Miguel A. Sierra

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.

Dyotropic Reactions: Mechanisms and Synthetic Applications†

In 1972, M. T. Reetz defined dyotropic (from the greek dyo, meaning two) rearrangements as a new class of pericyclic valence isomerizations in which two σ-bonds simultaneously migrate intramolecularly.1,2 Reactions in which the two migrating groups interchange their relative positions were designated as type I (Scheme 1A) whereas those of type II involve migration to new bonding sites without positional interchange (Scheme 1B,C). The uncatalyzed and concerted nature of these processes was also proposed.3,4 Nowadays, dyotropic transformations are standard tools for the construction of organic and organometallic molecules. Frequently, this unique rearrangement is the single entry to an efficient preparation of target molecules. Moreover, the discovery of new dyotropic reactions involving transition metals and excited states had widened the mechanistic scope of these processes to new reaction pathways well away from the original definition of uncatalyzed and concerted processes. This review comprehensively reports the dyotropic reactions studied since the seventies, accounts for the different reaction mechanisms for these rearrangements, and discusses their synthetic applications in organic and organometallic chemistry.

Electronic Structure of Alkoxychromium(0) Carbene Complexes : A Joint TD-DFT/Experimental Study

The joint computational (TD-DFT) experimental study of the UV-vis spectroscopy of alkoxychromium(0) carbene complexes accurately assigns the vertical transitions responsible for the observed spectra of these compounds. Both the LF and the MLCT band have a remarkably pi-pi* character, which has been demonstrated by the strong dependence of the absorptions with the donor/acceptor nature of the substituent in p-substituted styrylchromium(0) carbene complexes. The effect of the substituent is also related with the equilibrium geometry of the complexes and the occupations of the p atomic orbital of the carbene carbon atom. Additionally, the ferrocenyl moiety behaves in chromium(0) (Fischer) carbene complexes as a pi-donor group.

Computational and experimental tools in solving some mechanistic problems in the chemistry of Fischer carbene complexes

Well-established bonding situations of organometallic complexes and extensive applications in synthesis have been achieved during the past 25 years. In contrast, very little attention has been devoted to the intimate understanding of their reaction mechanisms. In this feature article, we show how the combined use of experimental and computational tools can be used to explore some reaction mechanisms of Fischer-type carbene complexes. The results obtained clearly demonstrate the usefulness of these combined tools to unravel the intimacies of different thermal and photochemical transformations, not only to explain already known processes but to predict new reactivity involving these fascinating complexes.

DFT study on the Diels-Alder cycloaddition between alkenyl-M(0) (M = Cr, W) carbene complexes and neutral 1,3-dienes.

The thermal Diels-Alder reaction between alkenylmetal(0) Fischer carbenes and 1,3-dienes (isoprene and cyclopentadiene) has been studied computationally within the density functional theory framework. The selectivity of the [4 + 2] cycloadditions between alkenyl-group 6 (Fischer) carbene complexes and isoprene is similar to the selectivity computed for the reactions involving Lewis acid complexed acrylates. The experimentally observed complete endo selectivity in the [4 + 2] cycloadditions of alkenyl-group 6 (Fischer) carbene complexes with cyclopentadiene, which takes place under kinetic control, may be due in part to the presence of stabilizing secondary orbital interactions. These interactions are stronger than the analogues in the metal-free processes. The [4 + 2] cycloadditions between alkenyl-group 6 (Fischer) carbene complexes and neutral dienes occur concertedly via transition structures which are more asynchronous and less aromatic than their non-organometallic analogues, a behavior which is extensible to the reactions between Lewis acid complexed acrylates.

Transmetalation Reactions from Fischer Carbene Complexes to Late Transition Metals: A DFT Study

Transmetalation reactions from chromium(0) Fischer carbene complexes to late-transition-metal complexes (palladium(0), copper(I), and rhodium(I)) have been studied computationally by density functional theory. The computational data were compared with the available experimental data. In this study, the different reaction pathways involving the different metal atoms have been compared with each other in terms of their activation barriers and reaction energies. Although the reaction profiles for the transmetalation reactions to palladium and copper are quite similar, the computed energy values indicate that the process involving palladium as catalyst is more favorable than that involving copper. In contrast to these transformations, which occur via triangular heterobimetallic species, the transmetalation reaction to rhodium leads to a new heterobimetallic species in which a carbonyl ligand is also transferred from the Fischer carbene to the rhodium catalyst. Moreover, the structure and bonding situation of the so far elusive heterobimetallic complexes are briefly discussed.

A straightforward synthesis of tetrameric estrone-based macrocycles.

A straightforward approach to macrocycles having four estrone-derived nuclei by the sequential Cu-catalyzed Huisgen azide-alkyne cycloaddition-Glaser-Eglington Cu homocoupling has been developed. Due to its efficiency and simplicity, this sequence is useful for application to different natural product scaffolds.

Regio- and diastereoselective stepwise [8 + 3]-Cycloaddition reaction between tropone derivatives and donor-acceptor cyclopropanes.

A novel SnCl4-catalyzed [8 + 3]-cycloaddition reaction between tropone derivatives and donor-acceptor aminocyclopropanes is described. The process leads to the formation of amino-substituted tetrahydrocyclohepta[b]pyrans with complete regio- and diastereoselectivity. Density functional theory calculations suggest that the cycloaddition occurs stepwise through an aromatic zwitterionic intermediate.

Intramolecular Pd(0)-catalyzed reactions of (2-iodoanilino)-aldehydes: a joint experimental-computational study.

An extensive joint experimental-computational density functional theory (DFT) study has been carried out to gain insight into the factors that control the chemoselectivity (i.e., acylation vs α-arylation reaction) of palladium-catalyzed cyclizations of (2-iodoanilino)-aldehydes. To this end, the nature of the tethers joining the aniline nitrogen and the aldehyde moiety, different palladium precatalysts and reaction conditions (base and temperature), as well as different additives (mono- and bidendate ligands) has been explored. The adequate selection of these variables allows for the control of the selectivity of the process. Thus, (2-iodoanilino)-aldehydes generally lead to the formation of nucleophilic addition derived products when Cs(2)CO(3)/Et(3)N is used as base. In contrast, the use of stronger bases like K(t)OBu (in the presence of PhOH) mainly forms α-arylation reaction products. The different reaction pathways leading to the experimentally observed reaction products have been studied by means of computational tools.

Platinum-catalysed bisindolylation of allenes: a complementary alternative to gold catalysis.

Pt versus Au: Platinum-catalysed addition of nucleophiles to allenes follows a distinctly different pathway to the process catalysed by gold(I) complexes; the platinum catalyst leads to different products with indoles involving a bisindolylation reaction, whereas gold(I) gives allyl indoles from a single addition (see scheme).