Aminoallylation of Carboxylic Acids: Metal- and Reagent-Free Hydrocarboxylation of Allenamides.

Metal-free hydrocarboxylation of allenamides with various functionalized carboxylic acids were achieved with complete regio- and stereocontrol (>49:1). This environmentally compatible transformation affords γ-acyloxyenamides with exclusive E-selectivity. Electron rich, electron poor, aliphatic, aryl, and heterocyclic carboxylic acids all gave excellent yields (avg. 89 %, 47 examples). We demonstrate the synthetic potential of this transformation in the late-stage modification of complex natural carboxylic acids and simple modification of the products to three-carbon synthons with ample opportunity for further diversification. DFT studies revealed that the reaction occurs in a stepwise manner through the intermediacy of a conjugated iminum species, which is rapidly captured by the carboxylate ion, resulting in the observed linear selectivity.

[3,3]-Acyloxy Rearrangement-Triggered Regioselective Hydration of δ-Acetoxy-α,ß-Alkynoates/Halo Alkynes.

Herein, we report a simple, efficient, highly regioselective, and broad-scope hydration method that is facilitated by an unusual interception of an electrophilic intermediate by water generated via acetate group participation during [3,3]-acyloxy rearrangement. Various carboxylate-directing groups including acetate, acrylates, pivalates, benzoate or its derivatives, and those derived from bioactive natural products were successfully implemented to direct the regioselective hydration for various functionalized δ-acyloxy-ß-ketoester synthesis. The reaction pathway was further confirmed by 18O labeling experiments, and to the best of our knowledge, this is the first report of hydration through an electrophilic intermediate generated during [3,3]-acyloxy rearrangement. Synthetic application includes the synthesis of a modifiable C5-carbon chain, five-, six-, and seven-membered heterocycles, and natural product diversification.

Correction: A synthetic study toward the core structure of (-)-apicularen A.

Correction for 'A synthetic study toward the core structure of (-)-apicularen A' by Tapas R. Pradhan et al., Org. Biomol. Chem., 2018, 16, 8810-8818.

A synthetic study toward the core structure of (-)-apicularen A.

A concise synthetic strategy towards the core structure of (-)-apicularen A has been described in an 11-step synthetic sequence from a known intermediate. The key steps include tandem isomerization followed by C-O and C-C bond-forming reactions and iodocyclization strategies for the synthesis of a bicyclic ether embedded in the macrolactone ring. The applied reagent-controlled Keck-Maruoka allylation, Lin Pu alkynylation and Ricket-Diels-Alder reactions were used to simplify the synthetic sequence of related natural products. An intramolecular Yamaguchi lactonization constructed the macrolactone core, while the attempt to install the C11 hydroxyl chiral centre either under catalytic hydrogenation conditions or oxidative conditions was not successful.

Harnessing the Polarizability of Conjugated Alkynes toward [2 + 2] Cycloaddition, Alkenylation, and Ring Expansion of Indoles.

Reported is the utilization of electronically biased conjugated alkynes in the development of highly diastereo- and regioselective dearomative [2 + 2] cycloadditions, alkenylations, and ring expansions of electron-rich indoles. Regioselective protonations of cross- and linear-conjugated alkynes were found to be crucial for accessing various cyclobutene-fused indoline and alkenylated indole derivatives. Furthermore, the facile ring expansion of [2 + 2] keto adducts, which were successfully synthesized from ynones, provided 1 H-benzo[ b]azepine scaffolds.

Regiodivergent Synthesis of 1,3- and 1,4-Enynes through Kinetically Favored Hydropalladation and Ligand-Enforced Carbopalladation.

Pd-catalyzed hydroalkynylations were developed that involve ligand-enabled regiodivergent addition of an alkyne to an allenamide, giving branched and linear products stereoselectively and facilitated by the neighboring amide group. Regioselectivity was achieved with the use of (o-OMePh)3 P and BrettPhos, which allowed the functionalization of various alkynes, including steroids, carbohydrates, alkaloids, chiral ligands, and vitamins. Based on the experimental results, it was proposed that hydro- and carbopalladation processes operated during the formations of the branched and linear products, respectively.

Synthesis of γ-Acetoxy ß-Keto Esters Through Regioselective Hydration of γ-Acetoxy-α,ß-alkynoates.

The Au(I)-catalyzed regioselective hydration of γ-acetoxy-α,ß-acetylinic ester by the assistance of a neighboring carbonyl group has been developed. Varieties of simple primary, secondary, and tertiary γ-acetoxy-α,ß-acetylinic esters, even those bearing sensitive functional group in the remote reaction sites, are selectively hydrated to the corresponding ß-keto esters. The reaction tolerates a wide variety of other carboxylates, such as benzoates, propionates, acrylates, and pivalates, including chiral carboxylates with retention of the configuration. The broad substrate scope, including the derivatization of complex natural products and neutral and open air conditions, makes this atom economical approach very practical. (18)O labeling experiments disclose that the oxygen transposition occurs from the carboxylate group to the triple bond, not from water.

Ring-closing metathesis (RCM) based synthesis of the macrolactone core of amphidinolactone A.

A convergent synthesis of the macrolactone core of amphidinolactone A has been achieved, in a 10 step linear sequence with 32% overall yield, through a ring-closing metathesis reaction as the macrolactonization step. The RCM precursor was obtained by the union of acid and alcohol fragments derived from (R)-epichlorohydrin and (R)-2,3-O-isopropylidene glyceraldehyde, respectively.