Catalytic Asymmetric [3+1]‐Cycloaddition Reaction of Ylides with Electrophilic Metallo‐enolcarbene Intermediates

The first asymmetric [3+1]‐cycloaddition was successfully achieved by copper(I) triflate/double‐sidearmed bisoxazoline complex catalyzed reactions of β‐triisopropylsilyl‐substituted enoldiazo compounds with sulfur ylides. This methodology delivered a series of chiral cyclobutenes in good yields with high enantio‐ and diastereoselectivities (up to 99 % ee , and >20:1 d.r.). Additionally, the [3+1]‐cycloaddition of catalytically generated metallo‐enolcarbenes was successfully extended to reaction with a stable benzylidene dichlororuthenium complex.     

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.     

Total Synthesis of (−)‐Perezoperezone through an Intermolecular [5+2] Homodimerization of Hydroxy p‐Quinone

The first copper‐catalyzed intermolecular [5+2] homodimerization of hydroxy p‐quinone is presented, furnishing bicyclo[3.2.1]octadienone core structures in typically good yields and excellent diastereoselectivities. Applying this synthetic approach enables a concise nine‐step total synthesis of (?)‐perezoperezone from commercially available 3,5‐dimethoxytoluene.     

Highly Enantioselective [3+2] Cycloaddition of Vinylcyclopropane with Nitroalkenes Catalyzed by Palladium(0) with a Chiral Bis(tert‐amine) Ligand

An enantioselective [3+2] cycloaddition of vinyl cyclopropane derived from 1,3‐indanedione with nitroalkenes catalyzed by palladium(0) with a chiral bis(tert‐amine) ligand was developed in high yields with good diastereoselectivities and excellent enantioselectivities. The resulting bis(tert‐amine)–palladium complex proved to be a highly efficient catalyst for this cycloaddition.     

Fulvene Synthesis by Rhodium(I)‐Catalyzed [2+2+1] Cycloaddition: Synthesis and Catalytic Activity of Tunable Cyclopentadienyl Rhodium(III) Complexes with Pendant Amides

It has been established that a Rh^I+/segphos complex catalyzes the [2+2+1] cycloaddition of 1,6‐diynes with cyclopropylideneacetamides to give substituted fulvenes in good yields. The reductive complexation of the product fulvenes with RhCl₃ in EtOH furnished the corresponding dinuclear cyclopentadienyl Rh^III complexes bearing a pendant amide moiety. These Rh^III complexes were highly active catalysts for oxidative annulation and cyclization through C(sp²)−H and C(sp³)−H functionalization.     

Organocatalytic Asymmetric Formal [3+2] Cycloaddition as a Versatile Platform to Access Methanobenzo[7]annulenes

Pharmaceutically and structurally important methanobenzo[7]annulenes were synthesized in very good yields with excellent enantio‐ and diastereoselectivities through an unprecedented organocatalytic formal [3+2] cycloaddition from readily available 2‐alkyl‐3‐hydroxynaphthalene‐1,4‐diones and alkyl vinyl ketones.     

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.     

Reversal of the Regiochemistry in the Rhodium‐Catalyzed [4+3] Cycloaddition between Vinyldiazoacetates and Dienes

A regio‐, diastereo‐, and enantioselective [4+3] cycloaddition between vinylcarbenes and dienes has been achieved using the dirhodium tetracarboxylate catalyst [Rh₂(S‐BTPCP)₄]. This methodology provides facile access to 1,4‐cycloheptadienes that are regioisomers of those formed from the tandem cyclopropanation/Cope rearrangement reaction of vinylcarbenes with dienes.     

Construction of Novel Tetrahydro‐β‐carboline‐1‐thione Spirooxindoles by Brønsted Acid Mediated Formal [3+3] Cyclization of 3‐Indolylmethanols with 3‐Isothiocyanato Oxindoles

p‐Toluenesulfonic acid mediated formal [3+3] cyclization of 3‐indolylmethanols with 3‐isothiocyanato oxindoles was realized. This transformation allowed for the synthesis of a series of novel tetrahydro‐β‐carboline‐1‐thione spirooxindoles in moderate to excellent yields (up to 99%) with generally good diastereoselectivities (up to >20:1). The structure of one product was determined by an X‐ray crystal structural analysis.     

Phosphine-catalyzed [4+2] cycloaddition of sulfamate-derived cyclic imines with allenoates: synthesis of sulfamate-fused tetrahydropyridines

Using n-PrPPh₂ as the nucleophilic catalyst, the [4+2] cycloaddition reaction of the sulfamate-derived cyclic imines with allenoates works efficiently to yield various sulfamate-fused tetrahydropyridines in high yields with excellent diastereoselectivities. Using amino acid-based bifunctional phosphine as chiral catalyst, an asymmetric [4+2] cycloaddition reaction was achieved, giving chiral sulfamate-fused tetrahydropyridines in high yields with good enantiomeric excesses.     

Merging [2+2] Cycloaddition with Radical 1,4‐Addition: Metal‐Free Access to Functionalized Cyclobuta[a]naphthalen‐4‐ols

A metal‐free [2+2] cycloaddition and 1,4‐addition sequence induced by S‐centered radicals has been achieved by treating benzene‐linked allene‐ynes with aryldiazonium tetrafluoroborates and DABCO‐bis(sulfur dioxide) in a one‐pot procedure. The reaction provides a greener and more practical access to functionalized cyclobuta[a]naphthalen‐4‐ols with valuable applications. More than 50 examples are demonstrated with excellent diastereoselectivity and chemical yields. The reaction pathway is proposed to proceed by the following steps:[2+2] cycloaddition, insertion of SO₂, 1,4‐addition, diazotization, and tautomerization.     

Enantioselective Synthesis of Highly Functionalized Dihydrofurans through Copper‐Catalyzed Asymmetric Formal [3+2] Cycloaddition of β‐Ketoesters with Propargylic Esters

An enantioselective synthesis of highly functionalized dihydrofurans through a copper‐catalyzed asymmetric [3+2] cycloaddition of β‐ketoesters with propargylic esters has been developed. With a combination of Cu(OTf)₂ and a chiral tridentate P,N,N ligand as the catalyst, a variety of 2,3‐dihydrofurans bearing an exocyclic double bond at the 2 position were obtained in good chemical yields and with good to high enantioselectivities. The exocyclic double bond can be hydrogenated in a highly diastereoselective fashion to give unusual cis‐2,3‐dihydrofuran derivatives, thus further enhancing the scope of this transformation.     

Highly Efficient and Diastereoselective Construction of Tricyclic Pyrrolidine‐Fused Benzo[b]thiophene 1,1‐dioxide Derivatives via 1,3‐Dipolar [3 + 2] Cycloaddition

A rapid and highly efficient 1,3‐dipolar [3 + 2] cycloaddition of nonstabilized azomethine ylides generated in situ with benzo[b]thiophene 1,1‐dioxides as the dipolarophiles has been developed. The efficient method affords tricyclic pyrrolidine‐fused benzo[b]thiophene 1,1‐dioxide derivatives in high to excellent yields (up to 99%) with excellent diastereoselectivities (up to >25:1 dr) under mild reaction conditions. The structure of a typical product was confirmed by X‐ray crystallography.     

Diastereo‐ and Enantioselective Copper(I)‐Catalyzed Intermolecular [3+2] Cycloaddition of Azomethine Ylides with β‐Trifluoromethyl β,β‐Disubstituted Enones

Reported herein is an asymmetric [3+2] cycloaddition reaction of azomethine ylides with β‐trifluoromethyl β,β‐disubstituted enones, a reaction which is enabled by a Ming‐Phos‐derived copper(I) catalyst (Ming‐Phos=chiral sulfinamide monophosphines, Figure 2 ). This method provides scalable and efficient access to the highly substituted pyrrolidines with a trifluoromethylated, all‐carbon quaternary stereocenter in good yields with up to greater than 20:1 d.r. and 98 % ee. The reaction has a broad substrate scope and tolerates a wide range of functional groups.     

Copper(I)‐Catalyzed Asymmetric [3+2]‐Cycloaddition of α‐Substituted Iminoesters with α‐Trifluoromethyl α,β‐Unsaturated Esters

Reported herein is an example of highly regio‐, diastereo‐ and enantioselective Cu(I)‐catalyzed intermolecular [3+2] cycloaddition reaction of α‐substituted iminoesters with α‐trifluoromethyl α,β‐unsaturated esters. This novel strategy provided a facile access to pyrrolidines with two skipped (aza)quaternary stereocenters including a CF₃ all‐carbon quaternary stereocenter. A broad substrate scope was observed and high yields (up to 94%) with excellent diastereoselectivity (up to >20 : 1 d.r.) and enantioselectivity (up to 98% ee) were obtained.     

Rhodium‐Catalyzed [3+2+2] and [2+2+2] Cycloadditions of Two Alkynes with Cyclopropylideneacetamides

It has been established that a cationic rhodium(I)/H₈‐binap complex catalyzes the [3+2+2] cycloaddition of 1,6‐diynes with cyclopropylideneacetamides to produce cycloheptadiene derivatives through cleavage of cyclopropane rings. In contrast, a cationic rhodium(I)/(S)‐binap complex catalyzes the enantioselective [2+2+2] cycloaddition of terminal alkynes, acetylenedicarboxylates, and cyclopropylideneacetamides to produce spiro‐cyclohexadiene derivatives which retain the cyclopropane rings.     

RhII‐Catalyzed [3+2] Cycloaddition of 2 H‐Azirines with N‐Sulfonyl‐1,2,3‐Triazoles

Rh^II‐catalyzed intermolecular [3+2] cycloaddition of 2 H‐azirines with N‐sulfonyl‐1,2,3‐triazoles is disclosed, in which a series of fully functionalized pyrroles is produced via rhodium azavinyl carbene intermediates. A distinct feature of this reaction is that the azavinyl carbene serves as a [2 C] equivalent, instead of as [1 C] or aza‐[3 C] synthons, which have been reported previously in cyclopropanations and [3+n] cycloadditions. Moreover, this methodology has also been successfully applied in the total synthesis of URB447 as well as the formal synthesis of Atorvastatin (Lipitor).     

Switchable [3+2] and [4+2] Heteroannulation of Primary Propargylamines with Isonitriles to Imidazoles and 1,6‐Dihydropyrimidines: Catalyst Loading Enabled Reaction Divergence

Isonitrile 1 due to its carbene‐like reactivity serves generally as a one‐carbon synthon in a diverse set of organic transformations. We report in this article that the isocyano group can also act as a polarized triple bond to undergo, as a two‐atom synthon, heteroannulation with primary propargylamines 15 . In addition, we serendipitously discovered that the reaction pathways can be modulated by simply changing the catalyst loading. In the presence of 0.1 equiv of Yb(OTf)₃ or TfOH, the reaction between 1 and 15 afforded exclusively imidazoles 16 by a formal [3+2] cycloaddition. At a higher catalyst loading (Yb(OTf)₃ (0.4 equiv) or TfOH (0.5 equiv)) under otherwise identical conditions, the same reaction furnished 1,6‐dihydropyrimidines 17 in good to excellent yields by way of a formal [4+2] cycloaddition process. Mechanistic investigations indicated that both annulations went through an amidine intermediate resulting from the insertion of the isocyano group to the NH bond of the primary amine. Subsequent catalyst‐loading‐dependent 5‐exo‐dig or 6‐endo‐dig cyclization provided selectively the two heterocycles, respectively.     

Rhodium‐Catalyzed Enantioselective [4+2] Cycloadditions of Vinylcarbenes with Dienes

The reaction of 2‐siloxycyclo‐1,3‐dienes with E‐vinyldiazoacetates in the presence of the bulky chiral dirhodium tetracarboxylate catalyst, Rh₂(R‐p‐PhTPCP)₄ results in an enantioselective [4+2] cycloaddition, in which three new stereogenic centers are formed. The [4+2] cycloadducts are generated as single diastereomers with high enantiocontrol (95–98 % ee). When the diene contains an additional stereogenic center, effective kinetic resolution can be achieved.     

Catalyst‐Free Regioselective [3+2] Cycloadditions of α,β‐unsaturated N‐arylnitrones with Alkenes to Access Functionalized Isoxazolidines: A DFT Study

The catalyst‐free regioselective [3+2]‐cycloaddition of α,β‐unsaturated N‐arylnitrones with alkenes are developed. The series of synthetically important functionalized isoxazolidines are prepared in good to excellent yields by step economic pathway under ligand and transition‐metal‐free conditions. The regioselective cycloaddition pathway supported by control experiment and computational study.