Nucleophilic Partners Research Articles

Meso-Tetraphenylporphyrin Iron Chloride Catalyzed Selective Oxidative Cross-Coupling of Phenols.

A novel catalytic system for oxidative cross-coupling of readily oxidized phenols with poor nucleophilic phenolic partners based on an iron meso-tetraphenylporphyrin chloride (Fe[TPP]Cl) complex in 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) was developed. The unique chemoselectivity of this reaction is attributed to the coupling between a liberated phenoxyl radical with an iron-ligated phenolic coupling partner. The conditions are scalable for preparing a long list of unsymmetrical biphenols assembled from a less reactive phenolic unit substituted with alkyl or halide groups.

Stereospecific and stereoconvergent cross-couplings between alkyl electrophiles

The development of metal-catalysed cross-coupling reactions between one electrophilic and one organometallic nucleophilic partner has revolutionized the practice of chemical synthesis, with coupling reactions between sp2 centres now commonplace in both academic and industrial research. Methods to allow coupling of sp3 centres are rapidly being developed, with many recent advances even enabling control of the absolute configuration of newly formed stereogenic centres. The related cross-electrophile couplings have not been developed as thoroughly owing to the challenge of obtaining cross-selectivity between two substrates with similar reactivity. However, the discovery of improved methods to address this challenge has led to significant recent progress. The development of enantioselective cross-electrophile coupling reactions is an emerging area of research. Both stereoconvergent and stereospecific variants have been reported for the synthesis of a range of products containing tertiary stereogenic centres. Many of these transformations build on lessons learnt from traditional (electrophile–nucleophile) cross-couplings of alkyl electrophiles. For example, all enantioselective transformations described to date use a nickel catalyst. Continued progression is likely to provide strategic disconnections for asymmetric synthesis of natural products and medicinal agents. The cross-electrophile coupling approach to stereocontrolled C–C bond formation provides a complementary alternative to traditional cross-coupling methods. This Perspective provides an overview of the recent development of nickel-catalysed asymmetric cross-electrophile coupling reactions. Both stereoconvergent and stereospecific examples are considered and mechanistic details are highlighted.

Carboxylate Salt Bridge‐Mediated Enamine Catalysis: Expanded Michael Reaction Substrate Scope and Facile Access to Antidepressant (R)‐Pristiq

AbstractWe report broad guidance on how to catalyze enantioselective aldehyde additions to nitroalkene or maleimide Michael electrophiles in the presence of unprotected acidic spectator groups, e.g., carboxylic acids, acetamides, phenols, catechols, and maleimide NH groups. Remarkably, these l‐threonine and l‐serine potassium salt‐catalyzed reactions proceed even when the nucleophilic and electrophilic Michael partners simultaneously contain acidic spectator groups. These findings begin to address the historical non‐compatibility of enantioselective catalytic reactions in the presence of acidic moieties and simultaneously encroach on the spectator group tolerances normally associated with cellular environments. A carboxylate salt bridge, from the catalyst enabled enamine to the Michael electrophile, is thought to facilitate the expanded Michael substrate profile. A practical outcome of these endeavours is a new synthetic route to (R)‐Pristiq, (−)‐O‐desmethylvenlafaxine, an antidepressant, in the highest yield known to date because no protecting groups are required.magnified image

Unified Synthesis of 1,2-Oxy-aminoarenes via a Bio-inspired Phenol-Amine Coupling

Summary 1,2-Aminophenols and their related nitrogen-containing heterocycles are ubiquitous in medicine, agriculture, and materials science. Here, we describe a bio-inspired and unified approach for their synthesis through a direct, catalytic aerobic coupling of phenols and amines. Key to the formation of the aromatic C–N bond is a facile condensation between the amine and an ortho -quinone, which triggers redox isomerization to an ortho -iminophenol before a series of downstream events. We discuss the factors that govern regioselectivity during aerobic ortho -oxygenation of the phenol and condensation of the amine, and we demonstrate synthetic utility by preparing a structurally diverse family of immunosuppressive heterocycles and the indole alkaloid cephalandole A. Our conditions involve a wide range of simple, un-activated substrates, occur at room temperature with an earth-abundant copper-catalyst and a commercially available diamine ligand, and produce water as the only stoichiometric by-product.

Further Studies on the Direct Synthesis of α,β‐Unsaturated Ketimines and α,β‐Enones by Chemoselective Dehydrative Addition of Functionalized Alkenes to Secondary Amides

AbstractDescribed in this paper are the results of an investigation on the extension of the C‐H alkyliminylation and acylation of alkenes with secondary amides. The nucleophilic partner has been extended to cover a series of functionalized alkenes bearing functional groups including ester, α,β‐unsaturated ester, uncongested ketone groups, as well as enol derivatives of acetaldehyde such as enol ether and enamides. The electrophilic partner has been extended from N‐(2,6‐dimethylphenyl) and N‐methyl amides to N‐n‐butyl, and N‐cyclohexyl amides. The results demonstrated that the method can be used to synthesize a number of functionalized α,β‐unsaturated ketimines and α,β‐enones in an efficient, high yielding, and one‐pot manner. The method was applied to a concise synthesis of (E)‐6‐styryltetrahydro‐2H‐pyran‐2‐one (5), an immediate intermediate in the syntheses of a series of styryllactone natural products including (±)‐goniothalamine (6), (±)‐goniothalamine oxide (7), (±)‐goniodiol (8), (±)‐leiocarpin A (9), (±)‐9‐deoxygoniopypyrone (10), and (±)‐7‐epi‐goniodiol (11).

Efficient Access to Chiral Trisubstituted Aziridines via Catalytic Enantioselective Aza‐Darzens Reactions

AbstractHerein, we report a Zn‐ProPhenol catalyzed aza‐Darzens reaction using chlorinated aromatic ketones as nucleophilic partners for the efficient and enantioselective construction of complex trisubstituted aziridines. The α‐chloro‐β‐aminoketone intermediates featuring a chlorinated tetrasubstituted stereocenter can be isolated in high yields and selectivities for further derivatization. Alternatively, they can be directly transformed to the corresponding aziridines in a one‐pot fashion. Of note, the reaction can be run on gram‐scale with low catalyst loading without impacting its efficiency. Moreover, this methodology was extended to α‐bromoketones which are scarcely used in enantioselective catalysis because of their sensitivity and lack of accessibility.

Efficient Access to Chiral Trisubstituted Aziridines via Catalytic Enantioselective Aza-Darzens Reactions.

Herein, we report a Zn-ProPhenol catalyzed aza-Darzens reaction using chlorinated aromatic ketones as nucleophilic partners for the efficient and enantioselective construction of complex trisubstituted aziridines. The α-chloro-β-aminoketone intermediates featuring a chlorinated tetrasubstituted stereocenter can be isolated in high yields and selectivities for further derivatization. Alternatively, they can be directly transformed to the corresponding aziridines in a one-pot fashion. Of note, the reaction can be run on gram-scale with low catalyst loading without impacting its efficiency. Moreover, this methodology was extended to α-bromoketones which are scarcely used in enantioselective catalysis because of their sensitivity and lack of accessibility.

Pyridine sulfinates as general nucleophilic coupling partners in palladium-catalyzed cross-coupling reactions with aryl halides.

Pyridine rings are ubiquitous in drug molecules; however, the pre-eminent reaction used to form carbon-carbon bonds in the pharmaceutical industry, the Suzuki-Miyaura cross-coupling reaction, often fails when applied to these structures. This phenomenon is most pronounced in 2-substituted pyridines, and results from the difficulty in preparing, the poor stability of, and low efficiency in reactions of pyridine-2-boronates. We demonstrate that by replacing these boronates with pyridine-2-sulfinates, a cross-coupling process of unrivalled scope and utility is realized. The corresponding 3- and 4-substituted pyridine variants are also efficient coupling partners. In addition, we apply these sulfinates in a library format to the preparation of medicinally relevant derivatives of the drugs varenicline (Chantix) and mepyramine (Anthisan).

Recent Advances of Oxidative Radical Cross‐Coupling Reactions: Direct α‐C(sp3)–H Bond Functionalization of Ethers and Alcohols

AbstractOxygen‐containing heterocycles are an important class of compounds with diverse biological activities. In recent years, direct α‐C–H functionalization of inexpensive and abundant readily available ethers and alcohols by oxidative radical cross‐coupling with different nucleophilic partners (C–H, N–H, O–H and S–S), leading to the construction of C–C and C–X (X=C, N, O, S) bonds, has emerged as one of the vital strategies among oxidative cross‐coupling reactions. Owing to the features of being atom‐economic, environmentally benign, having a simple operation and biologically properties, a series of ether α‐C(sp3)–H bond activation reactions have been developed by metal or metal‐free systems via the radical oxidative coupling pathway, since the radical oxidative coupling reactions have wide range of applications. This review aims to highlight the recent advances in direct α‐C(sp3)–H bond functionalization of ethers and alcohols via radical oxidative process.magnified image

Enhancement of Catalytic Activity Over AuPd Nanoparticles Loaded Metal Organic Framework Under Visible Light Irradiation

In this study, monometallic gold and palladium, and bimetallic gold/palladium were respectively deposited on chromium based amine-functionalized metal–organic framework (NH2-MIL-101) by using the impregnation method, with the aim to enhance the activity of Pd-catalyzed chemical reaction under the assistance of visible light at ambient temperatures. The oxidation state, size and location of metal nanoparticles were determined by XAFS and TEM. The physical properties of as-synthesized catalysts were also well characterized by UV–vis spectroscopy, BET and XRD. The catalytic activities of those metal nanoparticles deposited MOFs were studies for hydrolysis of ammonia borane and Suzuki–Miyaura coupling reaction. Compared with monometallic counterpart, the bimetallic gold/palladium showed much higher catalytic activity for hydrolysis of ammonia borane and Suzuki–Miyaura coupling reaction under visible light irradiation. The enhancement of the catalytic activity might be attributed to the synergistic effect between plasmonic bimetallic nanoparticles and metal organic framework in effective conversion of solar energy for generating electron rich palladium species to activate the electrophilic compounds as well as nucleophilic partner compounds. This investigation offers a new opportunity to explore the high-performance metal nanoparticle loaded MOFs photocatalysts for efficient utilization of sunlight in a wide range of chemical reactions.

Metallaphotoredox-catalysed sp(3)-sp(3) cross-coupling of carboxylic acids with alkyl halides.

In the past 50 years, cross-coupling reactions mediated by transition metals have changed the way in which complex organic molecules are synthesized. The predictable and chemoselective nature of these transformations has led to their widespread adoption across many areas of chemical research. However, the construction of a bond between two sp(3)-hybridized carbon atoms, a fundamental unit of organic chemistry, remains an important yet elusive objective for engineering cross-coupling reactions. In comparison to related procedures with sp(2)-hybridized species, the development of methods for sp(3)-sp(3) bond formation via transition metal catalysis has been hampered historically by deleterious side-reactions, such as β-hydride elimination with palladium catalysis or the reluctance of alkyl halides to undergo oxidative addition. To address this issue, nickel-catalysed cross-coupling processes can be used to form sp(3)-sp(3) bonds that utilize organometallic nucleophiles and alkyl electrophiles. In particular, the coupling of alkyl halides with pre-generated organozinc, Grignard and organoborane species has been used to furnish diverse molecular structures. However, the manipulations required to produce these activated structures is inefficient, leading to poor step- and atom-economies. Moreover, the operational difficulties associated with making and using these reactive coupling partners, and preserving them through a synthetic sequence, has hindered their widespread adoption. A generically useful sp(3)-sp(3) coupling technology that uses bench-stable, native organic functional groups, without the need for pre-functionalization or substrate derivatization, would therefore be valuable. Here we demonstrate that the synergistic merger of photoredox and nickel catalysis enables the direct formation of sp(3)-sp(3) bonds using only simple carboxylic acids and alkyl halides as the nucleophilic and electrophilic coupling partners, respectively. This metallaphotoredox protocol is suitable for many primary and secondary carboxylic acids. The merit of this coupling strategy is illustrated by the synthesis of the pharmaceutical tirofiban in four steps from commercially available starting materials.

Unusual reaction of bromoalkyl trifluoromethyl ketones with symmetrically disubstituted ethylenediamines. Theoretic investigation applying methods of density functional and multiparticle perturbation theory МР-2

Mechanism of a multistage reaction between α-bromotrifluoromethylenones and N,N′-dialkylethylenediamines was examined in detail using quantum chemical methods of density functional (non-empirical functional РВЕ, extended split TZp-basis) and multiparticle perturbation theory МР-2, basis 6-311+G(d,p), in the gas phase approximation, and also including solvents molecules (water and 2,2,2-trifluoroethanol). The specific solvation of transition states owing to the hydrogen bonds formation with solvent molecules is the main factor governing the direction of the reaction. Trifluoroethanol forms a strong H-bond with the carbonyl oxygen atom of the trifluoroacetyl group increasing its electrophilicity. It also solvates the departing bromide anion facilitating the occurrence of the S N 2-substitution reaction. An essential but less important factor is the ability of trifluoroethanol to play the role of a nucleophilic partner by forming hydrogen bonds at the expense of the unshared electron pair of the hydroxyl oxygen facilitating the proton abstraction from the nitrogen atom of the diamine attacking the carbon atom in the course of S N 2-substitution.

Catalytic Carbocation Generation Enabled by the Mesolytic Cleavage of Alkoxyamine Radical Cations.

A new catalytic method is described to access carbocation intermediates via the mesolytic cleavage of alkoxyamine radical cations. In this process, electron transfer between an excited state oxidant and a TEMPO-derived alkoxyamine substrate gives rise to a radical cation with a remarkably weak C-O bond. Spontaneous scission results in the formation of the stable nitroxyl radical TEMPO(.) as well as a reactive carbocation intermediate that can be intercepted by a wide range of nucleophiles. Notably, this process occurs under neutral conditions and at comparatively mild potentials, enabling catalytic cation generation in the presence of both acid sensitive and easily oxidized nucleophilic partners.

Catalytic Carbocation Generation Enabled by the Mesolytic Cleavage of Alkoxyamine Radical Cations

AbstractA new catalytic method is described to access carbocation intermediates via the mesolytic cleavage of alkoxyamine radical cations. In this process, electron transfer between an excited state oxidant and a TEMPO‐derived alkoxyamine substrate gives rise to a radical cation with a remarkably weak C−O bond. Spontaneous scission results in the formation of the stable nitroxyl radical TEMPO. as well as a reactive carbocation intermediate that can be intercepted by a wide range of nucleophiles. Notably, this process occurs under neutral conditions and at comparatively mild potentials, enabling catalytic cation generation in the presence of both acid sensitive and easily oxidized nucleophilic partners.

Nucleophile-Assisted Alkene Activation: Olefins Alone Are Often Incompetent

Emerging work on organocatalytic enantioselective halocyclizations naturally draws on conditions where both new bonds must be formed under delicate control, the reaction regime where the concerted nature of the AdE3 mechanism is of greatest importance. Without assistance, many simple alkene substrates react slowly or not at all with conventional halenium donors under synthetically relevant reaction conditions. As demonstrated earlier by Shilov, Cambie, Williams, Fahey, and others, alkenes can undergo a concerted AdE3-type reaction via nucleophile participation, which sets the configuration of the newly created stereocenters at both ends in one step. Herein, we explore the modulation of alkene reactivity and halocyclization rates by nucleophile proximity and basicity, through detailed analyses of starting material spectroscopy, addition stereopreferences, isotope effects, and nucleophile-alkene interactions, all obtained in a context directly relevant to synthesis reaction conditions. The findings build on the prior work by highlighting the reactivity spectrum of halocyclizations from stepwise to concerted, and suggest strategies for design of new reactions. Alkene reactivity is seen to span the range from the often overgeneralized "sophomore textbook" image of stepwise electrophilic attack on the alkene and subsequent nucleophilic bond formation, to the nucleophile-assisted alkene activation (NAAA) cases where electron donation from the nucleophilic addition partner activates the alkene for electrophilic attack. By highlighting the factors that control reactivity across this range, this study suggests opportunities to explain and control stereo-, regio-, and organocatalytic chemistry in this important class of alkene additions.

Silyl Radical Activation of Alkyl Halides in Metallaphotoredox Catalysis: A Unique Pathway for Cross-Electrophile Coupling.

A strategy for cross-electrophile coupling has been developed via the merger of photoredox and transition metal catalysis. In this report, we demonstrate the use of commercially available tris(trimethylsilyl)silane with metallaphotoredox catalysis to efficiently couple alkyl bromides with aryl or heteroaryl bromides in excellent yields. We hypothesize that a photocatalytically generated silyl radical species can perform halogen-atom abstraction to activate alkyl halides as nucleophilic cross-coupling partners. This protocol allows the use of mild yet robust conditions to construct Csp(3)-Csp(2) bonds generically via a unique cross-coupling pathway.

ChemInform Abstract: Direct Catalytic Asymmetric Mannich Reactions for the Construction of Quaternary Carbon Stereocenters.

AbstractThe first direct asymmetric Mannich reaction by using α‐branched ketones as nucleophilic partners is presented and gives an enantio‐ and diastereoselective access to various β‐amino ketones.

Silver(I)-Catalyzed Addition of Phenols to Alkyne Cobalt Cluster Stabilized Carbocations.

A smooth catalytic method to use phenols as the nucleophilic partner in the Nicholas reaction has been developed. The method uses either Ag(I) or Au(I) catalysts with AgClO4 or AgBF4 as the most efficient catalysts tested. Neither additional additives nor cocatalysts were required and the formation of the corresponding phenol adducts occurred in excellent yields. The process has the single limitation of the inability of less nucleophilic phenols (4-nitrophenol) to generate the corresponding adducts. Additionally, the reaction is highly diastereoselective. DFT calculations allow a catalytic cycle to be proposed that involves trimetallic intermediates; the rate-determining step of the reaction is hydroxy-group elimination in a cobalt-silver trimetallic intermediate.

ChemInform Abstract: Ruthenium‐Catalyzed Direct Arylations with Aryl Chlorides

AbstractReview: [50 refs.

ChemInform Abstract: The First Intermolecular Interrupted Imino‐Nazarov Reaction: Expeditious Access to Carbocyclic Nucleoside Analogues.

The analogous imino-variant of the Nazarov reaction suffers from unfavorable energetics associated with the ring closure process, thereby limiting the utility of this class of reactions. In this report, the realization of the first intermolecular interrupted imino-Nazarov reaction utilizing silylated pyrimidine derivatives as nucleophilic trapping partners culminated in an expedient synthetic route to carbocyclic nucleoside analogues. The potential application of silylated nucleobases to intercept the oxyallyl cation in other variants of the Nazarov reaction provides vast opportunities to develop new strategies for the formation of carbocyclic nucleoside analogues.