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The carbon‐carbon bond in three‐membered ring of 2,3‐diaryl aziridines was reductively cleaved to give the corresponding dibenzylamine derivatives by electrocyclic ring opening of N‐Li or N‐Na aziridines followed by reduction of the 2‐azaallyl anion formed with sodium borohydride in ethanol. Hydrocyanation of the 2‐azaallyl anion with trimethylsilyl cyanide gave a secondary amine bearing a cyano group at the benzylic position. The effects of substituents on the electrocyclic ring opening of N‐Li aziridines were also clarified. [ABSTRACT FROM AUTHOR]

The hydrocyanation of alkenes can be considered a straightforward methodology that gives access to different functionalized organic chemistry entities. This is due to nitrile's high versatility, which can easily undergo further transformations. However, this process has traditionally employed hazardous hydrogen cyanide as the hydrocyanation agent. Therefore, in the last decades, different protocols have been developed to accomplish this key organic transformation without needing to handle HCN. In this review, we aim to gather the most recent works published in the last couple of decades regarding the hydrocyanation of non‐activated olefins in the absence of gaseous hydrogen cyanide as nitrile source. In addition, special attention has been paid to the reaction mechanism working in each case. [ABSTRACT FROM AUTHOR]

We report facile and versatile procedures for the synthesis of exo - and endo -isomeric spirocyclic hybrids of pharmacophoric (1 R ,5 S)-8-azabicyclo[3.2.1]octane (nortropane) and 1,3-oxazinan-2-one fragments. Our approach consists of the hydrocyanation of endo - and exo -isomeric N -Cbz-protected nortropane-3-spiroepoxides, the reduction of hydroxy nitriles into amino alcohols, the synthesis of N -alkylated amino alcohols via reductive amination, the spirocyclization of the amino alcohols, N -alkylation of the unsubstituted 1,3-oxazinan-2-one fragment in the spiro compounds, and removal of the Cbz protecting groups. [ABSTRACT FROM AUTHOR]

A Pd‐catalyzed synthesis of 5‐iminopyrrolones from propiolamides was developed, which featured wide substrate scope and good yields. This efficient conversion involved a tandem hydrocyanation, E to Z isomerization of alkenes, and nitrile/amide cyclization. Control experiments show the intermediacy of β‐cyanation products, and the Z‐isomers was efficiently converted to the target products by Pd/L2 catalysis only after the cyanation reagent was completely consumed. [ABSTRACT FROM AUTHOR]

Nitriles are versatile and highly desired chemical intermediates for a range of products. Their economic large-scale production requires highly efficient and selective synthesis. The nickel-catalyzed hydrocyanation of C=C double bonds provides such selective and 100% atom-economical access to nitriles, but the catalysts hitherto lack activity and longevity. Yet, the literature focusing on increased catalytic activity or optimized operational procedures is scarce, at the least. Here, we present a thorough investigation and optimization of operational procedures using a commercially available diphosphite ligand and styrene as a model substrate. This led us to achieve a TOF20 of more than 300,000 h−1. [ABSTRACT FROM AUTHOR]

We herein describe a palladium‐catalyzed hydrocyanation of propiolamides for the stereodivergent synthesis of trisubstituted acrylonitriles. This synthetic method tolerated various primary, secondary and tertiary propiolamides. The cautious selection of a suitable ligand is essential to the success of this stereodivergent process. Control experiments indicate the intermediacy of E‐acrylonitriles, which lead to Z‐acrylonitriles via isomerization. The density functional theory calculations suggests that the bidentate ligand L2 enables a feasible cyclometallation/isomerization pathway for the E to Z isomerization, while the monodentate ligand L1 inhibits the isomerization, leading to divergent stereoselectivity. The usefulness of this method can be demonstrated by the readily derivatization of products to give various E‐ and Z‐trisubstituted alkenes. In addition, the E‐ and Z‐acrylonitrile products have also been successfully employed in cycloaddition reactions. [ABSTRACT FROM AUTHOR]

Route to the synthesis of enantiomerically pure ethyl (S)-3-cyano-5-methylhexanoate, (S)-5, a key chiral intermediate for Pregabalin has been improved. The racemic β-cyano diester, 3 was prepared in 98% purity via gelatine catalysed Knoevenagel condensation of diethylmalonate with isovaleraldehyde followed by hydrocyantion of α,β-unsaturated diester 14 using acetone cyanohydrin and K2CO3. Racemic diethyl 2-(1-cyano-3-methylbutyl)malonate, rac-3, has been resolved using lipase from Thermomyces lanuginosus immobilised in form of crosslinked enzyme aggregates, CLEAs. The CLEAs were made by employing commercial soymilk as an additional protein source and a reaction was carried out in a moving basket reactor. The immobilised enzyme was found to be stable in many organic solvents and temperature up to 50 °C. The resolution reaction was studied in a basket reactor at 50% substrate loading in calcium acetate buffer, pH 7.5 at 30 °C by using 20% w/w enzyme loading. The apparent kinetic parameters were Vmax,app = (8.74 ± 0.43) mM/h/g and Km,app = (1.5 ± 0.07) M (correlation coeff. r = 0.98). The desired ethyl (S)-3-cyano-5-methylhexanoate, (S)-5 is obtained in 90-92% theoretical yield and e.e > 99%. The advantages of this improved process are mild reaction conditions; an alternate method for hydrocyanation step avoiding the use of highly toxic potassium cyanide at large scale operation and an immobilised enzyme that can be reused for at least 11 recycles. [ABSTRACT FROM AUTHOR]

The fully regio‐ and stereoselective Zn‐catalyzed hydrocyanation of ynamides is reported and represents a general access to various trisubstituted E‐α‐enamidonitriles. The catalyst‐free photoisomerization selectively yields the energetically comparable Z‐stereoisomer. Finally, the synthetic potential of these new α‐enamidonitriles was evaluated through the synthesis of original heterocycles. [ABSTRACT FROM AUTHOR]

We investigated the previously unknown enantioselective Ni‐catalyzed hydrocyanation of 1,3‐diarylpropenes (homostilbenes). For this purpose, a series of (E)‐homostilbenes were prepared by (microwave‐assisted) Pd‐catalyzed coupling of allylic alcohols with aryl‐boronic acids. Employing our established catalyst system formed from Ni(cod)2 and a TADDOL‐derived chiral phosphine‐phosphite ligand and using TMSCN as an in situ source of HCN, the hydrocyanation of various homostilbenes was studied. The synthetic usefulness of the methodology was demonstrated in a short synthesis of the new (allo‐) colchicine analogue 7‐cyano‐11‐methoxy‐colchinol involving an PIDA‐mediated oxidative cyclization of the corresponding hydrocyanation product to set up the 7‐membered ring. The absolute configuration of 2,4‐diphenylbutyronitrile was assigned by comparison of experimental and calculated ECD spectra. [ABSTRACT FROM AUTHOR]

A highly branched regioselective nickel(0)‐catalyzed hydrocyanation of mono‐ and 1,1‐disubstituted allenes as well as an asymmetric hydrocyanation of 1,1‐disubstituted allenes are reported herein, giving access to branched tertiary and quaternary β,γ‐allylic nitriles. For the regioselective hydrocyanation of terminal allenes, a nickel(0)/Biphephos catalytic system applicable to a substrate scope containing functional groups such as ester, THP‐group, primary aliphatic iodide, and a free carboxylic acid, provides yields up to 96%. By applying a catalytic system of Ni(0)/TADDOL‐based bisphosphite catalyst to 1,1‐disubstituted allenes, branched quaternary allylic nitriles are obtained in yields up to 99% and enantioselectivities up to 86%. Both protocols take advantage of a manageable HCN source and evidence good atom economy. In addition, the reaction's synthesis utility is highlighted by gram‐scale reactions with subsequent assorted transformation of the nitrile group as well as alkylation of the tertiary nitriles in α‐position. [ABSTRACT FROM AUTHOR]

An exclusively regioselective hydrocyanation of monofluoroalkenes has been developed, with which a series of aliphatic quaternary α-fluoronitriles were synthesized in a facile and efficient manner. This novel method is featured with mild conditions, good functional groups compatibilities, and high reactivity. [ABSTRACT FROM AUTHOR]

The hydrocyanation of 2-arylmethyleneindan-1,3-diones with potassium hexacyanoferrate(II) as a nontoxic cyanating agent to synthesize 2-(1,3-dioxoindan-2-yl)-2-arylacetonitriles in the presence of benzoyl chloride as a promoter and potassium carbonate as a base by a one-pot procedure is described. The use of nontoxic and inexpensive cyanide source, high yield and simple workup procedures are the advantages of this protocol.

A Ni/Co co‐catalyzed reductive hydrocyanation of various alkynes was developed for the production of saturated nitriles. Hydrocyanic acid is generated in situ from safe and readily available formamide. Formamide played multiple roles as a cyano source, dehydrant, and reductant for the NiII pre‐catalyst and vinyl nitriles, along with acting as the co‐solvent in this reaction. Detailed mechanistic investigation supported a pathway via hydrocyanation of C≡C bond and the subsequent reduction of C=C bond. Wide substrate scope, the employment of a cheap and stable nickel salt as pre‐catalyst, a safe cyano source and convenient experimental operation render this hydrocyanation practical for the laboratory synthesis of saturated nitriles. [ABSTRACT FROM AUTHOR]

A highly regio‐ and stereoselective hydrocyanation of 1,3‐enynes was implemented by nickel/diphosphine catalysts. A wide range of highly regio‐ and stereoselective alkenyl nitriles were efficiently prepared. In this transformation, both the tethered alkene and the ligand play key roles in the reactivity and selectivity. The origin of regioselectivity was understood preliminarily by DFT studies. [ABSTRACT FROM AUTHOR]

A mild, efficient and highly regioselective addition of trimethylsilyl cyanide (TMSCN) to α,β-unsaturated diesters has been achieved by using MgI2 etherate as catalyst under solvent-free conditions. This protocol provides the corresponding β-cyano esters in high yields. [ABSTRACT FROM AUTHOR]

A universal, practical and scalable organocatalytic hydrocyanation manifold to provide β‐substituted acrylonitriles bearing an electron‐withdrawing functionality has been implemented. The catalytic manifold operates under the reactivity generation principle "a good nucleophile generates a strong base", and it uses 1,4‐diazabicyclo[2.2.2]octane (DABCO) as the catalyst, activated terminal alkynes as substrates and acetone cyanohydrin as the cyanide source. The acrylonitriles obtained as E,Z mixtures are straightforwardly resolved by simple flash chromatography delivering the pure isomers in preparative amounts. [ABSTRACT FROM AUTHOR]

A general and efficient rhodium‐catalyzed asymmetric cyanide‐free hydrocyanation of alkenes has been developed. Based on the asymmetric hydroformylation/condensation/aza‐Cope elimination sequences, a broad scope of substrates including mono‐substituted, 1,2‐, and 1,1‐disubstituted alkenes (involving natural product R‐ and S‐limonene) were employed, and a series of valuable chiral nitriles are prepared with high yields (up to 95 %) and enantioselectivities (up to 98 % ee). Notably, the critical factor to achieve high enantioseletivies is the addition of catalytic amount of benzoic acid. This novel methodology provides an efficient and concise synthetic route to the intermediate of vildagliptin and anagliptin. [ABSTRACT FROM AUTHOR]

Abstract Nickel-catalyzed regioselective hydrocyanation of terminal alkynes is described. A tosylamide functionality at the propargyl position was the most suitable group for controlling the regiochemistry for C CN bond formation as well as rate enhancement. A gram-scale synthesis was achieved by minimizing the catalyst loading to 2 mol%. The major HCN adduct could be transformed to the corresponding indoline through construction of a benzylic quaternary carbon under iron catalysis. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

A straightforward gram‐scale preparation of cyclohexa‐1,4‐diene‐based hydrogen cyanide (HCN) surrogates is reported. These are bench‐stable but formally release HCN and rearomatize when treated with Lewis acids. For BCl3, the formation of the isocyanide adduct [(CN)BCl3]− and the corresponding Wheland complex was verified by mass spectrometry. In the presence of 1,1‐di‐ and trisubstituted alkenes, transfer of HCN from the surrogate to the C−C double bond occurs, affording highly substituted nitriles with Markovnikov selectivity. The success of this transfer hydrocyanation depends on the Lewis acid employed; catalytic amounts of BCl3 and (C6F5)2BCl are shown to be effective while B(C6F5)3 and BF3⋅OEt2 are not. Acid‐free! Bench‐stable cyclohexa‐1,4‐diene‐based hydrogen cyanide (HCN) surrogates are reported to engage in transfer hydrocyanation of alkenes upon treatment with certain boron Lewis acids. The success also depends on the equilibrium position between the intermediate isocyano‐ and cyanoborate isomers. Tertiary nitriles are obtained with exclusive Markovnikov selectivity. [ABSTRACT FROM AUTHOR]

This article describes the formal synthesis of quebrachamine based on regio- and stereoselective hydrocyanation of 1,3-disubstituted allenes. Allenyl C C double bonds are effectively discriminated through Ni-catalyzed hydrocyanation and a CN group is utilized as a synthon of piperidine ring. Several steps from HCN adduct afforded known intermediates to quebrachamine. [ABSTRACT FROM AUTHOR]

Abstract: A new class of CF3 substituted alkylidenemalonates were synthesized and used as a substrate for conjugate cyanation reaction. Ionic liquid has been used as an organocatalyst under solvent‐free and mild reaction conditions. The present protocol exhibited remarkable catalytic activity using a favourable cyanide source i. e. acetone cyanohydrin. Excellent yields were obtained for a wide range of substrates and the high reactivity is presumptively attributed to the basicity of an ionic liquid used. Mechanistic insights were studied using NMR spectroscopy and a probable catalytic cycle was proposed. [ABSTRACT FROM AUTHOR]

The conjugate hydrocyanation of chalcone derivatives using ethyl cyanoacetate as an organic cyanide source at room temperature under open air and transition metal-free conditions was described. The protocol has advantages of using relatively cheap, less toxic, stable and easy-to-handle cyanating reagent, high yield, and mild reaction condition. [ABSTRACT FROM AUTHOR]

Biocatalysts originating from Badamu ( Prunus communis) have been applied to catalyze the asymmetric synthesis of ( R)-4-methylsulfanylmandelonitrile, a key building block of thiamphenicol and florfenicol. Here, four hydroxynitrile lyase (HNL) isozymes from Badamu were cloned and heterologously expressed in Pichia pastoris. The biochemical properties and catalytic performances of these isozymes were comprehensively explored to evaluate their efficiency and selectivity in asymmetric synthesis. Among then, PcHNL5 was identified with outstanding activity and enantioselectivity in asymmetric hydrocyanation. Under the optimized mild biphasic reaction conditions, seventeen prochiral aromatic aldehydes were converted to valuable chiral cyanohydrins with good yields (up to 94%) and excellent optical purities (up to >99.9% ee), which provide a facile access to numerous chiral amino alcohols, hypoglycemic agents, angiotension converting enzyme (ACE) inhibitors and β-blockers. This work therefore underlines the importance of discovering the most potent biocatalyst among a group of isozymes for converting unnatural substrates into value-added products. [ABSTRACT FROM AUTHOR]

A nickel-catalyzed hydrocyanation triggered by hydronickelation of the carbon-carbon double bonds of allenes followed by cyclopropane cleavage is described. The observed regio- and stereochemistries in the products are strongly influenced by the initial hydronickelation step, and allenyl- and methylenecyclopropanes reacted smoothly to promote the cleavage of cyclopropane. In contrast, this cleavage was not observed with vinylidenecyclopropanes, because the initial hydronickelation does not give a suitable intermediate for cleavage of the cyclopropanes. [ABSTRACT FROM AUTHOR]

An active nickel catalyst prepared in situ from a Ni(II) compound, phosphine ligand, and zinc powder was found to be an efficient catalyst system for the hydrocyanation of various alkenes using acetone cyanohydrin as a safer cyano source. The combination of NiCl 2 ·6H 2 O and 1,3-bis(diphenylphosphino)propane was the most efficient catalyst precursor in DMF. Under the optimized conditions, various styrenes, heterocyclic alkenes, and aliphatic alkenes were converted to their corresponding nitriles in excellent yields. [ABSTRACT FROM AUTHOR]