Disubstituted Ketenes Research Articles

Pericyclic Cascade with Chirality Transfer: Reaction Pathway and Origin of Enantioselectivity of the Hetero‐Claisen Approach to Oxindoles

Cascade reactions[1] are of increasing value in organic synthesis due to their potential for expedient generation of molecular complexity. Pericyclic cascades[1,2] are especially appealing by virtue of their often predictable and exquisite stereochemical control. The diverse pericyclic cascades devised for target-oriented syntheses often act on substrates bearing well-recognized structural motifs with amply documented reactivity requirements and stereochemical properties. Nevertheless, the interplay between theory and experiment continues to uncover novel cascade mechanisms with new or underexplored reactivity patterns. Indeed, for the 2+2 cycloadditions of ketenes with 1,3-dienes[3] and imines,[4] the pericyclic mechanisms once formulated have recently been revised to cascades of more than one elementary mechanistic step. Other more elaborate pericyclic cascades of synthetic interest have also been elucidated by computations.[5] We recently developed an efficient enantioselective route to 3,3-disubstituted oxindoles from chiral nitrones and disubstituted ketenes, but the origin of the asymmetric induction remained unclear from existing mechanistic proposals.[6] We now propose a novel pericyclic cascade composed of a 3+2 cycloaddition and a hetero-[3,3]-sigmatropic rearrangement, featuring chirality transfer in each of the two constituent steps, which proves crucial in engendering impressive enantioselectivity.

ChemInform Abstract: Enantioselective Synthesis of Spirocyclic Oxindole‐β‐lactones via N‐Heterocyclic Carbene‐Catalyzed Cycloaddition of Ketenes and Isatins.

Chiral N-heterocyclic carbenes were found to be efficient catalysts for the formal [2+2] cycloaddition reaction of disubstituted ketenes and isatins to give the corresponding spirocyclic oxindole-β-lactones in good yields with good diastereo-selectivities and excellent enantioselectivities. Ring opening with Grignard reagents or decarboxylation of the oxindole spirocyclic-β-lactone gave the corresponding 3-hydroxy- or 3-alkylenyloxindoles in good yields.

Formal [3+2] Cycloaddition of Ketenes and Oxaziridines Catalyzed by Chiral Lewis Bases: Enantioselective Synthesis of Oxazolin‐4‐ones

Choose the right cat.: A highly enantioselective synthesis of oxazolin-4-ones by the formal [3+2] cycloaddition of ketenes and a racemic oxaziridines has been developed (see scheme; cat.=N-heterocyclic carbenes for disubstituted ketenes or cinchona alkaloids for monosubstituted ketenes, Ts=4-toluenesulfonyl).

NHC‐Mediated Chlorination of Unsymmetrical Ketenes: Catalysis and Asymmetry

AbstractNHCs promote the efficient chlorination of unsymmetrical disubstituted ketenes with a range of chlorinating agents; chiral NHCs display promising levels of asymmetric induction in the chlorination process with up to 61 % ee observed using 2,3,4,5,6,6‐hexachlorocyclohexa‐2,4‐dienone.

Enantioselective Synthesis of Spirocyclic Oxindole‐β‐lactones via N‐Heterocyclic Carbene‐Catalyzed Cycloaddition of Ketenes and Isatins

AbstractChiral N‐heterocyclic carbenes were found to be efficient catalysts for the formal [2+2] cycloaddition reaction of disubstituted ketenes and isatins to give the corresponding spirocyclic oxindole‐β‐lactones in good yields with good diastereoselectivities and excellent enantioselectivities. Ring opening with Grignard reagents or decarboxylation of the oxindole spirocyclic‐β‐lactone gave the corresponding 3‐hydroxy‐ or 3‐alkylenyloxindoles in good yields.

New Insights into the Torquoselectivity of the Staudinger Reaction

To understand the torquoselectivity and the electronic effects of the Staudinger reaction, a study using a combination of experiments and DFT calculations has been conducted for the reactions of an unsymmetric cyclic ketene and cyclic imines with different electronic properties. The predominant formation of the donor-in beta-lactams, the torquoelectronically disfavored products, was observed for the first time. The Hammett analyses reveal a close relationship between the donor-out/donor-in product ratio and the electronic nature of the imines. The kinetic competition experiments and DFT calculations indicate that the two-step Staudinger reaction shows different rate-determining steps in the donor-in and donor-out pathways. Our investigations reveal that the torquoelectronic control in the Staudinger reaction is quite different from that in the ring-opening reaction of cyclobutene derivatives. The diastereoselectivity of the Staudinger reaction involving an unsymmetric disubstituted ketene cannot be simply rationalized or predicted by the torquoelectronic model.

Chiral N‐Heterocyclic Carbene‐Catalyzed Formal [4+2] Cycloaddition of Ketenes with Enones: Highly Enantioselective Synthesis of trans‐ and cis‐δ‐Lactones

A chiral N-heterocyclic carbene was found to be an efficient catalyst for the [4+2] cycloaddition of disubstituted ketenes to enones to give δ-lactones with α-quaternary-β-tertiary stereocenters (see scheme). Both the trans- and cis-isomers of the δ-lactones could be obtained in good yields with high diastereo- and enantioselectivities by in situ thermodynamically controlled epimerization and kinetically controlled protonation, respectively.

Concise Assembly of Highly Substituted Furan-Fused 1,4-Thiazepines and Their Diels−Alder Reactions with Benzynes

A facile and highly efficient three-component reaction of thiazole or benzothiazole carbenes, disubstituted ketenes, and activated alkynes is disclosed. With this methodology, a polysubstituted ring system containing furo[2,3-c]thiazepine core can be constructed from simple and readily accessible starting materials in good yields. The scope and limitation of this transformation were investigated in detail by using various thiazole carbene, ketene, and alkyne components. Furthermore, the synthetic utilities of these unique polyheterocyclic compounds were demonstrated via their Diels-Alder reactions with benzynes to furnish thiazepine-fused 7-oxanorbornadiene derivatives in excellent yields.

Hexamethyldisilazane Sodium Salt as Highly Active Lewis Base Catalyst for the Staudinger Reaction

Hexamethyldisilazane sodium salt (NaHMDS) has been found to be a highly active Lewis base catalyst for the Staudinger reaction with disubstituted ketenes and imines. This organocatalyst gave highly substituted β-lactams in nearly quantitative yield in a very short time of five minutes even at temperatures as low as -78 °C.

Thermal Cyclization of N‐[2‐(2‐Propenyl)‐1‐naphthyl]ketenimines: Intramolecular Diels—Alder Reaction versus [1,5] Hydrogen Migration. Synthesis of Dibenz[b,h]acridines and Benzo[h]quinolines.

Abstract The thermal treatment of N-(2-propenyl)-1-naphthylamines provided the expected aza-Claisen rearranged products, 2-(2-propenyl)-1-naphthylamines and benz[g]indoles, these last derived from an intramolecular hydroamination reaction on those primary products. The 2-(2-propenyl)-1-naphthylamines were converted into their triphenylphosphazene derivatives, which by aza-Wittig reaction with disubstituted ketenes yielded N-[2-(2-propenyl)-1-naphthyl] ketenimines. The heating of these ketenimines in boiling toluene induced their cyclization either via an intramolecular Diels–Alder reaction, to afford dibenz[b,h]acridines, or via [1,5] hydrogen migration from the sp3 carbon atom of the propenyl substituent to the central carbon atom of the ketenimine fragment, followed by a 6π electrocyclic ring closure, to give benzo[h]quinolines.

Thermal cyclization of N-[2-(2-propenyl)-1-naphthyl] ketenimines: intramolecular Diels–Alder reaction versus [1,5] hydrogen migration. Synthesis of dibenz[ b, h]acridines and benzo[ h]quinolines

The thermal treatment of N-(2-propenyl)-1-naphthylamines provided the expected aza-Claisen rearranged products, 2-(2-propenyl)-1-naphthylamines and benz[ g]indoles, these last derived from an intramolecular hydroamination reaction on those primary products. The 2-(2-propenyl)-1-naphthylamines were converted into their triphenylphosphazene derivatives, which by aza-Wittig reaction with disubstituted ketenes yielded N-[2-(2-propenyl)-1-naphthyl] ketenimines. The heating of these ketenimines in boiling toluene induced their cyclization either via an intramolecular Diels–Alder reaction, to afford dibenz[ b, h]acridines, or via [1,5] hydrogen migration from the sp 3 carbon atom of the propenyl substituent to the central carbon atom of the ketenimine fragment, followed by a 6π electrocyclic ring closure, to give benzo[ h]quinolines.

Asymmetric Synthesis of Highly Substituted β‐Lactones by Nucleophile‐Catalyzed [2+2] Cycloadditions of Disubstituted Ketenes with Aldehydes

α,α-Disubstituted β-lactones can be obtained by the cycloaddition of the corresponding ketenes with aldehydes (see scheme). For the first time, a chiral PPY derivative, 1, serves as an efficient catalyst for the asymmetric synthesis of β-lactones (PPY=4-pyrrolidin-1-ylpyridine). To date, this is the only catalyst that is effective for enantioselective cycloadditions of disubstituted ketenes with aldehydes.

One‐Pot Synthesis and Conformational Features of N,N′‐Disubstituted Ketene Aminals.

AbstractFor Abstract see ChemInform Abstract in Full Text.

One-pot synthesis and conformational features of n,n'-disubstituted ketene aminals.

N,N'-Disubstituted ketene aminals are bioisosteres of thioureas and are useful building blocks in many synthetic operations. A convenient one-pot synthesis of N,N'-disubstituted ketene aminals from activated methylene compounds and isothiocyanates is described. Most of these aminals exist in rotameric equilibrium around the central C=C bonds in solution, and the rotamers are stabilized by intramolecular hydrogen bonding both in solution and in solid states.

Synthesis ofN-Cyanomethyl Substituted Heterocyclic Ketene Aminals

Abstract Heterocyclic ketene aminals 1 react with chloroacetonitrile in the presence of sodium hydride to give the N-alkylated products 2. The disubstituted heterocyclic ketene aminal 3 react also with the same reagent to give the N-alkylated product 4.

Substituent effects on the ketene asymmetric stretching frequency

Asymmetric stretching frequencies of disubstituted ketenes gave a good correlation to substituent constants with the newly parameterized Swain-Lupton equation. Frequencies were predicted for unknown ketenes.

Synthesis of monogermylated disubstituted ketenes

Synthesis of monogermylated disubstituted ketenes