Electrophilic Cyanation Research Articles

Ultrasound-assisted fabrication of N-cyano-N-arylbenzenesulfonamides at ambient temperature: improvements with biosynthesized Ag/feldspar nanocomposite

A mild and effective method for ultrasound-assisted N-sulfonylation of arylcyanamides with aryl sulfonyl chloride is introduced at ambient temperature; synthesis of assorted derivatives of N-cyano-N-arylbenzenesulfonamide as electrophilic cyanation agent can be further improved using Ag/feldspar nanocomposite, accessible via an simple, eco-friendly and inexpensive method using Hedera helix leaf extract. The important advantages of this method include clean conditions, high purity and yield, and easy workup procedure with minimum generation of waste. The structure and morphology nanocatalyst were characterized by energy-dispersive X-ray spectroscopy, field emission scanning electron microscope, transmission electron microscopy, X-ray powder diffraction and elemental mapping.

Ni-Catalyzed Reductive Cyanation of Aryl Halides and Phenol Derivatives via Transnitrilation.

Herein, we report a Ni-catalyzed reductive coupling for the synthesis of benzonitriles from aryl (pseudo)halides and an electrophilic cyanating reagent, 2-methyl-2-phenyl malononitrile (MPMN). MPMN is a bench-stable, carbon-bound electrophilic CN reagent that does not release cyanide under the reaction conditions. A variety of medicinally relevant benzonitriles can be made in good yields. Addition of NaBr to the reaction mixture allows for the use of more challenging aryl electrophiles such as aryl chlorides, tosylates, and triflates. Mechanistic investigations suggest that NaBr plays a role in facilitating oxidative addition with these substrates.

5-(Cyano)dibenzothiophenium Triflate: A Sulfur-Based Reagent for Electrophilic Cyanation and Cyanocyclizations.

The synthesis of 5‐(cyano)dibenzothiophenium triflate 9, prepared by activation of dibenzo[b,d]thiophene‐5‐oxide with Tf2O and subsequent reaction with TMSCN is reported, and its reactivity as electrophilic cyanation reagent evaluated. The scalable preparation, easy handling and broad substrate scope of the electrophilic cyanation promoted by 9, which includes amines, thiols, silyl enol ethers, alkenes, electron rich (hetero)arenes and polyaromatic hydrocarbons, illustrate the synthetic potential of this reagent. Importantly, Lewis acid activation of the reagent is not required for the transfer process. We additionally report herein biomimetic cyanocyclization cascade reactions, which are not promoted by typical electrophilic cyanation reagents, demonstrating the superior ability of 9 to trigger challenging transformations.

5‐(Cyano)dibenzothiophenium Triflate: A Sulfur‐Based Reagent for Electrophilic Cyanation and Cyanocyclizations

AbstractThe synthesis of 5‐(cyano)dibenzothiophenium triflate 9, prepared by activation of dibenzo[b,d]thiophene‐5‐oxide with Tf2O and subsequent reaction with TMSCN is reported, and its reactivity as electrophilic cyanation reagent evaluated. The scalable preparation, easy handling and broad substrate scope of the electrophilic cyanation promoted by 9, which includes amines, thiols, silyl enol ethers, alkenes, electron rich (hetero)arenes and polyaromatic hydrocarbons, illustrate the synthetic potential of this reagent. Importantly, Lewis acid activation of the reagent is not required for the transfer process. We additionally report herein biomimetic cyanocyclization cascade reactions, which are not promoted by typical electrophilic cyanation reagents, demonstrating the superior ability of 9 to trigger challenging transformations.

A one-pot electrophilic cyanation–functionalization strategy for the synthesis of disubstituted malononitriles

Malononitriles are valuable synthetic intermediates for many applications, including the synthesis of herbicides and other biologically active molecules, and the synthesis of chiral ligands for asymmetric catalysis. This article describes the development of a procedure for the conversion of primary nitriles to malononitriles using dimethylmalononitrile, a commercial, non-toxic, carbon-bound source of electrophilic cyanide. This procedure avoids the use of toxic cyanide or malononitrile as a starting material. This protocol is further applied to the dicyanation of benzyl Grignard reagents, generated from benzyl bromides, yielding fully functionalized malononitriles from a nitrile-free precursor.

The Mechanism of Copper-Catalyzed Trifunctionalization of Terminal Allenes.

A highly selective copper-catalyzed trifunctionalization of allenes has been established based on diborylation/cyanation with bis(pinacolato)diboron (B2 pin2 ) and N-cyano-N-phenyl-p-toluenesulfonamide (NCTS). The Cu-catalyzed trifunctionalization of terminal allenes is composed of three catalytic reactions (first borocupration, electrophilic cyanation, and second borocupration) that provide a densely functionalized product with regio-, chemo- and diastereoselectivity. Allene substrates have multiple reaction-sites, and the selectivities are determined by the suitable interactions (e.g., electronic and steric demands) between the catalyst and substrates. We employed DFT calculations to understand the cascade copper-catalyzed trifunctionalization of terminal allenes, providing densely-functionalized organic molecules with outstanding regio-, chemo- and diastereoselectivity in high yields. The selectivity challenges presented by cumulated π-systems are addressed by systematic computational studies; these give insight to the catalytic multiple-functionalization strategies and explain the high selectivities that we see for these reactions.

Mechanism and Origins of Regioselectivity of Copper-Catalyzed Borocyanation of 2-Aryl-Substituted 1,3-Dienes: A Computational Study.

Density functional theory calculations were performed to investigate the copper-catalyzed borocyanation of 2-aryl-substituted 1,3-dienes. The computations show that the regioselectivity of the overall reaction is governed by the combination of the inherent regioselectivity of the borocupration and electrophilic cyanation steps. The π-conjugation effect of the 1,3-diene makes the terminal carbon atoms more electrophilic compared with the internal carbon atoms, which coupled with the steric effect results in the 4,3- and 1,2-borocupration being intrinsically more favorable than the other possibilities. The steric repulsion around the breaking Cu-C bond was found to be the key factor in determining the regioselectivity of the electrophilic cyanation. The origins of the experimentally observed ligand-controlled regioselectivity were ascribed to the electronic and steric effects. For the bulky XantPhos ligand, the 4,3-borocupration was found to be more favorable than the 1,2-borocupration due to the steric repulsion around the forming Cu-C bond, resulting in the formation of the 4,3-borocyantion product. On the other hand, the reversed regioselectivity with a small PCy3 ligand is mainly caused by the electronic effect that the π-electron-withdrawing aryl group at the C2 atom makes the C1 atom more electrophilic than the C4 atom, enabling the 1,2-borocupration to be more favorable than the 4,3-borocupration.

Electrophilic cyanation of allylic boranes: synthesis of β,γ-unsaturated nitriles containing allylic quaternary carbon centers.

The electrophilic cyanation of allylic boranes, a process that is applicable to the construction of allylic quaternary carbon centers, is reported. The reaction has a broad substrate scope with a high functional group tolerance. The results represent an unprecedented and powerful tool for preparing synthetically useful β,γ-unsaturated nitriles, including derivatives that have been difficult to access using existing methods. The synthetic utility of the method was further demonstrated by functional group interconversions of the cyano group of the products.

Enantioselective Electrophilic Cyanation of Boron Enolates: Scope and Mechanistic Studies.

Chiral β-ketonitriles bearing a stereogenic carbon center at the α-position are an important class of compounds, many of which serve as useful synthetic intermediates for the preparation of chiral 1,3-aminoalcohols, β-hydroxy nitriles, and related derivatives. Although the enantioselective electrophilic cyanation of enolate equivalents is one of the most promising approaches for the synthesis of chiral β-ketonitriles, the available methods are largely limited to reactions of 1,3-dicarbonyl compounds. Herein, we report on enantioselective electrophilic cyanation of boron enolates, which are readily prepared from α,β-unsaturated ketones and diisopinocampheylborane (Ipc2 BH) to afford chiral β-ketonitriles with a high level of enantioselectivity. The present method is scalable and provides facile access to both enantiomers of chiral β-ketonitriles. Analysis of the in situ generated boron enolates by NMR revealed that hydroboration proceeds in a stereospecific manner, providing α,α-disubstituted boron enolates in the form of single isomers. Furthermore, the results of DFT calculations suggest that the cyanation of the boron enolates with p-toluenesulfonyl cyanide (TsCN) proceeds in a highly enantioselective manner through a unique six-membered ring transition state.

Cover Feature: Enantioselective Electrophilic Cyanation of Boron Enolates: Scope and Mechanistic Studies (Chem. Eur. J. 64/2018)

Cover Feature: Enantioselective Electrophilic Cyanation of Boron Enolates: Scope and Mechanistic Studies (Chem. Eur. J. 64/2018)

Regiodivergent Copper Catalyzed Borocyanation of 1,3-Dienes.

Copper catalyzed multi-functionalization of unsaturated carbon-carbon bonds is a powerful tool for the generation of complex molecules. We report a regiodivergent process that allows a switch between 1,4-borocupration and 4,1-borocupration of 1,3-dienes upon a simple change in ligand. The subsequently generated allyl coppers are trapped in an electrophilic cyanation to selectively generate densely functionalized and synthetically versatile 1,2- or 4,3-borocyanation products.

Transition-Metal-Catalyzed Cyanation by Using an Electrophilic Cyanating Agent, N-Cyano-N-phenyl-p-toluenesulfonamide (NCTS).

The ability to introduce a nitrile group into a biologically active compound is very useful in organic synthesis, owing to the importance of nitrile groups in transformations and tuning molecular properties. To date, nucleophilic cyanation has been the most used strategy for this purpose, whilst electrophilic cyanation reactions are less developed. Recently, the electrophilic cyanation reagent N-cyano-N-phenyl-p-toluenesulfonamide (NCTS) has received increasing attention, owing to its superior properties in terms of safety and practicality. This Focus Review summarizes recent progress in transition-metal-catalyzed cyanation reactions that use NCTS.

Unprecedented Synthesis of 2‐Aminochromones and 2‐Aminoquinolones through an Electrophilic C–Cyanation and 6‐exo‐dig Cyclization Cascade with the Intermediary of β‐Ketonitriles

AbstractFor the first time, a domino electrophilic cyanation, using environmentally benign electrophilic cyanating reagent N‐cyano‐N‐phenyl‐p‐toluenesulfonamide (NCTS) to form β‐ketonitriles, and 6‐exo‐dig cyclization were employed for the synthesis of 2‐aminochromones and 2‐aminoquinolones in very good yields. This protocol can also be regulated to get β‐ketonitriles as the products.

Recent developments and applications of cyanamides in electrophilic cyanation.

Nitriles are widely present in various natural products, pharmaceuticals, agrochemicals and dyes. In addition, nitriles are an essential building unit in organic synthesis, which can be readily converted into numerous functional groups. Consequently, the development of new methods for the synthesis of nitriles has gained significant attention in organic synthesis. Over the past few decades, particularly, aryl nitriles were obtained by the cyanation of aryl halides employing metallic/nucleophilic cyano group sources. However, these methods suffer from high catalyst loading and toxic cyano sources. To overcome these problems, various organic cyano group sources have been explored in recent years for the synthesis of nitriles. Among them, cyanamides have attracted significant attention due to their ready availability, ease of handling, and nontoxic and inexpensive nature. In this review, we have summarized the recent developments and applications of cyanamides in the electrophilic cyanation of various nucleophiles.

Cu-catalyzed regioselective borylcyanation of 1,3-dienes.

Catalytic regioselective generation of an allyl-Cu complex through Cu-B(pin) (pin = pinacolato) addition to 1,3-dienes followed by reaction with an electrophilic cyanation reagent to afford multifunctional organoboron compounds is presented. Reactions of a wide range of 1,3-dienes with different substitution patterns promoted by an easily accessible phosphine-Cu complex proceed with high yields and regioselectivity.

Recent Advances in the Synthesis of β-Ketonitriles

β-Ketonitriles are an important class of compounds in the field of organic and medicinal chemistry. Over the past decades, numerous efforts have been devoted to the development of new and efficient methodologies for the synthesis of these derivatives, and a number of efficient methods to accomplish this have been developed in recent years. In this context, this short review highlights recent advances in the synthesis of β-ketonitriles.1 Introduction2 Acylation of Alkyl Nitriles3 Electrophilic Cyanation of Ketone Enolates4 Electrophilic Cyanation of β-Keto Carbonyl Compounds5 Transition-Metal-Catalyzed Carbonylative Coupling Reactions6 Miscellaneous Examples7 Outlook

Catalytic Activation of 1-Cyano-3,3-dimethyl-3-(1H)-1,2-benziodoxole with B(C6F5)3 Enabling the Electrophilic Cyanation of Silyl Enol Ethers.

The Lewis acidic activation of a hypervalent iodine reagent containing a transferable cyano group, 1-cyano-3,3-dimethyl-3-(1H)-1,2-benziodoxole (CDBX), with B(C6F5)3, to achieve the catalytic electrophilic cyanation of silyl enol ethers is presented. Mechanistic studies indicate that CDBX is activated through coordination of its cyano group to B(C6F5)3, thus enabling the electrophilic cyanation reaction to occur.

Catalytic Asymmetric Electrophilic Cyanation of 3-Substituted Oxindoles.

The first example of catalytic asymmetric electrophilic cyanation of 3-substituted oxindoles has been achieved using readily accessible 4-acetylphenyl cyanate as the cyano source. Thus, a series of all-carbon quaternary center 3-aryl-3-cyano oxindoles were prepared using a zinc complex of a chiral pincer ligand as the catalyst in high yields (up to 95%) and excellent enantioselectivities (up to >99% ee) in the presence of 4 Å MS and 2,6-lutidine in THF at 0 °C.

Development of Decarboxylative Cyanation Reactions for C-13/C-14 Carboxylic Acid Labeling Using an Electrophilic Cyanating Reagent.

Degradation-reconstruction approaches for isotope labeling synthesis have been known for their remarkable efficiency, but applications are scarce due to some fundamental limitations of the chemistries developed to date. The decarboxylative cyanation reaction, as a degradation-reconstruction approach, is especially useful in rapid carboxylic acid carbon isotope labeling, however development toward its application as a widespread technique has stalled at the early stages due to numerous limitations which include somewhat narrow applicability. Employing the electrophilic cyanating reagent N-cyano-N-phenyl-p-toluenesulfonamide (NCTS) as the cyano source, efficient decarboxylative cyanation chemistry has been developed for aryl and alkyl carboxylic acids respectively with two rationally designed reaction pathways. The reactions provided good yields of nitrile products from carboxylic acids, with complete retention of isotopic purity from the [13CN]-NCTS used. The reaction conditions are relatively mild requiring no oxidant and no excess toxic heavy metal and the reagent [13/14CN]-NCTS is a stable, easy-to-handle crystalline solid that can be prepared quickly and effectively from the readily available [13/14C]-KCN. The following work describes this novel and efficient method for alkyl and aryl carboxylic acid isotopic labeling using a single reagent.

Enantioselective electrophilic cyanation of β-keto amides catalysed by a cinchona organocatalyst

An operationally simple protocol for the enantioselective electrophilic α-cyanation of β-keto amides catalyzed by cinchona-derived catalysts has been demonstrated. The resulting products could be obtained with good to high enantioselectivities (up to 88% ee) and with excellent yields (up to 94%) by employing the mild active 4-acetylphenyl cyanate as the cationic cyano source in the catalytic asymmetric α-cyanation reaction.