One-step synthesis of N-alkyl-2-aryl-2-oxoacetamides and N,N-dialkyl-2-aryl-4H-1,3-benzodioxine-2,4-dicarboxamides

Alkyl isocyanides react with 2-hydroxybenzaldehyde or 2-hydroxy-5-nitrobenzaldehyde to afford N-alkyl-2-aryl-2-oxoacetamides and N²,N⁴-dialkyl-2-aryl-4H-1,3-benzodioxine-2,4-dicarboxamides in nearly 1:1 ratios. Treatment of 2,6-dimethylphenyl isocyanide with 2-hydroxy-5-nitrobenzaldehyde affords only the 2-oxoacetamide derivative.     

Acceleration of the Passerini reaction in the presence of nucleophilic additives

An accelerating effect of nucleophilic additives was revealed for the Passerini multi-component reaction. The influence of aqueous solutions on the reaction rate was studied in detail and the direct involvement of water in the bond-making step was attributed as the basis of an accelerating effect. Other nucleophiles were tested as alternatives to water; as a result N-hydroxysuccinimide is proposed as an accelerant of the Passerini reaction.     

Recent Applications of α-Metalated Isocyanides in Organic Synthesis

Being both nucleophilic and electrophilic, α-metalated isocyanides can add to polar double bonds, forming heterocycles. They are also synthons for α-metalated primary amines. This article describes recent or improved procedures for their use in organic synthesis: (1) In heterocyclic syntheses to give 2-oxazolines, 2-imidazolines, 2-thiazolines, oxazoles and oligooxazoles, thiazoles, triazoles, imidazolinones, pyrroles, 5,6-dihydro-1,3-oxazines and -thiazines, and (via cycloaddition with nitrones) 2-imidazolidinones. (2) In the field of formylaminomethylenation, for example transformation of estrone methyl ether and a keto sugar into the corresponding α-formylaminoacrylic esters, and the conversion of aldehydes and ketones by 3- and 4-pyridyl-methyl isocyanides into N-(1-pyridyl-1-alkenyl)formamides and their hydrolysis to 3- and 4-acylpyridines. (3) In connection with the use of α-metalated isocyanides as synthons for α-metalated primary amines, the author demonstrates how they may be used for preparation of 1,2- and 1,3-amino alcohols, 1,2-diamines, 2,3-diaminoalkanoic acids and for synthesis of higher amino acids starting from simple amino acids.     

The Isocyanide–Cyanide Rearrangement; Mechanism and Preparative Applications

Until recently the isocyanide–cyanide rearrangement was of interest almost solely as an example of a unimolecular gas-phase reaction, and kinetic studies had been carried out in only a few simple cases. Kinetic measurements in solution were made possible only by the discovery and suppression of a parallel free-radical chain process which leads to the same products. The rate of the isomerization is almost independent of the structure of the starting material and of the substituents present. An exception is provided by extreme steric hindrance in three dimensions which, as in tris-α-substituted triptycyl isocyanides, leads to a considerable increase in the activation energy. The results can be interpreted in terms of a purely sigmatropic mechanism, as predicted by ab initio calculations. The preparative application of this rearrangement reaction requires the suppression of side reactions and can best be carried out by flash pyrolysis; yields are then almost quantitative. Allyl isocyanides react without allyl isomerization, optically active isocyanides with complete retention of configuration. New, economically interesting syntheses for the known nonsteroidal anti-inflammatory drugs ibuprofen and (S)-naproxene are described. The application of the useful synthetic building blocks, the optically active β-acyloxy cyanides, which are formed from optically active α-amino acids, will be demonstrated.     

One-pot synthesis of highly functionalized stable ketenimines of 2,2,2-trifluoro-N-aryl-acetamides

Three-component reaction of alkyl isocyanides and dialkyl acetylenedicarboxylates in the presence of 2,2,2-trifluoro-N-aryl-acetamides in dichloromethane at ambient temperature afforded dialkyl 2-(N-(aryl)-2,2,2-trifluoroacetamido)-3-(alkylimino) methylene-succinate derivatives in excellent yields.     

Efficient Solvent‐Free Synthesis of Benzothiazine‐Fused Pyrrolo[3,4‐c]coumarins: Cycloaddition Reactions between Coumarin‐Based Dihydrobenzothiazoles and Isocyanides

A new and unusual synthesis of benzothiazine‐fused pyrrolo[3,4‐c]coumarins, involving the ring‐opening of coumarin‐based dihydrobenzothiazoles and subsequent [4+1] cycloaddition reaction with isocyanides, was described. Thus, simple heating of various 3‐(2,3‐dihydro‐2‐methylbenzo[d]thiazol‐2‐yl)coumarins with isocyanides produced the title compounds in good yields under solvent‐free conditions.     

Synthesis of Novel α‐(Acyloxy)‐α‐(quinolin‐4‐yl)acetamides by a Three‐Component Reaction between an Isocyanide,Quinoline‐4‐carbaldehyde,and Arenecarboxylic Acids

Novel α‐(acyloxy)‐α‐(quinolin‐4‐yl)acetamides were synthesized by the Passerini three‐component reaction between an isocyanide, quinoline‐4‐carbaldehyde, and arenecarboxylic acids in H₂O. The reactions were carried out in one pot at room temperature with quantitative yields.     

A Novel Synthesis of Quinazolines by Cyclization of 1‐(2‐Isocyanophenyl)alkylideneamines Generated by the Treatment of 2‐(1‐Azidoalkyl)phenyl Isocyanides with NaH

A new and efficient method for the synthesis of quinazolines has been developed. Thus, N‐[2‐(1‐azidoalkyl)phenyl]formamides 1 are dehydrated with POCl₃ to give the corresponding 2‐(1‐azidoalkyl)phenyl isocyanides 2 , which are then treated with NaH in DMF at 0° to give quinazolines 6 in satisfactory yields via cyclization of 1‐(2‐isocyanophenyl)alkylideneamine intermediates 4 . This methodology can be applied to the synthesis of the 7‐azaanalogs of quinazolines, i.e., pyrido[3,4‐d]pyrimidines 9 .     

Synthesis and reactivity of asymmetrically substituted ansa-bridged zirconocene complexes: X-ray crystal structures of [Zr{R(H)C(η-C5Me4)(η-C5H4)}Cl2] (R = Bu, Bu) and [Zr{Bu(H)C(η-C5Me4)(η-C5H4)}(CH2Ph)2]

The dialkyl complexes, (R = Prⁱ, R′ = Me (2a), CH₂Ph (3a); R = Buⁿ, R′ = Me (2b), CH₂Ph (3b); R = Bu^t, R′ = Me (2c), CH₂Ph (3c); R = Ph, R′ = Me (2d), CH₂Ph (3d)), have been synthesized by the reaction of the ansa-metallocene dichloride complex, [Zr{R(H)C(η⁵-C₅Me₄)(η⁵-C₅H₄)}Cl₂] (R = Prⁱ (1a), Buⁿ (1b), Bu^t (1c), Ph (1d)), and two molar equivalents of the alkyl Gringard reagent. The insertion reaction of the isocyanide reagent, CNC₆H₃Me₂-2,6, into the zirconium-carbon σ-bond of 2 gave the corresponding η²-iminoacyl derivatives, [Zr{R(H)C(η⁵-C₅Me₄)(η⁵-C₅H₄)}{η²-MeCNC₆H₃Me₂-2,6}Me] (R = Prⁱ (4a), Buⁿ (4b), Bu^t (4c), Ph (4d)). The molecular structures of 1b, 1c and 3b have been determined by single-crystal X-ray diffraction studies.     

Organometallic chemistry and catalysis on gold metal surfaces

As in transition metal complexes, CN-R ligands adsorbed on powdered gold undergo attack by amines to give putative diaminocarbene groups on the gold surface. This reaction forms the basis for the discovery of a gold metal-catalyzed reaction of CN-R, primary amines (R′NH₂) and O₂ to give carbodiimides (R′-NCN-R). An analogous reaction of CO, RNH₂, and O₂ gives isocyanates (R-NCO), which react with additional amine to give urea (RNH)₂CO products. The gold-catalyzed reaction of CN-R with secondary amines (HNR′₂) and O₂ gives mixed ureas RNH(CO)NR′₂. In another type of gold-catalyzed reaction, secondary amines HN(CH₂R)₂ react with O₂ to undergo dehydrogenation to the imine product, RCHN(CH₂R). Of special interest is the high catalytic activity of gold powder, which is otherwise well-known for its poor catalytic properties.