Enol Silanes Research Articles

Ultrasound-Assisted Remote Benzylic C(sp3)-H Alkylation of N-Fluoroamides with Enol Silanes.

We have developed an ultrasound-assisted remote benzylic C(sp3)-H alkylation of N-fluorobenzamides with enol silanes; a series of β-aryl substituted propiophenones was generated in good to high yields. This reaction represents a formal C(sp3)-C(sp3) coupling and features simplicity, high efficiency, and wide substrate scope in a multiple-step sequential process, which involves N-F homolysis, 1,5-hydrogen atom transfer, benzylic radical addition, oxidation by copper(II) salt, and removal of the trimethylsilyl group. Also, DFT theoretical calculations and Marcus theory were employed to consolidate the proposed reaction mechanism.

Cyclic Sulfoximines as Methyl and Perdeuteromethyl Transfer Agents and Their Applications in Photoredox Catalysis.

Benzo[1,3,2]dithiazole-1,1,3-trioxides are bench-stable and easy-to-use reagents. In photoredox catalysis, they generate methyl and perdeuteromethyl radicals which can add to a variety of radical acceptors, including olefins, acrylamides, quinoxalinones, isocyanides, enol silanes, and N-Ts acrylamide. As byproduct, a salt is formed which can be regenerated to the original methylating agent. Flow chemistry provides an option for reaction scale-up further underscoring the synthetic usefulness of these methylation reagents. Mechanistic investigations suggest a single-electron transfer (SET) pathway induced by photoredox catalysis.

Cyclic Sulfoximines as Methyl and Perdeuteromethyl Transfer Agents and Their Applications in Photoredox Catalysis

AbstractBenzo[1,3,2]dithiazole‐1,1,3‐trioxides are bench‐stable and easy‐to‐use reagents. In photoredox catalysis, they generate methyl and perdeuteromethyl radicals which can add to a variety of radical acceptors, including olefins, acrylamides, quinoxalinones, isocyanides, enol silanes, and N‐Ts acrylamide. As byproduct, a salt is formed which can be regenerated to the original methylating agent. Flow chemistry provides an option for reaction scale‐up further underscoring the synthetic usefulness of these methylation reagents. Mechanistic investigations suggest a single‐electron transfer (SET) pathway induced by photoredox catalysis.

Examining the Scope of Deriving β-Aryl Enones from Enol Silanes as Ketone Equivalents via Pd(II)-Mediated Sequential Dehydrosilylation and Arylation.

Silyl enol ethers were examined as a masked source of saturated ketones to derive β-aryl enones and their derivatives by dehydrosilylation to generate enones in situ and subsequent oxidative arylation with arylboronic acids as transmetallation coupling partners using relayed Pd(II) catalysis in one pot under base-free conditions. Oxygen was found to be an efficient and green oxidant to enable both dehydrosilylation of enol silanes and arylation. Additionally, arylation conditions can be custom-designed to take advantage of aryl halides as an alternative source of arylating agents. The preparative scope was investigated with 35 examples (up to 95% yield), and mechanistic studies implied a cationic Pd(II)-based catalytic system.

Preparation of New Chiral Building Blocks by a Mukaiyama–Michael Reaction of 2-(Phenylsulfonyl)cyclopent-2-en-1-one

AbstractA highly enantio- and diastereoselective Mukaiyama–­Michael reaction of 2-(phenylsulfonyl)cyclopent-2-en-1-one by using an enol silane of tert-butyl thiopropionate is described. The product was formed in 87% yield with a dr of 27:1 and 91% ee under stoichiometric conditions, whereas the yield, dr, and ee were 89%, 49:1, and 88% ee, respectively, under catalytic conditions. A highly stereoselective epimerization of the product of the Mukaiyama–Michael reaction which proceeds in 77% yield with a dr of 22:1 is also described. Because both enantiomers of the ligand for this Mukaiyama–Michael reaction are available, a method for the synthesis of all four stereoisomers of the product as useful chiral building blocks has been established.

One-Pot Enol Silane Formation–Allylation of Ketones Promoted by Trimethylsilyl Trifluoromethanesulfonate

AbstractKetones and related substrate classes undergo enol silane formation in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) and triethylamine, reaction conditions that also promote the in situ ionization of allyl propionates. When these two processes are performed in one pot, allylation of the ketone is observed in high yields. Aldehydes, esters, and thioesters also serve as enol silane precursors under these conditions. When unsymmetrical allyl cations are employed, regioselectivity depends upon the electronic and steric properties of the substituents.

Synthetic Access to α-Oxoketene Aminals by the Nucleophilic Addition of Enol Silane-Derived Palladium(II) Enolates to Carbodiimides.

Synthetically important α-oxoketene aminal intermediates can now be accessed from readily available and inexpensive carbodiimides as starting materials via the nucleophilic addition of palladium enolates derived from enol silane precursors. This operationally simple method features mild reaction conditions, including open air atmosphere, ligand-free metal catalysis, broad substrate scope, and multi-gram scalability. Select synthetic applications that take advantage of the enamine character of α-oxoketene aminals and involve C-nucleophilic additions to electrophilic systems, including an α,β-unsaturated ester, an azo dicarboxylate, an aralkyl halide, and an aldehyde, are demonstrated.

Asymmetric Addition of Enol Silanes to In Situ Generated N-Acyliminium Ions

Key words confined acids - enol silanes - acyliminium ions - asymmetric catalysis - pyrrolidinyl ketones

Synthesis of Enantioenriched Fluorinated Enol Silanes Enabled by Asymmetric Reductive Coupling of Fluoroalkylacylsilanes and 1,3-Enynes and Brook Rearrangement

Synthesis of Enantioenriched Fluorinated Enol Silanes Enabled by Asymmetric Reductive Coupling of Fluoroalkylacylsilanes and 1,3-Enynes and Brook Rearrangement

Catalytic Asymmetric Additions of Enol Silanes to In Situ Generated Cyclic, Aliphatic N-Acyliminium Ions.

Strong and confined imidodiphosphorimidate (IDPi) catalysts enable highly enantioselective substitutions of cyclic, aliphatic hemiaminal ethers with enol silanes. 2‐Substituted pyrrolidines, piperidines, and azepanes are obtained with high enantioselectivities, and the method displays a broad tolerance of various enol silane nucleophiles. Several natural products can be accessed using this methodology. Mechanistic studies support the intermediacy of non‐stabilized, cyclic N‐(exo‐acyl)iminium ions, paired with the confined chiral counteranion. Computational studies suggest transition states that explain the observed enantioselectivity.

Katalytische asymmetrische Additionen von Enolsilanen an in situ erzeugte zyklische, aliphatischeN‐Acyliminiumionen

AbstractStarke und sterisch umzäunte Imidodiphosphorimidatkatalysatoren (IDPi) ermöglichen hochenantioselektive Substitutionen von zyklischen, aliphatischen Hemiaminalethern mit Enolsilanen. 2‐Substituierte Pyrrolidine, Piperidine und Azepane werden mit hoher Enantioselektivität erhalten, und die Methode zeigt eine breite Toleranz gegenüber verschiedenen Enolsilanen. Mehrere Naturstoffe lassen sich mit dieser Methode gewinnen. Mechanistische Studien bestärken die Bildung des Ionenpaares zwischen nicht‐stabilisierten, zyklischenN‐(exo‐Acyl)iminiumionen, und dem sterisch umzäunten chiralen Gegenanion. Theoretische Studien legen Übergangszustände nahe, welche die beobachtete Enantioselektivität erklären.

The Silicon–Hydrogen Exchange Reaction: Catalytic Kinetic Resolution of 2-Substituted Cyclic Ketones

AbstractWe have recently reported the strong and confined, chiral acid-catalyzed asymmetric ‘silicon−hydrogen exchange reaction’. One aspect of this transformation is that it enables access to enantiopure enol silanes in a tautomerizing σ-bond metathesis, via deprotosilylation of ketones with allyl silanes as the silicon source. However, until today, this reaction has not been applied to racemic, 2-substituted, cyclic ketones. We show here that these important substrates readily undergo a highly enantioselective kinetic resolution furnishing the corresponding kinetically preferred enol silanes. Mechanistic studies suggest the fascinating possibility of advancing the process to a dynamic kinetic resolution.

Catalytic Asymmetric Aldolization of Propanal Enol Silanes

Key words confinement - asymmetric catalysis - stereoselectivity - Mukaiyama reaction

Synthesis of α-Difluoromethyl Aryl Ketones through a Photoredox Difluoromethylation of Enol Silanes.

We report here an efficient and highly straightforward access to α-difluoromethylated ketones through a visible light-mediated difluoromethylation of readily available enol silanes. The method, which takes advantage of the polyvalence of Hu's reagent, N-tosyl-S-difluoromethyl-S-phenylsulfoximine, used here as a CHF2 radical precursor under catalytic photoredox conditions, is practical, scalable, and provides the corresponding α-CHF2 ketones in good to excellent yields.

Electrochemically driven desaturation of carbonyl compounds.

Electrochemical techniques have long been heralded for their innate sustainability as efficient methods to achieve redox reactions. Carbonyl desaturation, as a fundamental organic oxidation, is an oft-employed transformation to unlock adjacent reactivity through the formal removal of two hydrogen atoms. To date, the most reliable methods to achieve this seemingly trivial reaction rely on transition metals (Pd or Cu) or stoichiometric reagents based on I, Br, Se or S. Here we report an operationally simple pathway to access such structures from enol silanes and phosphates using electrons as the primary reagent. This electrochemically driven desaturation exhibits a broad scope across an array of carbonyl derivatives, is easily scalable (1-100 g) and can be predictably implemented into synthetic pathways using experimentally or computationally derived NMR shifts. Systematic comparisons to state-of-the-art techniques reveal that this method can uniquely desaturate a wide array of carbonyl groups. Mechanistic interrogation suggests a radical-based reaction pathway.

The Silicon-Hydrogen Exchange Reaction: A Catalytic σ-Bond Metathesis Approach to the Enantioselective Synthesis of Enol Silanes.

The use of chiral enol silanes in fundamental transformations such as Mukaiyama aldol, Michael, and Mannich reactions as well as Saegusa–Ito dehydrogenations has enabled the chemical synthesis of enantiopure natural products and valuable pharmaceuticals. However, accessing these intermediates in high enantiopurity has generally required the use of either stoichiometric chiral precursors or stoichiometric chiral reagents. We now describe a catalytic approach in which strongly acidic and confined imidodiphosphorimidates (IDPi) catalyze highly enantioselective interconversions of ketones and enol silanes. These “silicon–hydrogen exchange reactions” enable access to enantiopure enol silanes via tautomerizing σ-bond metatheses, either in a deprotosilylative desymmetrization of ketones with allyl silanes as the silicon source or in a protodesilylative kinetic resolution of racemic enol silanes with a carboxylic acid as the silyl acceptor.

One-pot enol silane formation-Mukaiyama aldol reactions: Crossed aldehyde-aldehyde coupling, thioester substrates, and reactions in ester solvents

Trimethylsilyl trifluoromethanesulfonate (TMSOTf) and a trialkylamine base promote both in situ enol silane/silyl ketene acetal formation and Mukaiyama aldol addition reactions between a variety of reaction partners in a single reaction flask. Isolation of the required enol silane or silyl ketene acetal is not necessary. For example, crossed aldol reactions between α-disubstituted aldehydes and non-enolizable aldehydes yield β-hydroxy aldehydes in good yield. In a related reaction, the common laboratory solvent ethyl acetate functions as both an enolate precursor and a green reaction solvent. When thioesters are employed as enolate precursors, high yields for additions to non-enolizable aldehydes are routinely observed.

Cyclic Hypervalent Iodine Reagents: Enabling Tools for Bond Disconnection via Reactivity Umpolung.

The efficient synthesis of organic compounds is an important field of research, which sets the basis for numerous applications in medicine or materials science. Based on the polarity induced by functional groups, logical bond disconnections can be deduced for the elaboration of organic compounds. Nevertheless, this classical approach makes synthesis rigid, as not all bond disconnections are possible. The concept of Umpolung has been therefore introduced: by inverting the normal polarity of functional groups, new disconnections become possible. Among the tools for achieving Umpolung, hypervalent iodine reagents occupy a privileged position. The electrophilicity of the iodine atom and the reactivity of the hypervalent bond allow access to electrophilic synthons starting from nucleophiles. Nevertheless, some classes of hypervalent iodine reagents can be too unstable for many applications, in particular involving metal catalysis. In this context, cyclic hypervalent iodine reagents, especially benziodoxolones (BXs), have been known for a long time to be more stable than their acyclic counterparts, yet their synthetic potential had not been fully exploited. In this Account, we report our efforts since 2008 on the use of BX reagents in the development of new transformations in organic synthesis, which showed for the first time their versatility as synthetic tools. Our work started with electrophilic alkynylation, as alkynes are one of the most important functional groups in organic chemistry, but are usually introduced as nucleophiles. We used ethynylbenziodoxolones (EBXs) in the direct alkynylation of nucleophiles, such as keto esters, thiols, or phosphines. The reagents could then be applied to the gold- and palladium-catalyzed alkynylation of C-H bonds on (hetero)arenes, leading to a more efficient alternative to the Sonogashira reaction. More complex reactions were then developed with formations of several bonds in a single transformation. Gold- and platinum-catalyzed cyclization/alkynylation domino processes gave access to new types of alkynylated heterocycles. Multifunctionalization of olefins became possible through intramolecular oxy- and amino-alkynylations. (Enantioselective) copper-catalyzed oxy-alkynylation of diazo compounds led to stereocenters with perfect atom economy. Finally, EBXs were also used for the alkynylation of radicals generated under photoredox conditions. Since 2013, we then extended the use of BX reagents to other transformations. Azidobenziodoxol(on)ess (ABXs) were used in the azidation of keto esters, enol silanes, and styrenes. New more stable derivatives were introduced. Cyanobenziodoxolones (CBXs) enabled the cyanation of stabilized enolates, thiols, and radicals. Finally, new BX reagents were developed for the Umpolung of indoles and pyrroles. They could be used in metal-catalyzed directed C-H functionalizations, as well as in Lewis acid mediated oxidative coupling to give functionalized bi(hetero)arenes. In the past decade, our group and others have shown that BX reagents are not only "structural beauties", but also extremely useful reagents in synthetic chemistry. A toolbox of cyclic hypervalent iodine reagents is now available to achieve Umpolung-based disconnections. We are convinced that the field is still in its infancy, and many new reagents and transformations still remain to be discovered.

One-Pot Enol Silane Formation-Alkylation of Ketones with Propargyl Carboxylates Promoted by Trimethylsilyl Trifluoromethanesulfonate.

Ketones readily undergo conversion to enol silanes in the presence of a trialkylamine base and trimethylsilyl trifluoromethanesulfonate (TMSOTf) and add to propargyl cations to yield β-alkynyl ketones. The propargyl cations are generated in the same reaction flask through the TMSOTf-promoted ionization of propargyl acetates or propargyl propionates. A range of enol silane precursors and propargyl carboxylates reacts efficiently (20 examples, up to 99% yield). Cyclization of a representative product in the presence of TMSOTf provided 61% yield of the trisubstituted furan.

Chalcone and cinnamate synthesis via one-pot enol silane formation-Mukaiyama aldol reactions of ketones and acetate esters

Aryl alkyl ketones, acetate esters, and acetamides undergo facile one-pot enol silane formation, Mukaiyama aldol addition, and dehydrosilyloxylation in the presence of an amine base and excess trimethylsilyl trifluoromethanesulfonate. The chalcone and cinnamate products are generally recovered in high yield. The relative stoichiometry of the trimethylsilyl trifluoromethanesulfonate and amine base reagents determines whether the reaction yields the β-silyloxy carbonyl product or the α,β-unsaturated carbonyl.