Extending Pummerer reaction chemistry. development of a strategy for the regio- and stereoselective oxidative cyclization of 3-(omega-nucleophile)-tethered indoles

The brominative cyclization of diastereomeric beta-silyloxy tryptophan derivatives proceeded with divergent regiochemistry (C(2) or C(3) addition), depending on the relative stereochemistry of the silyloxy substituent. This lack of C(2) vs C(3) regiochemical predictability led to the development of a new approach, which featured Pummerer-type chemistry on an indole C(2) sulfoxide or sulfide substrate, for steering nucleophilic addition to C(3) of the indole. Extension of this transformation from carboxylate nucleophiles to carbon analogues such as allylsilane, silyl enol ether, and silyl ketene iminal bearing substrates led to the formation of spirocyclic oxindole derivatives in good yields with complete regioselectivity for C(3) cyclization and with good diastereoselectivity where relevant.     

Gold-catalyzed assembly of heterobicyclic systems

We have described an efficient gold-catalyzed double cyclization of 1,5-enynes to afford a range of heterobicyclic compounds, including oxabicylclo[3.2.1]octenes, azabicyclo[3.2.1]octenes, oxaspiro[5.4]decene, azaspiro[5.4]decene, oxaspiro[5.5]undecene, oxabicyclo[4.3.0]nonene, azabicyclo[4.3.0]nonene, and oxabicyclo[4.4.0]decene. The mechanism of this reaction is proposed to involve a chemoselective gold-based alkyne activation, carbocyclization, intramolecular nucleophilic addition, followed by protodemetalation. The most notable aspect of this process is the efficient and diastereospecific interception of the reactive intermediate of the initial 6-endo-dig (or 5-endo-dig) cyclization with either oxygen- or nitrogen-based nucleophiles.     

Ruthenium-catalyzed aromatization of enediynes via highly regioselective nucleophilic additions on a pi-alkyne functionality. A useful method for the synthesis of functionalized benzene derivatives

TpRu(PPh3)(CH3CN)2 PF6 (10 mol %) catalyst effected the nucleophilic addition of water, alcohols, aniline, acetylacetone, pyrroles, and dimethyl malonate to unfunctionalized enediynes under suitable conditions (100 degrees C, 12-24 h) and gave functionalized benzene products in good yields. In this novel cyclization, nucleophiles very regioselectively attack the internal C1' alkyne carbon of enediynes to give benzene derivatives as a single regioisomer. Experiments with methoxy substituents exclude the possible involvement of naphthyl cations as reaction intermediates in the cyclization of (o-ethynylphenyl) alkynes. Deuterium-labeling experiments indicate that the catalytically active species is ruthenium-pi-alkyne rather than ruthenium-vinylidene species. This hypothesis is further confirmed by the aromatization of o-(2'-iodoethynyl)phenyl alkynes with alcohols. We propose a nucleophilic addition/insertion mechanism for this nucleophilic aromatization on the basis of a series of experiments.     

Gold(I)-Catalyzed Bis-Cyclization of Allenynes for the Synthesis of Strained and Planar Polycyclic Compounds

A gold-catalyzed cascade cyclization of naphthalene-tethered allenynes gave strained fused phenanthrene derivatives. The reaction proceeds through the nucleophilic reaction of an alkyne with the activated allene to generate a vinyl cation intermediate, followed by arylation with a tethered naphthalene ring to form the 4H-cyclopenta[def]phenanthrene (CPP) scaffold. When using aryl-substituted substrates on the alkyne terminus, the gold-catalyzed reaction produced dibenzofluorene derivatives along with the CPP derivatives. Selective formation of CPP and dibenzofluorene derivatives depending on the reaction conditions is also presented.     

Gold-catalyzed deoxygenative nazarov cyclization of 2,4-dien-1-als for stereoselective synthesis of highly substituted cyclopentenes

Treatment of 2,4-dien-1-als with allylsilanes and PPh(3)AuSbF(6) (3 mol %) led to formation of 1,4-bis(allyl)cyclopentenyl products; this gold catalyst is superior to commonly used Lewis acids according to catalyst screening. Such gold-catalyzed deoxygenative cyclizations are compatible with various oxygen-, amine-, sulfur-, hydrogen-, and carbon-based nucleophiles. The value of this new catalysis is demonstrated by the diverse annulations of 2,4-dien-1-als with electron-rich alkenes and arenes, providing an easy access to complicated cyclopentenyl frameworks. Structural analysis of annulation products reveals evidence for the participation of Nazarov cyclization. This deoxygenative cyclization is extensible to a tandem intramolecular cyclization/nucleophilic addition cascade, giving polycyclic carbo- or oxacyclic compounds with controlled stereochemistry. This new gold catalysis is applied to a short synthesis of natural compounds of the brazilane family, including brazilane, O-trimethyl-, and O-tetramethyl brazilane.     

Gold-catalyzed reactions of 2-alkynyl-phenylamines with alpha,beta-enones

[reaction: see text] The gold-catalyzed reaction of 2-alkynyl-phenylamines with alpha,beta-enones represents a new general one-pot entry into C-3-alkyl-indoles by sequential reactions. Gold-catalyzed sequential cyclization/alkylation, N-alkylation/cyclization, or N-alkylation/cyclization/alkylation reactions leading to different indoles can be directed by changing the 2-alkynyl-phenylamine 1/alpha,beta-enone 3 ratio and the reaction temperature. Unusual gold-catalyzed rearrangement reaction of indoles are observed at 140 degrees C. New gold-catalyzed formation of propargyl-alkyl ether under mild conditions and the hydration reaction of N-acetyl-2-ethynyl-phenylamine are reported.     

Synthesis of Ethyl 2-Cyano-3-Methylthio-3'-Arylaminoacrylate From Low Nucleophilic Amine

The synthesis of ketene N,S-acetals has attracted a considerable attention as building blocks in organic synthesis, especially in the preparation of heterocycles^[1]. The addition reaction of ketene S,S-acetals with highly nucleophilic amines, such as alkylamines, can easily afford the corresponding ketene N,S-acetals, under gentle condition, which could be converted into conjugated ketene aminals by reaction with a second equivalent of the same or a different amine^[2,3]. However, this addition reaction with low nucleophilic amines, such as arylamine or heterocyclic amine, can hardly give the corresponding ketene N,S-acetals under gentle conditions. If under powerful condition,such as refluxing, the addition reaction affords a mixture of the N,S-acetals and conjugated ketene aminals^[4]. Recent studies showed that this addition reaction with low nucleophilic amines affords the corresponding ketene N,S-acetals in the presence of a catalyst^[5].     

金催化剂在联烯亲核加成反应中的应用

金催化联烯亲核加成反应是形成碳碳、碳氮、碳氧以及碳硫键的重要方法.综述了近年来金催化含碳、含氮、含氧以及含硫亲核试剂与联烯的亲核加成反应以及在不对称杂环化合物合成中的应用,并对各种反应历程的特点及其影响因素进行了讨论.     

Efficient pyrrole synthesis using double nucleophilic addition to alpha,beta-unsaturated imines with plural nucleophiles

[reaction: see text] 2,3,5-Trisubstituted pyrroles were prepared in a regioselective manner using the double nucleophilic addition of alpha,alpha-dialkoxy ketene silyl acetals and ketene sily thioacetals or trimethylsilyl cyanide to alpha,beta-unsaturated imines followed by acid-promoted cyclization and oxidation with DDQ. Using this methodology an imidazole glycerol phosphate dehydratase inhibitor (IGPDI) possessing a monopyrrole aldehyde moiety was synthesized.     

Mechanism of the N-protecting group dependent annulations of 3-aryloxy alkynyl indoles under gold catalysis: a computational study

The mechanism of the gold-catalyzed annulations of 3-aryloxy alkynyl indoles developed by Tu et al. was studied by DFT calculations. It was found that both indole derivatives of electron-donating and electron-withdrawing protective groups would first undergo the 5-exo-dig cyclization simultaneously upon activation by cationic [PR(3)Au(+)] species. However, divergent reactivity of the resulting spirocyclic intermediate in competitive 1,2-alkenyl migration and nucleophilic water addition reactions towards C3 was predicted. When protected by electron-donating group, the 1,2-alkenyl migration occurs to generate a tricyclic intermediate, from which an aromatic Claisen rearrangement/nucleophilic addition sequence results in the observed 1,2-phenoxy migration. In case of electron-withdrawing group, the 1,2-alkenyl migration would be unfavorable. Instead, the nucleophilic addition of water oxygen to C3 is more facile, and leads to the hemiketal intermediate. The possible roles of water-cluster and OTf anion as proton shuttles in both reactions were also evaluated.     

金催化炔基苯并二𫫇英环化合成8-羟基异香豆素的理论研究

Density functional theory（DFT） calculations were carried out on the gold-catalyzed cyclization of alkynyl benzodioxin to 8-hydroxy-isocoumarin reaction to show the molecular mechanism of the reaction. The conclusions obtained from this work are different from those in the previous experimental study. The results show that water molecule acts as both the reactant and the proton shuttle, and promotes the reaction with gold complexes under mild conditions. The nucleophilic addition site of water on the substrate is the C（sp³） atom on the side of the substrate far away from the oxabenzene ring, resulting in C（sp³）—O bond breaking in the substrate. The formation of new C—O bond and the cleavage of C—O bond in the substrate follow a step-by-step mechanism. The oxygen in the side-product acetone comes from the contribution of water in the reaction system. The regioselectivity of the reaction originates from the polarization of alkynyl π-electrons induced by substituents.     

Gold(I)-catalyzed regioselective inter-/intramolecular addition cascade of di- and triynes for direct construction of substituted naphthalenes

The gold-catalyzed cascade intermolecular addition-intramolecular carbocyclization reaction of dialkynylbenzenes was developed. In this reaction, regioselective addition of an external nucleophile toward the terminal alkyne and subsequent 6-endo-dig cyclization proceeded to give the 1,3-disubstituted naphthalenes in good yields. The direct synthesis of disubstituted chrysenes via a gold-catalyzed addition and double cyclization cascade using a triyne-type substrate was also achieved.     

Gold-catalyzed highly efficient access to 3(2H)-furanones from 2-oxo-3-butynoates and related compounds

[reaction: see text] The gold-catalyzed cyclization reactions of 2-oxo-3-butynoic esters or disubstituted-1,2-diones with a variety of nucleophiles are described, which offer an efficient and straightforward route to substituted 3(2H)-furanones under mild reaction conditions. The Au(III) catalysts are also highly effective in the hydration of these activated alkynes.     

The multieffects of DMF and DBU on the [5 + 1] benzannulation of nitroethane and α‐alkenoyl ketene‐(S,S)‐acetals: Hydrogen bonding and electrostatic interactions

A density functional theory (DFT) study was performed to elucidate the mechanism for the [5 + 1] benzannulation of nitroethane and α‐alkenoyl ketene‐(S,S)‐acetals. The calculation results are consistent with experimental findings, showing that the reaction proceeds via deprotonation of nitroethane, nucleophilic addition, intramolecular cyclization, elimination of HNO₂, and the keto‐enol tautomerization sequence. It was disclosed that N,N‐dimethylformamide (DMF) and 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) act as not only solvent and nonnucleophilic base, respectively, but also catalysts in the reaction by stabilizing the transition states (TSs) and intermediates via intermolecular hydrogen bonds and electrostatic interactions. Besides, the effective orbital interaction of the reaction site in TS also contributes to the intramolecular cyclization step. The new mechanistic insights obtained by DFT calculations highlight that the hydrogen bonds and electrostatic interactions are key factors for the [5 + 1] benzannulation of nitroethane and α‐alkenoyl ketene‐(S,S)‐acetals. © 2015 Wiley Periodicals, Inc.     

全氟和多氟烷基磺酸的研究 XI: 全氟3-氧杂戊磺酸全氟苯酯的合成及其和亲核试剂的反应

Pentafluorophenyl and p-chlorotetrafluorophenyl-3- oxaperfluoroalkanesulfonates XCF2CF2OCF2CF2SO3C6F4Y (1) (Y=F, p-Cl) were synthesized by the reaction of 3-oxaperfluoroalkanesulfonyl fluoride with the corresponding sodium phenoxide in good yield. 1 reacted with various nucleophilic reagents more readily than phenyl perfluoroalkanesulfonates. The reactivity of nucleophiles toward 1 is parallel to the pKa values of their corresponding acids. All nucleophiles used (except C6H5S^-) attacked sulfur of 1 giving RfSO2Nu. Treatment of 1 with CH3CO^-2 produced perfluorophenyl acetate. When equivalent amount of KF was added to the reaction mixture the yield of the acetate decreased and main product was acetyl fluoride. This showed that the reaction followed the course of intermediary mixed anhydride formed through the attack of CH3CO^-2 on sulfur of 1. But when 1 was treated with ArS^- the only reaction occurred was C-O scission of the sulfenate by the nucleophilic attack of ArS^- on the fluorinated benzene ring to give the totrasubstituted perfluorobenzene, 1, 2, 4, 5-C6F2 (SAr)4. In contrast to the nucleophilic reaction of the mono-substituted pentafluorobenzene it was shown that in all reactions with nucleophiles para or ortho di-substituted compounds such as ReSO3C6F4Nu were not found.     

Synthesis of hetero- and carbocycles by nucleophilic substitution at sp carbon

Vinylic halides having alcohol, sulfonamide, active methine, and thiol moieties as nucleophiles cyclize to hetero- and carbocycles by intramolecular nucleophilic substitution at the sp² carbon centers. The density functional theory calculations suggest that the cyclization proceeds through S_N2-type substitution (the in-plane vinylic nucleophilic substitution, S_NVσ), when vinyl halides are substituted with oxygen, nitrogen, and carbon nucleophiles. The substitution with sulfur nucleophiles, in contrast, proceeds through both routes of S_NVσ and out-of-plane vinylic nucleophilic substitution (S_NVπ).     

Crystallographic/experimental electron density characterizations and reactions with nucleophiles of beta-enaminonitriles possessing a pyrrolobenzazepine core

In connection with a total synthesis of cephalotaxine (1a), we have examined the addition of various nucleophilic reagents to [ABC] subunits 2 and 7 possessing a pyrrolobenzazepine core. In fact, this reaction implicates invariably the carbonyl group of 2. Regarding the reaction of 7 with nucleophiles, the most striking aspect is the complete lack of reactivity of the enaminonitrile moiety. For instance, the condensation of 7 with methylmagnesium bromide involves exclusively the cleavage of the dioxole ring, yielding regioisomers 9 and 10. With the aim of understanding the unexpected reactivity of 2 and 7 toward nucleophiles, crystallographic studies of 2 and 7 and an experimental electron density determination of 7 were carried out. The marked reactivity of the carbonyl group of 2 was interpreted by invoking the weakness of the amide resonance, due to a pronounced delocalization of the N(9) lone pair over the enaminonitrile moiety. The electron density study of 7 reveals this electron delocalization along the enaminonitrile fragment, highlighted and quantified through the bond geometries, topological indicators, and atomic charges, a phenomenon that is responsible for the failure of the addition of nucleophilic species.     

Utilization of an oxonia-Cope rearrangement as a mechanistic probe for Prins cyclizations

An oxonia-Cope rearrangement was used as an internal clock reaction to probe the mechanism of the Prins cyclization reaction and the subsequent nucleophilic capture of the resultant tetrahydropyranyl cation. The oxonia-Cope rearrangement was shown to occur rapidly under typical Prins cyclization conditions when the oxocarbenium ion resulting from the rearrangement is similar to or lower in energy than the starting oxocarbenium ion. Oxonia-Cope rearrangements can be disfavored by destabilizing the resultant oxocarbenium ion or by stabilizing an intermediate tetrahydropyranyl cation. Stereoselectivity in the nucleophilic capture was dramatically affected by the reactivity of the nucleophile and electrophile. More reactive partners combined rapidly to give axial-substituted Prins products through a least-motion pathway. High selectivity for the equatorial-substituted tetrahydropyran was observed for less reactive nucleophiles and electrophiles.     

Peroxycarbenium-mediated C-C bond formation: applications to the synthesis of hydroperoxides and peroxides

The Lewis acid-mediated reaction of alkene nucleophiles with peroxyacetals provides an effective route for the synthesis of homologated peroxides and hydroperoxides. In the presence of Lewis acids such as TiCl(4), SnCl(4), and trimethylsilyl triflate, peroxyacetals and peroxyketals undergo reaction with allyltrimethylsilane, silyl enol ethers, and silyl ketene acetals to afford homoallyl peroxides, 3-peroxyketones, and 3-peroxyalkanoates, respectively. Reactions of peroxyacetals are Lewis acid dependent; TiCl(4) promotes formation of ethers while SnCl(4) and trimethylsilyl triflate promote formation of peroxides. Lewis acid-promoted reactions of silylated hydroperoxyacetals furnish silylated hydroperoxides, which can be deprotected to homologated hydroperoxides. Hydroperoxyketals undergo Lewis acid-mediated allylation to furnish 1,2-dioxolanes via attack of hydroperoxide on the intermediate carbocation. Lewis acid-mediated cyclization of unsaturated peroxyacetals furnishes 1,2-dioxanes, 1,2-dioxepanes, and 1,2-dioxacanes through 6-endo/exo, 7-endo/endo, and 8-endo/endo pathways. The corresponding reactions involving 6-endo/endo and 5-endo/exo pathways were unsuccessful.     

One-pot synthesis of 3-fluoro-4-(trifluoromethyl)quinolines from pentafluoropropen-2-ol and their molecular modification

Pentafluoropropen-2-ol (PFP) was prepared by the reaction of hexafluoroacetone (HFA) with Mg/TMSCl. The one-pot tandem sequential reactions of PFP via Mannich addition with aldimines followed by Friedel-Crafts cyclization and aromatization afforded the title quinolines. A variety of corresponding 3-substituted quinolines were derived from the title quinoline by nucleophilic substitution of 3-fluorine with nucleophiles. A defluorinative transformation of the 4-trifluoromethyl group of the title quinoline with hydrazine afforded pyrazoloquinoline.