Addition Of Carbon Nucleophiles Research Articles

Germaborene reactivity study - addition of carbon nucleophiles, cycloaddition reactions, coordination chemistry.

MeNHC substituted germaborenium cation 2 was synthesized directly in reaction of bromo-substituted germaborene 1b with MeNHC. The adamantyl isonitrile substituted germaborenium cation 4 was obtained stepwise: substitution of the chloride atom against adamantyl isonitrile at the B-Cl unit in 1a, simultaneous migration of the chloride to the germanium atom followed by chloride abstraction using Na[BArF 4] gives the germaborenium cation 4. Substitution of the bromide atom in 1b against carbon monoxide followed by bromide abstraction using Ag[Al(OtBuF)4] leads to compound 6 exhibiting a B[double bond, length as m-dash]C double bond substituted at the boron atom by a germylium cation. Treating the germaborene [Ge[double bond, length as m-dash]B-Ph] (1c) with selenium, a cycloaddition product 7 was characterised featuring a GeBSe heterocycle. Carbon dioxide reacts with 1b to give a four membered ring molecule 8 as the product of a B-C and Ge-O bond formation. In reaction of 1b with dimethylbutadiene, a product 9 of a [2 + 4] cycloaddition was isolated. Transition metal fragments [Fe(CO)4 (10), CuBr (11), AuCl (12)] show coordination at the germaborene double bond. Molecular structures of the germaborene coordination compounds 10-12 are presented and the ligand properties are discussed. After treating the germaborene [Ge[double bond, length as m-dash]B-Br] (1b) with [Cp*Al]4, insertion of a Cp*Al moiety into the B-Br bond was found (13).

Asymmetric Synthesis of Chiral Sulfimides through the O-Alkylation of Enantioenriched Sulfinamides and Addition of Carbon Nucleophiles.

Chiral sulfimides, the aza-analogues of sulfoxides, are valuable compounds in organic synthesis and medicinal chemistry. Herein, we report an efficient method for preparing chiral sulfimides from easily available enantioenriched sulfinamides. The key step of this method is a stereospecific oxygen-selective alkylation of enantioenriched sulfinamides, which is accomplished by using isopropyl iodide, K2 CO3 , and DMPU. The resulting chiral sulfinimidate esters are transformed to chiral sulfimides by the nucleophilic addition of the Grignard reagents under simple conditions. This transformation enables access to the enantioenriched diaryl or dialkyl sulfimides bearing two similar carbon substituents, which are difficult to synthesize by previous methods.

Asymmetric Synthesis of Chiral Sulfimides through the O‐Alkylation of Enantioenriched Sulfinamides and Addition of Carbon Nucleophiles

AbstractChiral sulfimides, the aza‐analogues of sulfoxides, are valuable compounds in organic synthesis and medicinal chemistry. Herein, we report an efficient method for preparing chiral sulfimides from easily available enantioenriched sulfinamides. The key step of this method is a stereospecific oxygen‐selective alkylation of enantioenriched sulfinamides, which is accomplished by using isopropyl iodide, K2CO3, and DMPU. The resulting chiral sulfinimidate esters are transformed to chiral sulfimides by the nucleophilic addition of the Grignard reagents under simple conditions. This transformation enables access to the enantioenriched diaryl or dialkyl sulfimides bearing two similar carbon substituents, which are difficult to synthesize by previous methods.

Divergent Synthesis of Fluorinated Alkenes, Allenes, and Enynes via Reaction of 2-Trifluoromethyl-1,3-enynes with Carbon Nucleophiles.

Herein, inorganic base K3PO4 promoted divergent synthesis of CF3-substituted allenes, cyclopentenes, alkynes, and fluorinated enynes via regioselective nucleophilic addition of carbon nucleophiles to 2-trifluoromethyl-1,3-enynes was developed. With the choice of different carbon nucleophiles, various fluorinated compounds could be obtained under K3PO4/DMF reaction system. When malononitriles were used as nucleophiles, CF3-substituted allenes, cyclopentenes, and alkynes could be obtained, respectively. By using 1,3-dicarbonyl compounds as nucleophiles, ring-monofluorinated 4H-pyrans could be prepared, and 1,1-difluoro-1,3-enynes could be furnished with the participation of diethyl malonate. Moreover, these five kinds of fluorinated allenes, alkenes, and enynes are valuable building blocks.

Ruthenium(ii)-catalyzed regioselective 1,6-conjugate addition of umpolung aldehydes as carbanion equivalents.

One of the most efficient and reliable approaches to construct C–C bonds involves the conjugate addition of carbon nucleophiles to electron-deficient ketones. Yet, 1,6-conjugate additions of extended conjugated systems largely remain underexplored due to difficulties in controlling the regioselectivity. Herein, we report umpolung aldehydes as carbanion equivalents for highly regioselective 1,6-conjugate addition reactions to unsaturated ketones, with preliminary studies of the enantioselective variant. The synergy of ruthenium(ii) catalyst and electron-rich, bidentate phosphine ligand is essential for the reactivity and selectivity under mild reaction conditions.

Iterative addition of carbon nucleophiles to N,N-dialkyl carboxamides for synthesis of α-tertiary amines.

A protocol for the synthesis of α-tertiary amines was developed by iterative addition of carbon nucleophiles to N,N-dialkyl carboxamides. Nucleophilic 1,2-addition of organolithium reagents to carboxamides forms anionic tetrahedral carbinolamine (hemiaminal) intermediates, which are subsequently treated with bromotrimethylsilane (Me3SiBr) followed by organomagnesium (Grignard) reagents, organolithium reagents or tetrabutylammonium cyanide, affording α-tertiary amines. Employment of (trimethylsilyl)methylmagnesium bromide as the 2nd nucleophile allowed for aza-Peterson olefination of the resulting α-tertiary (trimethylsilyl)methylamines with acidic work-up, resulting in the formation of 1,1-diarylethylenes.

Stereodivergent Nucleophilic Additions to Racemic β-Oxo Acid Derivatives: Fast Addition Outcompetes Stereoconvergence in the Archetypal Configurationally Unstable Electrophile.

Additions of carbon nucleophiles to racemic α-stereogenic β-oxo acid derivatives that deliver enantiomerically enriched tertiary alcohols are valuable, but uncommon. This article describes stereodivergent Cu-catalyzed borylative cyclizations of racemic β-oxo acid derivatives bearing tethered pro-nucleophilic olefins to deliver highly functionalized cyclopentanols containing four contiguous stereogenic centers. The reported protocol is applicable to a range of β-oxo acid derivatives, and the diastereomeric products are readily isolable by typical chromatographic techniques. α-Stereogenic-β-keto esters are typically thought to have extreme or spontaneous configurational fragility, but mechanistic studies for this system reveal an unusual scenario wherein productive catalysis occurs on the same time scale as background substrate racemization and completely outcompetes on-cycle epimerization, even under the basic conditions of the reaction.

Direct AlCl3-catalyzed transformation of benzyl THP ethers and allyl benzyl ethers

THP and allyl groups are frequently used for the protection of alcohols. In this study, novel direct transformations of benzyl THP ethers and allyl benzyl ethers, protected forms of alcohols, are reported. TMSN3 and AlCl3 were employed as key azide reagent and catalyst to perform direct conversion of benzyl THP ethers and allyl benzyl ethers to azido compounds. In addition, direct nucleophile additions of carbon nucleophiles to benzyl THP ethers and allyl benzyl ethers were successfully accomplished in the presence of catalytic AlCl3. The results indicate that this novel method could be applied to various direct transformations of benzyl THP ethers and allyl benzyl ethers such as azidation, allylation, and alkynylation.

Enantiodivergent Formation of C-P Bonds: Synthesis of P-Chiral Phosphines and Methylphosphonate Oligonucleotides.

Phosphorus Incorporation (PI, abbreviated Π) reagents for the modular, scalable, and stereospecific synthesis of chiral phosphines and methylphosphonate nucleotides are reported. Synthesized from trans-limonene oxide, this reagent class displays an unexpected reactivity profile and enables access to chemical space distinct from that of the Phosphorus-Sulfur Incorporation reagents previously disclosed. Here, the adaptable phosphorus(V) scaffold enables sequential addition of carbon nucleophiles to produce a variety of enantiopure C-P building blocks. Addition of three carbon nucleophiles to Π, followed by stereospecific reduction, affords useful P-chiral phosphines; introduction instead of a single methyl group reveals the first stereospecific synthesis of methylphosphonate oligonucleotide precursors. While both Π enantiomers are available, only one isomer is required-the order of nucleophile addition controls the absolute stereochemistry of the final product through a unique enantiodivergent design.

Mild and efficient addition of carbon nucleophiles to condensed pyridines: influence of structure and limits of applicability

A number of azolo- and azinopyridines with varying substituents and annulated heterocycles were synthesized and examined in dearomatization reactions with carbon nucleophiles. Depending on the structure, the resulting covalent σ-adducts were formed either under basefree conditions or in Et3N-promoted process to give functionalized condensed dihydropyridines. Quantum-chemical calculations of the global electrophilicity index derived from FMO energies of azolopyridine series were performed to explain reactivity toward neutral and anionic C-nucleophiles. These values may be useful for qualitative prediction of particular reactivity pattern.

Nitrosoalkenes: Underappreciated Reactive Intermediates for Formation of Carbon–Carbon Bonds

This Account describes studies carried out by my group during the past decade on both intra- and intermolecular conjugate additions of carbon nucleophiles to nitrosoalkenes. Using the Denmark protocol for the generation of nitrosoalkenes from α-chloro-O-silyloximes, a number of bridged and fused bicyclic ring systems can be prepared via the intramolecular version of this process. Intermolecular conjugate addition reactions of nitrosoalkenes with a wide variety of ester enolates as coupling partners can also be achieved efficiently using a similar procedure. Some stereochemical aspects of these nucleophilic additions have been studied with both acyclic and cyclic nitrosoalkenes. This methodology has been applied as key steps in synthetic approaches to some complex indole and Myrioneuron alkaloids.1 Introduction2 Conjugate Additions of Nitrosoalkenes2.1 Background2.2 Intramolecular Reactions2.3 Intermolecular Reactions2.4 Stereochemical Aspects3 Applications to Natural Product Synthesis3.1 Angustilodine and Related Alkaloids3.2 Approach to Apparicine-Type Alkaloids3.3 Myrioneurinol4 Summary and Outlook

CuH-Catalyzed Enantioselective Ketone Allylation with 1,3-Dienes: Scope, Mechanism, and Applications.

Chiral tertiary alcohols are important building blocks for the synthesis of pharmaceutical agents and biologically active natural products. The addition of carbon nucleophiles to ketones is the most common approach to tertiary alcohol synthesis but traditionally relies on stoichiometric organometallic reagents that are difficult to prepare, sensitive, and uneconomical. We describe a mild and efficient method for the copper-catalyzed allylation of ketones using widely available 1,3-dienes as allylmetal surrogates. Homoallylic alcohols bearing a wide range of functional groups are obtained in high yield and with good regio-, diastereo-, and enantioselectivity. Mechanistic investigations using density functional theory (DFT) implicate the in situ formation of a rapidly equilibrating mixture of isomeric copper(I) allyl complexes, from which Curtin-Hammett kinetics determine the major isomer of the product. A stereochemical model is provided to explain the high diastereo- and enantioselectivity of this process. Finally, this method was applied to the preparation of an important drug, ( R)-procyclidine, and a key intermediate in the synthesis of several pharmaceuticals.

Cu-catalyzed C-C bond formation of vinylidene cyclopropanes with carbon nucleophiles.

The development of Cu-catalyzed addition of carbon nucleophiles to vinylidene cyclopropanes was reported. The reactions with 1,1-bisborylmethane provided homopropargylic boronate products by forming a C-C bond at the terminal carbon atom of the allene moiety of vinylidene cyclopropanes. Alkynyl boronates are also suitable nucleophile precursors in reactions with vinylidene cyclopropanes, and skipped diynes were obtained in high yields. In addition, the Cu-enolate generated from the initial addition of nucleophilic copper species to vinylidene cyclopropanes can be intercepted by an external electrophile. As such, vinylidene cyclopropane serves as a linchpin to connect a nucleophile and an electrophile by forming two carbon-carbon bonds sequentially.

Reaction of 2-(2-Oxo-1,2-dihydro-3H-pyrrol-3-ylidene)- malononitriles with C-Nucleophiles. Synthesis of New Spiro-Fused Pyrrole Derivatives

Base-catalyzed nucleophilic addition of carbon nucleophiles to the exocyclic double bond of 2-(5-aryl-4-methyl-2-oxo-1,2-dihydro-3H-pyrrol-3-ylidene)malononitriles afforded spiro-fused pyrrole derivatives, 7-amino-3-aryl-4-methyl-1-oxo-8-oxa-2-azaspiro[4.5]deca-3,6,9-triene-6-carbonitriles. The products can be regarded as rare structural analogs of biologically active spirans based on isatin.

Recent Advances in Catalytic Asymmetric Synthesis of Tertiary Alcohols via Nucleophilic Addition to Ketones

AbstractChiral tertiary alcohols are an important class of organic compounds which have found wide applications in both academia and industry. Therefore, various synthetic strategies towards these compounds have already been developed. Among them, the catalytic asymmetric addition of carbon nucleophiles to ketones is the most desirable route owing to its straightforwardness as well as its economic, efficient and versatile advantages. This review summarizes and discusses the recent achievements in this field classified according to the reaction types. Special attention is paid to the mechanisms, advantages and limitations of each reaction. In addition, the applications of these catalytic processes in the synthesis of related natural products, pharmaceuticals or their analogues are briefly discussed as well.magnified image

A Practical and General Amidation Method from Isocyanates Enabled by Flow Technology

AbstractThe addition of carbon nucleophiles to isocyanates represents a conceptually flexible and efficient approach to the preparation of amides. This general synthetic strategy has, however, been relatively underutilized owing to narrow substrate tolerance and the requirement for less favourable reaction conditions. Herein, we disclose a high‐yielding, mass‐efficient, and scalable method with appreciable functional group tolerance for the formation of amides by reaction of Grignard reagents with isocyanates. Through the application of flow chemistry and the use of substoichiometric amounts of CuBr2, this process has been developed to encompass a broad range of substrates, including reactants found to be incompatible with previously published procedures.

A Practical and General Amidation Method from Isocyanates Enabled by Flow Technology.

The addition of carbon nucleophiles to isocyanates represents a conceptually flexible and efficient approach to the preparation of amides. This general synthetic strategy has, however, been relatively underutilized owing to narrow substrate tolerance and the requirement for less favourable reaction conditions. Herein, we disclose a high-yielding, mass-efficient, and scalable method with appreciable functional group tolerance for the formation of amides by reaction of Grignard reagents with isocyanates. Through the application of flow chemistry and the use of substoichiometric amounts of CuBr2 , this process has been developed to encompass a broad range of substrates, including reactants found to be incompatible with previously published procedures.

Amine-Promoted anti-Markovnikov Addition of 1,3-Dicarbonyl Compounds with Terminal Alkynes under Rhenium Catalysis

Amines have been identified to greatly accelerate the intermolecular anti-Markovnikov addition of carbon nucleophiles to unactivated terminal alkynes. Using a combination of [ReBr(CO)3(thf)]2 and iPr2NEt, construction of cyclic all-carbon quaternary centers was achieved with various 1,3-ketoesters, diketones, and diesters with lower catalyst loading under milder conditions. The type of addition could be easily controlled by choice of additive, highlighting the unique features of rhenium catalysis

Exploring bis-(amino)cyclopropenylidene as a non-covalent Brønsted base catalyst in conjugate addition reactions.

Bis-(amino)cyclopropenylidene has been utilised as a non-covalent Brønsted base catalyst in the 1,6-conjugate addition of carbon nucleophiles to p-QMs. This protocol makes it possible to access unsymmetrical diaryl- and triarylmethanes in good to excellent yields. Further, this catalyst was also explored in the 1,4-conjugate addition of carbon nucleophiles to enone systems.

Development of Selective Peptide Catalysts with Secondary Structural Frameworks.

Enzymes are biogenic catalysts that enable the vital activity of organisms. Enzymes promote reactions in a selective manner with a high level of substrate recognition ability. The development of such a sophisticated catalyst has been one of the goals for chemists. A synthetic peptide is the prime candidate to realize an enzyme-like catalyst. Considering that the catalytic function of enzymes derives from their molecular structures, the key for the creation of a peptide catalyst might be the introduction of a specific three-dimensional structure. Our motivation was to find a peptide catalyst with a versatile secondary structural framework and apply the peptide to a variety of selective reactions. Although helical-peptide-catalyzed asymmetric epoxidation of enones is popular, no other highly enantioselective reaction with a helical peptide has been reported. It was found that resin-supported α-helical polyleucine promoted asymmetric conjugate addition of a carbon nucleophile to enones via the formation of an iminium intermediate at the N-terminal amino group. By changing the helical chain to a repetitive Leu-Leu-Aib (Aib = α-aminoisobutyric acid) sequence and introducing a few amino acids to the N-terminus, a highly enantioselective peptide catalyst was obtained. The helical peptide catalyst was applicable for a tandem enamine/iminium-mediated reaction and asymmetric epoxidation of enones. Although the extension of the helical peptide to conjugate addition of a nucleophile to an enal was not successful simply by attaching proline to the N-terminus of the helix, the incorporation of a β-turn motif was effective to improve the catalytic performance. In the sequence of such a turn-helix-type peptide, the helical part was seemingly distant from the N-terminal amino group; however, the hydrophobicity, structure, and chirality of the helix largely affected the reaction. The turn-helix-type peptide promoted a wide range of asymmetric reactions: conjugated additions of hydride and carbon nucleophiles to enals via the iminium activation and α-oxyamination of aldehydes via the enamine activation. The peptides with turn-helix and helix frameworks were also employed for several reactions that were difficult to achieve with low-molecular-weight catalysts: enzyme-cocatalyzed asymmetric oxidation in water, diastereo- and enantioselective cyclopropanation, regioselective reduction of dienals, kinetic resolution of planar-chiral compounds, and desymmetrization to induce planar chirality. To explore other types of peptide catalysts, a combinatorial library screening was performed. On the way, it was revealed that a histidyl residue assisted to accelerate a reaction via reversible addition to an iminium intermediate. Through the screening of random peptide libraries, novel peptide sequences for efficient and enantioselective conjugate addition were discovered. Although we have no information about the molecular structure of the newly found peptides, they can be an entry point for establishing a versatile framework of peptide catalysts.