Silyl Enol Ethers Research Articles

Catalytic asymmetric defluorinative allylation of silyl enol ethers.

The stereocontrolled installation of alkyl fragments at the alpha position of ketones is a fundamental yet unresolved transformation in organic chemistry. Herein we report a new catalytic methodology able to construct α-allyl ketones via defluorinative allylation of silyl enol ethers in a regio-, diastereo- and enantioselective manner. The protocol leverages the unique features of the fluorine atom to simultaneously act as a leaving group and to activate the fluorophilic nucleophile via a Si-F interaction. A series of spectroscopic, electroanalytic and kinetic experiments demonstrate the crucial interplay of the Si-F interaction for successful reactivity and selectivity. The generality of the transformation is demonstrated by synthesising a wide set of structurally diverse α-allylated ketones bearing two contiguous stereocenters. Remarkably, the catalytic protocol is amenable for the allylation of biologically significant natural products.

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The alkoxy radicals derived from cyclic hemiacetals are generated through visible‐light‐induced electron transfer with NaI and Ph3P as the catalyst. Subsequent β‐scission generates carbon‐centered radicals, which are trapped by cinnamic acids, aryl alkenes, vinylboronic acid and silyl enol ether to deliver the corresponding C—C bond forming products. More details are discussed in the article by Wang et al. on page 259–264.image

Synthesis of cyclic silyl enol ethers from α-Aryl-α-diazoketones: new building blocks for preparation of indanones and α,β-unsaturated ketones

A new strategy for in situ generation of vinyl cation intermediates from α-diazocarbonyl compounds is described in this paper.

Developing a transition-metal-free green protocol for the electrophilic hydrazination of silyl enol ethers using diazo electrophiles with EtOH–H2O as a safe solvent

We report a metal catalyst-free, HF-free and open-flask green protocol for the electrophilic hydrazination of enoxy silanes at an energy-efficient room temperature, taking advantage of the eco-safe EtOH–H2O solvent.

A Cu-BOX catalysed enantioselective Mukaiyama-aldol reaction with difluorinated silyl enol ethers and acylpyridine N-oxides.

A Cu(II)/BOX complex catalyses the enantioselective addition of difluorinated silyl enol ethers to acylpyridine N-oxides. The reaction provides difluorinated chiral tertiary alcohols of great interest in medicinal chemistry. These compounds are obtained in moderate to excellent yields and with high enantioselectivities. The stereochemical outcome of the reaction has been explained by DFT calculations.

N,N'-Diaryldihydrophenazines as a Sustainable and Cost-Effective Alternative to Precious Metal Complexes in the Photoredox-Catalyzed Alkylation of Aryl Alkyl Ketones.

An inexpensive and highly efficient metal-free alternative to commonly used Ru- and Ir-based catalysts was proposed. It was shown that the new 2,7-di-tert-butyl-5,10-bis(4-trifluoromethylphenyl)-5,10-dihydrophenazine outcompeted the iridium phenylpyridyl complex in photoredox activity in the alkylation of silyl enol ethers yielding aryl alkyl ketones. The reaction occurred under visible light irradiation at room temperature and was also applicable to drug derivatives (ibuprofen and naproxen). In-depth photophysical, electrochemical, and quantum chemical studies showed that the aforementioned N,N-diaryldihydrophenazine exhibited enhanced properties that were essential for the photoredox catalysis (a long-lived triplet excited state, strong reducing ability, high stability of the radical cations formed in single-electron-transfer event, and chemical inertness of the catalyst with respect to reactants). Importantly, the substituted N,N'-diaryldihydrophenazines could be obtained directly from diaryl amines; a facile, easily handled and scaled-up one-pot synthetic procedure was elaborated.

Total Synthesis of Puberuline C.

Puberuline C (1) is an architecturally complex C19-diterpenoid alkaloid with a unique ring fusion pattern. The 6/7/5/6/6/6-membered rings (ABCDEF-rings) contain one tertiary amine and six oxygen functionalities, and possess 12 contiguously aligned stereocenters, three of which are quaternary. These structural features of 1 make its chemical construction exceptionally challenging. Here, we disclose the first total synthesis of 1. The synthesis was accomplished from 2-cyclohexenone (9) by integrating radical cascade and Mukaiyama aldol reactions as the key transformations. A double Mannich reaction fused the A- and E-rings, and Sonogashira coupling attached the C-ring, efficiently leading to ACE-rings with the requisite 19 carbons of 1. The chemically stable tertiary chloride of the ACE-ring structure was then transformed to the corresponding bridgehead radical, which participated in the simultaneous cyclization of the B- and F-rings via a highly organized radical cascade process. This unusual step installed five contiguous stereocenters, including two quaternary carbons, without damaging the preexisting multiple polar functionalities. Subsequently, the intramolecular Mukaiyama aldol reaction between silyl enol ether and acetal was realized by applying a combination of SnCl4 and ZnCl2, forging the last remaining D-ring of the hexacycle. Finally, 3 was elaborated into 1 through regio- and stereoselective functionalizations of the BCD-rings. Our novel radical-based strategy achieved the total synthesis of 1 in 32 total steps from simple 9, demonstrating the power of the radical cascade reaction to streamline the assembly of highly complex molecules.

Formation, Reactivity and Decomposition of Aryl Phospha-Enolates.

Two lithium phospha-enolates [RP=C(Sii Pr3 )OLi]2 were prepared by reaction of triisopropyl silyl phosphaethynolate, i Pr3 SiPCO, with aryl lithium reagents LiR (R=Mes: 1,3,5-trimethyl phenyl; or Mes*: 1,3,5,-tri-tertbutyl phenyl). Monomer/dimer aggregation of the enolates can be modulated by addition of 12-crown-4. Substitution of lithium for a heavier alkali metal was achieved through initial formation of a silyl enol ether, followed by reaction with KOt Bu to form the corresponding potassium phospha-enolate [MesP=C(Sii Pr3 )OK]2 . On addition of water, the enolates are protonated to afford RP=C(Sii Pr3 )(OH). For the sterically less demanding system (R=Mes), this phospha-enol rapidly tautomerises to the corresponding acyl phosphine MesP(H)C(Sii Pr3 )(O), which on heating extrudes CO. In contrast, bulkier phospha-enol (R=Mes*) is stable to rearrangement at room temperature and thermally decomposes to RH and i Pr3 SiPCO.

Visible Light‐Promoted Ring‐Opening Alkenylation of Cyclic Hemiacetals through β‐Scission of Alkoxy Radicals

Comprehensive SummaryThe chemistry of alkoxy radicals was extensively explored during the period of 1960s to 1990s, but it has remained dormant for the past few decades. Recently, alkoxy radicals attract the attentions again, because new methods for generating alkoxy radical species have emerged. These newly developed methods are mainly based on the photolysis by visible light under mild conditions, thus allowing for new transformations of the carbon‐centered radical species that are generated from the β‐scission or hydrogen abstraction of the alkoxy radicals. Herein, we demonstrate that the alkoxy radicals derived from cyclic hemiacetals can be generated through visible‐light‐induced electron transfer with sodium iodide and triphenylphosphine as the catalyst. The alkoxy radicals subsequently undergo β‐scission to generate carbon‐centered radicals, which are trapped by cinnamic acids, aryl alkenes, vinylboronic acid and silyl enol ether to deliver the corresponding C—C bond forming products. This catalytic method for ring‐opening alkenylation reaction of cyclic hemiacetal derivatives under visible‐light irradiation conditions demonstrates the compatibility of the visible light‐promoted alkoxy radical generation method with various carbon radical trapping processes. This work opens up new possibilities for the application of alkoxy radicals in organic synthesis.

Resolving the Mechanistic Complexity in Triarylborane-Induced Conjugate Additions

Previous studies have shown that the catalytically active species in the Lewis acid-catalyzed addition reactions of allyl silanes or silyl enol ethers to carbonyl compounds or Michael acceptors are often silylium-carbonyl adducts rather than the adducts of the carbonyl group with the Lewis acid used for the induction of the reaction. Indirect evidence for such catalyst variations has so far been derived from double-label crossover experiments and comparisons of absolute reaction rates. We have now performed a detailed investigation on the kinetics and mechanism of the triarylborane-initiated conjugate addition reactions of allylsilanes and silyl enol ethers to α,β-unsaturated carbonyl compounds. NMR spectroscopic monitoring of such reactions gave rise to sigmoidal kinetic profiles, allowing us to directly follow the change of the catalytically active Lewis acid from triarylboranes in the induction period to silylium ions during the main part of the reaction. Crossover experiments and the isolation of four- and five-membered cyclic intramolecular trapping products provided further insight into the mechanism. DFT calculations of various mechanistic variants and kinetic modeling elucidated the operation of a complex reaction network, which rationalizes the experimental observations.

Substitution-Dependent Ring-Opening Hydrosilylation or Dehydrogenative Hydrosilylation of Cyclopropyl Aldehydes and Ketones Catalyzed by Au Nanoparticles.

The reaction between hydrosilanes and aryl-substituted cyclopropyl aldehydes or ketones catalyzed by Au nanoparticles supported on TiO2 provides two distinct ring-opening reaction motifs depending on the substituents. 2-Aryl-substituted cyclopropyl carbonyl compounds form linear enol ethers via formal silyl hydride addition on the carbon atom bearing the aryl group. Under the reaction conditions, the hydrosilylation adducts undergo hydrolytic silyl deprotection to form acyclic aldehydes or ketones. For 2,2-arylalkyl- or 2,2-diaryl-substituted cyclopropyl carbonyl compounds, a ring-opening dehydrogenative hydrosilylation pathway is solely observed yielding chromatographically stable silyloxy-1,3-dienes. In the presence of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), the reaction is inhibited, indicative of a radical pathway. The proposed intermediate α-cyclopropyl silyloxy radicals undergo radical-clock ring-opening to form benzyl radicals, which may either be captured by the hydrosilane H atom (for 2-aryl-substituted substrates) to form linear silyl enol ethers or eliminate H2 and form silyloxy-1,3-dienes in the case of the bulkier 2,2-disubstituted ones.

Excited-State Palladium-Catalyzed α-Selective C1-Ketonylation.

C-Glycosides are important carbohydrate mimetics found in natural products, bioactive compounds, and marketed drugs. However, stereoselective preparation of this class of glycomimetics remains a significant challenge in organic synthesis. Herein, we report an excited-state palladium-catalyzed α-selective C-ketonylation strategy using readily available 1-bromosugars to access a range of C-glycosides. The reaction features excellent α-selectivity and mild conditions that tolerate a wide range of functional groups and complex molecular architectures. The resulting α-ketonylsugars can serve as versatile precursors for their β-isomers and other C-glycosides. Preliminary experimental and computational studies of the mechanism suggest a radical pathway involving the formation of palladoradical and glycosyl radical that undergoes polarity-mismatched coupling with silyl enol ether, affording the desired α-ketonylsugars. Insight into the reactivity and mechanism will inspire new reaction development and provide straightforward access to both α- and β-C-glycosides, greatly expanding the chemical and patent spaces of glycomimetics.

Asymmetric preparation of 2,4,6‐trisubstituted dihydropyridazinones

AbstractModular three‐component synthesis of highly enantioenriched 2,4,6‐trisubstituted dihydropyridazinones was developed through the nucleophilic substitution of α‐bromoacetates with silyl enol ethers and subsequent condensation with hydrazine derivatives.

Photocatalytic Addition Reactions of Ketene Silyl Acetals with Alkenes through Formation of α-Carbonyl Radicals.

Addition reactions of ketene silyl acetals with alkenes that do not have an electron-withdrawing group are generally difficult because the nucleophilicity of ketene silyl acetals and the electrophilicity of alkenes are not sufficient. Herein, we report photocatalytic addition reactions of ketene silyl acetals with alkenes that proceed through formation of α-carbonyl radicals. In the presence of an appropriate protic additive, the reactions proceeded smoothly under blue-light irradiation to afford the desired products in moderate to high yields.

Chiral nickel(II) complex catalyzed asymmetric (3 + 2) cycloaddition of α‐diazo pyrazoleamides with 2‐siloxy‐1‐alkenes

A highly efficient asymmetric (3 + 2) cycloaddition of α-diazo pyrazoleamides with silyl enol ethers was realized by employing a chiral N,N'-dioxide-Ni(II) complex catalyst. The process includes the formation of chiral nickel carbenoid intermediate and the following enantioselective cycloaddition reaction. The desired dihydrofuran O,O-acetal derivatives were obtained in good yields (up to 90%) with high enantioselectivity (up to 99% ee) under mild reaction conditions within short reaction time. On the basis of the determination of the catalyst structure, a possible transition state mode was proposed.

Asymmetric Total Synthesis of Brasiliquinones B and C via Oxidative Cyclization of a Hydroquinone-Silyl Enol Ether Hybrid.

The asymmetric total synthesis of angucycline antibiotics (S)-brasiliquinones B and C was accomplished. The benz[a]anthraquinone core was constructed via oxidative cyclization of a hydroquinone-silyl enol ether hybrid. The resultant pentacyclic acetal was converted to the silyl enol ether, which was treated with Pd(II)/O2 to afford brasiliquinone C, after multistep conversion including dehydrogenation, desilylation and deacetalization, and hydroquinone oxidation. The (S)-configuration of natural brasiliquinones was confirmed based on the stereochemical correlation with the synthetic products.

Silver-Catalyzed Intermolecular Cross- and Homo-Coupling Reactions of Silyl Enol Ethers

Silver-Catalyzed Intermolecular Cross- and Homo-Coupling Reactions of Silyl Enol Ethers

β-C–H Functionalization of Silyl Enol Ethers under Dual Nickel and Organophotoredox Catalysis

β-C–H Functionalization of Silyl Enol Ethers under Dual Nickel and Organophotoredox Catalysis

Block Copolymer Synthesis by a Sequential Addition Strategy from the Organocatalytic Group Transfer Polymerization of Methyl Methacrylate to the Ring‐Opening Polymerization of Lactide

Sequential block copolymerization involving comonomers belonging to different classes, e.g., a vinyl-type monomer and a heterocycle, is a challenging task in macromolecular chemistry, as corresponding propagating species do not interconvert easily from one to the other by crossover reactions. Here, it is first evidenced that 1-methoxy 2-methyl 1-trimethylsilyloxypropene (MTS), i.e., a silyl ketene acetal (SKA)-containing initiator, can be used in presence of the P4 -t-Bu phosphazene organic base to control the ring-opening polymerization (ROP) of racemic lactide (rac-LA). The elementary reaction, which rapidly transforms SKA groups into propagating alkoxides, can be leveraged to directly synthesize well-defined poly(methyl methacrylate)-b-polylactide block copolymers. This is achieved using P4 -t-Bu as the single organic catalyst and MTS as the initiator for the group transfer polymerization of methyl methacrylate, followed by the ROP of rac-LA. Both polymerization methods are implemented under selective and controlled/living conditions at room temperature in THF. This sequential addition strategy further expands the scope of organic catalysis of polymerizations for macromolecular engineering of block copolymers involving propagating species of disparate reactivity.

Coupling of 2H-Chromenes with Silyl Ketene Acetals Enabled by Borane Catalysis

Coupling of 2<i>H</i>-Chromenes with Silyl Ketene Acetals Enabled by Borane Catalysis