Disubstituted Ketenes Research Articles

Enantioselective Formal 1,2-Diamination of Ketenes with Iminosulfinamides: Asymmetric Synthesis of Unnatural α,α-Disubstituted α-Amino Acid Derivatives.

A method was developed for the enantioselective formal 1,2-diamination of disubstituted ketenes using iminosulfinamides as nitrogen sources. The protocol involves the addition of lithium iminosulfinamides to ketenes to form N-iminosulfinyl amide metalloenolates. These metalloenolates then undergo a [2,3]-sigmatropic rearrangement to yield unnatural α,α-disubstituted α-amino acid derivatives with high enantiopurity. The chirality present at the sulfur atom in the iminosulfinamides is effectively transferred to α carbon of the resulting products, facilitating the highly enantioselective amination of ketenes.

Asymmetric synthesis of enantioenriched α-allyl esters through Pd(BINAPHANE)-catalysed allylation of disubstituted ketenes.

Pd2dba3·CHCl3 (2.5 mol%)-BINAPHANE (5 mol%) was used to promote the first catalytic enantioselective allylation of disubstituted ketenes to give α-allyl esters. The ester products were formed in good to excellent yields (61-93% yield for 13 examples, 16 examples in all), with moderate to good enantioselectivity (68-80% ee for 7 examples).

Lewis‐Säure‐katalysierte formale (3+2)‐Cycloaddition von Bicyclo[1.1.0]butanen mit Ketenen

AbstractDesign, Synthese und Anwendung von Benzolbioisosteren haben in den letzten 20 Jahren viel Aufmerksamkeit erfahren. In jüngster Zeit haben sich Bicyclo[2.1.1]hexane als äußerst attraktive Bioisostere für ortho‐ und meta‐substituierte Benzole erwiesen. In diesem Artikel beschreiben wir eine milde, skalierbare und übergangsmetallfreie Methode zur Herstellung von hochsubstituierten Bicyclo[2.1.1]hexanen über eine Lewis‐Säure‐katalysierte (3+2)‐Cycloaddition von Bicyclo[1.1.0]butanketonen mit disubstituierten Ketenen. Die Reaktion zeigt eine hohe Toleranz gegenüber funktionellen Gruppen, wie die erfolgreiche Herstellung verschiedener 3‐Alkyl‐3‐Aryl‐ sowie 3,3‐Bisalkyl‐Bicyclo[2.1.1]hexan‐2‐onen belegt (26 Beispiele, bis zu 89 % Ausbeute). Die Folgechemie an der exozyklischen Ketonfunktion wird ebenfalls demonstriert.

Lewis Acid Catalyzed Formal (3+2)-Cycloaddition of Bicyclo[1.1.0]butanes with Ketenes.

Design, synthesis and application of benzene bioisosteres have attracted a lot of attention in the past 20 years. Recently, bicyclo[2.1.1]hexanes have emerged as highly attractive bioisosteres for ortho- and meta-substituted benzenes. Herein we report a mild, scalable and transition-metal-free protocol for the construction of highly substituted bicyclo[2.1.1]hexan-2-ones through Lewis acid catalyzed (3+2)-cycloaddition of bicyclo[1.1.0]-butane ketones with disubstituted ketenes. The reaction shows high functional group tolerance as documented by the successful preparation of various 3-alkyl-3-aryl as well as 3,3-bisalkyl bicyclo[2.1.1]hexan-2-ones (26 examples, up to 89 % yield). Postfunctionalization of the exocyclic ketone moiety is also demonstrated.

1,4-Aryl migration in ketene-derived enolates by a polar-radical-crossover cascade

The arylation of carboxylic acid derivatives via Smiles rearrangement has gained great interest in recent years. Both radical and ionic approaches, as well as radical-polar crossover concepts, have been developed. In contrast, a reversed polar-radical crossover approach remains underexplored. Here we report a simple, efficient and scalable method for the preparation of sterically hindered and valuable α-quaternary amides via a polar-radical crossover-enolate oxidation-aryl migration pathway. A variety of easily accessible N-alkyl and N-arylsulfonamides are reacted with disubstituted ketenes to give the corresponding amide enolates, which undergo upon single electron transfer oxidation, a 1,4-aryl migration, desulfonylation, hydrogen atom transfer cascade to provide α-quaternary amides in good to excellent yields. Various mono- and di-substituted heteroatom-containing and polycyclic arenes engage in the aryl migration reaction. Functional group tolerance is excellent and substrates as well as reagents are readily available rendering the method broadly applicable.

Asymmetric Synthesis of Bicyclic Pyrazolidinones through Alkaloid-Catalyzed [3+2]-Cycloadditions of Ketenes and Azomethine Imines.

A versatile asymmetric synthesis of bicyclic pyrazolidinones through alkaloid‐catalyzed formal [3+2]‐ and [3+2+2]‐cycloadditions of ketenes with azomethine imines is described. The methodology was found to be tolerant of ketene and a variety of monosubstituted ketenes (R=alkyl, OAc). The products were formed in good to excellent yields (71–99 % for 24 examples, 39 examples in all), with good to excellent diastereoselectivity in many cases (dr 3 : 1 to 27 : 1 for 22 examples), and with excellent enantioselectivity for most examples (≥93 % ee for 34 products). In the case of most disubstituted ketenes, the reaction proceeded through a [3+2+2]‐cycloaddition to form structurally interesting bicyclic pyrazolo‐oxadiazepinediones with moderate diastereoselectivity (dr up to 3.7 : 1) and as racemic mixtures (3 examples). The method represents the first unambiguous example of an enantioselective reaction between ketenes and a 1,3‐dipole.

Oxindole synthesis via polar-radical crossover of ketene-derived amide enolates in a formal [3 + 2] cycloaddition.

Herein we introduce a simple, efficient and transition-metal free method for the preparation of valuable and sterically hindered 3,3-disubstituted oxindoles via polar–radical crossover of ketene derived amide enolates. Various easily accessible N-alkyl and N-arylanilines are added to disubstituted ketenes and the resulting amide enolates undergo upon single electron transfer oxidation a homolytic aromatic substitution (HAS) to provide 3,3-disubstituted oxindoles in good to excellent yields. A variety of substituted anilines and a 3-amino pyridine engage in this oxidative formal [3 + 2] cycloaddition and cyclic ketenes provide spirooxindoles. Both substrates and reagents are readily available and tolerance to functional groups is broad.

Construction of Saturated Oxazolo[3,2-b][1,2]oxazines via Tandem [3+2]-Cycloaddition/[1,3]-Rearrangement of Cyclic Nitronates and Ketenes.

Reaction of six-membered cyclic nitronates with disubstituted ketenes affords hitherto unknown saturated oxazolo[3,2-b][1,2]oxazines possessing up to four contiguous stereogenic centers. The process involves a tandem of [3+2]-cycloaddition across the C═O bond of ketene, followed by a spontaneous [1,3]-rearrangement of transient vinylidene-substituted bicyclic nitrosoacetals. DFT calculations of the mechanism suggest that the [1,3]-O,C-shift proceeds through a recyclization of a biradical intermediate formed by an unusually mild homolytic cleavage of the N-O bond. The resulting products can be utilized as precursors of other fused 1,2-oxazines derivatives, in particular 1,2-oxazino-1,2,4-triazin-3-ones.

Diastereoselective Synthesis of γ‐Lactones through Reaction of Sulfoxonium Ylides, Aldehydes, and Ketenes: Substrate Scope and Mechanistic Studies

AbstractIn this article, we describe the synthesis of γ‐lactones through the reaction of sulfoxonium ylides, aldehydes, and disubstituted ketenes. The one‐pot sequential method provides access to γ‐lactones from disubstituted ketenes, in moderate to excellent yields, and with good diastereoselectivity favoring the trans‐diastereomer (dr up to 92 : 8). The reaction mechanism was investigated by performing labeling, crossover, and various control experiments. The results of those experiments support the reaction mechanism involving betaine formation, reaction of the betaine with a ketene to form an enolate intermediate, [3,3]‐sigmatropic rearrangement of an enolate intermediate, and finally, 5‐exo‐tet cyclization to afford the γ‐lactone product.

Formal Insertion of Thioketenes into Donor-Acceptor Cyclopropanes by Lewis Acid Catalysis.

Donor-acceptor cyclopropanes were reacted under Lewis acid catalysis with 3-thioxocyclobutanones as surrogates for disubstituted thioketenes. A broad scope of 2-substituted tetrahydrothiophenes with a semicyclic double bond was obtained under mild conditions with high functional group tolerance and in excellent yield. A sequence of a formal [3 + 2]-cycloaddition followed by the subsequent release of disubstituted ketene is postulated as the mechanism.

ChemInform Abstract: Synthesis of Allenyl Esters by Horner—Wadsworth—Emmons Reactions of Ketenes Mediated by Isopropylmagnesium Bromide.

The synthesis of conjugated allenyl esters (tri-substituted allenes) was achieved by magnesium(II)-mediated Horner–Wadsworth–Emmons reaction of methyl bis(2,2,2-trifluoroethyl)phosphonoacetate with disubstituted ketenes. In addition, a novel access to α-fluorinated allenyl carboxamides (tetrasubstituted allenes) is presented.

ChemInform Abstract: Phosphine‐Catalyzed Diastereoselective Synthesis of β‐Lactones from Disubstituted Ketenes and α‐Chiral Oxyaldehydes.

AbstractCyclization of ketenes with glyceraldehyde acetonides gives β‐lactones diastereoselectively.

Synthesis of Allenyl Esters by Horner–Wadsworth–Emmons Reactions of Ketenes Mediated by Isopropylmagnesium Bromide

The synthesis of conjugated allenyl esters (tri-substituted allenes) was achieved by magnesium(II)-mediated Horner–Wadsworth–Emmons reaction of methyl bis(2,2,2-trifluoroethyl)phosphonoacetate with disubstituted ketenes. In addition, a novel access to α-fluorinated allenyl carboxamides (tetrasubstituted allenes) is presented.

BF3·OEt2-mediated alkenylation of pyrroles with α-oxo ketene dithioacetals

BF3·OEt2-mediated alkenylation of pyrroles with α-oxo ketene dithioacetals was efficiently realized, affording mono- and disubstituted ketene pyrrolyl acetals. In the cases of using N-unprotected pyrrole, the reactions gave ketene bipyrrolyl acetals as well as N,O-chelated BF2 complexes. Diverse C–S transformations were achieved for the monosubstituted products, yielding N-heterocycles or multisubstituted olefins.

ChemInform Abstract: Phosphine‐Catalyzed Asymmetric Synthesis of β‐Lactones from Disubstituted Ketenes and Aldehydes.

AbstractIn terms of yield, diastereoselectivity, and enantioselectivity this reaction works best for arylalkylketenes and diarylketenes with p‐substituted arylaldehydes resulting in substituted β‐lactones or β‐hydroxyacids after hydrolysis.

Asymmetric synthesis of γ-lactones through reaction of sulfoxonium ylides, aldehydes, and ketenes

A method for the enantioselective synthesis of γ-lactones through the reaction of enantioenriched sulfoxonium ylides, aldehydes, and ketenes was developed. Enantioenriched (98% ee) aminosulfoxonium ylide was subjected to reaction with a variety of aldehydes (both aromatic and aliphatic) and disubstituted ketenes, leading to the formation of α,β-substituted γ-lactones in moderate to very good diastereoselectivity (dr up to 95:5) and with enantiomeric excesses of up to 79% ee. Best levels of enantioselectivity were observed in the reactions of enantioenriched aminosulfoxonium ylide with isobutyraldehyde and various alkylarylketenes.

Chiral Lewis Acid Catalyzed Asymmetric Cycloadditions of Disubstituted Ketenes for the Synthesis of β-Lactones and δ-Lactones

Highly diastereo- and enantioselective [2 + 2]- and [4 + 2]-cycloadditions of disubstituted ketenes were realized by chiral Lewis acid catalysis. A series of arylalkylketenes underwent the reaction smoothly with isatins and β,γ-unsaturated α-ketoesters, providing optically active β-lactones and δ-lactones with vicinal chiral centers in excellent yields (up to 99%) and enantioselectivities (up to 99% ee), as well as exclusively high diastereoselectivities under 0.2-2 mol % catalyst loading.

ChemInform Abstract: Diastereoselective Reaction of Sulfoxonium Ylides, Aldehydes and Ketenes: An Approach to trans‐γ‐Lactones.

In this paper, a novel approach to γ-lactones from the reaction of sulfoxonium ylides, aldehydes, and ketenes is described. The new ylide-based method provides access to γ-lactones from disubstituted ketenes, in good yields, and with good diastereoselectivity favoring the trans-diastereomer (11 examples with dr ≥ 82:18, dr up to 92:8).

Diastereoselective Reaction of Sulfoxonium Ylides, Aldehydes and Ketenes: An Approach to trans-γ-Lactones

In this paper, a novel approach to γ-lactones from the reaction of sulfoxonium ylides, aldehydes, and ketenes is described. The new ylide-based method provides access to γ-lactones from disubstituted ketenes, in good yields, and with good diastereoselectivity favoring the trans-diastereomer (11 examples with dr ≥ 82:18, dr up to 92:8).

BINAPHANE-Catalyzed Asymmetric Synthesis of trans-β-Lactams from Disubstituted Ketenes and N-Tosyl Arylimines

The development of a BINAPHANE-catalyzed formal [2 + 2]-cycloaddition of disubstituted ketenes and inexpensive N-tosyl arylimines that provides access to a variety of highly substituted β-lactams (16 examples) is described. The BINAPHANE catalytic system displays moderate to excellent enantioselectivity (up to 98% ee) and high diastereoselectivity in most cases, favoring formation of the trans-diastereomer (13 examples with dr ≥ 90:10).