Metal‐Free [2+2+2] Cycloaddition of Ynamides and Nitriles: Mild and Regioselective Synthesis of Fully Substituted Pyridines

A metal‐free trimolecular [2+2+2] cycloaddition of internal ynamides and nitriles for de novo synthesis of fully substituted pyridines is disclosed. With the versatile Brønsted acid catalyst HNTf₂, the mild intermolecular cyclotrimerization process proceeds with complementary chemoselectivity and excellent regioselectivity.     

Enantioselective Nucleophilic β‐Carbon‐Atom Amination of Enals: Carbene‐Catalyzed Formal [3+2] Reactions

An enantioselective β‐carbon amination for enals is disclosed. The nitrogen atom from a protected hydrazine with suitable electronic properties readily behaves as a nucleophile. Addition of the nitrogen nucleophile to a catalytically generated N‐heterocyclic‐carbene‐bound α,β‐unsaturated acyl azolium intermediate constructs a new carbon–nitrogen bond asymmetrically. The pyrazolidinone products from our catalytic reactions are common scaffolds in bioactive molecules, and can be easily transformed into useful compounds such as β³‐amino‐acid derivatives.     

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.     

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.

     

Gold‐Catalyzed Formal Dehydro‐Diels–Alder Reactions of Ene‐Ynamide Derivatives Bearing Terminal Alkyne Chains: Scope and Mechanistic Studies

A new protocol for the synthesis of a variety of N‐containing aromatic heterocycles by a formal gold‐catalyzed dehydro‐Diels–Alder reaction of ynamide derivatives has been developed. Deuterium‐labeling experiments and kinetic studies support the involvement of a dual gold catalysis mechanism in which a gold acetylide moiety adds onto an aurated keteneiminium.     

An Amine‐Catalyzed Enantioselective [3+2] Cycloaddition of Azomethine Ylides and α,β‐Unsaturated Aldehydes: Applications and Mechanistic Implications

The catalytic enantioselective [3+2] cycloaddition between azomethine ylides and α,β‐unsaturated aldehydes catalyzed by α,α‐diphenylprolinol has been studied in detail. In particular, the reaction has been extended to the use of 2‐alkenylidene aminomalonates generated in situ as azomethine ylide precursors. These reactions lead to the formation of pyrrolidines containing a 5‐alkenyl side chain with potential for chemical manipulation. Moreover, a detailed and concise computational study has been carried out to understand the exact nature of the mechanism of this reaction and especially the consequences derived from the incorporation of the chiral secondary amine catalyst on the reaction pathway.     

Synthesis of Aminopyridines and Aminopyridones by Cobalt‐Catalyzed [2+2+2] Cycloadditions Involving Yne‐Ynamides: Scope,Limitations, and Mechanistic Insights

An in‐depth study of the cobalt‐catalyzed [2+2+2] cycloaddition between yne‐ynamides and nitriles to afford aminopyridines has been carried out. About 30 nitriles exhibiting a broad range of steric demand and electronic properties have been evaluated, some of which open new perspectives in metal‐catalyzed arene formation. In particular, the use of [CpCo(CO)(dmfu)] (dmfu=dimethyl fumarate) as a precatalyst made possible the incorporation of electron‐deficient nitriles into the pyridine core. Modification of the substitution pattern at the yne‐ynamide allows the regioselectivity to be switched toward 3‐ or 4‐aminopyridines. Application of this synthetic methodology to the construction of the aminopyridone framework using a yne‐ynamide and an isocyanate was also briefly examined. DFT computations suggest that 3‐aminopyridines are formed by formal [4+2] cycloaddition between the nitrile and the intermediate cobaltacyclopentadiene, whereas 4‐aminopyridines arise from an insertion pathway.     

Efficient Synthesis of Substituted 3‐Azabicyclo[3.1.0]hexan‐2‐ones from 2‐Iodocyclopropanecarboxamides Using a Copper‐Free Sonogashira Coupling

The copper‐free Sonogashira coupling between N‐substituted cis‐ 2‐iodocyclopropanecarboxamides and terminal aryl‐, heteroaryl‐alkynes or enynes, followed by 5‐exo‐dig cyclization of the nitrogen amide onto the carbon–carbon triple bond, provides a remarkably efficient access to a variety of substituted 4‐methylene‐3‐azabicyclo[3.1.0]hexan‐2‐ones in excellent yields. Protonation of these latter enamides generates bicyclic N‐acyliminium ions that can be involved in Pictet–Spengler cyclizations leading to new 3‐azabicyclo[3.1.0]hexan‐2‐ones, possessing a quaternary stereocenter at C4, with high diastereoselectivities. This strategy constitutes an attractive complementary alternative to the classical route that relies on the addition of organometallic reagents to cyclopropyl imides.     

Reaction of an N‐Heterocyclic Carbene‐Stabilized Silicon(II) Monohydride with Alkynes: [2+2+1] Cycloaddition versus Hydrogen Abstraction

An in depth study of the reactivity of an N‐heterocyclic carbene (NHC)‐stabilized silylene monohydride with alkynes is reported. The reaction of silylene monohydride 1 , tBu₃Si(H)Si←NHC, with diphenylacetylene afforded silole 2 , tBu₃Si(H)Si(C₄Ph₄). The density functional theory (DFT) calculations for the reaction mechanism of the [2+2+1] cycloaddition revealed that the NHC played a major part stabilizing zwitterionic transition states and intermediates to assist the cyclization pathway. A significantly different outcome was observed, when silylene monohydride 1 was treated with phenylacetylene, which gave rise to supersilyl substituted 1‐alkenyl‐1‐alkynylsilane 3 , tBu₃Si(H)Si(CH?CHPh)(C?CPh). Mechanistic investigations using an isotope labelling technique and DFT calculations suggest that this reaction occurs through a similar zwitterionic intermediate and subsequent hydrogen abstraction from a second molecule of phenylacetylene.     

Theory of the Formation and Decomposition of N‐Heterocyclic Aminooxycarbenes through Metal‐Assisted [2+3]‐Dipolar Cycloaddition/Retro‐Cycloaddition

The theoretical background of the formation of N‐heterocyclic oxadiazoline carbenes through a metal‐assisted [2+3]‐dipolar cycloaddition (CA) reaction of nitrones R¹CH?N(R²)O to isocyanides C?NR and the decomposition of these carbenes to imines R¹CH?NR² and isocyanates O?C?NR is discussed. Furthermore, the reaction mechanisms and factors that govern these processes are analyzed in detail. In the absence of a metal, oxadiazoline carbenes should not be accessible due to the high activation energy of their formation and their low thermodynamic stability. The most efficient promotors that could assist the synthesis of these species should be “carbenophilic” metals that form a strong bond with the oxadiazoline heterocycle, but without significant involvement of π‐back donation, namely, Au^I, Au^III, Pt^II, Pt^IV, Re^V, and Pd^II metal centers. These metals, on the one hand, significantly facilitate the coupling of nitrones with isocyanides and, on the other hand, stabilize the derived carbene heterocycles toward decomposition. The energy of the LUMO_CNR and the charge on the N atom of the C?N group are principal factors that control the cycloaddition of nitrones to isocyanides. The alkyl‐substituted nitrones and isocyanides are predicted to be more active in the CA reaction than the aryl‐substituted species, and the N,N,C‐alkyloxadiazolines are more stable toward decomposition relative to the aryl derivatives.     

Ni‐Catalyzed [4+3+2] Cycloaddition of Ethyl Cyclopropylideneacetate and Dienynes: Scope and Mechanistic Insights

A detailed study of the Ni‐catalyzed [4+3+2] cycloaddition reaction between ethyl cyclopropylideneacetate and dienynes has been conducted, resulting in the development of a new method for the synthesis of compounds containing nine‐membered rings. We studied the reactivity of various dienynes, together with their substituent and conformational effects. The mechanism of the reaction was probed by examining the stoichiometric reactions of the Ni complexes and dienynes.     

[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].     

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.