Anion-stabilizing Groups Research Articles

Decarboxylative and dehydrative coupling of dienoic acids and pentadienyl alcohols to form 1,3,6,8-tetraenes

Dienoic acids and pentadienyl alcohols are coupled in a decarboxylative and dehydrative manner at ambient temperature using Pd(0) catalysis to generate 1,3,6,8-tetraenes. Contrary to related decarboxylative coupling reactions, an anion-stabilizing group is not required adjacent to the carboxyl group. Of mechanistic importance, it appears that both the diene of the acid and the diene of the alcohol are required for this reaction. To further understand this reaction, substitutions at every unique position of both coupling partners was examined and two potential mechanisms are presented.

Synthesis of Substituted 1,4-Dioxenes through O-H Insertion and Cyclization Using Keto-Diazo Compounds.

1,4-Dioxenes present interesting potential as synthetic intermediates and as unusual motifs for incorporation into biologically active compounds. Here, an efficient synthesis of functionalized 1,4-dioxenes is achieved in two steps. Using keto-diazo compounds, a ruthenium catalyzed O-H insertion with β-halohydrins followed by treatment with base results in cyclization with excellent selectivity, through O-alkylation of the keto-enolate. A variety of halohydrins and anion-stabilizing groups in the diazo-component are tolerated, affording novel functionalized dioxenes. Enantioenriched β-bromohydrins provide enantioenriched 1,4-dioxenes.

Carbanion-accelerated Claisen rearrangements: asymmetric induction with chiral phosphorus-stabilized anions.

The carbanion-accelerated Claisen rearrangement has been extended to include phosphorus carbanion-stabilizing groups. The appropriately substituted allyl vinyl ethers are synthesized by the nucleophilic addition of allyl oxides to phosphorus-substituted allenes, which are obtained in one step from simple starting materials. The phosphorus-stabilized, carbanion-accelerated Claisen rearrangements proceed rapidly at room temperature in high yield, and the rearrangements are highly site- and stereoselective. The first examples of asymmetric induction in the Claisen rearrangement with chiral, phosphorus, anion-stabilizing groups are described. The observed asymmetric induction is highly dependent on the structure of the auxiliary and the metal counterion involved. Both internal and relative diastereoselectivity are high. A model for the observed sense of internal diastereoselectivity is proposed that is founded in the current understanding of the structure of phosphorus-stabilized anions.

ChemInform Abstract: Use of Metal Complexation in the Synthesis of Medium-Ring Acetylenic Lactones.

Abstract The hexacarbonyldicobalt complexes of several appropriately designed acetylenic lactone precursors have been prepared, and lactones containing Co2(CO)6-complexed triple bonds in seven-, ten-, and eleven-membered rings obtained. The latter were best obtained through a retro-Dieckmann fragmentation of 2-(hydroxybutynyl) derivatives of 1,3-clohexanedione. Attempts to extend this reaction to cyclohexanones bearing other anion-stabilizing groups in the 2-position or to 1,3-cyclopentanediones were unsuccessful. Decomplexation afforded the metal-free 11-ring lactone, characterized crystallographically. Treatment of this system with basic reagents led to dimerization. In the case of the smaller rings, cyclization of the complexed acetylenic hydroxyacids under Mukaiyama conditions (2-chloro-N-methylpyridinium iodide, CH2Cl2, reflux) succeeded in modest yields.

Benzyl and phenylthiomethyl silanes: a new class of bifunctional linchpins for type II anion relay chemistry (ARC).

A new class of bifunctional linchpins bearing electrophilic sites beta or gamma to a silyl group have been designed, synthesized, and demonstrated to be competent in tricomponent unions exploiting Type II Anion Relay Chemistry (ARC). High diastereoselectivities were observed when a phenyl moiety (R(2)) served as an anion-stabilizing group (ASG) adjacent to a methyl susbtituent (R(1)), while diastereomeric mixtures were obtained when a phenylthiol moiety served as the ASG, irrespective of alpha-substitution.

Anion Relay Chemistry: An Effective Tactic for Diversity Oriented Synthesis

An effective one-flask multicomponent linchpin coupling protocol employing the concept of anion relay chemistry (ARC) was developed. This concept calls for addition of an anion (5) to an epoxide (6), bearing on a distal carbon a trialkyl silyl group and an anion stabilizing group (ASG), to furnish upon epoxide ring opening oxyanion 7. Addition of HMPA or other polar solvents to trigger a solvent controlled 1,4-Brook rearrangement then leads to a new distal anion (8), which in turn is available to react with a variety of second electrophiles.

Cyclisations of Organolithiums onto Aromatic Rings

A review on synthesis of bicyclic and polycyclic arom. compds. contg. condensed five-membered rings by cyclization of lithiated arom. hydrocarbons and their functional derivs. An intramol. nucleophilic attack of lithiated arom. and alkylarom. compds. results in cyclization with formation of indene and fluorene five-membered rings and migration of lithium to appropriate position in the newly formed condensed arom. system. Anion-stabilizing groups, particularly sulfur- or amide-contg. functional groups, are able to retard the rearomatization step and may lead to dearomatized products. Activated benzene compds. undergo dearomatizing cyclization with formation of dihydro-benzoheterocycles, e.g., cyclic sulfones; lithiation-induced heterocyclization of N,N-dimethyltriazenes afforded hexahydro-benzotriazines. Cyclization of benzamides, promoted by LDA, gave substituted isoindolones. A no. of kainoids, pyrrolidinedicarboxylic acids, were prepd. by LDA-promoted stereospecific heterocyclization of 1-acyl-N-benzyl-3-pyrrolecarboxamide. Recent optimization of such reactions, particularly those employing arom. amides, has allowed them to be used as key steps in a no. of syntheses of natural products and their analogs. [on SciFinder (R)]

2,3]‐Sigmatropic Rearrangements of Didehydropiperidinium Ylids.

AbstractFor Abstract see ChemInform Abstract in Full Text.

2,3]-Sigmatropic rearrangements of didehydropiperidinium ylids

The [2,3]-sigmatropic rearrangements of ammonium ylids derived from 1,2,5,6-tetrahydropyridine have been studied: both rearrangement and elimination processes are observed, with rearrangement favoured when aprotic solvents are used in the reaction. The presence of anion-stabilizing substituents on the nucleophilic carbon atom of the intermediate ylid species involved in the tranformation also engenders rearrangement; when certain aryl substituents or two anion-stabilizing groups are present, elimination is not observed, and electron-donating ylid substituents retard rearrangement whilst enhancing elimination.

Synthesis and Aza-[2,3]-Wittig Rearrangements of Vinylaziridines: Scope and Limitations.

cis- and trans-2,3-Trisubstituted vinylaziridines have been prepared from cis- and trans-epoxy alcohols, respectively, and used as substrates in the aza-[2,3]-Wittig rearrangement. Five different anion-stabilizing groups have been investigated for their efficiency to promote the rearrangement, and it was found that N-tert-butyl acetyl vinylaziridines were superior in this reaction, affording the corresponding cis-2,6-tetrahydropyridines (>90%) as single isomers when treated with LDA. Similarly, the corresponding (Z)-propenylaziridines gave trans,trans-2,3,6-trisubstituted tetrahydropyridines as the sole products while the (E)-propenylaziridines afforded the cis,cis-2,3,6-derivatives with equally high selectivity. The scope and limitations of the process have been investigated by varying the structure of the substrate, and the mechanism of the rearrangement has been probed to some extent; the mechanistic picture is more complex than assumed previously.

ChemInform Abstract: Asymmetric (2,3)‐Wittig Rearrangements with Chiral, Phosphorus Anion Stabilizing Groups.

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Asymmetric [2,3]-Wittig rearrangements with chiral, phosphorus anion-stabilizing groups

The [2,3]-Wittig rearrangement of a chirally-modified phosphorus stabilized anion proceeds readily and with excellent diastereo- and enantioselectivity for allyloxymethyl and ( Z)-2-butenyloxymethyl derivatives.

On the origin of geminal regioselectivity in the ene reaction of singlet oxygen with substituted alkenes

The geminal regioselectivity observed in the ene reaction between singlet oxygen and alkenes with anion-stabilizing groups is rationalized on the basis of a perepoxide intermediate, in which in analogy to the nucleophilic attack on protonated epoxides, the perepoxide is opened preferentially at the CO bond weakened by the substituent.

Use of metal complexation in the synthesis of medium-ring acetylenic lactones

The hexacarbonyldicobalt complexes of several appropriately designed acetylenic lactone precursors have been prepared, and lactones containing Co 2(CO) 6-complexed triple bonds in seven-, ten-, and eleven-membered rings obtained. The latter were best obtained through a retro-Dieckmann fragmentation of 2-(hydroxybutynyl) derivatives of 1,3-clohexanedione. Attempts to extend this reaction to cyclohexanones bearing other anion-stabilizing groups in the 2-position or to 1,3-cyclopentanediones were unsuccessful. Decomplexation afforded the metal-free 11-ring lactone, characterized crystallographically. Treatment of this system with basic reagents led to dimerization. In the case of the smaller rings, cyclization of the complexed acetylenic hydroxyacids under Mukaiyama conditions (2-chloro- N-methylpyridinium iodide, CH 2Cl 2, reflux) succeeded in modest yields.

ChemInform Abstract: The Peterson Olefination Reaction

The Peterson olefination reaction provides a useful method for the preparation of alkenes from α-silyl carbanions and carbonyl compounds. As alkenes hold a pivotal role in synthetic methodology for the introduction of vicinal functionality, particularly in a stereoselective manner, the Peterson reaction is increasing in importance in the reaction repertoire. This chapter discusses the reaction and its advantages over comparable methods such as the Wittig reaction. Although elimination of β-silylalkoxides, was noted in 1947, it was not until Peterson described the preparation of functionalized alkenes from α-silyl carbanions in 1968 that the full potential of the reaction became apparent. Alkenes are usually only isolated directly from the condensation when an anion-stabilizing group is present in the carbanion; if not, the β-hydroxysilane is formed. Many examples of the formation of alkenes from β-hydroxysilanes are cited in the literature. These eliminations are discussed in this chapter, although they strictly should not be called Peterson olefination reactions. However, the “common” organic reactions of β-hydroxysilanes which follow the usual pathways—such as the thermolytic elimination of esters derived from those alcohols—are omitted. The central nature of the Peterson reaction to organosilicon chemistry has led all reviews in this area to discuss the subject to some extent. In addition, the reaction itself has been reviewed previously. Keywords: Peterson olefination; mechanisms; scope; limitations; diastereoselective synthesis; hydroxysilanes; silyl carbions; carbonyl groups; unsaturation; silyl-nitrogen compounds; silyl-sulfur compounds; silyl selenium compounds; functional groups; carbonyl compounds; electrophiles; Homo-Peterson reaction; Brook rearrangement; Sila-Pummerer rearrangements; Wittig reaction; experimental procedures

Conversion of canavanine to α-keto-γ-guanidinooxybutyrate and to vinylglyoxylate and 2-hydroxyguanidine

It was observed previously that hydroxyguanidine is formed in the reaction of canavanine(2-amino-4-guanidinooxybutanoate) with amino acid oxidases. The present work shows that hydroxyguanidine is formed by a nonenzymatic β,-γ-elimination reaction following enzymatic oxidation at the α-C and that the abstraction of the β-H is general-base catalyzed. The elimination reaction requires the presence in the α-position of an anion-stabilizing group—the protonated imino group (iminium ion group) or the carbonyl group. The iminium ion group is more activating than the carbonyl group. Elimination is further facilitated by protonation of the guanidinooxy group. The other product formed in the elimination reaction was identified as vinylglyoxylate (2-oxo-3-butenoate), a very highly electrophilic substance. The product resulting from hydrolysis following oxidation was identified as α-keto-γ-guanidinooxybutyrate (ketocanavanine). The ratio of hydroxyguanidine to ketocanavanine depended upon the concentration and degree of basicity of the basic catalyst and on pH. In the presence of semicarbazide, the elimination reaction was prevented because the imino group in the semicarbazone derivative of ketocanavanine is not significantly protonated. Incubation of canavanine with 5′-deoxypyridoxal also yielded hydroxyguanidine. Since the elimination reactions take place under mild conditions, they may occur in vivo following oxidation at the α-C of l-canavanine (ingested or formed endogenously) or of other amino acids with a good leaving group in the γ-position (e.g., S-adenosylmethionine, methionine sulfoximine, homocyst(e)ine, or cysteine-homocysteine mixed disulfide) by an l-amino acid oxidase, a transaminase, or a dehydrogenase. Therefore, vinylglyoxylate may be a normal metabolite in mammals which at elevated concentrations may contribute to the in vivo toxicity of canavanine and of some of the other above-mentioned amino acids.

Studies on prodrugs. 10. Possible mechanism of N-dealkylation of N-masked norfloxacins having several active methylene groups.

As a prodrug approach to norfloxacin (NFLX, 2), we have prepared several N-masked NFLXs (1a-f) and studied the cleavage mechanism of the C-N bond of N-masked NFLXs utilizing the following experiments: (1) the oxidation of N-masked NFLXs (1a-f) with m-chloroperbenzoic acid (MCPBA) and their subsequent cleavage to 2 in chloroform at room temperature or at 50 degrees C; (2) the liberation of NFLX from N-masked NFLXs after oral administration in mice. It was found that the chemical oxidative dealkylation of N-masked NFLXs proceeded when anion-stabilizing groups (e.g., CN, COR, COOR) are present on the alpha carbon of the nitrogen atom. In in vivo experiments, N-masked NFLXs having acidic hydrogens on the alpha carbon to the nitrogen atom also liberated NFLX (2) after oral administration.

ChemInform Abstract: Trimethylenemethane Metal Complexes

Publisher Summary This chapter discusses the developments and up-to-date review of trimethylenemethane metal complexes. Tris(carbonyl)-n4-trimethylenemethaneiron(0) was the first trimethylenemethane metal complex to be synthesized and was obtained from the reaction of 3-chloro-2-chloromethylprop-1-ene with [Fez2(CO)9] or Na2[Fe(CO)4]. The thermal extrusion of a simple molecule from an n3-allyl complex, to generate an n4-trimethylenemethane metal complex, was originally observed by Emerson. The ability of [Pd(PPh3)4] to promote the elimination of trimethylsilyl acetate from the allyl silane 31a and generate a highly reactive n3-trimethylenemethane palladium intermediate, which is considered to be of the form [Pd{n3-C(CH2)3}(PPh3)w2], was first observed by Trost and Chan. The structure of this complex has been substantiated by a single crystal X-ray study. A gas-phase electron diffraction study of tris(carbonyl)-n4-trimethylenemethaneiron establishes that the carbonyl ligands and a trigonalpyramidal trimethylenemethane ligand are in a staggered conformation about the iron with the central carbon being closer to the iron center than the outer methylene carbons. Initial studies have shown that iron trimethylenemethane complexes are susceptible to electrophilic attack. The cycloaddition of trimethylenemethane to alkenes can be envisaged as the Diels–Alder (471 + 2 π) reaction for the synthesis of five-membered rings. In the special cases of substituents that are good anion-stabilizing groups, the allyl carbonate 77 (Z = CN) serves as a suitable trimethylenemethane precursor.