Iridium‐Catalyzed Enantioselective Allylic Substitution of Unstabilized Enolates Derived from α,β‐Unsaturated Ketones

We report Ir‐catalyzed, enantioselective allylic substitution reactions of unstabilized silyl enolates derived from α,β‐unsaturated ketones. Asymmetric allylic substitution of a variety of allylic carbonates with silyl enolates gave allylated products in 62–94 % yield with 90–98 % ee and >20:1 branched‐to‐linear selectivity. The synthetic utility of this method was illustrated by the short synthesis of an anticancer agent, TEI‐9826.     

Silicon‐Directed Rhenium‐Catalyzed Allylic Carbaminations and Oxidative Fragmentations of γ‐Silyl Allylic Alcohols

A highly regioselective allylic substitution of β‐silyl allylic alcohols has been achieved that provides the branched isomer as a single product. This high level of regiocontrol is achieved through the use of a vinyl silane group that can perform a Hiyama coupling providing 1,3‐disubstituted allylic amines. An unusual oxidative fragmentation product was also observed at elevated temperature that appears to proceed by a Fleming–Tamao‐type oxidation–elimination pathway.     

Latent Nucleophiles in Lewis Base Catalyzed Enantioselective N‐Allylations of N‐Heterocycles

Latent nucleophiles are compounds that are themselves not nucleophilic but can produce a strong nucleophile when activated. Such nucleophiles can expand the scope of Lewis base catalyzed reactions. As a proof of concept, we report that N‐silyl pyrroles, indoles, and carbazoles serve as latent N‐centered nucleophiles in substitution reactions of allylic fluorides catalyzed by Lewis bases. The reactions feature broad scopes for both reaction partners, excellent regioselectivities, and produce enantioenriched N‐allyl pyrroles, indoles, and carbazoles when chiral cinchona alkaloid catalysts are used.     

Copper‐Catalyzed Enantioselective Allylic Alkylation with a γ‐Butyrolactone‐Derived Silyl Ketene Acetal

Herein, we report a Cu‐catalyzed enantioselective allylic alkylation using a γ‐butyrolactone‐derived silyl ketene acetal. Critical to the development of this work was the identification of a novel mono‐picolinamide ligand with the appropriate steric and electronic properties to afford the desired products in high yield (up to 96 %) and high ee (up to 95 %). Aryl, aliphatic, and unsubstituted allylic chlorides bearing a broad range of functionality are well‐tolerated. Spectroscopic studies reveal that a Cu^I species is likely the active catalyst, and DFT calculations suggest ligand sterics play an important role in determining Cu coordination and thus catalyst geometry.     

Concise Synthesis of Multisubstituted Isoquinolines from Pyridines by Regioselective Diels–Alder Reactions of 2‐Silyl‐3,4‐pyridynes

A four‐step regioselective synthesis of multisubstituted isoquinoline derivatives from 3‐bromopyridines was developed by the Diels–Alder (DA) reactions of 2‐silyl‐3,4‐pyridynes with furans, followed by functional‐group transformations. In particular, the silyl group at the C2‐position of the 3,4‐pyridynes played two important roles: firstly, it functioned as the directing group for the DA reaction, and secondly, it served to introduce diverse substituents at the C1‐position of the isoquinolines by electrophilic ipso‐substitution.     

Gold‐Catalyzed Cascade Reactions of Furan‐ynes with External Nucleophiles Consisting of a 1,2‐Rearrangement: Straightforward Synthesis of Multi‐Substituted Benzo[b]furans

A gold‐catalyzed cycloisomerization of silyl‐protected 2‐(1‐alkynyl)‐2‐alken‐1‐(2‐furanyl)‐1‐ols with various nucleophiles including water, alcohol, aniline, sulfonamide, and electron‐rich arene has been developed. The method provides a highly efficient access to 5,7‐disubstituted or 2,5,7‐trisubstituted benzo[b]furans with a wide diversity of substituents under mild reaction conditions, which are not easily available by other methods. Remarkably, an interesting rearrangement of the alkyl group from C2 to the C3 position of the furan ring takes place during the cyclization process. The following gold‐assisted allylic substitution enables an elaboration of benzo[b]furans on its side chain of the C5 position with a wide range of functional groups.     

Anilines as C‐Nucleophiles in Ir‐Catalyzed Intramolecular Asymmetric Allylic Substitution Reactions

Anilines generally act as N‐nucleophiles in transition‐metal‐catalyzed allylic substitution reactions. In this paper, a highly enantioselective intramolecular Friedel–Crafts‐type allylic alkylation of aniline derivatives was realized by using an iridium catalyst derived from [Ir(cod)Cl]₂ and (R _a)‐BHPphos. Various tetrahydroisoquinilin‐5‐amines were obtained in moderate to good yields, excellent enantioselectivity and regioselectivity under mild reaction conditions. BHPphos=N ‐benzhydryl‐N ‐phenyldinaphthophosphoramidite.     

Regioselective Transition‐Metal‐Free Allyl–Allyl Cross‐Couplings

Readily prepared allylic zinc halides undergo S_N2‐type substitutions with allylic bromides in a 1:1 mixture of THF and DMPU providing 1,5‐dienes regioselectively. The allylic zinc species reacts at the most branched end (γ‐position) of the allylic system furnishing exclusively γ,α′‐allyl–allyl cross‐coupling products. Remarkably, the double bond stereochemistry of the allylic halide is maintained during the cross‐coupling process. Also several functional groups (ester, nitrile) are tolerated. This cross‐coupling of allylic zinc reagents can be extended to propargylic and benzylic halides. DFT calculations show the importance of lithium chloride in this substitution.     

Catalytic Asymmetric Formation of δ‐Lactones from Unsaturated Acyl Halides

Previously unexplored enantiopure zwitterionic ammonium dienolates have been utilized in this work as reactive intermediates that act as diene components in hetero‐Diels–Alder reactions (HDAs) with aldehydes to produce optically active δ‐lactones, subunits of numerous bioactive products. The dienolates were generated in situ from E/Z mixtures of α,β‐unsaturated acid chlorides by use of a nucleophilic quinidine derivative and Sn(OTf)₂ as co‐catalyst. The latter component was not directly involved in the cycloaddition step with aldehydes and simply facilitated the formation of the reactive dienolate species. The scope of the cycloaddition was considerably improved by use of a complex formed from Er(OTf)₃ and a simple commercially available norephedrine‐derived ligand that tolerated a broad range of aromatic and heteroaromatic aldehydes for a cooperative bifunctional Lewis‐acid‐/Lewis‐base‐catalyzed reaction, providing α,β‐unsaturated δ‐lactones with excellent enantioselectivities. Mechanistic studies confirmed the formation of the dienolate intermediates for both catalytic systems. The active Er^III complex is most likely a monomeric species. Interestingly, all lanthanides can catalyze the title reaction, but the efficiency in terms of yield and enantioselectivity depends directly on the radius of the Ln^III ion. Similarly, use of the pseudolanthanides Sc^III and Y^III also resulted in product formation, whereas the larger La^III and other transition metal salts, as well as main group metal salts, proved to be inefficient. In addition, various synthetic transformations of 6‐CCl₃‐ or 4‐silyl‐substituted α,β‐unsaturated δ‐lactones, giving access to a number of valuable δ‐lactone building blocks, were investigated.     

Iridium‐Catalyzed Enantioselective Intermolecular Indole C2‐Allylation

The enantioselective intermolecular C2‐allylation of 3‐substituted indoles is reported for the first time. This directing group‐free approach relies on a chiral Ir‐(P, olefin) complex and Mg(ClO₄)₂ Lewis acid catalyst system to promote allylic substitution, providing the C2‐allylated products in typically high yields (40–99 %) and enantioselectivities (83–99 % ee) with excellent regiocontrol. Experimental studies and DFT calculations suggest that the reaction proceeds via direct C2‐allylation, rather than C3‐allylation followed by in situ migration. Steric congestion at the indole‐C3 position and improved π–π stacking interactions have been identified as major contributors to the C2‐selectivity.     

Versatile Homoallylic Boronates by Chemo‐, SN2′‐, Diastereo‐ and Enantioselective Catalytic Sequence of Cu−H Addition to Vinyl‐B(pin)/Allylic Substitution

A highly chemo‐, diastereo‐ and enantioselective catalytic method that efficiently combines a silyl hydride, vinyl‐B(pin) (pin=pinacolato) and (E)‐1,2‐disubstituted allylic phosphates is introduced. Reactions, best promoted by a Cu‐based complex with a chiral sulfonate‐containing N‐heterocyclic carbene, are broadly applicable. Aryl‐, heteroaryl‐, alkenyl‐, alkynyl‐ and alkyl‐substituted allylic phosphates may thus be converted to the corresponding homoallylic boronates and then alcohols (after C−B bond oxidation) in 46–91 % yield and in up to >98 % S_N2′:S_N2 ratio, 96:4 diastereomeric ratio and 98:2 enantiomeric ratio. The reasons why an NHC−Cu catalyst is uniquely effective (vs. the corresponding phosphine systems) and the basis for different trends in stereoselectivity are provided with the aid of DFT calculations.     

Synthesis of Branched Alkylboronates by Copper‐Catalyzed Allylic Substitution Reactions of Allylic Chlorides with 1,1‐Diborylalkanes

Reported herein is a copper‐catalyzed S_N2′‐selective allylic substitution reaction using readily accessible allylic chlorides and 1,1‐diborylalkanes, a reaction which proceeds with chemoselective C?B bond activation of the 1,1‐diborylalkanes. In the presence of a catalytic amount of [Cu(IMes)Cl] [IMes=1,3‐bis(2,4,6‐trimethylphenyl)imidazole‐2‐ylidene] and LiOtBu as a base, a range of primary and secondary allylic chlorides undergo the S_N2′‐selective allylic substitution reaction to produce branched alkylboronates. The synthetic utilities of the obtained alkylboronates are also presented.     

Simple palladium‐catalyzed C–N bond formation for poor nucleophilicity of aminonaphthalenes

Aromatic amines is not used commonly in allylic amination, presumably because of their less nucleophilic nature compared with the more extensively used benzylamine or relatively stable anionic nitrogen nucleophiles. An eco‐friendly method for C–O bond activation of allylic acetates using palladium associated with ligands in water leading to N‐allylation was described in this study. The palladium‐catalyzed allylic amination of allylic acetate with aminonaphthalenes gave 34–95% yields to the corresponding N‐allylic aminonaphthalenes. Copyright © 2011 John Wiley & Sons, Ltd.     

Enantioselective Addition of Cyclic Enol Silyl Ethers to 2‐Alkenoyl‐Pyridine‐N‐Oxides Catalysed by CuII–Bis(oxazoline) Complexes

Asymmetric reactions involving (E)‐3‐aryl‐1‐(pyridin‐2‐yl‐N‐oxide)prop‐2‐en‐1‐ones and cyclic enol silyl ethers show good yields and excellent enantioselectivities (up to 99.9 % ee) when catalysed by bis(oxazoline)–Cu^II complexes. Different reaction pathways can be followed by different enol silyl ethers: with 2‐(trimethylsilyloxy)furan, a Mukaiyama–Michael adduct is obtained, whereas a hetero Diels–Alder cycloadduct was formed by using (1,2‐dihydronaphthalen‐4‐yloxy)trimethylsilane. In the latter reaction, the absolute configuration of the product is consistent with a reagent approach to the less hindered Re face of the coordinated substrate in the reactive complex.     

Regio‐ and Stereoselective Allylic Substitutions of Chiral Secondary Alkylcopper Reagents: Total Synthesis of (+)‐Lasiol, (+)‐13‐Norfaranal,and (+)‐Faranal

Chiral secondary alkylcopper reagents were prepared from chiral secondary alkyl iodides by a retentive I/Li exchange followed by a retentive transmetalation with CuBr?P(OEt)₃. Switching the solvent to THF significantly increased their configurational stability and made these copper reagents suitable for regioselective allylic substitutions. The optically enriched copper species underwent S_N2 substitutions with allylic bromides (up to >99 % S_N2 regioselectivity). The addition of ZnCl₂ and the use of chiral allylic phosphates allowed to switch the regioselectivity towards S_N2′ substitution (up to >99 % S_N2′ regioselectivity) and to perform highly selective anti‐S_N2′ substitutions with absolute control over two adjacent stereocenters. This method was applied in the total synthesis of the three ant pheromones (+)‐lasiol, (+)‐13‐norfaranal, and (+)‐faranal (up to 98:2 dr, 99 % ee).     

PEG‐4000‐promoted palladium‐catalyzed N‐allylation in water: aminonaphthalene as an example

An environmentally friendly, efficient catalytic process using palladium associated with ligands in a PEG4000–water system leading to N‐allylation was described in this study. PEG‐4000 was found to improve the palladium‐catalyzed allylic amination of allylic acetates with aminonaphthalenes and gave overall good to high yields of the corresponding N‐allylic aminonaphthalenes. Copyright © 2012 John Wiley & Sons, Ltd.     

The Brønsted Acid Catalyzed,Enantioselective Vinylogous Mannich Reaction

The first catalytic, enantioselective vinylogous Mannich reaction of acyclic silyl dienolates is reported. A second‐generation 2,2′‐dihydroxy‐1,1′‐binaphthyl (BINOL)‐based phosphoric acid has been developed and further optimized as an enantioselective organocatalyst. Upon protonation of the imines, chiral contact ion pairs are generated in situ and attacked highly diastereoselectively by the nucleophile. γ‐Substituted silyl dienolates that lead to more highly substituted Mannich products with a second stereogenic center in good diastereoselectivity have been employed in these reactions. The reaction path has been elucidated with NMR spectroscopy and mass spectrometry, which suggest that the protic reaction medium found to be optimal in these reactions serves to trap the cationic silicon species as silanol. A crystal structure of a phosphoric acid bound imine was obtained that provides insight into the binding mode and a rationale for the stereochemical course of the reaction.     

Silyl‐ and Disilanyl‐BODIPYs: Synthesis via Catalytic Dehalosilylation and Spectroscopic Properties

We describe herein the first synthesis of silyl‐ and disilanyl‐BODIPYs through transition‐metal‐catalyzed dehalosilylation of iodo‐BODIPYs using a Pd(P(t Bu)₃)₂/Et₃N/toluene system. Various mono‐ and bis‐silyl‐BODIPYs, mono‐ and bis‐disilanyl‐BODIPYs and bis‐BODIPYs linked by silylene and SiOSi groups were synthesized by using this straightforward method. Silyl‐ and disilanyl‐substitution significantly modifies the spectroscopic properties of the BODIPY, in which the fluorescence quantum yields of the silyl‐BODIPYs are remarkably increased, whereas the emission spectra of disilanyl‐BODIPYs are red‐shifted due to effective σ(SiSi)–π(BODIPY) conjugation.     

A highly efficient synthesis of (Z)‐1‐aryl‐2‐silyl‐1‐ stannylethenes and their conversion to (E)‐2‐ arylethenyl‐, (Z)‐2‐(2‐pyridyl)ethenyl‐ and allenyl‐silanes

A Pd(dba)₂–P(OEt)₃ combination allowed the silastannation of arylacetylenes, 1‐hexyne or propargyl alcohols with tributyl(trimethylsilyl)stannane to take place at room temperature, producing (Z)‐2‐silyl‐1‐stannyl‐1‐substituted ethenes in high yields. Novel silyl(stannyl)ethenes were fully characterized by ¹H‐, ¹³C‐, ²⁹Si‐ and ¹¹⁹Sn‐NMR as well as infrared and mass analyses. Treatment of a series of (Z)‐1‐aryl‐2‐silyl‐1‐stannylethenes and (Z)‐1‐(3‐pyridyl)‐2‐silyl‐1‐stannylethene with hydrochloric acid or hydroiodic acid in the presence of tetraethylammonium chloride (TEACl) or tetrabutylammonium iodide (TBAI) led to the exclusive formation of (E)‐trimethyl(2‐arylethenyl)silanes with high stereoselectivity. A similar reaction of (Z)‐1‐(2‐anisyl)‐2‐silyl‐1‐stannylethene also produced E‐type trimethyl[2‐(2‐anisyl)ethenyl]silane, while (Z)‐trimethyl [2‐(2‐pyridyl)ethenyl]silane was produced exclusively from (Z)‐1‐(2‐pyridyl)‐2‐silyl‐1‐stannylethene. Protodestannylation of (Z)‐1‐[hydroxy(phenyl)methyl]‐2‐silyl‐1‐stannylethene with trifluoroacetic acid took place via the β‐elimination of hydroxystannane, providing trimethyl(3‐phenylpropa‐1,2‐dienyl)silane quite easily. The destannylation products were also fully characterized. Copyright © 2007 John Wiley & Sons, Ltd.     

α‐d‐Glucofuranose and α‐d‐allofuranose diacetonides and silyl ether of α‐d‐glucofuranose diacetonide in dithiophosphorylation reactions

α‐d ‐Glucofuranose and α‐d ‐allofuranose diacetonides react with 2,4‐diorganyl 1,3,2,4‐dithiadiphosphetane‐2,4‐disulfides to form optically active dithiophosphonates in 78–81% yields, which are transformed into the corresponding ammonium salts in 90–97% yields by the treatment of n‐hexadecylamine. The S‐silyldithiophosphonate was prepared in 93% yield by the reaction of 2,4‐bis(butoxyphenyl) 1,3,2,4‐dithiadiphosphetane‐2,4‐disulfide with silyl ether of α‐d ‐glucofuranose diacetonide. One of the salts obtained possesses antibacterial activity against Staphylococcus aureus ATCC 6538‐P.