Active Methylene Isocyanides Research Articles

NaH-promoted one-pot synthesis of 5-amidoimidazoles from arylamines, carbon disulfide and isocyanides.

A novel, convenient and efficient protocol to access functionalized 5-amidoimidazoles is developed via one-pot synthesis from readily available materials of arylamines, carbon disulfide and isocyanides. The transformation was realized at room temperature and provided 5-amidoimidazoles in moderate to good yields in the presence of NaH. In addition, control experiments indicated that the process might be achieved via the base-induced cyclization of activated methylene isocyanides with N,N-disubstituted thioureas that produced from the reaction of amines and carbon disulfide.

An N‐Trifluoromethylation/Cyclization Strategy for Accessing Diverse N‐Trifluoromethyl Azoles from Nitriles and 1,3‐Dipoles

AbstractN‐Trifluoromethyl azoles are valuable targets in medicinal chemistry, but their synthesis is challenging. Classical preparation of N‐CF3 azoles relies on the functional group interconversions but suffers from tedious N‐pre‐functionalization and unfriendly agents. Introduction of the CF3 onto the nitrogen of heterocycles provides a direct route to such motifs, but the N‐trifluoromethylation remains underdeveloped. Reported here is an alternative and scalable cyclization strategy based on NCF3‐containing synthons for constructing N‐CF3 azoles. The approach involves the N‐trifluoromethylation of nitriles followed by a [3+2] cyclization between resulting N‐CF3 nitrilium derivatives and 1,3‐dipoles. PhICF3Cl was an effective CF3 source for the transformation. As a result, a generic platform is established to divergently synthesize N‐trifluoromethylated tetrazoles, imidazoles, and 1,2,3‐triazoles by using sodium azide, activated methylene isocyanides, and diazo compounds as dipoles.

An N-Trifluoromethylation/Cyclization Strategy for Accessing Diverse N-Trifluoromethyl Azoles from Nitriles and 1,3-Dipoles.

N-Trifluoromethyl azoles are valuable targets in medicinal chemistry, but their synthesis is challenging. Classical preparation of N-CF3 azoles relies on the functional group interconversions but suffers from tedious N-pre-functionalization and unfriendly agents. Introduction of the CF3 onto the nitrogen of heterocycles provides a direct route to such motifs, but the N-trifluoromethylation remains underdeveloped. Reported here is an alternative and scalable cyclization strategy based on NCF3 -containing synthons for constructing N-CF3 azoles. The approach involves the N-trifluoromethylation of nitriles followed by a [3+2] cyclization between resulting N-CF3 nitrilium derivatives and 1,3-dipoles. PhICF3 Cl was an effective CF3 source for the transformation. As a result, a generic platform is established to divergently synthesize N-trifluoromethylated tetrazoles, imidazoles, and 1,2,3-triazoles by using sodium azide, activated methylene isocyanides, and diazo compounds as dipoles.

Cu/base co-catalyzed [3+3] cycloaddition for the synthesis of highly functionalized 4-fluoropyridines.

An efficient, straightforward and general method for the de novo synthesis of highly functionalized 4-fluoropyridines was developed via a cooperative copper- and base-catalyzed [3+3] cycloaddition of active methylene isocyanides with difluorocyclopropenes. The resulting 4-fluoropyridines can be readily diversified by various nucleophiles.

External Reductant‐free Stepwise [3+2] Cycloaddition/Reductive Cyclization from 2‐Nitrochalcones and Isocyanides: Synthesis of Pyrrolo[3,4‐c]quinoline N‐oxides

AbstractA novel and unprecedented route for the synthesis of pyrrolo[3,4‐c]quinoline N‐oxides is described. The synthetic approach involves a stepwise [3+2] cycloaddition/reductive cyclization from readily available 2‐nitrochalcones and activated methylene isocyanides. The unique feature of this transformation is the reductive cyclization of C−N bond forming without any external reductants. Moreover, the application of pyrrolo[3,4‐c]quinoline N‐oxides is realized to formed pyrrolo[3,4‐c]quinoline derivatives.

Base-mediated [3+2] annulation of trifluoroacetimidoyl chlorides and isocyanides: An improved approach for regioselective synthesis of 5-trifluoromethyl-imidazoles

A t-BuOK-mediated [3 + 2] cycloaddition reaction of trifluoroacetimidoyl chlorides and active methylene isocyanides for the synthesis of 5-trifluoromethyl-imidazoles has been developed. Under mild reaction conditions, the transformation proceeds smoothly in the presence of t-BuOK to afford an array of structurally diverse 5-trifluoromethyl-imidazoles with high efficiency.

Cyclization of Active Methylene Isocyanides with α-Oxodithioesters Induced by Base: An Expedient Synthesis of 4-Methylthio/Ethoxycarbonyl-5-acylthiazoles

Cyclization of tosylmethyl isocyanide with α-oxodithioesters in the presence of KOH is reported for the synthesis of 4-methylthio-5-acylthiazoles. Similarly, ethyl isocyanoacetate underwent cyclization with α-oxodithioesters to form 4-ethoxycarbonyl-5-acylthiazoles in the presence of DBU/EtOH. Mechanisms for the formation of thiazoles are proposed. These thiazoles can also be obtained by Takeda reaction, in which thiazole-4,5-anhydride is acylated with aromatic compounds followed by esterification; however, that approach requires two steps and suffers from the formation of a regioisomeric mixture of products.

Synthesis of 2,3,4-trisubstituted pyrrole derivatives via [3 + 2] cyclization of activated methylene isocyanides with 4-(arylidene)-2-substituted oxazol-5(4H)-ones

An efficient base-catalyzed [3 + 2] cyclization between isocyanides and 4-(arylidene)-2-substituted oxazol-5(4H)-ones has been successfully developed to form 2,3,4-trisubstituted and 2,2,3,4-tetrasubstituted pyrrole derivatives.

Copper‐Catalyzed Reaction of Aryl Isocyanides with Active Methylene Isocyanides and Arylsulfonothioates: Synthesis of Sulfur‐Containing Trisubstituted Imidazoles

AbstractA Copper‐catalyzed reaction of aryl isocyanides with active methylene isocyanides and arylsulfonothioates is developed for the synthesis of sulfur‐containing trisubstituted imidazoles. This reaction not only forms new C−C, C−N, and C−S bonds in one step, but also provides a new strategy for the construction of trisubstituted imidazoles based on the isocyanide‐isocyanide [3+2] cycloaddition.magnified image

Cyclization of Activated Methylene Isocyanides with Methyl N(N),N′-Di(tri)substituted Carbamimidothioate: A Novel Entry for the Synthesis of N,1-Aryl-4-tosyl/ethoxycarbonyl-1H-imidazol-5-amines

Base-induced cyclization of active methylene isocyanides with carbamimidothioates for the synthesis of N,1-aryl-4-tosyl/ethylcarboxy-1H-imidazol-5-amines is reported. The diversity of the reactions is exemplified by using various carbamimidothioates obtained from symmetrical N,N-disubstituted, unsymmetrical N,N,N-trisubstituted, and unsymmetrical N,N-disubstituted thioureas. This diversity is further enriched by different isocyanides. A mechanism for the formation of the title compounds is proposed.

A rhodium-catalyzed three-component reaction of arylisocyanides, trifluorodiazoethane, and activated methylene isocyanides or azomethine ylides: an efficient synthesis of trifluoroethyl-substituted imidazoles

A novel method for the synthesis of trifluoroethyl-substituted imidazoles is reported via a rhodium-catalyzed three-component reaction of isocyanides, 2,2,2-trifluorodiazoethane and activated methylene isocyanides or azomethine ylides.

Base-mediated regioselective [3+2] annulation of ketenimines and isocyanides: efficient synthesis of 1,4,5-trisubstituted imidazoles.

A novel base-mediated regioselective [3+2] annulation of active methylene isocyanides with ketenimines has been developed. In the presence of t-BuOK, a wide range of ketenimines readily react with active methylene isocyanides in DMF at 40 °C to afford 1,4,5-trisubstituted imidazoles efficiently.

Anion Relay Enabled [3 + 3]-Annulation of Active Methylene Isocyanides and Ene-Yne-Ketones.

A new anion relay enabled [3 + 3]-annulation of active methylene isocyanides and conjugated ene-yne-ketones was developed for the efficient and straightforward synthesis of biologically valuable furo[3,2-c]pyridine derivatives. In this transformation, a sequential through-bond and through-space anion relay chemistry cascade is involved, which is initiated by an intermolecular Michael addition. Three new bonds and two rings are sequentially constructed from readily available acyclic precursors.

Tandem Synthesis of Pyrrolo[2,3-b]quinolones via Cadogen-Type Reaction.

A tandem [3 + 2] cycloaddition/reductive cyclization of nitrochalcones with activated methylene isocyanides for the efficient synthesis of pyrrolo[2,3-b]quinolones is reported. In this reaction, the in situ generated dihydropyrroline acts as the internal reductant to convert the nitro into an electrophilic nitroso group, which undergoes subsequent C-N bond formation. Transition-metal-free, simple experimental procedure and ready accessibility of starting materials characterize the present transformation.

Base-Induced Cyclization of Active Methylene Isocyanides with Xanthate Esters: An Efficient Method for the Synthesis of 5-Alkoxy-4-(tosyl/ethoxycarbonyl)-1,3-thiazoles

Sodium hydride-induced cyclization of 1-[(isocyanomethyl)sulfonyl]-4-methylbenzene or ethyl isocyanoacetate with various xanthate esters gave 5-alkoxy-4-tosylthiazoles or ethyl 5-alkoxythiazol-4-ylcarboxylates, respectively, in good to excellent yields. The xanthate ester S-methyl O-phenyl dithiocarbonate gave 5-(methylsulfanyl)-4-tosyl-1,3-thiazole when treated with 1-[(isocyanomethyl)sulfonyl]-4-methylbenzene under similar conditions.

A Novel Methodology for Synthesis of 1,5,6-Trisubstituted 2(1<i>H</i>)-Pyrazinones of Biological Interest

In this report, we describe a new method for the synthesis of densely functionalized 2(1H)-pyrazinones. Treatment of mesoionic 1,3-oxazolium-5-olates with carbanions derived from activated methylene isocyanides (p-toluenesulfonylmethyl isocyanide (TosMIC) and ethyl isocyanoacetate) causes a novel ring transformation affording 2(1H)-pyrazinones in moderate to high yields. The cytotoxicity and antibacterial activity of some of the obtained products were studied and some of the products exhibited tumor-specific cytotoxicity.

Synthesis of 2,5-Bis(hetero)aryl 4′-Substituted 4,5′-Bisoxazoles via Copper(I)-Catalyzed Domino Reactions of Activated Methylene Isocyanides with 2-Phenyl- and 2-(2-Thienyl)-4-[(aryl/heteroaryl)(methylthio)methylene]oxazol-5(4H)-ones

An efficient straightforward synthesis of 2,5,4'-trisubstituted 4,5'-bisoxazoles via copper(I)-catalyzed domino reactions of 2-phenyl- and 2-(2-thienyl)-4-[(aryl/heteroaryl)methylene]-5-oxazolones with activated methylene isocyanides has been reported. The overall domino process comprised of formation of one C-C and two C-O bonds involves initial nucleophilic ring opening of oxazolones by cupriomethylene isocyanides followed by sequential construction of two oxazole rings in the presence of copper catalyst. The broad substrate scope and excellent functional group compatibility of the reaction has been demonstrated by employing a variety of heteroaryl- and aryl-substituted oxazolones and activated methylene isocyanides, yielding bisoxazoles with three potential points of diversity. A probable mechanism for this novel copper-catalyzed domino process has been proposed.

ChemInform Abstract: An Easy Access to 4,5‐Disubstituted Thiazoles via Base‐Induced Click Reaction of Active Methylene Isocyanides with Methyl Dithiocarboxylates.

AbstractThe method allows a simple and rapid approach to the title compounds (23 examples).

An Easy Access to 4,5-Disubstituted Thiazoles via Base-Induced Click Reaction of Active Methylene Isocyanides with Methyl Dithiocarboxylates

An efficient synthesis of 4,5-disubstituted thiazoles via base-induced cyclization of active methylene isocyanides such as tosylmethyl isocyanide, ethyl isocyanoacetate, and arylmethyl isocyanides with methyl arene- and hetarenecarbodithioates is reported. This synthesis could be a new click chemistry reaction, since it is simple, rapid, and often avoids purification steps. In addition, this method allow us a clear and general synthesis of novel 4,5-diarylthiazoles.

ChemInform Abstract: Tandem [5 + 1] Annulation—Isocyanide Cyclization: Efficient Synthesis of Hydroindolones.

AbstractA new strategy for the construction of functionalized hydroindoles (III) and (VI) starting from activated methylene isocyanides (II) and (V) and 1,5‐dielectrophilic 5‐oxo‐2,6‐dienoates (I) and (IV) (and their equivalents) is described.