Cycloaddition Of Allenes Research Articles

Switchable Chemo‐, Regio‐ and Pseudo‐Stereodivergence in Palladium‐Catalyzed Cycloaddition of Allenes

AbstractHere, we report a strategy enabling triple switchable chemo‐, regio‐, and stereodivergence in newly developed palladium‐catalyzed cycloadditions of allenes. An asymmetric pseudo‐stereodivergent cycloaddition of allenes bearing a primary leaving group at the α‐position, where a dynamic kinetic asymmetric hydroalkoxylation of racemic unactivated allenes was the enantio‐determining step, is realized, providing four stereoisomers [(Z,R), (Z,S), (E,S), and (E,R)] containing a di‐substituted alkene scaffold and a stereogenic center. By tuning reaction conditions, a mechanistically distinctive cycloaddition is uncovered selectively with the same set of substrates. By switching the position of the leaving group of allenes, a cycloaddition involving an intermolecular O‐attack is disclosed. Diverse mechanisms of the cycloaddition reactions of allenes enable rapid access to structurally and stereochemically diverse 3,4‐dihydro‐2H‐1,4‐benzoxazines in high efficiency and selectivity.

Switchable Chemo-, Regio- and Pseudo-Stereodivergence in Palladium-Catalyzed Cycloaddition of Allenes.

Here, we report a strategy enabling triple switchable chemo-, regio-, and stereodivergence in newly developed palladium-catalyzed cycloadditions of allenes. An asymmetric pseudo-stereodivergent cycloaddition of allenes bearing a primary leaving group at the α-position, where a dynamic kinetic asymmetric hydroalkoxylation of racemic unactivated allenes was the enantio-determining step, is realized, providing four stereoisomers [(Z,R), (Z,S), (E,S), and (E,R)] containing a di-substituted alkene scaffold and a stereogenic center. By tuning reaction conditions, a mechanistically distinctive cycloaddition is uncovered selectively with the same set of substrates. By switching the position of the leaving group of allenes, a cycloaddition involving an intermolecular O-attack is disclosed. Diverse mechanisms of the cycloaddition reactions of allenes enable rapid access to structurally and stereochemically diverse 3,4-dihydro-2H-1,4-benzoxazines in high efficiency and selectivity.

Tandem Isomerization/α,β-Site-Selective and Enantioselective Addition Reactions of N-(3-Butynoyl)-3,5-dimethylpyrazole Induced by Chiral π-Cu(II) Catalysts.

Allenes are important building blocks, and derivatization of products via cycloadditions of allenes could become a powerful strategy for constructing carbocyclic and heterocyclic rings. However, the development of catalytic site-selective and enantioselective cycloaddition reactions of allenes still presents significant challenges. Here, we report chiral π-Cu(II)-complex-catalyzed isomerization of N-(3-butynoyl)-3,5-dimethyl-1H-pyrazole to generate N-allenoylpyrazole in situ and subsequent α,β-site-selective and enantioselective [3 + 2], [4 + 2], or [2 + 2] cycloaddition or conjugate addition reactions. The asymmetric environment created by the intramolecular π-Cu(II) interactions provides the corresponding adducts in moderate to high yield with excellent enantioselectivity. To the best of our knowledge, this is the first successful method for chiral-Lewis-acid-catalyzed tandem isomerization/α,β-site-selective and enantioselective cycloaddition or conjugate addition reactions of latent non-γ-substituted allenoyl derivative.

Fluorine-Activated and -Directed Allene Cycloadditions with Nitrile Oxides and Imine Oxides: Synthesis of Ring-Fluorinated Isoxazole Derivatives.

In this study, 1,1-difluoroallenes underwent a regioselective [2+3] cycloaddition with nitrile oxides and imine oxides in the presence of a AuCl catalyst. (E)-4-Alkylidene-5,5-difluoroisoxazolines and -isoxazolidines were obtained in regioselective and diastereoselective manners by employing aurated difluoroallylic cation intermediates. The synthesized 5,5-difluoroisoxazolines were readily aromatized through dehydrofluorination or allylic fluorine substitution to provide 5-fluoroisoxazoles.

Lewis Acid-Promoted [2 + 2] Cycloadditions of Allenes and Ketenes: Versatile Methods for Natural Product Synthesis.

ConspectusCycloaddition reactions are an effective method to quickly build molecular complexity. As predicted by the Woodward-Hoffmann rules, concerted cycloadditions with alkenes allow for the constructions of all possible stereoisomers of product by use of either the Z or E geometry. While this feature of cycloadditions is widely used in, for example, [4 + 2] cycloadditions, translation to [2 + 2] cycloadditions is challenging because of the often stepwise and therefore stereoconvergent nature of these processes. Over the past decade, our lab has explored Lewis acid-promoted [2 + 2] cycloadditions of electron-deficient allenes or ketenes with alkenes. The concerted, asynchronous cycloadditions allow for the synthesis of various cyclobutanes with control of stereochemistry.Our lab developed the first examples of Lewis acid-promoted ketene-alkene [2 + 2] cycloadditions. Compared with traditional thermal conditions, Lewis acid-promoted conditions have several advantages, such as increased reactivity, increased yield, improved diastereoselectivity, and, for certain cases, inverse diastereoselectivity. Detailed mechanistic studies revealed that the diastereoselectivity was controlled by the size of the substituent and the barrier of a deconjugation event. However, these reactions required the use of stoichiometric amounts of EtAlCl2 because of the product inhibition, which led us to investigate catalytic enantioselective [2 + 2] cycloadditions of allenoates with alkenes. Through the use of chiral oxazaborolidines, a broad range of cyclobutanes can be prepared with the control of enantioselectivity. Mechanistic experiments, including 2D-labled alkenes and Hammett analysis, illuminate likely transition state models for the cycloadditions. Additional studies led to the development of Lewis acid-catalyzed intramolecular stereoselective [2 + 2] cycloadditions of chiral allenic ketones/esters with alkenes.The methods we developed have been instrumental in the synthesis of several families of natural products. Specifically, one key lactone motif in (±)-gracilioether F was constructed by a ketene-alkene [2 + 2] cycloaddition and subsequent regioselective Baeyer-Villiger oxidation sequence. Enantioselective allenoate-alkene [2 + 2] cycloadditions allowed for the synthesis of (-)-hebelophyllene E. Another attempt of applying this method in the synthesis of (+)-[5]-ladderanoic acid failed to deliver the desired cyclobutane because of an unexpected rearrangement. The key cyclobutane was later assembled by a stepwise carboboration/Zweifel olefination process. Finally, the stereoselective [2 + 2] cycloadditions of allenic ketones and alkenes was applied in the syntheses of (-)-[3]-ladderanol, (+)-hippolide J, and (-)-cajanusine.

Regio‐ and Stereoselective, Intramolecular [2+2] Cycloaddition of Allenes, Promoted by Visible Light Photocatalysis

AbstractEnallenylamides have been utilized for the synthesis of heterobicycle[4.2.0]octane derivatives via Ir/hν promoted [2+2] cycloaddition reaction. The reaction specifically targets the distal double bond of the allene moiety, and results in the exclusive formation of the trans product. The process is conducted at room temperature and under an inert atmosphere. An extensive study on the substituent propensities during the cycloaddition step revealed variable effects. Electron‐withdrawing groups conjugated with the double bond participating in the cycloaddition either hindered the process or reduced its yield. Conversely, electron‐donating substituents enhanced the efficiency, resulting in product yields ranging from 60% to 88%. Our study also demonstrated the influence of protecting groups on the reaction pathway.

Reagent-Controlled Regioselective Intramolecular [2+2] Cycloaddition between Vinylsilanes and Allenes.

This paper provides the first report of the intramolecular [2+2] cycloaddition of vinylsilane. The [2+2] cycloaddition of allenes is a useful reaction that can synthesize cyclobutanes. However, no previous works have attempted to control the regioselectivity between the two double bonds of allenes only by changing the reaction conditions, although there have been some reports of the regioselective [2+2] cycloaddition of allenes by changing the substrate. In this study, we have succeeded in controlling intramolecular [2+2] cycloaddition reactions at the proximal and distal positions of allenes simply by changing the reaction conditions. We found that the atomic radius of silicon is very important for perfect control of the reaction's sites. The structures of all key compounds were determined by the crystal sponge method which could identify the structures of liquid compounds.

NEW ADVANCES IN THE SYNTHESIS OF CYCLOALKA[b]INDOLS

The review summarizes data on the synthesis of compounds whose backbone is a cycloalka[b]indole heterocycle. Approaches to the synthesis of homologous structures are considered, ranging from a carbocyclic fragment with three carbon atoms to eight-membered analogues. Examples of cyclizations are presented, including those with induction of chiral centers using appropriate catalytic systems, with different enantio- and diastereoselectivity. Attention is paid to carbocyclization reactions occurring in the presence of metal complexes, lithium alkylates, inter- or intramolecular cycloaddition of allenes, activated alkenes with 1,3-dipolarophiles or diene-like systems. In the preparation of cycloprop[b]indoles, [2+1]-cycloaddition reactions of indoles with various carbenes are most often used. In approaches to the synthesis of indoles annelated with cyclobutane, [2+2]-cycloaddition reactions are used. To obtain indoles, to which 2,3-annelated carbocycles of medium size, synthetic methods are effectively used, including the use of indole derivatives, 3-nitroindole derivatives as starting materials, intra- and intermolecular reactions of 3-ethynyl-, 3-allenyl -, 3-alkenyl- or functionalized 2-alkyl-substituted indoles in the presence of complexes of palladium, gold, rhodium, copper, silver, indium, organophosphorus acids and their amides, trifluoroethanol, hexafluoroisopropanol, organic sulfo- or trifluoroacetic acids. Methods of photochemical exposure are known, leading to cyclopenta[b]indoles. In the preparation of these heterocycles, cycloaddition reactions of 1,3-dipoles generated from (2-indolyl)diarylmethanols to dipolarophiles are successfully used. Equally effective are cycloaddition reactions of 2-vinylindole derivatives to activated alkenes or carbonyl compounds in the presence of various catalysts, leading to di- or tetrahydrocarbazoles or their seven-membered homologues. One of the frequently used approaches to obtain cycloalka[b]indoles are reactions based on catalyzed transformations of indole-substituted cyclopropanes or intermolecular interaction of cyclopropanes with indoles under various conditions.

DFT study on stereoselective Rh-catalyzed intramolecular [2 + 2 + 2] cycloaddition of allene–ene–ynes

CAT catalyzes the reaction of 1a to generate intermediate INT2, which is a common intermediate to generate final products 2a and 3a.

Regio- and Diastereoselective Formal [2+2] Cycloaddition of Allenes with Amino-Functionalized Alkenes by Rare-Earth-Catalyzed C(sp2 )-H Activation.

The [2+2] cycloaddition of allenes with alkenes is of much interest and importance as a straightforward route for the construction of four-membered carbocycles but has remained much underexplored to date. Herein we report for the first time the intermolecular regio- and diastereoselective formal [2+2] cycloaddition of a wide range of allenes with amino-functionalized alkenes by half-sandwich rare-earth catalysts. The reaction proceeded through an allene C(sp2 )-H activation mechanism initiated by the site-selective deprotonation of the allene unit by a rare-earth metal alkyl species followed by alkene insertion into the resulting metal-allenyl bond and the subsequent intramolecular cycloaddition to an allene C=C bond. This protocol offers a unique route for the synthesis of a new family of cyclobutane and cyclobutene derivatives which were difficult to access previously.

Regio‐ and Diastereoselective Formal [2+2] Cycloaddition of Allenes with Amino‐Functionalized Alkenes by Rare‐Earth‐Catalyzed C(sp2)−H Activation

AbstractThe [2+2] cycloaddition of allenes with alkenes is of much interest and importance as a straightforward route for the construction of four‐membered carbocycles but has remained much underexplored to date. Herein we report for the first time the intermolecular regio‐ and diastereoselective formal [2+2] cycloaddition of a wide range of allenes with amino‐functionalized alkenes by half‐sandwich rare‐earth catalysts. The reaction proceeded through an allene C(sp2)−H activation mechanism initiated by the site‐selective deprotonation of the allene unit by a rare‐earth metal alkyl species followed by alkene insertion into the resulting metal‐allenyl bond and the subsequent intramolecular cycloaddition to an allene C=C bond. This protocol offers a unique route for the synthesis of a new family of cyclobutane and cyclobutene derivatives which were difficult to access previously.

Gold-catalyzed cycloadditions of allenes via metal carbenes.

In recent years, gold-catalyzed cycloadditions of allenes, especially those involving a gold carbene intermediate, have received significant interest, as they avoid the utilization of potentially hazardous and inaccessible diazo compounds as starting materials for carbene generation. Cycloaddition reactions consisting of the uncomplicated addition of two or more unsaturated functional groups are one of the most efficient synthetic methodologies for the rapid assembly of carbo- and heterocyclic structures from simple acyclic precursors. In this review, we introduce an overview of the advances in the gold-catalyzed cycloaddition of allenes via a metal carbene intermediate and categorize these reactions according to the reaction types of the cycloadditions.

Low-Temperature Intramolecular [4+2] Cycloaddition of Allenes with Arenes for the Synthesis of Diene Ligands.

The intramolecular [4+2] cycloaddition between arenes and allenes first reported by Himbert gives rapid access to rigid polycyclic scaffolds. Herein, we report a one-pot oxyalkynylation/cycloaddition reaction proceeding under mild conditions (23-90 °C) and providing complex polycyclic architectures with high efficiency, and atom and step economy. The bicyclo[2.2.2]octadiene products were obtained with a wide variety of useful functional groups and were successfully applied as chiral ligands for metal catalysis. Computational studies gave a first rationalization of the low activation energy for the cycloaddition based on counter-intuitive favorable dispersive interactions in the transition state.

Low‐Temperature Intramolecular [4+2] Cycloaddition of Allenes with Arenes for the Synthesis of Diene Ligands

AbstractThe intramolecular [4+2] cycloaddition between arenes and allenes first reported by Himbert gives rapid access to rigid polycyclic scaffolds. Herein, we report a one‐pot oxyalkynylation/cycloaddition reaction proceeding under mild conditions (23–90 °C) and providing complex polycyclic architectures with high efficiency, and atom and step economy. The bicyclo[2.2.2]octadiene products were obtained with a wide variety of useful functional groups and were successfully applied as chiral ligands for metal catalysis. Computational studies gave a first rationalization of the low activation energy for the cycloaddition based on counter‐intuitive favorable dispersive interactions in the transition state.

Recent advances in [3+2] cycloaddition of allenes with 1,3-carbonyl ylides; Rh(ii)-catalyzed access to bridged polyoxocarbocyles

This study summarizes the stereochemical outcomes of [3+2] cycloaddition of allene molecules with 1,3-dipolar carbonyl ylides derived from Rh(ii) carbene-mediated diazo decomposition for the formation of highly diastereoselective poly oxacarbocycles.

An Enolate‐Structure‐Enabled Anionic Cascade Cyclization Reaction: Easy Access to Complex Scaffolds with Contiguous Six‐, Five‐, and Four‐Membered Rings

AbstractCatalyst‐free addition of ketone enolate to non‐activated multiple C−C bonds involves non‐complementary reaction partners and typically requires super‐basic conditions. On the other hand, highly aggregated or solvated enolates are not reactive enough to undergo direct addition to alkenes or alkynes. Herein, we report a new anionic cascade reaction for one‐step assembly of intriguing molecular scaffolds possessing contiguous six‐, five‐, and four‐membered rings, representing a formal [2+2] enol–allene cycloaddition. Reaction proceeds under very mild conditions and with excellent diastereoselectivity. Deeper mechanistic and computational studies revealed unusually slow proton transfer phenomenon in cyclic ketone intermediate and explained peculiar stereochemical outcome.

Catalytic Enantiodivergent Michael Addition by Subtle Adjustment of Achiral Amino Moiety of Dipeptide Phosphines.

SummaryOver the past decades, asymmetric catalysis has been intensely investigated as a powerful tool for the preparation of numerous chiral biologically active compounds. However, developing general and practical strategies for preparation of both enantiomers of a chiral molecule via asymmetric catalysis is still a challenge, particularly when the two enantiomers of a chiral catalyst are not easily prepared from natural chiral sources. Inspired by the biologic system, we report herein an unprecedented catalytic enantiodivergent Michael addition of pyridazinones to enones by subtle adjustment of achiral amino moiety of dipeptide phosphine catalysts. These two dipeptide phosphine catalysts, P5 and P8, could deliver both enantiomers of a series of N2-alkylpyridazinones in good yields (up to 99%) with high enantioselectivities (up to 99% ee) via the catalyst-controlled enantiodivergent addition of pyridazinones to enones.

Cobalt(I)-catalyzed [6π+2π]-cycloaddition of allenes to N-carbethoxy(phenoxy)azepines for the synthesis of 9-azabicyclo[4.2.1]nona-2,4-dienes

The [6π+2π]-cycloaddition of allenes to N-carbethoxyazepine or N-carbophenoxyazepine catalyzed by the Co(acac)2(dppe)/Zn/ZnI2 system was performed for the first time and gave previously unknown substituted 9-azabicyclo[4.2.1]nona-2,4-dienes and 16-azatricyclo[9.4.1.02,10]hexadeca-2,12,14-trienes in 75–95% yields. The structures of the resulting azacyclic compounds were reliably proved using NMR spectroscopy and X-ray diffraction analysis. The obtained 9-azabicyclo[4.2.1]nona-2,4-dienes and 16-azatricyclo[9.4.1.02,10]hexadeca-2,12,14-trienes showed high antitumor activities in vitro against Jurkat, K562, U937 and HL60 cancer cell lines.

Phosphine‐Catalyzed [4+1] Cycloadditions of Allenes with Methyl Ketimines, Enamines, and a Primary Amine

AbstractUnprecedented phosphine‐catalyzed [4+1] cycloadditions of allenyl imides have been discovered using various N‐based substrates including methyl ketimines, enamines, and a primary amine. These transformations provide a one‐pot access to cyclopentenoyl enamines and imines, or (chiral) γ‐lactams through two geminal C−C bond or two C−N bond formations, respectively. Several P‐based key intermediates including a 1,4‐(bis)electrophilic α,β‐unsaturated ketenyl phosphonium species have been detected by 31P NMR and HRMS analyses, which shed light on the postulated catalytic cycle. The synthetic utility of this new chemistry has been demonstrated through a gram‐scaling up of the catalytic reaction as well as regioselective hydrogenation and double condensation to form cyclopentanoyl enamines and fused pyrazole building blocks, respectively.

Phosphine-Catalyzed [4+1] Cycloadditions of Allenes with Methyl Ketimines, Enamines, and a Primary Amine.

Unprecedented phosphine-catalyzed [4+1] cycloadditions of allenyl imides have been discovered using various N-based substrates including methyl ketimines, enamines, and a primary amine. These transformations provide a one-pot access to cyclopentenoyl enamines and imines, or (chiral) γ-lactams through two geminal C-C bond or two C-N bond formations, respectively. Several P-based key intermediates including a 1,4-(bis)electrophilic α,β-unsaturated ketenyl phosphonium species have been detected by 31 P NMR and HRMS analyses, which shed light on the postulated catalytic cycle. The synthetic utility of this new chemistry has been demonstrated through a gram-scaling up of the catalytic reaction as well as regioselective hydrogenation and double condensation to form cyclopentanoyl enamines and fused pyrazole building blocks, respectively.