Β-amino Nitriles Research Articles

Direct Cyanoalkylation of Imines Driven by a Photoactive Electron Donor-Acceptor Complex.

β-Amino nitriles are important molecular scaffolds. Cyanoalkylation of imines is the most straightforward method for the construction of these scaffolds. In this study, we report the novel cyanoalkylation of imines via radical coupling enabled by a photoactive electron donor-acceptor complex. This strategy is characterized by mild conditions, broad reaction scopes, and high atom economy. The scalability and practicality of this strategy are demonstrated by a 40 g continuous flow system from which a variety of important pharmaceutical-related molecules were obtained.

Cyanomethylation of imines enabled by a mild deprotonation of acetonitrile using a combination of TMSCF3 and CsF

β-Amino acids are important structural units in chemistry and biology. Herein we reported a method to synthesize β-amino nitriles, the crucial synthetic precursor to β-amino acids. By using a nucleophilic base-complex, in situ generated from TMSCF3 and CsF, addition of acetonitrile to a series of aromatic imines offered the corresponding β-amino nitriles in excellent yields. Moreover, other electron withdrawing group bearing methyl group could be deprotonated to produce a good nucleophile under this mild conditions.

Enantioselective Amino- and Oxycyanation of Alkenes via Organic Photoredox and Copper Catalysis.

The β-amino nitrile moiety and its derivatives frequently appear in natural product synthesis, in drug design, and as ligands in asymmetric catalysis. Herein, we describe a direct route to these complex motifs through the amino- and oxycyanation of olefins utilizing an acridinium photooxidant in conjunction with copper catalysis. The transformation can be rendered asymmetric by using a serine-derived bisoxazoline ligand. Mechanistic studies implicate olefin-first oxidation. The scope of amines for the aminocyanation reaction has been greatly expanded by undergoing a cation radical intermediate as opposed to previous N-centered radical-initiated aminocyanations. Furthermore, alkyl carboxylic acids were included as nucleophiles in this type of transformation for the first time without any decarboxylative side reactions.

Microfluidics Biocatalysis System Applied for the Synthesis of N-Substituted Benzimidazole Derivatives by Aza-Michael Addition

Benzimidazole scaffolds became an attractive subject due to their broad spectrum of pharmacological activities. In this work, a methodology was developed for the synthesis of N-substituted benzimidazole derivatives from benzimidazoles and α, β-unsaturated compounds (acrylonitriles, acrylate esters, phenyl vinyl sulfone) catalyzed by lipase TL IM from Thermomyces lanuginosus in continuous-flow microreactors. Investigations were conducted on reaction parameters such as solvent, substrate ratio, reaction temperature, reactant donor/acceptor structures, and reaction time. The transformation is promoted by inexpensive and readily available lipase in methanol at 45 °C for 35 min. A wide range of β-amino sulfone, β-amino nitrile, and β-amino carbonyl compounds were efficiently and selectively synthesized in high yields (76–97%). All in all, a microfluidic biocatalysis system was applied to the synthesis of N-substituted benzimidazole derivatives, and could serve as a promising fast synthesis strategy for further research to develop novel and highly potent active drugs.

Electrochemical radical–radical cross-coupling: direct access to β-amino nitriles from unactivated imines and alkyl nitriles

The direct access to β-amino nitriles from unactivated imines and alkyl nitriles by electrochemical radical–radical cross-coupling was described.

Transition Metal- and Base-Free Electrochemical aza-Michael Addition of Aromatic aza-Heterocycles or Ts-Protected Amines to α,β-Unsaturated Alkenes Mediated by NaI

A highly efficient and mild electrochemical protocol has been developed for the aza-Michael addition of aromatic aza-heterocycles or Ts-protected amines with α,β-unsaturated alkenes to give corresponding β-amino sulfone, β-amino nitrile, β-amino ester, and β-amino ketone in moderate to excellent yields. The chemistry proceeded using NaI as a redox mediator in an undivided cell at ambient temperature. Unlike the conventional aza-Michael additions, the utilization of strong acid, base, or transition metal-based catalysts is circumvented. In addition, it was observed the electrochemically in-situ-generated molecular iodine has higher activity than that under nonelectrochemical reaction conditions.

Enantioselective direct Mannich reaction of functionalized acetonitrile to N-Boc imines catalyzed by quaternary phosphonium catalysis

Quaternary phosphonium ion-pair or a salt derived from amino acid has been developed to catalyze the Mannich-type reaction of α-substituted ethyl cyanoacetates and 2-(2-nitrophenyl) acetonitrile to N-Boc imines. Experiments shown that more active cyanoacetates could be catalyzed by the gentle phosphonium ion-pair catalysis, while 2-(2-nitrophenyl) acetonitrile as the substrate has to be activated by quaternary phosphonium salts and strong base. All the reactions gave the corresponding highly functionalized chiral β-amino nitriles products with good yields, high diastereo- and enantioselectivities in mild conditions.

ChemInform Abstract: Copper‐Catalyzed Aza‐Michael Addition of Aromatic Amines or Aromatic Aza‐Heterocycles to α,β‐Unsaturated Olefins.

AbstractThe reactions are carried out in the presence of a Cu complex, formed from CuCl/KOtBu and a specified ligand.

Copper-Catalyzed Aza-Michael Addition of Aromatic Amines or Aromatic Aza-Heterocycles to α,β-Unsaturated Olefins.

A highly efficient and mild Cu-catalyzed conjugate addition reaction of aromatic amines and aromatic aza-heterocycles to α,β-unsaturated olefins is described. The transformation is promoted by 3-7 mol % of a Cu complex generated in situ from a mixture of inexpensive CuCl, a readily available phosphine or imidazolium salt, and KOt-Bu at ambient temperature. A wide range of β-amino sulfone, β-amino nitrile, and β-amino carbonyl compounds is efficiently and selectively synthesized in high yields (62-99%).

Conversion of 3,3,3-Trisubstituted Prop-1-ynes with tert-Butylhydrazine into 3,3,3-Trisubstituted Propionitriles Catalyzed by TpRh(C2H4)2/P(2-furyl)3.

The combination of TpRh(C2H4)2 (Tp = tris(pyrazol-1-yl)borate) and P(2-furyl)3 catalyzes the reaction of tertiary alkyl-substituted alkynes with tert-butylhydrazine, leading to the formation of 3,3,3-trisubstituted propionitrile derivatives. This reaction system is applicable to 1,1-disubstituted propargyl alcohols and amines to afford the corresponding β-cyanohydrins and β-amino nitriles, respectively. The catalytic cycle involves the formation of a vinylidenerhodium complex as a key intermediate.

Enantioselective construction of vicinal tetrasubstituted stereocenters by the mannich reaction of silyl ketene imines with isatin-derived ketimines.

A highly enantioselective Mannich reaction of silyl ketene imines with isatin-derived ketimines has been realized by using a chiral N,N'-dioxide/Zn(II) catalyst. A variety of β-amino nitriles containing congested vicinal tetrasubstituted stereocenters were obtained with excellent outcomes (up to 98 % yield, >19:1 d.r. and 99 % ee). Based on the experimental investigations, a possible transition state has been proposed to explain the origin of the asymmetric induction.

Ureidopeptide‐Based Brønsted Bases: Design, Synthesis and Application to the Catalytic Enantioselective Synthesis of β‐Amino Nitriles from (Arylsulfonyl)acetonitriles

The addition of cyanoalkyl moieties to imines is a very attractive method for the preparation of β-amino nitriles. We present a highly efficient organocatalytic methodology for the stereoselective synthesis of β-amino nitriles, in which the key to success is the use of ureidopeptide-based Brønsted base catalysts in combination with (arylsulfonyl)acetonitriles as synthetic equivalents of the acetonitrile anion. The method gives access to a variety of β-amino nitriles with good yields and excellent enantioselectivities, and broadens the stereoselective Mannich-type methodologies available for their synthesis.

Asymmetric Synthesis of β‐Amino Nitriles through a ScIII‐Catalyzed Three‐Component Mannich Reaction of Silyl Ketene Imines

A range of β-amino nitriles containing contiguous tertiary and quaternary stereogenic carbon centers were synthesized by using the title reaction. The reaction was catalyzed by a chiral N,N′-dioxide scandium(III) complex under mild reaction conditions. Based on experimental investigations, a possible transition state has been proposed to explain the origin of asymmetric inductivity.

Synthesis of Oxindolyl Pyrazolines and 3-Amino Oxindole Building Blocksviaa Nitrile Imine [3 + 2] Cycloaddition Strategy

The [3 + 2] dipolar cycloaddition reaction of nitrile imines with 3-alkylidene oxindoles is described. The pyrazoline spiroadducts were obtained in high yields and with excellent regio- and diastereoselectivities. These spirocyclic intermediates have been elaborated to synthetically versatile 3-amino oxindole building blocks such as β-amino nitrile, 1,3-diamine, and pyrrolo[2,3-b]indoline derivatives.

Gel-spun carbon nanotubes/polyacrylonitrile composite fibers. Part I: Effect of carbon nanotubes on stabilization

Addition of carbon nanotubes (CNTs) in polyacrylonitrile (PAN) fibers significantly improves the mechanical properties of the resulting carbon fibers. This study focuses on the effect of different types of CNTs on chemical, mechanical and structural changes during the stabilization of gel-spun CNT/PAN composite fibers. Among the different types of CNTs, it was observed that CNTs containing more walls had lower reinforcement efficiency than CNTs containing fewer walls. Similarly CNTs containing fewer walls exhibited higher orientation of the ladder polymer and greater effect on the formation of β-amino nitrile in the stabilized fibers. Wide angle X-ray diffraction, infrared spectroscopy, and scanning electron microscopy were used to determine the optimum stabilization time. Additionally, it was found that the higher tension applied during stabilization improved the properties of the stabilized fibers, and the addition of CNTs increased the maximum tension that the fiber can bear.

Efficient synthesis of fluorinated α- and β-amino nitriles from fluoroalkylated α,β-unsaturated imines

A simple and efficient synthesis of fluoroalkylated α-amino nitrile ( 4) derivatives by regioselective 1,2-addition of trimethylsilyl cyanide to fluoroalkylated α,β-unsaturated imines ( 1) is described. Fluoroalkylated β-amino nitriles ( 7) are also prepared by regioselective 1,2-addition of α-carbanions derived from acetonitrile to fluoroalkylated α,β-unsaturated imines ( 1). Fluoroalkylated α-( 4) and β-amino nitriles ( 7) are also prepared through an ‘one pot’ procedure by reaction of enaminophosphonate 2 with BuLi, addition of aldehydes and subsequent addition of either trimethylsilyl cyanide or α-carbanion derived from acetonitrile. Basic hydrolysis of α-( 4) and β-amino nitriles ( 7) gives fluoroalkylated α-( 5) and β-amino acids ( 8).

ChemInform Abstract: Yb(CN)3-Catalyzed Reaction of Aziridines with Cyanotrimethylsilane. A Facile Synthesis of Optically Active Pure β-Amino Nitriles.

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ChemInform Abstract: Treatment of N,N-Dibenzylamino Alcohols with Sulfonyl Chloride Leads to Rearranged β-Chloro Amines, Precursors to β-Amino Acids, and Not to Tetrahydroisoquinolines.

Very recently, the unexpected formation of 3-substituted 1,2,3,4-tetrahydroisoquinolines starting from N,N-dibenzyl-protected β-amino alcohols was reported. The authors claimed that treatment with tosyl chlorides induced intramolecular Friedel−Crafts alkylation. Reexamination of the reactions in our laboratory clearly proved rearranged chloro amines instead of the initially assumed tetrahydoisoquinoline structures. The chloro amines investigated can be employed as highly useful intermediates for an EPC synthesis of β-amino nitriles and β-amino acids.

Palladium-catalyzed Asymmetric Mannich-type Reactions of α-Cyanoketones with N-Boc Aldimines

However, a highly enantioselective Mannich reaction of α- cyanoketones with simple imines remains elusive; although, if successfully promoted with a practically accessible chiral catalyst under air- and moisture-tolerant conditions, it could provide a highly attractive, convergent approach toward optically active β-amino nitriles. As part of research program related to the development of synthetic methods for the enantioselective construction of stereogenic carbon centers,

Product-Catalyzed Addition of Alkyl Nitriles to Unactivated Imines Promoted by Sodium Aryloxide/Ethyl(trimethylsilyl)acetate (ETSA) Combination

The first transition-metal-free addition of alkyl nitriles to unactivated imines was developed using a catalytic combination of 4-MeOC(6)H(4)ONa and TMSCH(2)CO(2)Et to promote the reaction. The corresponding beta-amino nitriles are obtained in good to almost quantitative isolated yields under mild conditions. A mechanism involving an autocatalytic pathway is proposed on the basis of experimental observations.