Acylsilanes Research Articles

Organocatalyzed Hydroacylation of Enones by Photosensitization of Acyl Silanes.

A mild protocol for hydroacylation of enones through photosensitization of acyl silanes with thioxanthone under blue light (455 nm) irradiation is reported. A Brønsted acid is used as a cocatalyst in the reaction. The versatility of the method is demonstrated through inter- and intramolecular hydroacylation reaction. The hydroacylation product is applied for synthesizing an anti-HCV agent. Mechanistic insights are also provided through control experiments.

Sustainable chemical synthesis: making molecules using visible-light irradiation

The discovery of new strategies to increase the sustainability of chemical manufacturing is of critical importance to many sectors. To this end, photochemistry offers significant potential, as the irradiation of molecules and catalysts with visible light (considered a safe and renewable chemical reagent) can provide access to known molecules in a more sustainable fashion or novel molecular scaffolds that cannot be accessed via traditional means. Acyl silanes are a fascinating functional group which, upon irradiation with blue light, undergo rearrangement to generate reactive intermediates. Recent studies into the reactivity of acyl silanes within our research group has led to the discovery of a series of new photochemical methods to access unique molecular scaffolds using only visible-light irradiation, circumventing the use of precious metal catalysts and additives.

Asymmetric Cu(I)-Catalyzed Conjugate Borylation of α,β-Unsaturated Acyl Silanes

AbstractWe report the development of a Cu(I)-catalyzed conjugate borylation of α,β-unsaturated acyl silanes using bis(pinacoloto)diboron. Racemic borylations of β-aryl- and β-alkyl-substituted silyl enones were achieved using ligand-free conditions to access β-borylated acyl silanes in up to 97% yield. Josiphos enabled the synthesis of enantioenriched boronic esters in up to 58% yield and 94% ee. The racemic reaction was demonstrated on 5.0 mmol scale and isolation of the boronic esters was achieved using simple filtration and normal-phase chromatography. This work supplements known methods to access boronic esters from electron-deficient olefins using Cu(I) catalysis.

Brook Rearrangement as Trigger for Dearomatization Reaction: Synthesis of Non-Aromatic N-Heterocycles.

The [1,2]-Brook rearrangement stands as a potent technique for constructing complex molecules. In this study, we showcase its power in the dearomatization of aromatic N-heterocycles. Through a concise four-step process that integrates lithiation, nucleophilic addition, Brook rearrangement and dearomatization reaction, we demonstrate a versatile strategy for generating diverse non-aromatic N-heterocycles which exhibit ambident reactivities. Various acyl silanes, halo-pyridines, and quinolines have been explored within this context. The synthetic utility of this methodology is demonstrated through the construction of complex architectures.

Benzoyldiisopropylchlorosilane: a visible light photocleavable alcohol protecting group.

Silyl chlorides are highly valuable and popular reagents for the protection of alcohols. In this edge article we introduce a photocleavable alcohol protecting group on the basis of acyl silanes. To achieve this, acylchlorosilanes that represent a new class of acylsilanes were developed. They can be easily synthesized in a concise sequence of three steps in high overall yield. Alcohol silyl protection takes place under established mild conditions, akin to those associated with classical silicon-based protecting groups. The removal of the Si-group is achieved at room temperature through exposure to visible light (456 nm) in methanol. We demonstrate a broad spectrum of substrates with remarkable tolerance toward diverse functional groups, highlighting a substantial level of orthogonality with respect to other protecting groups. Furthermore, we showcase the robustness of this approach against various transformations.

Directed, Remote Dirhodium C(sp3)-H Functionalization, Desaturative Annulation, and Desaturation.

Iminodirhodium reactive intermediates generated in situ from O-tosyloximes using Rh2(esp)2 in CH2Cl2 at rt were exploited for an agile trichotomy of challenging transformations: (1) remote C-H functionalizations using an exceptionally broad diversity of inorganic and organic nucleophiles including several unconventional examples, for example, ethers and acyl silanes; (2) desaturative annulation, a biomimetic 1,3-methylene C-C ring-closure with an overall loss of two hydrogens; and (3) directed desaturation for the acceptor-less, regioselective creation of γ,δ- or γ,δ,ε,ζ-olefins. Compared with typical iminyl transition-metal-mediated and 1,5-hydrogen atom-transfer (1,5-HAT) processes, iminodirhodium intermediates are largely underexplored, especially with respect to C(sp3)-H centers and, yet, have the potential to be transformative by virtue of their substrate breadth, regiocontrol, and elusive reaction modality. A substrate scope includes benzylic, allylic, propargylic, tertiary, and α-alkyloxy centers.

Functionalized Cyclopentenes via the Formal [4+1] Cycloaddition of Photogenerated Siloxycarbenes from Acyl Silanes.

This work describes the first formal cycloaddition reaction of photogenerated nucleophilic carbenes derived from acylsilanes with electrophilic dienes. The resulting transient donor-acceptor cyclopropane rearranges to its stable and highly functionalized cyclopentene isomer in an unprecedented metal-free process. The cyclopropanation-vinyl cyclopropane rearrangement sequence was corroborated by computational calculations. The cyclopropane formation corresponds to a higher energetic barrier, and the vinylcyclopropane-cyclopentene rearrangement proceeds through different mechanisms, although of comparable energies, depending on the stereochemistry of the cyclopropane.

Cobalt-catalysed acyl silane directed ortho C-H functionalisation of benzoyl silanes.

Despite their synthetic utility, practical methods to prepare diversely functionalized aromatic acyl silanes (benzoyl silanes) remain scarce. We herein report that cobalt complexes can successfully engage acyl silanes as weakly coordinating directing groups to catalyse the ortho C-H functionalisation of benzoyl silanes. Under Cp*Co(III) catalysis, installation of allyl or amido functionality at the 2-position of benzoyl silanes was achieved, while reaction with internal alkynes led to a desilylative annulation to afford indenone scaffolds. A Co(II)/dppp catalytic system was also investigated to achieve the acyl silane directed hydroarylative cyclisation of 1,6-enynes to access unique benzoyl silane derivatives.

Photo-Brook rearrangement of acyl silanes as a strategy for photoaffinity probe design.

Photoaffinity labeling (PAL) is a powerful tool for the identification of non-covalent small molecule–protein interactions that are critical to drug discovery and medicinal chemistry, but this approach is limited to only a small subset of robust photocrosslinkers. The identification of new photoreactive motifs capable of covalent target capture is therefore highly desirable. Herein, we report the design, synthesis, and evaluation of a new class of PAL warheads based on the UV-triggered 1,2-photo-Brook rearrangement of acyl silanes, which hitherto have not been explored for PAL workflows. Irradiation of a series of probes in cell lysate revealed an iPr-substituted acyl silane with superior photolabeling and minimal thermal background labeling compared to other substituted acyl silanes. Further, small molecule (+)-JQ1- and rapamycin-derived iPr acyl silanes were shown to selectively label recombinant BRD4-BD1 and FKBP12, respectively, with minimal background. Together, these data highlight the untapped potential of acyl silanes as a novel, tunable scaffold for photoaffinity labeling.

Polymer Skeletal Editing via Anionic Brook Rearrangements.

This report communicates the first example of polymer backbone metamorphosis affected by anionic 1,2-Brook rearrangement of acyl silane moieties. Introduction of the acyl silane functionality into a polymer backbone was achieved via acyclic diene metathesis copolymerization (ADMET) of diene 1 and two dienes. We demonstrate that, using organolithium species and cyanide as nucleophiles, the backbones of resulting copolymers can be triggered to undergo highly efficient 1,2-Brook rearrangement, which transforms the poly(acyl silane)s into poly(silyl ether)s. Furthermore, the carbanion intermediate of the 1,2-Brook rearrangement can be intercepted by ketone electrophiles to give rise to polymers with quaternary stereogenic centers in the backbone and pendant functionality. Such structural editing of polymer backbones enables a new retrosynthetic paradigm for silicon-containing polymers that could not be accessed by traditional means.

Photo Click Reaction of Acylsilanes with Indoles.

Light‐mediated coupling of acylsilanes with indoles is reported. This photo click reaction occurs under mild conditions (415 nm) mostly in quantitative yield and provides stable silylated N,O‐acetals via light mediated siloxycarbene generation with subsequent indole‐N‐H insertion. We show that this very efficient and fully atom economic coupling process can be applied to conjugate complex systems, as documented by the clicking of carbohydrates with indole alkaloids. The method is also applicable to the conjugation of polymer chains. The linking acetal moiety can be readily cleaved and it is also shown that wavelength‐selective coupling and cleavage with acyl silanes bearing a second photoactive moiety is possible. This is documented by a successful polymerization/depolymerization sequence and by a polymer folding/unfolding process.

Photo Click Reaction of Acylsilanes with Indoles

AbstractLight‐mediated coupling of acylsilanes with indoles is reported. This photo click reaction occurs under mild conditions (415 nm) mostly in quantitative yield and provides stable silylated N,O‐acetals via light mediated siloxycarbene generation with subsequent indole‐N‐H insertion. We show that this very efficient and fully atom economic coupling process can be applied to conjugate complex systems, as documented by the clicking of carbohydrates with indole alkaloids. The method is also applicable to the conjugation of polymer chains. The linking acetal moiety can be readily cleaved and it is also shown that wavelength‐selective coupling and cleavage with acyl silanes bearing a second photoactive moiety is possible. This is documented by a successful polymerization/depolymerization sequence and by a polymer folding/unfolding process.

Acyl silane directed Cp*Rh(III)-catalysed alkylation/annulation reactions.

Studies into the Cp*Rh(iii)-catalysed hydroarylation of alkenes with aryl acyl silanes led to the discovery of a new synthetic strategy to access unique silicon derived indene frameworks. Rather than protodemetalation of the metal enolate formed following insertion of an alkene into the aryl C-H bond, intramolecular aldol condensation of the acyl silane occurred to generate a series of 2-formyl- and 2-acetyl-3-silyl indenes. This represents only the second example of rhodium-catalysed C-H functionalisation employing acyl silanes as weakly coordinating directing groups and the intramolecular aldol condensation strategy was extended to access analogous silicon derived benzofurans.

1,2-Amino Alcohols via Cr/Photoredox Dual-Catalyzed Addition of α-Amino Carbanion Equivalents to Carbonyls.

Herein, we report the synthesis of protected 1,2-amino alcohols starting from carbonyl compounds and α-silyl amines. The reaction is enabled by a Cr/photoredox dual catalytic system that allows the in situ generation of α-amino carbanion equivalents which act as nucleophiles. The unique nature of this reaction was demonstrated through the aminoalkylation of ketones and an acyl silane, classes of electrophiles that were previously unreactive toward addition of alkyl-Cr reagents. Overall, this reaction broadens the scope of Cr-mediated carbonyl alkylations and discloses an underexplored retrosynthetic strategy for the synthesis of 1,2-amino alcohols.

Insights into the Stability of Siloxy Carbene Intermediates and Their Corresponding Oxocarbenium Ions.

Siloxy carbenes, formed thermally or photochemically from acyl silanes via a 1,2-Brook rearrangement, are intriguing reactive intermediates that partake in a range of chemical reactions. To gain further insight into the properties of this class of carbenes, the thermodynamic stabilities of a series of known siloxy carbenes were explored on the basis of hydrogenation enthalpies. Calculations were conducted at the B3LYP-D3(BJ) level (using dispersion-corrected DFT) on siloxy carbenes (X-C-OSiR3, singlet and triplet state), oxocarbenium ions (X-CH-OSiR3+), and their hydrogen addition products (X-CH2-OSiR3). Overall, strong correlation between singlet-triplet gaps and hydrogenation enthalpies was observed. Carbene stabilization enthalpy (CSE) values were also determined to provide additional insight into the structural features that influence the stability of siloxy carbenes.

Morpholine Ketene Aminal as Amide Enolate Surrogate in Iridium-Catalyzed Asymmetric Allylic Alkylation.

Morpholine ketene aminal is employed in iridium-catalyzed asymmetric allylic alkylation reactions as a surrogate for amide enolates to prepare γ,δ-unsaturated β-substituted morpholine amides. Kinetic resolution or, alternatively, stereospecific substitution affords the corresponding products in high enantiomeric excess. The utility of the products generated by this method has been showcased by their further elaboration into amines, ketones, or acyl silanes. A putative catalytic intermediate (η3 -allyl)iridium(III) with achiral P,Olefin-ligand was synthetized and characterized for the first time.

Morpholine Ketene Aminal as Amide Enolate Surrogate in Iridium‐Catalyzed Asymmetric Allylic Alkylation

AbstractMorpholine ketene aminal is employed in iridium‐catalyzed asymmetric allylic alkylation reactions as a surrogate for amide enolates to prepare γ,δ‐unsaturated β‐substituted morpholine amides. Kinetic resolution or, alternatively, stereospecific substitution affords the corresponding products in high enantiomeric excess. The utility of the products generated by this method has been showcased by their further elaboration into amines, ketones, or acyl silanes. A putative catalytic intermediate (η3‐allyl)iridium(III) with achiral P,Olefin‐ligand was synthetized and characterized for the first time.

Visible light induced free radical promoted cationic polymerization using acylsilanes

Within this work, a novel visible light photoinitiation system for cationic polymerization of oxiranes such as cyclohexene oxide (CHO) and vinyl monomers such as isobutyl vinyl ether (IBVE) and N-vinylcarbazole (NVC) using tetrakis(2,4,6-trimethylbenzoyl)silane (TTBS) is described. Polymerizations were successfully initiated at room temperature upon irradiation in the visible region (λinc > 400) in bulk or methylene chloride solutions of these monomers and TTBS, in the presence of onium salts such as diphenyliodonium hexafluorophosphate (Ph2I+PF6−) and triphenylsulfonium hexafluorophosphate (Ph3S+PF−). Partial decomposition of TTBS by short irradiation time and keeping the polymerization solution in the dark yielded poly(cyclohexene oxide) (PCHO) bearing acyl silane terminal groups. Further use of the resultant polymer as photoinitiator in free radical polymerization of MMA and free radical promoted cationic polymerizations of CHO yielded PCHO-b-PMMA and chain extended PCHO, respectively.

Acyl Radical Chemistry via Visible-Light Photoredox Catalysis.

Visible light photoredox catalysis has enabled easy access to acyl radicals under mild reaction conditions. Reactive acyl radicals, generated from various acyl precursors such as aldehydes, α-ketoacids, carboxylic acids, anhydrides, acyl thioesters, acyl chlorides, or acyl silanes, can undergo a diverse range of synthetically useful transformations, which were previously difficult or inaccessible. This review summarizes such recent progress of visible-light-driven acyl radical generation using transition metal photoredox catalysts, metallaphotocatalysts, hypervalent iodine catalysts or organic photocatalysts.

α-β Unsaturated Acylsilanes as Surrogates of Acrolein for Morita-Baylis-Hillman Reactions

α-β Unsaturated Acylsilanes as Surrogates of Acrolein for Morita-Baylis-Hillman Reactions