Ana Arrieta

The mechanism of the ketene-imine (staudinger) reaction in its centennial: still an unsolved problem?

[Reaction: see text]. Although Staudinger reported the reaction between ketenes and imines 100 years ago (1907), this process is still the most general and useful method for the synthesis of beta-lactams and their derivatives. This reaction is a [2 + 2] thermal cycloaddition in which two chiral centers may be generated in one preparative step. Staudinger reactions involving alpha,beta-unsaturated imines or ketenes have issues concerning the [2 + 2] or [4 + 2] periselectivity of the reaction. This Account discusses how the main factors that determine the regiochemical and stereochemical outcomes of this reaction were elucidated with computational and experimental data. This fruitful interplay between theory and experiment has revealed that the [2 + 2] cycloaddition is actually a two-step process. The first step is a nucleophilic addition of the nitrogen atom of the imine on the sp-hybridized carbon atom of the ketene. This attack forms a zwitterionic intermediate that evolves toward the final beta-lactam cycloadduct. The second step can be viewed as a four-electron conrotatory electrocyclization that is subject to torquoelectronic effects. When alpha,beta-unsaturated imines are used, the zwitterionic intermediates yield either the corresponding 4-vinyl-beta-lactams or the alternative 3,4-dihydropyridin-2(1 H)-ones. In this latter case, the cyclization step consists of a thermal disrotatory electrocyclization. In the context of stereoselectivity, it is usually assumed that the first step takes place through the less hindered side of the ketene. The cis-trans selectivity of the reaction depends on the geometry of the imine. As the general rule, ( E)-imines form cis-beta-lactams whereas ( Z)-imines yield trans-beta-lactams. Most of the experimental results point to the two-step model. The asymmetric torquoselectivity of the conrotatory ring closure of the second step accounts for the stereochemical discrimination in the reaction of chiral ketenes or chiral imines. Nevertheless, recent studies have revealed that isomerization paths in the imine or in the zwitterion may determine the stereochemistry of the reaction. Thus, if the rotation about the N1-C4 bond of the zwitterion intermediate is faster than the cyclization, the formation of trans-beta-lactams from ( E)-imines is biased. Alternatively, in some cases, the ( E)-( Z) isomerization of the starting imines prior to the cycloaddition steps also results in the formation of trans-cycloadducts. Although the main variables that govern the outcome of the reaction have been elucidated, there are still several aspects of the reaction yet to be disclosed. Finally, the discovery of the catalytic version of the reaction is a new and formidable mechanistic challenge and will be a nice playground for forthcoming theoretical-experimental discussions.

Highly stereoselective synthesis of α-hydroxy β-amino acids through β-lactams: application to the synthesis of the taxol and bestatin side chains and related systems.

Abstract Formation of α-hydroxy β-lactams, followed chemical elaboration at C 4 and further βlactam cleavage afforded functionalised α-hydroxy β-amino acids or their derivatives in a highly stereoselective manner.

N,N-Dimethylchlorosulfitemethaniminium chloride (SOCl2-DMF) a versatile dehydrating reagent.☆

Abstract N,N-dimethylchlorosulfitemethaniminium chloride formed from thionyl chloride and dimethylformamide was found and efficient reagent for the synthesis of acyl azides from carboxylic acids and nitriles from oximes. It is also highly efficient for the direct synthesis of beta-lactams from carboxylic acids and imines avoiding the use of acid chlorides.

Efficient tautomerization hydrazone-azomethine imine under microwave irradiation. Synthesis of [4,3′] and [5,3′]bipyrazoles

Abstract Microwave irradiation induces the thermal isomerization of pyrazolyl hydrazones to the corresponding azomethine imines which undergo 1,3-dipolar cycloaddition with electron-poor dipolarophiles in a few min with good yields. By classical heating, several dipolarophiles do not react in comparable reaction conditions. Regiochemistry of bipyrazoles obtained from unsymmetrical dipolarophiles has been inferred by spectroscopic experiments.

Tandem [8 + 2] cycloaddition--[2 + 6 + 2] dehydrogenation reactions involving imidazo[1,2-a]pyridines and imidazo[1,2-a]pyrimidines.

The reaction between benzynes and imidazo[1,2-a]pyridines (pyrimidines) to form benzo[a]imidazo[5,1,2-cd]indolizines and 2,3,9c-triazocyclopenta[j,k]fluorenes has been studied computationally and experimentally. It is found that these reactions take place via tandem [(pi)8(s) + (pi)2(s)] and [(sigma)2(s) + (pi)6(s) + (sigma)2(s)] processes. The [8 + 2] cycloaddition steps are essentially barrierless, and the aromatization steps occur via highly synchronous aromatic transition structures. From an experimental standpoint, the reaction is feasible under microwave irradiation and using 2-(trimethylsilyl)phenyl triflates as benzyne precursors. Depending on the substitution pattern in the starting triflate a complete regiocontrol of the reaction can be achieved. The tetracyclic compounds thus prepared emitted blue light when excited at 365 nm and exhibited interesting photophysical properties.

Surpassing Torquoelectronic Effects in Conrotatory Ring Closures: Origins of Stereocontrol in Intramolecular Ketenimine–Imine [2+2] Cycloadditions

Unexpectedand almost perfect stereochemical control is obtained in the title reactions [Eq. (a)], although torquoelectronic theory predicts negligible stereoselection. According to ab initio and DFT calculations, this stereocontrol is determined by the geometry of the first transition state of the stepwise mechanism. In good agreement with the model proposed, the presence of an additional methylene group attached to the iminic nitrogen atom promotes a significant loss of stereocontrol.

Formation of γ-oxoacids and 1H-pyrrol-2(5H)-ones from α,β-unsaturated ketones and ethyl nitroacetate.

Michael addition of ethyl nitroacetate on α,β-unsaturated ketones followed by Nef oxidation under hydrolytic conditions yields γ-oxoacids instead of the corresponding α,δ-dioxoesters. A concerted decarboxylation step is proposed on the basis of computational results. Finally, conversion of the γ-ketoacids thus prepared into 1H-pyrrol-2(5H)-ones by reaction with primary amines under Paal-Knorr conditions is also reported.

Trans-stereoselectivity in the reaction between homophthalic anhydride and imines.

The reaction between homophthalic anhydride and imines in the presence of TiCl4 and diisopropyl ethyl amine is trans-selective. Under these conditions, the reaction using homochiral imines can be highly diastereoselective, thus allowing the synthesis of enantiopure 1,2,3,4-tetrahydro-1-oxoquinoline-4-carboxylic acids.

Syntheses of β-lactams from acetic acids and imines induced by phenyl dichlorophosphate reagent

Abstract The development of a practical method for the preparation of vinylamino-β -lactams from Dane salts and Schiff bases is described. Among the reagents known to produce β-lactams from imines and acetic acids, only phenyl dichlorophosphate and 1-methyl-2-chloropyridinium iodide are suitable for the synthesis of vinylamino- β-lactams. Reaction of acetic acids with ethanolimine derivatives promoted by phenyl dichlorophosphate affords oxazolidines instead β-lactams. Protection of the hydroxyl group as the trimethylsilyl ether in the starting Schiff bases provides a convenient route to the corresponding β-lactams instead oxazolidines. Some observations on the scope of the method are made.

Role of the isomerization pathways in the Staudinger reaction. A theoretical study on the interaction between activated ketenes and imidates

Abstract Theoretical studies on the Staudinger reaction between methoxyketene and a simple imidate provide an explanation for the trans stereoselectivity observed. The key step responsible for this unusual outcome is the facile interconversion between two zwitterionic intermediates through a biradical transition state.