Photoinduced Formation of Cubyl Aryl Thioethers and Synthesis of Monocubyl Analogue of Dapsone.

1,4-Disubstituted cubyl aryl thioethers were generated from the corresponding iodocubanes and aryl thiolates upon UV irradiation in dimethyl sulfoxide at room temperature. This simple procedure was found to be compatible with a variety of substituted aryl thiolates. This finding paved the way to a synthesis of the monocubyl analogue of dapsone, a key molecule in the treatment of leprosy, also known as Hansen's disease, and of acne.

Intra- and Intermolecular Cation-π Interactions between Onium Salts and Alkynes/Acetylene: Experimental and Theoretical Insights.

Cation-π interactions between various onium salts, alkynes, and acetylene were studied, taking into account the substituents of the triple bond, the nature of the anions, and the polarity of the solvent, through a combination of MP2 calculations and experiments. In an intramolecular setting, these data (including single-crystal X-ray crystallography) concurred with the stability of folded conformers of alkynyl onium salts, even substituted with electron-withdrawing groups. To examine the contribution of these interactions on the alkyne electronic population, a thorough in silico study was carried out using natural bonding orbital analysis of the conformers. Intramolecular interactions from sulfonium salt tethered to phenylalkyne were highlighted, as illustrated above by the computed folded conformation (MP2) along with noncovalent interaction (NCI) analysis. Furthermore, investigations of intermolecular interactions, involving acetylene or phenylacetylene with various onium ions, revealed the high energy interactions of their complexes with phenyldimethylsulfonium chloride, as illustrated above with the complex PhC≡CH/PhMe2SCl (MP2 calculations and NCI analysis).

Organocatalyzed enantio- and diastereoselective isomerization of prochiral 1,3-cyclohexanediones into nonalactones bearing distant stereocenters.

The lactonization of 2-(2-nitrophenyl)-1,3-cyclohexanediones containing an alcohol side chain and up to three distant prochiral elements is reported by isomerization under the mediation of simple organocatalysts such as quinidine. Through a process of ring expansion, strained nonalactones and decalactone are produced with up to three stereocenters in high er and dr (up to 99 : 1). Distant groups, including alkyl, aryl, carboxylate and carboxamide moieties, were examined.

Domino Ring Expansion: Regioselective Access to 9-Membered Lactones with a Fused Indole Unit from 2-Nitrophenyl-1,3-cyclohexanediones.

The domino anionic fragmentation of 2-nitrophenyl-1,3-cyclohexanediones containing an electrophilic appendage such as aldehyde and epoxide is disclosed. This reaction, initiated by a series of nucleophiles, involves the generation of an intermediate hydroxylate followed by the regioselective formation and fragmentation of an intermediate lactolate into enolate. This strategy, devoid of any protecting group, enlarges the initial ring and provides an original access to decorated 9-membered lactones with a fused indole unit.

Lithium Amide Protected against Hydrolysis by Aggregated Lithium Halides: An MS + DFT Investigation.

Supported by mass spectrometry experiments, DFT computations indicate that the lithium amide of a 3-aminopyrrolidine (lithium benzhydryl(1-benzylpyrrolidin-3-yl)amide, 1-Li) is protected, up to a certain limit, against hydrolysis when it is aggregated with a strongly polar partner such as LiCl, LiBr, or MeLi.

A Combined 1 H/6 Li†NMR DOSY Strategy Finally Uncovers the Structure of Isopropyllithium in THF.

Despite its common use in synthesis, the structure of isopropylliyhium in THF has never been determined, a dimer being generally proposed but not supported. This paper fills this data gap through a sophisticated NMR study that shows that, in THF at low-temperature, isopropyllithium is in the form of a 1:2 mixture of a trisolvated monomer and a disolvated dimer in equilibrium. The presence of the monomer, never evoked before, together with a hypo-solvation of the dimer hinted by DFT calculations, provides a rational explanation to the remarkable reactivity of this organolithium reagent in ethereal solvents.

A Lithium Amide Protected Against Protonation in the Gas Phase: Unexpected Effect of LiCl.

In cold THF and in the presence of LiCl, a lithium pyrrolidinylamide forms a 1:1 mixed aggregate, which is observed directly by ESI-MS. Gas-phase protonation of this species leads to selective transfer of H(+) to the chlorine, suggesting that LiCl shields the amide nitrogen and prevents its direct protonation.

Intramolecular carbolithiation of heterosubstituted alkynes: an experimental and theoretical study.

A series of heterosubstitued alkynes was successfully submitted to the intramolecular carbolithiation of their triple bond. We show that the addition is stereoselective because of the control exerted by the terminal substituent X on the geometry of the transition state. A complementary DFT study suggests that the addition is anti when a strong Li-X interaction occurs.

Carbolithiation of chloro-substituted alkynes: a new access to vinyl carbenoids.

The intramolecular carbolithiation of a series of chloro-substituted alkynes leads to exocyclic alkylidene carbenoids of which both nucleophilic and electrophilic characters can be drove. A sole stereoselective 5-exo-dig addition takes place, probably because of a strong and persisting Li-Cl interaction arising before the transition state.

Influence of the acetylenic substituent on the intramolecular carbolithiation of alkynes: a DFT theoretical study.

A theoretical study of the intramolecular 5-exo-dig carbolithiation of substituted propargyl o-lithioaryl ethers, leading to dihydrobenzofurans, has been performed. The results show that a DFT description of the reaction (B3P86, 6-31G**) matches the experimental data provided that an explicit solvation by two molecules of THF is considered. To take place, the cyclization also implies that the acetylenic chain adopts a conformation in which a significant interaction arises between the lithium and the C≡C triple bond. Reaching the cyclization TS requires the passage of an activation barrier that should not be higher than 12-13 kcal mol(-1). From a thermodynamic point of view, the reaction is exothermic whatever the substituent R (from approximately -40 to -62 kcal mol(-1)). In the starting substrate, a supplementary interaction between the Li and a substituent at the propargylic position can develop, influencing the future double-bond configuration. Thus, derivatives exhibiting an R-Li interaction tend to provide E olefins. In contrast, when no coordination between the lithium cation and the terminal R occurs, syn carbolithiation takes place, and the configuration of the exocyclic olefin is likely to be Z. This hypothesis accounts for most of the experimental results published before.

First substoichiometric version of the catalytic enantioselective addition of an alkyllithium to an aldehyde.

A substoichiometric enantioselective version of the extremely fast nucleophilic addition of Alk-Li to RCHO is made possible thanks to a thorough analysis of the aggregation phenomena involved in the reaction: calculated quantities of LiCl must be added to the medium at the right time to keep the catalytic cycle running.

Are sp lithiated carbons more nucleophilic than sp2 or sp3 ones? A comparative DFT study of the condensation of propynyllithium aggregates on formaldehyde.

The interaction between 1-propynyllithium, taken as a model of sp organolithium compound, and formaldehyde has been investigated with DFT theoretical methods. The unsolvated monomer, homogeneous dimer, trimer, tetramer, and hexamer have been considered, as well as the mixed aggregates with lithium dimethylamide in various oligomeric forms. In most cases, the separate entities, their docking complexes, the transition states, and the condensation products have been characterized. Overall, the general reaction scheme remains the same whatever the hybridization and the aggregation. However, the dimeric sp nucleophiles are expected to be more reactive (at least in kinetic conditions), while monomeric sp(3) entities would be the best nucleophiles in kinetic and thermodynamic conditions, even if its docking is the least exothermic. This work also suggests that the aggregation plays a relatively limited role on the model reaction.

Enantioselective conjugate addition of a lithium ester enolate catalyzed by chiral lithium amides: a possible intermediate characterized.

Two 1:1 noncovalent mixed aggregates between a lithium enolate and two diastereomeric lithium amides have been identified spectroscopically in THF. The NMR data, as well as DFT theoretical calculations, shine some light on a puzzling reversal of induction, observed when switching from one diastereomer of the amide to the other in the enantioselective Michael addition of the lithium enolate to an unsaturated ester.

A case of anti carbolithiation of alkynes resulting from intramolecular lithium coordination.

The mechanism of the intramolecular carbolithiation of lithiated propargylic ether 2 has been investigated both experimentally and theoretically. The results show that the action of one equivalent of n-butyllithium on 1 is sufficient to trigger halogen-lithium exchange and the subsequent heterocyclization step. Interestingly, the reaction stops at the stage of dihydrobenzofuran 6; no spontaneous elimination of lithium ethylate was observed. The fact that the E configuration of this adduct was exclusively produced suggests that the reaction proceeds by following an unprecedented anti addition on the alkyne. According to DFT calculations, this unexpected outcome is related to the intramolecular coordination of the lithium by one oxygen atom of the terminal acetal appendage: the O-Li interaction, which persists all along the ring-closure process, drives the cation to the E site of the final olefin. The calculations also show that in the absence of this coordination (as in conformers B and C of acetal 2), the Z olefin that results from a classical syn addition of the aryllithium should be obtained. The experiments were repeated with allene 1d. In this case, one equivalent of n-butyllithium suffices to trigger not only the exchange and the cyclization, but also the final elimination of lithium ethoxide. The DFT results indicate that the intramolecular addition of the original aryllithium on the central carbon atom of the allene 2b yields the expected benzofuran skeleton 3b, which bears a lithiated lateral chain at the 3-position. Both cyclizations go through low-lying transition states, as is expected for rapid reactions at low temperature.

Origin of the detrimental effect of lithium halides on an enantioselective nucleophilic alkylation of aldehydes.

The effect of lithium halides on the enantioselectivity of the addition of methyllithium on o-tolualdehyde, in the presence of chiral lithium amides derived from chiral 3-aminopyrrolidines (3APLi), has been investigated. The enantiomeric excess of the resulting 1-o-tolylethanol was found to drop upon addition of significant amounts of LiCl, introduced before the aldehyde. The competitive affinity between the lithium amide, the methyllithium, and the lithium halides in THF was examined by multinuclear NMR spectroscopy and DFT calculations. The results showed that the original mixed aggregate of the chiral lithium amide and methyllithium is rapidly, totally, and irreversibly replaced by a similar 1:1 complex involving one lithium chloride or bromide and one lithium amide. While the MeLi/LiX substitution occurs with some degree of epimerization at the nitrogen for the endo-MeLi:3APLi complex, it is mostly stereospecific for the exo-type arrangements of the aggregate. The thermodynamic preference for mixed aggregates between 3APLi and LiX was confirmed by static DFT calculations: the data show that the LiCl and LiBr aggregates are more stable than their MeLi counterparts by more than 10 kcal.mol(-1) provided THF is explicitly taken into account. These results suggest that a sequestration of the source of chirality by the lithium halides is at the origin of the detrimental effect of these additives on the ee of the model reaction.

First-principles molecular dynamics evaluation of thermal effects on the NMR (1)J(Li,C) spin-spin coupling.

Car-Parrinello (CP) molecular dynamics were applied to sample conformations of various models of organolithium aggregates which are chosen to estimate (1)J(Li,C) NMR coupling constants. The results show that the deviations from the values computed using static (optimized) geometries are small provided no large-amplitude motions occur within the timescale of the simulations. In the case of the vinyllithium dimer, for which rotation of the vinyl chain is observed, this approach allows analysis of the various contributions to the experimentally measured constants. For the trisolvated methyllithium monomer, partial decoordination of solvating dimethyl ether is observed and results in a significant shift of (1)J(Li,C). All these results highlight that a varied physicochemical machinery is hidden behind general empirical formulas, such as the Bauer-Winchester-Schleyer rule used experimentally.

A DFT theoretical study of the condensation of aggregates of sp2 organolithium compounds on formaldehyde.

[Chemical reaction: See text] The interaction between three different sp2 organolithium compounds (vinyllithium, 2-methoxyvinyllithium and phenyllithium) and formaldehyde has been investigated using DFT theoretical methods. The unsolvated monomers and dimers have been considered and compared to the 1:1 mixed aggregates formed with lithium dimethylamide. In all cases, the separate entities, their docking complexes, the transition states, and the condensation products have been characterized and compared to the corresponding situations involving methyllithium, taken as a prototypic sp3 nucleophile. Regarding the monomers, this study shows that, in the three cases considered, formaldehyde forms a pretransition state complex in which the oxygen of the carbonyl interacts with the lithium cation along one of its lone pair. A small energy barrier (< or =2.1 kcal.mol(-1)) brings to the transition state, then to the lithium alcoholate resulting from the largely exothermic condensation (approximately 40 kcal.mol(-1)). The structure of the homogeneous dimers considered in a second step has been optimized and lead to arrangements in which a planar quadrilateral C-Li-C-Li is always obtained. In the presence of formaldehyde, these entities provide complexes exhibiting lithium-oxygen interaction similar to those occurring with the monomers. For the dimers, the geometry at the TS evokes a pi-complex between the C=O and the lithium cation, particularly pronounced in the case of phenyllithium. The resulting alcoholates are obtained following a larger exothermic reaction (approximately 55 kcal.mol(-1)). The heterogeneous dimers with lithium dimethylamide have been finally examined. In these cases, the aldehyde can orientate toward either the carbon or the nitrogen, leading to the expected lithium alcoholate or alpha-amino alcoholate, respectively. Whatever the orientation, the complexes present characteristics close to those calculated for the homogeneous dimer complexes. These similarities are conserved at the transition state.

Influence of the correlation, aggregation, and solvation on ab initio computed Li-C, Li-N, and Li-Li NMR coupling constants.

The (1)J and (3)J(C-Li), (1)J(N-Li), and (2)J(Li-Li) NMR coupling constants have been calculated for various homogeneous and heterogeneous aggregates of methyllithium and lithium dimethylamide at the HF and MP2 levels of calculation. Ethereal solvation has also been taken into account either through a continuum model or through the explicit introduction of Me(2)O molecules. The results obtained are in good general agreement with the experimental data available for methyllithium itself or model alkyllithiums and supports the empirical rule proposed by Bauer, Winchester, and Schleyer to evaluate (1)J(C-Li) provided that calculations include solvent and/or aggregation effects.

A NMR and theoretical study of the aggregates between alkyllithium and chiral lithium amides: control of the topology through a single asymmetric center.

The complexes between methyllithium and chiral 3-aminopyrrolidine (3-AP) lithium amides bearing a second asymmetric center on their lateral amino group were studied using multinuclear ((1)H, (6)Li, (13)C, (15)N) low-temperature NMR spectroscopies in tetrahydrofuran-d(8). The results indicate that lithium chelation forces the pyrrolidine ring of the 3-AP to adopt a norbornyl-like conformation and that robust 1:1 noncovalent complexes between methyllithium and 3-AP lithium amides form in the medium. A set of (1)H-(1)H and (1)H-(6)Li NMR cross-coupling correlations shows that the binding of methyllithium can take place along the "exo" or the "endo" face of this puckered structure, depending on the relative configuration of the lateral chiral group. This aggregation step renders the nitrogen of the 3-amino group chiral, the "exo" and "endo" topologies corresponding to the (S) and (R) configurations, respectively, of this atom. Density functional theory calculations show that the "exo" and "endo" arrangements are, for both diastereomers, almost isoenergetic even when solvent is taken into account. This result suggests that the formation of the mixed aggregates is under strict kinetic control. A relationship between the topology of these complexes and the sense of induction in the enantioselective alkylation of aromatic aldehydes by alkyllithiums is proposed.