Enantioselective Syntheses of 3,4-Dihydropyrans Employing Isochalcogenourea-Catalyzed Formal (4+2)-Cycloadditions of Allenoates.

We herein successfully demonstrate the use of chiral isochalcogenoureas as Lewis Base catalysts for a variety of (4+2)-cycloaddition reactions of allenoates and different Michael acceptors. In all cases the same structural key-motive, a dihydropyran with a (Z)-configurated exocyclic double bond could be accessed as the major regio- and diastereoisomer in an enantioselective manner. Furthermore, these chiral dihydropyrans were successfully engaged in different follow-up transformations.

Synthesis of 3,4-Disubstituted Maleimide Derivatives via Phosphine-Catalyzed Isomerization of α-Succinimide-Substituted Allenoates Cascade γ'-Addition with Aryl Imines.

3,4-disubstituted maleimides find wide applications in various pharmacologically active compounds. This study presents a highly effective approach for synthesizing derivatives of 3,4-disubstituted maleimides through the direct isomerization of α-succinimide-substituted allenoates, followed by a cascade γ'-addition and aryl imines using PR3 as a catalyst. The resulting series of 3,4-disubstituted maleimides exhibited excellent stereoselectivities, achieving yields of up to 86%. To our knowledge, the phosphine-mediated γ'-addition reaction of allenoates is seldom reported.

Phosphine-Catalyzed γ'-Carbon 1,6-Conjugate Addition of α-Succinimide Substituted Allenoates with Para-Quinone Methides: Synthesis of 4-Diarylmethylated 3,4-Disubstituted Maleimides.

In this paper, an interesting γ'-carbon 1,6-conjugate addition for phosphine-catalyzed α-succinimide substituted allenoates has been disclosed. A wide array of substrates was found to participate in the reaction, resulting in the production of diverse 4-diarylmethylated 3,4-disubstituted maleimides with satisfactory to outstanding yields. Furthermore, a plausible mechanism for the reaction was proposed by the investigators.

Chiral Isochalcogenourea-Catalysed Enantioselective (4+2) Cycloadditions of Allenoates.

Allenoates are versatile building blocks which are primarily activated and controlled using chiral tert. phosphine and tert. amine Lewis bases. We herein report the first example of allenoate activation by using chiral isochalcogenoureas (IChU) for formal (4+2) cycloaddition reactions. Compared to established phosphine and amine catalysis, the use of these easily available Lewis bases enables new stereoselective reaction pathways proceeding with high enantioselectivities, diastereoselectivities, and in good yields. In addition, the factors governing enantioselectivity and the origin of the observed differences compared to other commonly used Lewis bases are explained.

(3+2) Annulation of 4-Acetoxy Allenoate with Aldimine Enabled by AgF-Assisted P(III)/P(V) Catalysis.

A phosphine-catalyzed (3+2) annulation of 4-acetoxy allenoate and aldimine with the assistance of AgF is described. The success of this reaction hinges on the metathesis between the enolate-phosphonium zwitterion and AgF, leading to a key intermediate comprising of silver enolate and a fluorophosphorane P(V)-moiety. The former is able to undergo a Mannich reaction with aldimine, whereas the latter initiates a cascade sequence of AcO-elimination/aza-addition, thus furnishing the P(III)/P(V) catalysis. By taking advantage of the silver enolate, a preliminary attempt at an asymmetric variant was conducted with the combination of an achiral phosphine catalyst and a chiral bis(oxazolinyl)pyridine ligand (PyBox), giving moderate enantioselectivity.

Towards an asymmetric ß-selective addition of azlactones to allenoates.

We herein report the asymmetric organocatalytic addition of azlactones to allenoates. Upon using chiral quaternary ammonium salt catalysts, i.e., Maruoka's binaphthyl-based spirocyclic ammonium salts, the addition of various azlactones to allenoates proceeds in a ß-selective manner with moderate levels of enantioselectivities (up to 83:17 er). Furthermore, the obtained products can be successfully engaged in nucleophilic ring opening reactions, thus giving highly functionalized α-amino acid derivatives.

One-Pot Synthesis of 1,3,4-Oxadiazines from Acylhydrazides and Allenoates.

The framework of 1,3,4-oxadiazine is crucial for numerous bioactive molecules, but only a limited number of synthetic methods have been reported for its production. In 2015, Wang's group developed a 4-(dimethylamino)pyridine (DMAP)-catalyzed [2 + 4] cycloaddition of allenoates with N-acyldiazenes, which provided an atom-efficient route for 1,3,4-oxadiazines. However, the practicality of this method was limited by the instability of N-acyldiazenes as starting materials. Building upon our ongoing research about the aerobic oxidation of hydrazides and their synthetic applications, we hypothesized that aerobic oxidative cycloadditions using acylhydrazides instead of N-acyldiazenes may provide a more practical synthetic route for 1,3,4-oxadiazines. In this manuscript, we describe a one-pot synthetic protocol for 1,3,4-oxadiazines from acylhydrazides and allenoates. The developed one-pot protocol consists of aerobic oxidations of acylhydrazides into N-acyldiazenes using NaNO2 and HNO3, followed by the DMAP-catalyzed cycloaddition of allenoate with the generated N-acyldiazenes. A variety of 1,3,4-oxadiazines were produced in good to high yields. In addition, the practicality of the developed method was demonstrated by a gram-scale synthesis of 1,3,4-oxadiazine.

Catalytic Asymmetric Syntheses of Alkylidenecyclopropanes from Allenoates with Donor-Acceptor and Diacceptor Diazo Reagents.

The first diastereo- and enantioselective cyclopropanation reactions of electron-deficient allenes with donor-acceptor and diacceptor diazo reagents are described. The desired enantioenriched alkylidenecyclopropanes (ACPs) were obtained in high yields with high diastereo- and enantioselectivities in the presence of Rh2 ((S)-TCPTAD)4 or Rh2 ((R)-BTPCP)4 catalysts (up to 95 % yield, >95 : 5 d.r. and 99 : 1 e.r.). This methodology gave a direct access to ACPs bearing multiple electron-deficient substituents and allows to further expand the availability of ACPs chemistry. Interestingly, during the examination of the scope of this reaction, the asymmetric intramolecular C-H insertion reaction into tert-butyl group was observed as a side reaction with up to 94 : 6 e.r.

Visible-Light-Assisted Gold-Catalyzed Fluoroarylation of Allenoates.

A strategically novel synthetic method for the fluoroarylation of allenic ester was developed that enables the expedient construction of a host of ß-fluoroalkyl-containing cinnamate derivatives. The reaction proceeds through visible-light-promoted gold redox catalysis, occurs smoothly under very mild reaction conditions, accommodates a large variety of functional groups, and more importantly allows the incorporation of fluorine and aryl groups with excellent regio- and stereoselectivity. The concomitant activation mode for both the allene motif and the hydrogen fluoride is key for the success of the reaction.

Enantioselective Catalytic [4+1]-Cyclization of ortho-Hydroxy-para-Quinone Methides with Allenoates.

The first highly asymmetric catalytic synthesis of densely functionalized dihydrobenzofurans is reported, which starts from ortho-hydroxy-containing para-quinone methides. The reaction relies on an unprecedented formal [4+1]-annulation of these quinone methides with allenoates in the presence of a commercially available chiral phosphine catalyst. The chiral dihydrobenzofurans were obtained as single diastereomers in yields up to 90 % and with enantiomeric ratios up to 95:5.

A Molecular Electron Density Theory Study of the Synthesis of Spirobipyrazolines through the Domino Reaction of Nitrilimines with Allenoates.

The reaction of diphenyl nitrilimine (NI) with methyl 1-methyl-allenoate yielding a spirobipyrazoline has been studied within molecular electron density theory (MEDT) at the MPWB1K/6-311G(d) computational level in dichloromethane. This reaction is a domino process that comprises two consecutive 32CA reactions with the formation of a pyrazoline intermediate. Analysis of the relative Gibbs free energies indicates that both 32CA reactions are highly regioselective, the first one being also completely chemoselective, in agreement with the experimental outcomes. The geometries of the TSs indicate that they are associated to asynchronous bond formation processes in which the shorter distance involves the C1 carbon of diphenyl NI. Despite the zwitterionic structure of diphenyl NI, the appearance of a pseudoradical structure at the beginning of the reaction path, with a very low energy cost, suggests that the 32CA reaction between diphenyl NI, a strong nucleophile, and the allenoate, a moderate electrophile, should be mechanistically considered on the borderline between pmr-type and cb-type 32CA reactions, somewhat closer to the latter.

Enantioselective γ-Addition of Pyrazole and Imidazole Heterocycles to Allenoates Catalyzed by Chiral Phosphine.

Chiral phosphines were found to catalyze the enantioselective asymmetric γ-addition of heteroaromatic compounds to allenoates in good yields with high enantiomeric ratios and regioselectivity in the presence of (S)-BINOL. Both pyrazole and imidazole could be employed in this process. The synthetic value of these γ-addition products was demonstrated by the preparation of biologically relevant molecules and structural scaffolds. Remarkably, the synthetic utility of this strategy was demonstrated through a two-step synthesis of a Janus kinase (JAK) inhibitor.

Palladium-Catalyzed Enantioselective Alkoxycarbonylation of Propargylic Carbonates with (R)- or (S)-3,4,5-(MeO)3 -MeOBIPHEP.

(R)- and (S)-3,4,5-(MeO)3 -MeOBIPHEP have been identified as the efficient chiral ligands for the palladium-catalyzed highly enantioselective synthesis of 2,3-allenoates from different types of easily available racemic propargylic carbonates with 90-98 % ee and decent yields. The potential of the products was demonstrated with high chirality transfer efficiency.

Cyclobuteno[60]fullerenes as Efficient n-Type Organic Semiconductors.

Cyclobuteno[3,4:1,2][60]fullerenes have been prepared in a straightforward manner by a simple reaction between [60]fullerene and readily available allenoates or alkynoates as organic reagents under basic and mild conditions. The chemical structure of the new modified fullerenes has been determined by standard spectroscopic techniques and confirmed by X-ray diffraction analysis. Some of these new fullerene derivatives exhibit a remarkable intrinsic electron mobility (determined by using flash-photolysis time-resolved microwave conductivity (FP-TRMC) measurements), which surpasses that of the well-known phenyl-C61-butyric acid methyl ester, thus behaving as promising n-type organic semiconductors.

Transition-Metal-Free Coupling of Alkynes with α-Bromo Carbonyl Compounds: An Efficient Approach towards ß,γ-Alkynoates and Allenoates.

A direct transition-metal-free coupling between alkynes and α-bromo carbonyl compounds has been developed with ultraviolet (UV) light in aqueous media. This method represents a facile approach to synthetically useful ß,γ-alkynyl esters and amides stereoselectively from two readily available starting materials. As an example of the synthetic application of the products, the alkynyl esters were readily converted into allenoates.

Bifunctional-Phosphine-Catalyzed Sequential Annulations of Allenoates and Ketimines: Construction of Functionalized Poly-heterocycle Rings.

A highly stereoselective sequential annulation reaction between γ-substituted allenoates and ketimines was reported. By using bifunctional N-acyl aminophosphine catalysts, poly-heterocycle rings were obtained with high stereocontrol in good to excellent yields. The desired products have four contiguous stereogenic centers (one quaternary and three tertiary carbon centers), and only one isomer was obtained in all reactions.

Phosphahelicenes in asymmetric organocatalysis: [3+2] cyclizations of γ-substituted allenes and electron-poor olefins.

The first use of phosphahelicene in enantioselective organocatalysis is reported. New chiral phosphahelicenes have been prepared and enable highly enantioselective [3+2] cyclization reactions between arylidene- or alkylidenemalononitriles and γ-substituted allenoates or cyanoallenes. These reactions afford cyclopentene derivatives in both high yields and diastereoselectivities, with enantiomeric excesses of up to 97 %.

A phosphine-catalyzed novel asymmetric [3+2] cycloaddition of C,N-Cyclic azomethine imines with δ-substituted allenoates.

Catalytic asymmetric [3+2] cycloadditions of C,N-cyclic azomethine imines with δ-substituted allenoates have been developed in the presence of (S)-Me-f-KetalPhos, affording functionalized tetrahydroquinoline frameworks in good yields with high diastereo- and good enantioselectivities under mild condition. The substrate scope has been also examined. This is the first time that δ-substituted allenoates have been applied as a δ,γ-C-C bond participated C2 synthon in asymmetric synthesis.

Isocyanide-based multicomponent reactions: concise synthesis of spirocyclic oxindoles with molecular complexity by using a [1,5]-hydrogen shift as the key step.

A concise multicomponent reaction of isocyanide, α-substituted allenoate, and methyleneindolinone has been disclosed. This protocol provides a fast and straightforward approach to synthesize unusual tricyclic oxindoles in an efficient and atom-economic manner. Mechanistically, the present cycloaddition may proceed through a cascade sequence involving double Michael addition, double cyclization, double [1,5]-hydrogen shift, and group migration. The introduction of a special alkyl group to the allenoate is believed to play a key role in the cascade reaction. This method also features a broad substrate scope, which is particularly useful for the delivery of a large number of compounds.

Asymmetric synthesis of spiropyrazolones through phosphine-catalyzed [4+1] annulation.

An enantioselective synthesis of spiropyrazolones from allenoate-derived MBH acetates and pyrazolones through a phosphine-mediated [4+1] annulation process has been developed. Spiropyrazolones were readily prepared in good chemical yields and good to high enantioselectivities. This is the first asymmetric example in which α-substituted allenoates were utilized as a C4 synthon for phosphine-catalyzed [4+1] annulation.