Synthesis of 4‐Aryl‐1,7‐naphthyridine‐2(1H)‐thiones by the Electrocyclic Reaction of 4‐(1‐Arylalk‐1‐enyl)‐3‐isothiocyanatopyridines Generated in situ from the Corresponding Isocyanides

A convenient synthis for 4‐substituted and 3,4‐disubstituted 1,7‐naphthyridine‐2(1H)‐thiones 7 has been developed. The method is based on the electrocyclic reaction of 4‐(1‐arylalk‐1‐enyl)‐3‐isothiocyanatopyridines 6 , generated in situ by the treatment of the respective isocyanides 5 with S₈ in the presence of a catalytic amount of selenium. The isocyanides 5 can be easily prepared from commercially available pyridin‐3‐amine by conventional organic reactions.     

Formal [4+1] Cycloaddition of o‐Aminobenzyl Chlorides with Isocyanides: Synthesis of 2‐Amino‐3‐Substituted Indoles

Reaction of substituted o‐aminobenzyl chlorides with isocyanides in the presence of a weak base (NaHCO₃) at room temperature afforded the diversely functionalized 2‐aminoindoles in good to excellent yields. A formal [4+1] cycloaddition of the in situ generated aza‐ortho‐xylylenes with isocyanides accounted for the reaction outcome.     

A convenient synthesis of functionalized pyrazolones bearing a highly twisted 1,3-butadiene moiety with skew geometry

Abstract

The four-component reaction among arylhydrazine, alkyl acetoacetate derivatives, alkyl isocyanides, and dialkyl acetylenedicarboxylates, leading to the formation of dialkyl 2-[(Z)-(alkylamino)(3-alkyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)methyl] fumarates is described. The structure of target compounds was confirmed using X-ray diffraction study. These pyrazolone derivatives contain a highly twisted exocyclic 1,3-butadiene moiety with skew (??=?87°) geometry.     

One‐Pot Three‐Component Synthesis of Highly Functionalized 2,3‐Dihydro‐1,3‐dioxo‐1H,5H‐pyrazolo[1,2‐a][1,2,4]triazoles

The reactive 1 : 1 zwitterionic intermediate formed by the addition of isocyanides to dialkyl acetylenedicarboxylates was trapped with 4‐arylurazoles to produce the highly functionalized pyrazolo[1,2‐a][1,2,4]triazoles 5 in good yields (Table). The structures of the products 5a – h were corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR), by EI‐MS, and elemental analysis. A possible mechanism for this reaction is proposed (Scheme).     

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.     

De Novo Synthesis of Imidazoles by Visible‐Light‐Induced Photocatalytic Aerobic Oxidation/[3+2] Cycloaddition/Aromatization Cascade

A visible‐light‐induced photocatalytic aerobic oxidation/[3+2] cycloaddition/aromatization cascade between secondary amines and isocyanides has been successfully developed. The reaction provides a general and efficient access to diversely substituted imidazoles and imidazo[1,5‐a]quinoxalin‐4(5 H)‐ones in good yields under mild conditions.     

Formation of Phosphorylated 3H‐Pyrroles from NefIsocyanidePerkow Adducts and Tosylmethyl Isocyanide

Imidoyl chlorides, generated from isocyanides and acyl chlorides, react with trialkyl phosphites, in a Perkow‐type reaction, to afford 3‐(alkylimino)‐2‐[(dialkyloxyphosphoryl)oxy]acrylates, which undergo a smooth reaction with tosylmethyl isocyanide (TsMIC) to furnish 4‐(alkylamino)‐3‐[(dialkyloxyphosphoryl)oxy]‐5‐[(4‐methylphenyl)sulfonyl]‐3H‐pyrrole‐3‐carboxylates in moderate‐to‐good yields.     

Synthesis of Highly Functionalized Isoxazolinediones from One-pot Reaction of Alkylidene Meldrum ’s Acid with Alkyl Isocyanides in the Presence of Arylhydroxylamines

Alkyl isocyanides undergo a smooth reaction with alkylidene Meldrum’s acids in the presence of arylhydroxylamines to produce N ¹-alkyl-2-(3,5-dioxo-2-aryltetrahydro-4-isoxazolyl)alkanamides in high yields.     

Synthesis of Highly Functionalized Isoxazolinediones from One-pot Reaction of Alkylidene <Emphasis Type="Italic">Meldrum</Emphasis>’s Acid with Alkyl Isocyanides in the Presence of Arylhydroxylamines

Summary. Alkyl isocyanides undergo a smooth reaction with alkylidene Meldrum’s acids in the presence of arylhydroxylamines to produce N ¹-alkyl-2-(3,5-dioxo-2-aryltetrahydro-4-isoxazolyl)alkanamides in high yields.     

[Ph3C][B(C6F5)4]: A Highly Efficient Metal‐Free Single‐Component Initiator for the Helical‐Sense‐Selective Cationic Copolymerization of Chiral Aryl Isocyanides and Achiral Aryl Isocyanides

Commercially available [Ph₃C][B(C₆F₅)₄] served as a highly efficient metal‐free and single‐component initiator not only for the carbocationic polymerization of polar and bulky aryl isocyanides with extremely high activity up to 1.2×10⁷ g of polymer/(mol_cat. h), but also for the helical‐sense‐selective polymerization of chiral aryl isocyanides and copolymerization with achiral aryl isocyanides to afford high‐molecular‐weight functional poly(aryl isocyanide)s with good solubility as well as AIE characteristics and/or a single‐handed helical conformation.     

Homoleptic Isocyanide Metalates

Novelties and surprises in the chemistry of metal isocyanides : The synthesis and structure determination of homoleptic isocyanide metalates [M(CNXyl)_m]⁻ (M=Co, m=4; M=Mn, m=5; Xyl=2,6-Me₂C₆H₃) indicate that we need to revise our understanding of transition metal–isocyanide interactions. Further investigations will be required to determine whether these salts with isocyanide metalate ions display a chemistry as rich as that of the analogous carbonyl metalates.     

Synthesis of four series of quinoline‐based heterocycles by reacting 2‐chloroquinoline‐3‐carbonitriles with various types of isocyanides

Four distinct sets of functionalized quinolines were synthesized by reacting 2‐chloroquinoline‐3‐carbonitriles with various types of isocyanides under appropriate conditions. The palladium‐catalysed reaction of less hindered aliphatic and aromatic isocyanides with 2‐chloroquinoline‐3‐carbonitriles yielded 2‐alkyl(aryl)‐1‐imino‐1H‐pyrrolo[3,4‐b]quinolin‐3(2H)‐one derivatives; however, the catalysed reaction of more hindered isocyanides such as tert‐butyl isocyanide produced the corresponding 3‐cyanoquinoline‐2‐carboxamides. Interestingly, chloroquinoline‐3‐carbonitriles reacted with ethyl isocyanoacetate in the presence of Cs₂CO₃ to generate imidazo[1,5‐a]quinoline derivatives; notably, tosylmethyl isocyanide under the same conditions formed unprecedented 2‐tosyl‐3‐cyanoquinolines.     

Efficient Synthesis of Novel Coumarin‐3‐carboxamides (=2‐Oxo‐2H‐1‐benzopyran‐3‐carboxamides) Containing Lipophilic Spacers

The novel coumarin‐3‐carboxamides (=2‐oxo‐2H‐1‐benzopyran‐3‐carboxamides) 5a – 5g containing lipophilic spacers were synthesized through the Ugi‐four‐component reaction (Scheme 1). The reactions of aromatic aldehydes 1 , 4,4′‐oxybis[benzenamine] or 4,4′‐methylenebis[benzenamine] as diamine 2 , coumarin‐3‐carboxylic acid (=2‐oxo‐2H‐benzopyran‐3‐carboxylic acid; 3 ), and alkyl isocyanides 4 lead to the desired substituted coumarin‐3‐carboxamides 5a – 5g at room temperature with high bond‐forming efficiency. These novel coumarin derivatives exhibit brilliant fluorescence at 544 nm in CHCl₃.     

Studies on poly(iminomethylenes)

A variety of simple alkyl and aryl isocyanides have been polymerized using 0.5% NiCl₂ in ethanol as a catalyst. The resulting poly(iminomethylenes) have been characterized by carbon-13 NMR spectroscopy and their polystyrene-equivalent molecular weights have been determined by gel permeation chromatography. Straight chain aliphatic isocyanides having from three to ten carbon atoms in the chain form readily solyble polymers having molecular weights (M_w) in the general range 10,000 to 30,000. Neopentyl isocyanide unlike tert-butyl isocyanide forms an insoluble polymer. A number of new soluble aryl isocyanide polymers have been obtained. However, aryl isocyanides having a single alkyl substituent (CH₃, C₂H₅, CF₃) in the ortho position give only insoluble polymers, whereas aryl isocyanides having alkyl substituents in both ortho positions (e.g., 2,6-(CH₃)₂C₆H₃NC and 2,4,6-(CH₃)₃C₆H₂NC) fail to polymerize under these conditions. The highest molecular weight soluble aryl isocyanide homopolymer is obtained from 3-CH₃OC₆H₄NC(M_w = 26,000). The trimethylsilyl substituted isocyanide (CH₃)₃SiCH₂CH₂NC has been obtained from LiCH₂NC and (CH₃)SiCH₂Cl and gives a brown soluble homopolymer with a molecular weight (M_w) of 19,000.     

The electron-impact-induced fragmentation of some alkyl isocyanides and α-branched alkyl cyanides

The HRP mass spectra of some alkyl isocyanides (R? NC in which R equals CH₃, C₂H₅, n-C₃H₇, n-C₄H₉ and t-C₄H₉) and two methyl branched alkyl cyanides (R? CN in which R equals i-C₃H₇ and t-C₄H₉) have been studied. Using metastable ion transitions and appearance potentials, the fragmentation patterns and spectral characteristics of the isocyanides can be given. A comparison has been made with the mass spectral data of the corresponding cyanides. Although the mass spectra of alkyl cyanides and isocyanides show close relationship, evidence could be obtained that this resemblance is not caused by rearrangement of the isocyanide into cyanide molecules. The main difference between the spectra of both compounds is caused by the strength of the α-bond, being weaker in the case of the isocyanides. The abundance of ions formed by α-bond cleavage decreases with increasing size of the alkyl group.     

Alkenyl Isocyanide Conjugate Additions: A Rapid Route to γ‐Carbolines

Isocyanides are exceptional building blocks, the wide deployment of which in multicomponent and metal‐insertion reactions belies their limited availability. The first conjugate addition/alkylation to alkenyl isocyanides is described, which addresses this deficiency. An array of organolithiums, magnesiates, enolates, and metalated nitriles add conjugately to β‐ and β,β‐disubstituted arylsulfonyl alkenyl isocyanides to rapidly assemble diverse isocyanide scaffolds. The intermediate metalated isocyanides are efficiently trapped with electrophiles to generate substituted isocyanides incorporating contiguous tri‐ and tetra‐substituted centers. The substituted isocyanides are ideally functionalized for elaboration into synthetic targets as illustrated by the three‐step synthesis of γ‐carboline N ‐methyl ingenine B.     

Poly(iminomethylene) copolymers

Copolymerization of an isocyanide giving an insoluble homopolymer with another isocyanide giving a soluble homopolymer in ethanol solution using 0.5–1% of a nickel (II) catalyst in many cases gives a soluble copolymer containing pendant groups arising from both isocyanides. Thus, methyl isocyanide, which gives an insoluble homopolymer, gives chloroform-soluble copolymers incorporating 39–44% of pendant methyl groups when copolymerized with equimolar amounts of tert-butyl isocyanide or several aryl isocyanides. Similarly, cyclohexyl isocyanide, which also gives an insoluble homopolymer, gives chloroform-soluble copolymers incorporating 43–59% of pendant cyclohexyl groups when copolymerized with equimolar amounts of several aryl isocyanides. The compositions, chloroform solubilities, and polystyrene equivalent molecular weights are given for 33 different copolymers obtained by copolymerizations of various equimolar binary mixtures of the monomers CH₃NC, (CH₃)₃CNC, cyclo-C₆H₁₁NC, C₂H₅NC, CH₃CH?CHNC,(CH₃)₂C?CHNC, 2,4,6-(CH₃)₃C₆H₂CH?CHNC, C₆H₅CH(CH₃)NC, CH₂?CHNC, (CH₃)₃CCH?CHNC, C₆H₅NC, 2- and 4-CH₃C₆H₄NC and 2-, 3-, 4-CH₃OC₆H₄NC using the nickel (II) catalyst system.     

On the Reaction between Alkyl Isocyanides and Ethynyl Phenyl Ketone in the Presence of N , N ′-Dimethylbarbituric Acid

 The reactive 1:1 intermediate produced in the reaction between alkyl isocyanides and ethynyl phenyl ketone was trapped with N,N ′-dimethylbarbituric acid to produce alkyl 1,3-dimethyl-2,4-dioxo-7-phenyl-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-5-carboxamides in good yields.     

Studies on the Reactivity of α-Cyano-α-isocyanoalkanoates – Versatile Synthons for the Assembly of Imidazoles

The reactivity and the synthetic potential of α-cyano-α-isocyanoalkanoates 2 were investigated. Interestingly, reaction of 2 with alkoxides gave (alkoxy)(alkyl)imidazoles 5 , whereas the analogous thiolates led to different products, namely substituted 4H-imidazoles 7 , together with compounds 6 , which formed by addition of thiolate to the isocyano group. Primary amines reacted, on one hand, in the same manner as thiolates to form of 4H-imidazoles 10 , and, on the other hand, cleavage of the molecule to the proposed unstable aminoimidazole 8 and the carbamate 9 was observed. Secondary amines add selectively to the isocyano group to form compounds 11 . Like simple isocyanides, α-cyano-α-isocyanoalkanoates 2 can be subjected to [4+1] cycloadditions and multicomponent reactions of the Passerini type. Mechanisms for the described reactions are discussed.     

Synthesis of 2,N,N‐Trisubstituted 1H‐Indole‐1‐carbothioamides from 2‐(Acylmethyl)phenyl Isocyanides

A convenient procedure for the synthesis of 2,N,N‐trisubstituted 1H‐indole‐1‐carbothioamides from 2‐(acylmethyl)phenyl isocyanides has been developed. Thus, these isocyanides are converted into (Z)‐ [1‐alkyl (or phenyl)‐2‐(2‐isothiocyanatophenyl)ethenyl] 1,1‐dimethylethyl carbonates via an easy two‐step sequence. Treatment with secondary amines gave thiourea intermediates which afforded with CF₃COOH (TFA) the desired products in fair‐to‐good yields.