Copper(I)‐Catalyzed Three‐Component Reaction of Terminal Propargyl Alcohols,Aldehydes, and Amines: Synthesis of 3‐Amino‐2‐pyrones and 2,5‐Dihydrofurans

A novel copper(I)‐catalyzed three‐component reaction for the efficient synthesis of 3‐amino‐2‐pyrones and 2,5‐dihydrofurans from propargyl alcohols, aldehydes, and amines has been developed. The starting materials are easily available and the scope of this method is broad. Through mechanistic studies, it is believed that the three‐component reaction consists of an A³‐coupling to propargylic amine, alkyne–allene isomerization, and intramolecular cyclization of the allenol to form a furan. In case of using ethyl glyoxalate as the aldehyde, a ring‐opening, lactonization, and isomerization process affords the 3‐amino‐2‐pyrones.     

Catalytic Three‐Component Domino Reaction for the Preparation of Trisubstituted Oxazoles

Multicomponent reactions are attractive for assembling functionalized heterocyclic compounds. To this end, an efficient gold‐catalyzed three‐component domino reaction to form oxazoles directly from imines, alkynes, and acid chlorides is presented. The reaction proceeds in a single synthetic step by using a gold(III)–N,N′‐ethylenebis(salicylimine) (salen) catalyst to give trisubstituted oxazoles in up to 96 % yield. The substrate scope, a mechanistic study exploring the role of the gold catalyst, and the synthetic applications of the oxazole products are discussed.     

A Three‐Component Enantioselective Cyclization Reaction Catalyzed by an Unnatural Amino Acid Derivative

A new diastereo‐ and enantioselective three‐component cyclization reaction is described. The reaction takes place between a ketone, a carboxylic acid, and a nitroalkene to yield a bicyclic octahydro‐2H‐indol‐2‐one scaffold possessing three chiral centers. This reaction involves a rearrangement of the nitro group under simple thermal conditions. A plausible mechanism is proposed for this new reaction based on DFT calculations and isotope‐labeling experiments. A new concise enantioselective synthesis of the alkaloid (+)‐pancracine is presented as an example of the potential of this novel organocatalytic cyclization reaction in the synthesis of natural products.     

[HCo(CO)4]‐Catalyzed Three‐component Cycloaddition of Epoxides,Imines, and Carbon Monoxide: Facile Construction of 1,3‐Oxazinan‐4‐ones

The three‐component [3+2+1] cycloaddition of epoxides, imines, and carbon monoxide to produce 1,3‐oxazinan‐4‐ones has been developed by using [HCo(CO)₄] as the catalyst. The reaction occurs for a wide variety of imines and epoxides, under 60 bar of CO pressure at 50 °C, to produce 1,3‐oxazinan‐4‐ones with different substitution patterns in high yields, and provides an efficient and atom‐economic route to heterocycles from simple and readily available starting materials. A plausible mechanism involves [HCo(CO)₄]‐induced ring‐opening of the epoxide, followed by sequential addition of carbon monoxide and the imine, and then ring closure to form the product accompanied by regeneration of [HCo(CO)₄].     

A Metal‐Free Three‐Component Reaction for the Regioselective Synthesis of 1,4,5‐Trisubstituted 1,2,3‐Triazoles

A metal‐free three‐component reaction to synthesize 1,4,5‐trisubstituted 1,2,3‐triazoles from readily available building blocks, such as aldehydes, nitroalkanes, and organic azides, is described. The process is enabled by an organocatalyzed Knoevenagel condensation of the formyl group with the nitro compound, which is followed by the 1,3‐dipolar cycloaddition of the azide to the activated alkene. The reaction features an excellent substrate scope, and the products are obtained with high yield and regioselectivity. This method can be utilized for the synthesis of fused triazole heterocycles and materials with several triazole moieties.     

Three‐Component Synthesis of Highly Functionalized 5‐Acetyloxazoles

By a flexible three‐component synthesis, alkoxy‐substituted enamides are easily available from lithiated alkoxyallenes, nitriles and carboxylic acids (see scheme). The treatment of these versatile intermediates with trifluoroacetic acid provided 5‐acetyloxazoles in moderate to good yields. Different substituents are possible at C‐2 and C‐5 and the 5‐acetyl group is a suitable handle for further synthetic transformations.

     

Generation of N‐Heterocycles via Tandem Reactions of N ′‐(2‐Alkynylbenzylidene)hydrazides

As a powerful synthon, N ′‐(2‐alkynylbenzylidene)hydrazides have been utilized efficiently for the construction of N‐heterocycles. Since N ′‐(2‐alkynylbenzylidene)hydrazides can easily undergo intramolecular 6‐endo cyclization promoted by silver triflate or electrophiles, the resulting isoquinolinium‐2‐yl amides can proceed through subsequent transformations including [3 + 2] cycloaddition, nucleophilic addition, and [3 + 3] cycloaddition. Several unexpected rearrangements via radical processes were observed in some cases, which afforded nitrogen‐containing heterocycles with molecular complexity. Reactive partners including internal alkynes, arynes, ketenimines, ketenes, allenoates, and activated alkenes reacted through [3 + 2] cycloaddition and subsequent aromatization, leading to diverse H‐pyrazolo[5,1‐a]isoquinolines with high efficiency. Nucleophilic addition to the in situ generated isoquinolinium‐2‐yl amide followed by aromatization also produced H‐pyrazolo[5,1‐a]isoquinoline derivatives when terminal alkynes, carbonyls, enamines, and activated methylene compounds were used as nucleophiles. Isoquinoline derivatives were obtained when indoles or phosphites were employed as nucleophiles in the reactions of N ′‐(2‐alkynylbenzylidene)hydrazides. A tandem 6‐endo cyclization and [3 + 3] cycloaddition of cyclopropane‐1,1‐dicarboxylates with N ′‐(2‐alkynylbenzylidene)hydrazides was observed as well. Small libraries of these compounds were constructed. Biological evaluation suggested that some compounds showed promising activities for inhibition of CDC25B, TC‐PTP, HCT‐116, and PTP1B.

     

Copper‐Catalyzed Formal [2+2+1] Heteroannulation of Alkenes,Alkylnitriles, and Water: Method Development and Application to a Total Synthesis of (±)‐Sacidumlignan D

A copper‐catalyzed three‐component reaction of alkenes, alkylnitriles, and water affords γ‐butyrolactones in good yields. The domino process involves an unprecedented hydroxy‐cyanoalkylation of alkenes and subsequent lactonization with the creation of three chemical bonds and a quaternary carbon center. The synthetic potential of this novel [2+2+1] heteroannulation reaction was illustrated by a concise total synthesis of (±)‐sacidumlignan D.     

Desilylation‐Activated Propargylic Transformation: Enantioselective Copper‐Catalyzed [3+2] Cycloaddition of Propargylic Esters with β‐Naphthol or Phenol Derivatives

A copper‐catalyzed asymmetric [3+2] cycloaddition of 3‐trimethylsilylpropargylic esters with either β‐naphthols or electron‐rich phenols has been realized and proceeds by a desilylation‐activated process. Under the catalysis of Cu(OAc)₂?H₂O in combination with a structurally optimized ketimine P,N,N‐ligand, a wide range of optically active 1,2‐dihydronaphtho[2,1‐b]furans or 2,3‐dihydrobenzofurans were obtained in good yields and with high enantioselectivities (up to 96 % ee). This represents the first desilylation‐activated catalytic asymmetric propargylic transformation.     

Copper‐Catalyzed Amine–Alkyne–Alkyne Addition Reaction: An Efficient Method For the Synthesis of γ,δ‐Alkynyl‐β‐amino Acid Derivatives

A simple and efficient method for the synthesis of γ,δ‐alkynyl‐β‐amino acid derivatives by a copper‐catalyzed three‐component amine–alkyne–alkyne addition reaction was developed. Various γ,δ‐alkynyl‐β‐amino acid derivatives were synthesized in moderate to good yields in one step. With chiral prolinol derivatives employed as the amine component, excellent diastereoselectivities (up to >99:1 diastereomeric ratio (dr)) were obtained. The scope of the reaction and further transformations of the resulting amino acid derivatives, such as deprotection and cyclization are also described.     

Enantioselective Generation of Adjacent Stereocenters in a Copper‐Catalyzed Three‐Component Coupling of Imines,Allenes, and Diboranes

A highly enantio‐ and diastereoselective copper‐catalyzed three‐component coupling affords the first general synthesis of homoallylic amines bearing adjacent stereocenters from achiral starting materials. The method utilizes a commercially available NHC ligand and copper source, operates at ambient temperature, couples readily available simple imines, allenes, and diboranes, and yields high‐value homoallylic amines that exhibit versatile amino, alkenyl, and boryl units.